ICUD Urogenital Infections

Urogenital Infections
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Urogenital Infections
Edition 2010
Editors
Kurt G. Naber
Anthony J. Scaeffer
Chris F. Heyns
Tetsuro Matsumoto
Daniel A. Shoskes
Truls E. Bjerklund Johansen
European Association of Urology
Mr. E.N. van Kleffenstraat 5, PO Box 30016, 6803 AA Arnhem, The Netherlands
First edition 2010
Copyright © 2010 European Association of Urology – International Consultation on Urological Diseases.

All rights reserved
No part of this publication may be reproduced, stored in a retrieval system, or transmitted by any means,
electronic, mechanical or photocopying without explicit permission from the copyright holder
No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a
matter of products liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in
particular, independent verification of diagnoses and drug dosages should be made
ISBN: 978-90-79754-41-0
Printed by Grafos, Spain
Cover illustration with thanks to:

Urban Sester, MD, PhD
Department of Internal Medicine IV
for Nephrology and Hypertension
Kirrberger Str., Bld. 6, Room. 1221
University Hospital Saarland
D-66421 Homburg/Saar, Germany
We would like to thank Ms Jen Tidman
for all of her editorial help and support in
producing this book

Contents
Foreword ................................................xiii 2. Aetiology, antimicrobial resistance

Paul Abrams, Christopher Chapple of uropathogens, antibiotic therapy
and policy ................................................ 69
Preface and Introduction ....................... xv
Chair: Gunnar Kahlmeter
Kurt G. Naber, Anthony J. Schaeffer, Chris F.
Heyns, Tetsuro Matsumoto, Daniel A. Shoskes, 2.1 Introduction ............................... 70
Truls E. Bjerklund Johansen Gunnar Kahlmeter
2.2 Uncomplicated and community
acquired urinary tract infections:
1. Pathogenesis of urinary tract aetiology and resistance ............ 72
infections ................................................... 1 Martin Sundquist, Gunnar Kahlmeter
Chair: Anthony J. Schaeffer 2.3 Complicated and healthcare
1.1 Introduction ................................. 2 associated urinary tract infections:
Anthony J. Schaeffer
aetiology and antimicrobial
1.2 Uropathogens and resistance ................................... 82
virulence factors .......................... 4 Martin Sundquist, Gunnar Kahlmeter
Ulrich Dobrindt, Jörg Hacker
2.4 Methicillin-resistant
1.3 Immunity, genetics and Staphylococcus aureus
susceptibility to urinary tract (MRSA) in urology ..................... 92
infection ..................................... 23 Satoshi Takahashi
Björn Wullt, Bryndis Ragnarsdottir,
2.5 ESBL and multi-resistance in
Hans Fischer, Jenny Grönberg-
Hernandez, Nataliya Lutay, urology ..................................... 102
Catharina Svanborg Tetsuro Muratani
1.4 Induction and modulation 2.6 Antimicrobials in urogenital
of host responses by infections .................................. 111
Florian M.E. Wagenlehner, Björn Wullt,
uropathogenic Escherichia Gianpaolo Perletti
coli structures ............................ 32
David J. Klumpp, Anthony J.
2.7 Antibiotic policy ...................... 127
Inge C. Gyssens
Schaeffer
1.5 Immunology of the
3. Urinary tract infections in special groups
urinary tract .............................. 42 of adult patients ................................... 147
Hartwig W. Bauer, Wolfgang G.
Bessler Chair: Kurt G. Naber
1.6 The role of biofilm infection in 3.1 Introduction ............................. 148
Kurt G. Naber
urogenital infections ................. 57
Peter Tenke, Bela Koves, Shinya 3.2 Diagnosis of uncomplicated
Uehara, Hiromi Kumon, Scott J. urinary tract infections ........... 151
Hultgren, Chia Hung Richard Colgan, Samantha Hyner,
vii
Contents
Stephanie Chu 5. Asymptomatic bacteriuria .................... 299

3.3 The quantitative urine Chair: Lindsay E. Nicolle
culture for the diagnosis of 5.1 Introduction – The evolution
urinary tract infection ............. 160 of asymptomatic bacteriuria .... 300
Lindsay E. Nicolle Lindsay E. Nicolle
3.4 Antibiotic treatment of 5.2 Asymptomatic bacteriuria – to
uncomplicated urinary tract treat or not to treat ................. 303
infection in premenopausal Lindsay E. Nicolle
women ...................................... 170 5.3 Asymptomatic bacteriuria with
Kurt G. Naber, Björn Wullt, Florian the model strain Escherichia
M.E. Wagenlehner
coli 83972 protects against
3.5 Urinary tract infections in symptomatic urinary tract
pregnancy ................................ 200 infections .................................. 314
Alexander D. Griffin, Richard Grady, Björn Wullt, Fredrik Sundén
Thomas M. Hooton
3.6 Urinary tract infections in
6. Urinary tract infections in children ...... 319
patients with diabetes
Chair: Rien J.M. Nijman
mellitus .................................... 216
Suzanne E. Geerlings 6.1 Introduction ............................. 320
Rien J.M. Nijman
3.7 Urinary tract infections in
postmenopausal women .......... 225 6.2 Classification of urinary tract
Raul Raz infections in children............... 323
Chang-Hee Han, Sang Don Lee
6.3 Diagnostic work-up of urinary
4. Prevention of recurrent urogenital
tract infections in adult women .......... 235 tract infections in children...... 328
Martin Westenfelder, Rolf Beetz
Chair: Thomas M. Hooton
6.4 Antimicrobial therapy of urinary
4.1 Introduction ............................. 236
Thomas M. Hooton
tract infections in children...... 344
Rolf Beetz, Martin Westenfelder
4.2 Antimicrobial prophylaxis in
6.5 Non-operative urological
women with recurrent
management of urinary tract
urinary tract infections ........... 240
Paola Lichtenberger, Thomas M. Hooton
infections in children............... 363
Stephen Shei-Dei Yang, Shang-Jen
4.3 Immunoactive prophylaxis of Chang
uncomplicated recurrent 6.6 Medical therapy versus
urinary tract infections ........... 252 surgery in vesicoureteral
Kurt G. Naber, Yong-Hyun Cho,
Tetsuro Matsumoto, Anthony J. Schaeffer
reflux from the view of the
paediatrician ............................ 374
4.4 Use of cranberry for prophylaxis Rolf Beetz
of uncomplicated recurrent
6.7 Vesico-ureteral reflux: An
urinary tract infections ........... 269
Henry Botto
American pediatric urologic
perspective ............................... 392
4.5 Probiotics for the prophylaxis of Richard Grady, Martin Koyle
uncomplicated recurrent urinary
tract infections in females....... 278
Peter Cadieux, Gregor Reid 7. Urinary tract infections in
4.6 Prevention of prematurity by nephropathies, transplant patients
early diagnosis and treatment and immunosupression ........................ 401
of bacterial urogenital Chair: Michael C. Bishop
infections – the role of 7.1 Introduction ............................. 402
bacterial vaginosis ................... 288 Michael C. Bishop
Udo B. Hoyme
viii
Contents
7.2 Emphysematous 9.3 Urinary catheters and drainage

pyelonephritis .......................... 404 systems: prevention and
Kiyohito Ishikawa treatment of urinary
7.3 Renal abscesses ....................... 413 tract infections ....................... 532
Kiyohito Ishikawa Peter Tenke, Bela Koves, Karoly Nagy
7.4 Polycystic renal disease .......... 419 9.4 Evolution of catheter material
Tamara Perepanova, Oleg Apolikhin for prevention of catheter-
7.5 Urinary tract infections associated urinary tract
in renal insufficiency and infections.................................. 541
dialysis ..................................... 426 U-Syn Ha, Yong-Hyun Cho
Reinhard Fünfstück, Kurt G. Naber, 9.5 Infections associated with the
Michael C. Bishop
artificial urinary sphincter ... 549
7.6 Urogenital infections in renal Alexander von Bargen, Margit Fisch
transplant patients – causes 9.6 Infections associated with
and consequences .................... 438 penile prostheses ................... 554
Daniel A. Shoskes, Ismail R. Saad Bela Koves, Peter Tenke, Karoly Nagy
8. Urinary tract infections in patients 10. Healthcare associated urinary tract

with underlying urological infections ............................................... 563
abnormalities ........................................ 449 Chair: Truls E. Bjerklund Johansen
Chair: Chris F. Heyns
10.1 Introduction ........................... 564
8.1 Introduction ............................. 450 Truls E. Bjerklund Johansen
Chris F. Heyns
10.2 Criteria for healthcare associated
8.2 Urinary tract infections in urinary tract infections: an
obstruction of the EAU/ESIU update on current
urinary tract ............................ 452 definitions ............................... 567
Chris F. Heyns Truls Bjerklund Johansen,
8.3 Urinary tract infections in Henry Botto, Mete Cek, Magnus Grabe,
patients with urolithiasis........ 481 Peter Tenke, Florian M.E. Wagenlehner,
Gianpaolo Zanetti, Alberto Trinchieri Kurt G. Naber
8.4 Epidemiology, diagnosis and 10.3 Epidemiology, treatment and
treatment of urinary tract prevention of healthcare-
infections in patients with associated urinary tract
spina bifida .............................. 497 infections ................................ 575
Dan Wood, Christopher Woodhouse Florian M.E. Wagenlehner, Mete Cek,
8.5 Urinary tract infections in Hiroshi Kiyota, Truls E. Bjerklund-
Johansen
patients with neurogenic
bladder ..................................... 507 10.4 Urinary tract infection in
James Salerno, Diana D. Cardenas long term care patients ......... 589
Lindsay E. Nicolle
9. Device associated urinary tract

infections ............................................... 519 11. Urosepsis ............................................... 601
Chair: Peter Tenke Chair: Bernhard Lobel
9.1 Introduction ............................. 520 11.1 Introduction ........................... 602
Peter Tenke Pierre Tattevin, Matthieu Revest,
9.2 Urinary catheters and Bernhard Lobel
drainage systems: definition, 11.2 Pathogenesis of sepsis as
epidemiology and risk factors ... 522 related to novel therapeutic
Paul A. Tambyah, Dariusz P. Olszyna, concepts .................................. 604
Peter Tenke, Bela Koves Evangelos J. Giamarellos-Bourboulis
ix
Contents
11.3 Urosepsis – from the view 13.3 Treatment of chronic

of the intensivist .................... 615 bacterial prostatitis ............... 728
Lifen Li, Bin Ouyang, Weide Zhong, Florian M.E. Wagenlehner, John N.
Xiangdong Guan Krieger
11.4 Urosepsis – from the view 13.4 Epididymitis and orchitis ...... 744
of the urologist ....................... 630 Thorsten Diemer, Florian M.E.
Florian M.E. Wagenlehner, Adrian Wagenlehner, Wolfgang Weidner
Platz, Wolfgang Weidner 13.5 Chronic urogenital
infections: alterations of
12. Prevention of infections associated sperm quality and potential
with urological surgery ........................ 645 impact on male fertility ......... 752
Wolfgang Weidner, Thorsten Diemer
Chair: Magnus Grabe
12.1 Introduction ........................... 646
Magnus Grabe 14. Sexually transmitted infectious
12.2 Hygiene and education .......... 649 diseases ................................................. 763
Bong-Suk Shim Chair: John N. Krieger
12.3 Sterilisation and disinfection 14.1 Introduction ........................... 764
of urological instruments John N. Krieger
for endoscopy and for 14.2 Sexually transmitted infectious
prostate biopsy ....................... 660 diseases (STDs): updated
Shingo Yamamoto, Ryoichi Hamasuna synopsis for practicing
12.4 Preoperative assessment urologists ................................ 765
of the patient, risk factors Peter Schneede, Boris Schlenker
identification and tentative 14.3 Urethritis ............................... 777
Ryoichi Hamasuna, Hiromasa
classification of surgical field
Tsukino
contamination in urologic
14.4 Pelvic infections in women .... 804
surgery ................................... 667 Gilbert G.G. Donders, Jasper Verguts
Magnus Grabe, Henry Botto, Mete
Cek, Peter Tenke, Florian M.E. 14.5 HIV Infection in urological
Wagenlehner, Kurt G. Naber, practice ................................... 830
Truls E. Bjerklund Johansen Seung-Ju Lee
12.5 Antibiotic prophylaxis 14.6 Male circumcision and HIV
in urological surgery, a infection risk .......................... 847
European viewpoint............... 686 John N. Krieger
Magnus Grabe
12.6 Antibiotic prophylaxis in 15. Special urogenital infections................ 861
urological surgery: a USA Chair: Tetsuro Matsumoto
viewpoint of best practice ...... 699 15.1 Introduction ........................... 862
Anthony J. Schaeffer, J. Stuart Tetsuro Matsumoto
Wolf Jr, Carol J. Bennett, Roger R.
Dmochowski, Brent K. Hollenbeck,
15.2 Urinary tuberculosis.............. 864
Severin Lenk, Mitsuru Yasuda
Margaret S. Pearle
15.3 Male genital tuberculosis ...... 877
Ekaterina Kulchavenya,
13. Epididymitis, orchitis, prostatitis Chul-Sung Kim
(male adnexitis) .................................... 711 15.4 Genitourinary tuberculosis
Chair: Wolfgang Weidner in a developing country
13.1 Introduction ........................... 712 (Vietnam): diagnosis and
Wolfgang Weidner treatment ............................... 892
13.2 Acute bacterial prostatitis ..... 714 Chuyen Vu Le, Nguyen Phuc
U-Syn Ha, Yong-Hyun Cho Cam Hoang
x
Contents
15.5 Guidelines for the treatment 16. Classification of urinary tract

of fungal urinary tract infections ............................................... 979
infections .............................. 903 Chair: Truls E. Bjerklund Johansen
Jack D. Sobel, John Fisher, 16.1 Critical review of current
Carol A. Kauffman definitions of urinary
15.6 Vulvovaginal candidosis ...... 912 tract infections and
Werner Mendling
proposal of an EAU/ESIU
15.7 Viral genitourinary classification system ............ 980
infections .............................. 928 Truls E. Bjerklund Johansen,
Laurent Vaucher, Darius A. Paduch Henry Botto, Mete Cek, Magnus
15.8 Genitourinary Grabe, Peter Tenke, Florian M.E.
schistosomiasis .................... 943 Wagenlehner, Kurt G. Naber
Ismail Khalaf, Ahmed A. Shokeir
15.9 Brucellosis: genitourinary References ............................................ 993
involvement ......................... 959
Ziad A. Memish, Georgios Pappas
15.10 Echinococcus/hydatid
disease: genitourinary
involvement ......................... 968
Georgios Pappas, Ziad A. Memish
xi
Foreword
The International Consultation on Urological Diseases (ICUD) was formed as a non-

governmental organization registered with the World Health Organization (WHO).
The ICUD has been responsible, with other professional organizations such as the
EAU and SIU, for more than 30 consultations on urological topics ranging from Penile
Cancer to Urological Trauma. The ICUD has modified the widely accepted Oxford
Centre for Evidence Based Medicine adaptation of the Agency for Health Care Policy
and Research (AHCPR) recommendations, thus allowing direct ‘mapping’ onto the
Oxford system [1]. The ICUD EBM method is now being used for ICUD Consultations.
The ICUD, through its vice-chairman Paul Abrams, with the co-operation of
the European Association of Urology (EAU), represented by Chris Chapple, asked
Kurt G. Naber to chair an International Consultation on Urogenital Infections. This
Consultation was held during the EAU Congress in March 2009 in Stockholm, in
cooperation with the European Section of Infection in Urology (ESIU), represented
by Truls E. Bjerklund Johansen, and other scientific societies, such as the Asian
Association of UTI/STD, represented by Tetsuro Matsumoto, the Society of Infection
and Inflammation in Urology (SIIU), represented by Daniel Shoskes, and the UTI
Commission of the International Society of Chemotherapy for Infection and Cancer
(ISC), represented by Kurt G. Naber.
This book provides the current state of the art knowledge about urogenital infec-
tions provided by international experts in their fields to assist not only urologists, but
also physicians from other medical specialities in their daily practice. All the recom-
mendations provided in the textbook followed the principle of evidence-based medi-
cine and a structured consensus process. We are delighted to recommend this book
as a milestone in recording the progress and research plans in the field of Urogenital
Infections.
Christopher Chapple
Paul Abrams
Adjunct General Secretary of the EAU
Chair of the ICUD
REFERENCE
1. Abrams P, Khoury S, and Grant A, Evidence – based medicine overview of the main steps
for developing and grading guideline recommendations. Prog Urol, 2007. 17(3): 681–4.
xiii
Preface and
Introduction
Urinary tract infections (UTIs) are among the most prevalent infectious diseases with
a substantial financial burden on society. Unfortunately, there are no good data con-
cerning the prevalence of various types of UTIs and their impact on the quality of life
of the affected population in Europe.
In the USA, UTIs are responsible for over 7 million physician visits annually,
including more than 2 million visits for cystitis [1]. Approximately 15% of all com-
munity-prescribed antibiotics in the USA are dispensed for UTI, at an estimated
annual cost of over US $1 billion [2]. Furthermore, the direct and indirect costs asso-
ciated with community-acquired UTIs in the USA alone exceed an estimated US $1.6
billion [1].
UTIs account for more than 100,000 hospital admissions annually, most often for
pyelonephritis [1]. They also account for at least 40% of all hospital-acquired infections
and are in the majority of cases catheter-associated [2]. Nosocomial bacteriuria devel-
ops in up to 25% of patients requiring a urinary catheter for > 7 days, with a daily risk
of 5% [3]. It has been estimated that an episode of nosocomial bacteriuria adds US
$500–1,000 to the direct cost of acute-care hospitalization [4]. In addition, the path-
ogens are fully exposed to the nosocomial environment, including selective pressure
by antibiotic or antiseptic substances. Nosocomial UTIs therefore comprise perhaps
the largest institutional reservoir of nosocomial antibiotic-resistant pathogens [3].
Therefore, prevention and best management of nosocomial UTI must have highest
priority worldwide in daily practice and research [5–6].
INTERNATIONAL CONSULTATION ON UROGENITAL INFECTIONS
The International Consultation on Urogenital Infections was initiated by the

International Consultation on Urological Diseases (ICUD), a non-governmental organ-
ization, and the European Association of Urology (EAU) during the EAU Congress on
March 25, 2008 in Milan, Italy, in cooperation with the European Section of Infection
in Urology (ESIU – a full section of the EAU) represented by Truls E. Bjerklund
Johansen, and other scientific societies, such as the Asian Association of UTI/STD,
represented by Tetsuro Matsumoto, the Society of Infection and Inflammation in
Urology (SIIU), represented by Daniel A. Shoskes, and the UTI Commission of the
xv
Preface and Introduction
International Society of Chemotherapy for Infection and Cancer (ISC), represented by

Kurt G. Naber. The aim was to provide the current state of the art knowledge about
urogenital infections in a textbook as a consensus of international experts in their
fields to assist not only urologists, but also physicians from other medical specialities
in their daily practice.
METHODS
The numerous aspects of urogenital infections were structured in 16 sections, cover-

ing the most important issues in this field. Each section was chaired by one expert,
who also assisted to identify other experts for the corresponding section. Each section
was then divided into several chapters, taking care that the experts (reporters) respon-
sible for each chapter came from different parts of the world. As far as appropriate
for each chapter a structured literature search was performed and the criteria used
were presented. The studies cited from the literature were rated according to the level
of evidence and the strength of the recommendations was graded accordingly (Tables
1 and 2). Each chapter was exposed to a vigorous consensus discussion within each
section and updated with the discussion and comments of the group as necessary. After
the consensus process in the sections all manuscripts were placed at the disposal of
all experts involved in this process. Finally, in a consensus conference held on March
17, 2009 in Stockholm, Sweden, to which all experts involved in this process had free
access, the overall concept and (within the sections) the detailed concept and recom-
mendations were again discussed until final consensus was reached. Thereafter all
manuscripts were edited in cooperation with the corresponding chairpersons. In the
last chapter a proposal for an updated classification of urinary tract infections is pre-
sented for further discussion, research and evaluation. All the recommendations
Table 1 Levels of evidence and grades of recommendations, according to [7].
Level Type of evidence

1a Evidence obtained from meta-analysis of randomized trials
1b Evidence obtained from at least one randomized trial
2a Evidence obtained from one well-designed controlled study without randomisation
2b Evidence obtained from at least one other type of well-designed quasi-experimental study
3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies
and case reports
4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities
Grade Nature of recommendation

A Based on clinical studies of good quality and consistency addressing the specific recommendations and including
at least one randomized trial
B Based on well-conducted clinical studies, but without randomized clinical trials
C Made despite the absence of directly applicable clinical studies of good quality
xvi
provided in the textbook followed the principle of evidence-based medicine and a struc-
tured consensus process.
LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATION
For the rating of the level of evidence and the grade of recommendation the follow-
ing system was used according to the Agency for Health Care Policy and Research
(AHCPR) using the ICUD modifications [7–8] as mentioned below.
The following ICUD modifications for grading the recommendations were used [8]:
Grade A recommendation (highly recommended) usually depends on consistent

level 1 evidence and often means that the recommendation is effectively manda-
tory and placed within a clinical care pathway. However, there will be occasions
where excellent evidence (level 1) does not lead to a Grade A recommendation, for
example, if the therapy is prohibitively expensive, dangerous or unethical. Grade A
recommendation can also follow from Level 2 evidence. However, a Grade A recom-
mendation needs a greater body of evidence if based on anything except Level 1
evidence.
Grade B recommendation (recommended) usually depends on consistent level
2 and/or 3 studies, or ‘majority evidence’ from randomized clinical trials.
Grade C recommendation (optional) usually depends on level 4 studies or ‘majority
evidence’ from level 2/3 studies or Delphi processed expert opinion.
Grade D recommendation (no recommendation is possible) could be used where the
evidence is inadequate or conflicting and when expert opinion is delivered without a
formal analytical process, such as by Delphi.
We would like to thank ICUD and EAU for providing this opportunity, all authors
for contributing to this textbook, Silvia de Bruin for organisational assistance and Jen
Tidman for editing the manuscripts.
We hope that by unifying forces we were able to provide the most important knowl-
edge for our colleagues in an easily accessible way to improve their daily practice and
we also hope that we have initiated better international cooperation to improve basic
and clinical research in this very important field for the benefit of our patients.
Stockholm, Sweden, March 2009
Kurt G. Naber (Chair) Anthony J. Schaeffer Chris F. Heyns

Straubing Chicago, Illinois Tygerberg
Germany USA South Africa
Tetsuro Matsumoto Daniel A. Shoskes Truls E. Bjerklund

Johansen
Kitakyushu Cleveland, Ohio Aarhus
Japan USA Denmark
xvii
REFERENCES
1. Foxman B, Epidemiology of urinary tract infections: incidence, morbidity, and economic

costs. Am J Med, 2002. 113 Suppl 1A: 5S–13S.
2. Ruden H, Gastmeier P, Daschner FD, and Schumacher M, Nosocomial and community-
acquired infections in Germany. Summary of the results of the First National Prevalence
Study (NIDEP). Infection, 1997. 25(4): 199–202.
3. Maki DG and Tambyah PA, Engineering out the risk for infection with urinary catheters.
Emerg Infect Dis, 2001. 7(2): 342–7.
4. Patton JP, Nash DB, and Abrutyn E, Urinary tract infection: economic considerations. Med
Clin North Am, 1991. 75(2): 495–513.
5. Johansen TE, Cek M, Naber KG, Stratchounski L, Svendsen MV, and Tenke P, Hospital
acquired urinary tract infections in urology departments: pathogens, susceptibility and use
of antibiotics. Data from the PEP and PEAP-studies. Int J Antimicrob Agents, 2006.
28 Suppl 1: S91–107.
6. Bjerklund Johansen TE, Cek M, Naber K, Stratchounski L, Svendsen MV, and Tenke P,
Prevalence of hospital-acquired urinary tract infections in urology departments. Eur Urol,
2007. 51(4): 1100–11; discussion 1112.
7. U.S. Department of Health and Human Services Public Health Service Agency for Health
Care Policy and Research, 1992: 115–127.
8. Abrams P, Khoury S, and Grant A, Evidence – based medicine overview of the main steps
for developing and grading guideline recommendations. Prog Urol, 2007. 17(3): 681–4.
xviii
Chapter |1|
Pathogenesis of urinary
tract infections
Chair: Anthony J. Schaeffer
CHAPTER OUTLINE
1.1 Introduction 2
1.2 Uropathogens and virulence factors 4
1.3 Immunity, genetics and susceptibility to urinary
tract infections 23
1.4 Induction and modulation of host responses by
uropathogenic Escherichia coli structures 32
1.5 Immunology of the urinary tract 42
1.6 The role of biofilm infection in urogenital infections 57
|1.1|
Introduction
Anthony J. Schaeffer
Department of Urology, Feinberg School of Medicine, Northwestern University
303 East Chicago Avenue, Chicago, Illinois 60611, USA
Phone: (312) 908-1615, Fax: (312) 908-7275, E-mail: jmz@northwestern.edu
Host pathogen interactions play a pivotal infections engage a more complex host
role in the initiation and development defense which is controlled by different
of urinary tract infections. The con- receptors and signaling pathways includ-
stant interplay involves bacterial viru- ing TOLL-like receptors that are criti-
lence and host defense factors and the cal for the innate immune response and
site and degree of infection is dictated by to initiate the defense against uropatho-
which component gains the upper hand. gens. The response is surprisingly low for
Dobrindt and Hacker review a variety of cystitis and asymptomatic bacteriuria,
virulence-associated factors that are most but for acute pyelonephritis and urosepsis
likely spatially and temporally regulated. an exaggerated innate immune response
Among the initial virulence factors are is effective which can result in renal scar-
adhesins which function not only to pro- ring. Chemokine receptor function is also
mote adherence but also are involved in critical for the innate response and it is
signaling between microorganisms and now apparent that genetic factors influ-
epithelial cells. Flagella promote move- ence the severity and type of response
ment of bacteria within the urinary tract. thus ultimately dictating the site and
A variety of other pathogens such as LPS severity of infection.
protect bacterial pathogens against the The host response is further elucidated
host immune system. The host response by Klumpp and Schaeffer who present the
to this attack is effective through the concept that uropathogens can modulate
innate immune system. the urothelial inflammatory response by
As outlined by Wullt et al., in resistant suppression of the NFkB dependent path-
hosts bacteriuria is transient, and com- way which not only promotes the initial
plete clearance of infection is achieved infection but also subsequent invasion.
by urine flow, mucosal microbicidal mole- UPEC binding to the urothelial surface
cules like defensins and recruited inflam- induces urothelial PI3 kinase activity
matory cells. They indicate that persistent that drives cytoskeletal reorganization
Introduction | 1.1 |
necessary for bacterial invasion, but They indicate that the formation of bio-
recent studies also point to additional sig- film consists of several steps including
naling events. Modulation of inflamma- deposition of the conditioning film fol-
tory responses and UPEC invasion are lowed by the attachment of microorgan-
coincident with FimH-induced urothelial isms and the final stage of formation of
apoptosis. Thus, in addition to inflamma- a biofilm structure. Resident bacteria
tion associated with acute infection, com- within biofilms are protected from anti-
plex early interactions between bacteria microbial agents. Biofilm plays a major
and the urothelium drive diverse host role in coating foreign bodies such as
responses critical to UTI pathogenesis. urethral catheters. Emerging data also
Bauer and Bessler further develop the indicate that biofilms can form in blad-
inflammatory response in urinary tract der epithelial cells where they are
infection. Macrophages, dendritic and termed intracellular bacterial commu-
other antigen-presenting cells orchestrate nities. Bacteria in these intracellular
the inflammatory and immune defenses niches can create a chronic quiescent
against the invading pathogens. This reservoir in the bladder which can per-
defense is complemented by the shedding sist undetected for months and lead to
of uropathogens with urothelial cells, bacterial relapse and then to recurrent
trapping of bacteria by mucus, and inter- infection.
mittent washout by urine. Tamm-Horsfall In summary, these excellent articles
protein which is capable of both medi- indicate the diversity and constant evo-
ating direct antimicrobial activity and lution of the host-bacterial interactions.
alerting immune cells, as well as secre- Continuing to study and understand
tory IgA, also play a major role. these intricate interplays is pivotal to our
Lastly, the role of biofilm in urogeni- ability to diagnose, treat and prevent uri-
tal infections is reviewed by Tenke et al. nary tract infections.
3
|1.2|
Uropathogens and virulence factors
Ulrich Dobrindt1, Jörg Hacker2
Julius-Maximilians-Universität Würzburg, Institut für Molekulare Infektionsbiologie, Röntgenring 11, 97070 Würzburg, Germany
1
Robert Koch-Institut, Nordufer 20, 13353 Berlin, Germany

2
ABSTRACT as well as signaling between the patho-

gens and the host. Capsules, smooth
LPS and other extracellular polysac-
Urinary tract infections (UTIs) are among
charides protect bacterial pathogens
the most frequently encountered infec-
against the host immune system. The
tions in developed countries. In contrast
knowledge of biochemical and metabolic
to many commensal bacteria, uropath-
traits of uropathogens associated with
ogens are equipped with a variety of
improved fitness, growth and survival
virulence-associated factors that promote
in the urinary tract is increasing as well
the establishment of infection in different
as that of different extra- and intracellu-
areas of the urinary tract. Expression of
lar bacterial lifestyles that are involved
these virulence factors is most likely spa-
in acute or recurrent UTI. In addition to
tially and temporally regulated. Among
such classical bacterial virulence factors
the first virulence factors required during
directly involved in the successful coloni-
host-pathogen interaction and the estab-
zation of the urinary tract, uropathogens
lishment of an UTI are adhesins which
may also inhibit the mucosal inflam-
function as adhesins or invasins, promote
matory response. It becomes more and
biofilm formation and are involved in sig-
more clear, that not only the presence of
naling between the microorganisms and
virulence-associated genes is required for
epithelial cells. Flagella do not only allow
pathogenesis, but also their functionality
ascension from the urethra to the bladder
and proper expression in the context of
and even further to the kidneys, but can
the urinary tract infection.
also function as adhesins and invasins.
In later stages of an infection, toxins may Key words: uropathogens, virulence
further support infection by destruction factors, siderophores, toxins, adhesins,
of epithelial cells, the release of nutri- flagella, capsule, invasion, urease, auto-
ents, protection against the host response transporter, metabolism
Uropathogens and virulence factors | 1.2 |
1. INTRODUCTION Other Gram-negative uropathogens,

Proteus spp. and Klebsiella spp., are often
Urinary tract infection (UTI) is one of associated with the occurrence of bladder
the most frequently occurring bacterial stone formation due to urease expression.
infections in industrialized countries Klebsiella spp. and Pseudomonas spp. are
[1] and is an unspecific bacterial infec- frequently characterized by multiple anti-
tion which can be caused by a variety of biotic resistances and they are a predomi-
pathogens. Usually, uropathogenic micro- nant cause of nosocomial UTI. Citrobacter
organisms derive from the patient’s own spp., Enterobacter spp. and Serratia spp.
faecal flora which, upon smear infection, are nosocomial uropathogens as well
can ascend via the urethra to the urinary ([4]; Table 1). Gram-positive bacteria
bladder and even further via the ure- (Enterococcus spp., Staphylococcus spp.)
ters to the kidneys. The most frequent play also an important role as uropatho-
causative agent of UTI is Escherichia gens in nosocomial infections. Due to their
coli (E. coli). Up to 80% of the acute com- natural resistance against cephalosporins,
munity acquired uncomplicated UTI are they are selected especially under inten-
caused by E. coli. Additionally, 20–40% of sive care conditions. Staphylococcus
the complicated UTI and approximately saprophyticus causes ambulantly acquired
40% of the nosocomial infections in nor- UTI of young women [5]. Many fastidi-
mal wards are UTI due to catheterization ous anaerobic bacteria that are normally
[2–3]. Uropathogenic E. coli (UPEC) differ not detected by the standard culture
from intestinal pathogenic and many non- conditions have been described in urine
pathogenic faecal E. coli by the expression specimens, but their role in UTI remains
of virulence-associated factors. A certain to be studied [6].
fraction of the faecal E. coli bacteria (up The number of UTI cases caused by fungi
to 20%) in healthy individuals represent is increasing. Candida spp. is the most
strains with uropathogenic potential. frequently observed fungal uropathogen.
Table 1 Spectrum and prevalence of uropathogenic microorganisms
Uropathogen Remarks
Outpatient Inpatient
Escherichia coli 80% 40% Most frequently occurring uropathogen
Proteus mirabilis 6% 11% Frequently associated with stone formation and

complicated UTI
Klebsiella, Enterobacter, Serratia, < 5% 25% Frequently associated with complicated and noso-
Citrobacter spp., Pseudomonas spp. comial UTI, multiple antibiotic resistances
Staphylococcus saprophyticus 7% < 5% Frequently associated with UTI in sexually active

young women
Staphylococcus aureus < 5% 16% Often in immuno-compromized patients
Staphylococcus epidermidis Important catheter-associated uropathogen
Enterococcus spp. Frequently associated with transplantations, up to

8% of the infections develop into urosepsis
Candida spp. < 1% 5% Frequently associated with antibiotic treatment

and immunosuppression, systemic infection
5
Chapter |1| Pathogenesis of urinary tract infections
Although C. albicans is the most common pathogens. The ability to cause disease
species encountered, non-albicans Candida cannot alone be attributed to their genus
species are also extremely prevalent [7]. and species, but rather depends on the
UTI caused by fungi is preferentially ability to express virulence-associated
observed in immune-compromised patients factors which crucially contribute to path-
and upon treatment with antibiotics that ogenicity and which distinguish uropath-
are excreted via the kidneys. ogenic from non-pathogenic variants. The
repertoire of virulence genes present in
a certain strain determines the type and
2. VIRULENCE-ASSOCIATED FACTORS severity of disease (Table 2). Individual
OF UROPATHOGENS virulence factors are needed only in cer-
tain stages of the infection. Consequently,
Microbial virulence mechanisms are their expression is temporally and spa-
critical for overcoming the normal host tially regulated in response to different
defences. Uropathogens are facultative growth conditions (Figure 1).
Table 2 Virulence factors of microbial uropathogens
Organism Virulence factor

E. coli Fimbriae/adhesins (Type 1-, type 3-, P-fimbriae, S-adhesin family, Afa/Dr adhesin family, curli)
Toxins (α-Hemolysin, CNF1)
Autotransporter serine proteases (Sat, Vat)
Autotransporter adhesins (Ag43, UpaG)
Iron acquisition systems (enterobactin, aerobactin, yersiniabactin, salmochelin, Iha, haem

receptors Hma, ChuA)
O antigen
Capsule
Flagella
Extracellular poylsaccharides (cellulose, PGA)
Proteus mirabilis Fimbriae/adhesins (MR/P, PMF, ATF, NAF, UCA, MR/K)
Toxin (HpmA hemolysin)
Autotransporter agglutinin and cytotoxin (Pta)
Capsule
Urease
Flagella
Metalloproteases
Iron acquisition (Amino acid deaminases)
Klebsiella pneumoniae Fimbriae/adhesins (Type 1, Type 3 (MR/K))
Capsule
O-antigen
Iron acquisition systems (enterochelin, aerobactin)
Urease
6
Organism Virulence factor

Pseudomonas aeruginosa Adhesins/fimbriae
Exotoxins (e.g., hemolysin)
Phospholipase C
Protease
Elastase
Pyochelin
Enterococcus spp. Adhesins (aggregation substance, D-mannose and D-glucose-containing carbohydrates)
Toxin (cytolysin)
Staphylococcus saprophyticus Adhesins (Surface associated protein Ssp, lipoteichoic acid, hemagglutinin/fibronectin
binding protein UafA, collagen binding SdrI, lipase Ssp, autolysin Aas)
Surface hydrophobicity
Toxin (Hemolysin)
Extracellular slime
Urease
Staphylococcus aureus Biofilm formation (PIA, Aap)
Toxins
Protease
MrpF
Iron acquisition systems (Isd, staphylobactin)
MSCRAMMs (fibronectin binding protein, laminin binding protein, elastin binding protein,
clumping factor)
Staphylococcus epidermidis Biofilm formation (PIA, Bap/Bhp)
Toxins
Citrobacter spp. Fimbriae/adhesin (Type 1 fimbriae, type 3 fimbriae)
Outer membrane proteins (OmpA)
Capsule (Vi)
Serratia marcescens Lipopolysaccharide
Mannose-resistant (MR) and mannose-sensitive (MS) fimbriae
Chitinase, lipase, chloroperoxidase, extracellular protein HasA
Candida spp. Adhesins (Agglutinin-like sequence genes (ALS), Hwp1)
Dimorphism, hyphae formation
Aspartyl proteinases (SAPs)
Lipases (LIPs), phospholipase B (PLB)
Iron-binding capacity
Metabolic adaptation
Resistance to phagocytosis
Ag43, antigen 43; PGA, poly-β-1,6-N-acetyl-D-glucosamine; PMF, Proteus mirabilis fimbriae; ATF, ambient-temperature fimbriae; NAF, non-
agglutinating fimbriae; MR/P, mannose-resistant Proteus-like hemagglutinin; MR/K, mannose-resistant Klebsiella-like hemagglutinin; UCA,
uroepithelial cell adhesin; MrpF, multiple peptide resistance factor; Pta; Proteus toxic agglutinin, PIA, polysaccharide inter-cellular adhesin.
7
Motility Capsules, LPS Adhesins

Adhesins OMVs, Toxins Invasins
Autotransporter adhesins Autotransporter SPATEs Modulins
Siderophores Metabolic traits
Urease Extracellular
Metabolic traits polysaccharides
I II III
Adhesion, Immune evasion Binding to ECM,
colonization, serum resistance plasminogen activation
autoaggregation tissue destruction Invasion
IBC formation
Figure 1 Virulence factors of uropathogenic bacteria required for host-pathogen interaction and different stages of the urinary
tract during infection.
Flagellated and motile bacteria reach the bladder epithelium. This promotes adhesion to the bladder epithelial cells. Together
with metabolic and other enzymatic activities (e.g. urease expression), adhesion enables colonization of the urinary tract. The
secretion of siderophores further supports the establishment of infection (I). LPS and capsules protect the colonizing bacteria
from the host immune response. Toxins that are secreted via specific secretion systems or outer membrane vesicles can be
involved in signaling between the pathogen and the host cells or destroy the superficial epithelial cells to release nutrients
and to gain access to the subjacent tissue (II). Adhesins may also mediate bacterial invasion of the bladder epithelial cells.
Bacteria can exist quiescently in late endosome-like compartments or rapidly multiply within the superficial cells, forming
biofilm-like communities. Release of bacteria from infected host cells before they complete exfoliation likely promotes bacterial
dissemination and persistence within the urinary tract. During efflux, UPEC often become filamentous thus also preventing
phagocytosis (III).
OMVs, outer membrane vesicles; LPS, lipopolysaccharide; SPATEs, serine protease autotransporter toxins of Enterobacteriaceae;
IBCs, intracellular biofilm-like communities; ECM, extracellular matrix.
3. ADHESINS II, and III) that recognize globotria-

sylceramide variants on the surface of
UTI usually starts with a specific colo- target cells, particularly in the kidney.
nization of uroepithelial cells by micro- Pyelonephritis isolates frequently express
organisms mediated by adhesins which the PapG II variant that binds the glo-
specifically bind to receptors present botetraosylceramide GbO4, a glycolipid
on the surface of uroepithelial cells. that is abundantly expressed on the sur-
Morphologically, fimbrial adhesins can be face of human urothelium. Cystitis iso-
distinguished from non-fimbrial adhesins lates more commonly express PapG III.
(Afa or Nfa). Whereas fimbriae represent This adhesin binds the globopentaosylce-
composite fibres which protrude from the ramide GbO5 [11–12].
cell surface, non-fimbrial adhesins are Type 1 fimbriae are produced by most
directly located on the outer membrane. E. coli, UPEC and commensal variants,
About 80% of all UPEC express P fim- and are meanwhile considered as one
briae (pyelonephritis-associated fimbriae) of the most important virulence factors
which bind to the globoseries of gly- involved in the colonization of the urinary
cosphingolipids that are anchored in the tract [13–15]. FimH recognizes mannose-
cell membrane preferentially of kidney containing host glycoprotein receptors
cells [8–10]. Three types of the PapG incl. uroplakin 1a and many other host
adhesin have been identified (PapG I, proteins [16–18]. FimH also mediates
8
bacterial invasion of host cells and con- Two different fimbrial adhesins have
tributes to the formation of intracellu- been described so far for uropathogenic
lar bacterial biofilms [19–20]. Binding of Klebsiella pneumoniae isolates including
FimH to α3β1 integrin subunits and most a type 1 fimbriae-like adhesin which also
likely other receptors within lipid rafts recognizes mannose-containing recep-
on bladder epithelial cells triggers sign- tors and so-called type 3 fimbriae. Type 3
aling cascades involving Rho GTPases, fimbriae mediate adhesion to several cell
the Src kinase, the PI 3-kinase, and the types in vitro [33–34], but their recep-
focal adhesion kinase (FAK) as well as tor has not been identified yet. Although
transient complex formation between the establishment of intracellular niches
α-actinin and vinculin. This results in during infection is more common in
actin rearrangements and subsequently UPEC, also uropathogenic K. pneumo-
bacterial uptake via the zipper mecha- niae have been shown to utilize quiescent
nism ([16, 19]; see also the chapter “Host intracellular reservoirs during infec-
responses to infection” by Klumpp and tion. Nevertheless, K. pneumoniae forms
Schaeffer). Internalized UPEC can qui- less intracellular biofilm-like communi-
escently exist in late endosome-like com- ties and has lower titres in bladder than
partments and may serve as a reservoir UPEC. These differences are at least par-
for recurrent UTI. Bacterial release into tially due to differences in type 1 fimbriae
the host cytosol stimulates bacterial expression [35–36].
growth and the formation of intracellular Afimbrial adhesins mediate adherence
biofilm-like communities [21–23]. to human epithelial cells and are located
Another important fimbrial adhesin, on the bacterial surface in amorphous
so-called S/F1C fimbriae, bind to sialic outer membrane-associated structures
acid-containing receptors.[24–25] S/F1C [37]. The afimbrial Afa and Dr adhesins
fimbriae can also bind to the Tamm- are expressed by UPEC. The Dr adhesin
Horsfall glycoprotein (THP) which is mediates bacterial adherence to poly-
exclusively expressed in the kidney and morphonuclear leukocytes (PMNs), thus
constitutes the most abundant protein decreasing bacterial killing. Members of
in human urine. As THP carries high- the Afa/Dr adhesin family differ in their
mannose as well as sialic acid sequences, ability to specifically bind to the base-
it can function as a ligand for fimbriated ment membrane protein type IV colla-
E. coli and thus reduce the number of bac- gen, the common epithelial cell receptor
teria present in urine.[26–27] According decay-accelerating factor (DAF, CD55)
to complete genome sequence data, indi- and carcinoembryonic antigen-related
vidual UPEC genomes comprise ten or cellular adhesion molecules (CEACAMs).
more different fimbrial determinants. Recognition of such membrane-bound
[28–30] Except for the already described receptors including GPI-anchored pro-
type 1-, P- and S/F1C fimbriae, the role teins known to be associated with lipid
of the other putative adhesins in UTI has rafts promotes eukaryotic cell signaling
not yet been characterized in detail [31]. and bacterial internalization (reviewed
Other uropathogens also express fim- in [38]).
brial and non-fimbrial adhesins (Table 2). Whereas adhesins of Gram-negative
Several types of fimbriae can be uropathogens have been quite well char-
expressed simultaneously by Proteus acterized so far, knowledge of adhes-
mirabilis (reviewed in [32]): The man- ins of Gram-positive bacteria involved
nose-resistant/ Proteus-like (MR/P) fim- in UTI is only slowly accumulating. In
briae, the P. mirabilis fimbriae (PMF), Staphylococcus aureus isolates from UTI
the uroepithelial cell adhesin (UCA), and several adhesins, so-called ‘microbial sur-
the ambient-temperature fimbriae (ATF). face components recognising adhesive
9
matrix molecules’ (MSCRAMMs) have formation in E. coli [47–51]. These factors

been detected including fibronectin bind- most likely also promote biofilm forma-
ing proteins, the laminin binding protein, tion in other Gram-negative uropathogens
the clumping factor but also the elastin as well as type 3 fimbriae that have been
binding protein [39]. S. saprophyticus recently described to contribute to biofilm
expresses a cell-wall anchored hemagglu- formation by different Gram-negative
tinin, the so-called uro-adherence factor A uropathogens, i.e. E. coli, Citrobacter
(UafA), that is associated with adherence koseri, Citrobacter freundii, Klebsiella
to eukaryotic cells in the urinary tract pneumoniae, and Klebsiella oxytoca [52].
[40]. Additional surface proteins such Especially nosocomial S. aureus and
as SdrI [41], Ssp [42], and the fibronec- S. epidermidis isolates have the ability to
tin-binding autolysin Aas [43] may also form biofilms on foreign materials. Non-
contribute to adhesion and possibly inter- specific factors such as surface charge and
nalization of S. saprophyticus into epithe- hydrophobicity are supposed to mediate
lial cells. initial adherence, but also specific factors
Internalization of S. saprophyticus into such as cell wall-associated teichoic acids
a human bladder carcinoma cell line has and proteins which interact with extracel-
been observed and discussed in the light lular matrix proteins play an important
of recurrent UTI [44]. Adhesive traits role as well as the “polysaccharide inter-
of enterococci are so far supposed to be cellular adhesin (PIA) [53–55]. In addition,
mediated by the aggregation substance, other factors such as the surface-associ-
a pheromone-inducible surface protein, ated protein Aap (accumulation-associated
which plays an important role during protein) and Bap/Bhp (biofilm-associated
the initiation of conjugation but also for protein) contribute to biofilm formation by
adherence to eukaryotic cell surfaces and S. epidermidis and S. aureus [56–57].
internalisation by enterocytes. In addition
to pheromones, serum can also induce the
expression of aggregation substance [45]. 5. SIDEROPHORE SYSTEMS
Adhesins of Candida albicans bind to
several extracellular matrix proteins of The availability of iron ions is an essen-
mammalian cells, such as fibronectin, tial prerequisite for successful coloniza-
laminin, fibrinogen and collagen type I tion of the urinary tract. To overcome iron
and IV (reviewed in [46]). limitation in the host, bacteria express
siderophores that scavenge iron from the
environment. In E. coli, different types of
4. BIOFILM FORMATION siderophores are expressed. Enterobactin
(or enterochelin) is expressed by pathogenic
For catheter-associated infections in and non-pathogenic E. coli. In contrast
general biofilm formation plays a major to enterobactin, aerobactin is frequently
role. Recently, the role of biofilm for- present in uropathogenic and other extrain-
mation during recurrent and chronic testinal pathogenic E. coli. Generally,
UTI has been intensively investigated UPEC encode multiple siderophore sys-
in E. coli (see also chapter “Biofilm” by tems in addition to enterobactin, e.g. sal-
Tenke et al.). Many different factors, such mochelin, yersiniabactin, and aerobactin.
as flagella, various fimbrial adhesins, [58] UPEC require haem for kidney colo-
curli, antigen 43 as well as cell surface- nization. Two haem receptors, Hma and
associated polysaccharides including ChuA, have been described so far.[59]
colanic acid and other capsular mate- Siderophore receptors may have dual
rial, poly-β-1,6-N-acetyl-D-glucosamine functions. The adhesin Iha was deter-
(PGA) and cellulose contribute to biofilm mined to be an E. coli urovirulence factor
10
in a mouse UTI model [60]. In addition, primarily the destruction of host cells to
Iha represents a catecholate siderophore release nutrients and iron, but sublytic
receptor that exhibits an adherence-en- HlyA concentrations seem to be more
hancing phenotype [61]. Interestingly, the physiologically relevant. Sublytic concen-
salmochelin siderophore receptor IroN also trations of HlyA stimulate the inactiva-
functions as an iron uptake receptor as tion of the serine/threonine kinase Akt,
well as an internalization factor promoting which plays a central role in host cell
the invasion of urothelial cells by UPEC in cycle progression, metabolism, vesicular
vitro [62]. trafficking, survival, and inflammatory
These and similar iron uptake sys- signaling pathways [71]. These findings
tems have also been described for other explain that sublytic HlyA concentra-
Gram-negative microorganisms such tions inhibit chemotaxis and bacterial
as Klebsiella spp. Interestingly, Proteus killing by phagocytes as well as stimula-
mirabilis does not express common tion of host apoptotic and inflammatory
siderophores. Alternatively, iron can be pathways [72–76]. In this context, LPS
acquired with α-keto acids, phenylpyru- is important for targeting of HlyA to the
vate and indolepyruvate [63] and eight host cell membrane: HlyA in association
different iron transport mechanisms have with LPS is presented via the CD14/LPS
been detected according to the complete binding protein recognition system to the
genome sequence of P. mirabilis strain eukaryotic cell surface, where intracellu-
HI4320 [64]. In Gram-positive bacte- lar-Ca2+ signaling is initiated via specific
ria, only little is known about molecular activation of the small GTPase RhoA [73].
details of iron acquisition. The isd genes Approximately 30% of UPEC strains
(iron-regulated surface determinant) of code for the cytotoxic necrotizing factor 1
S. aureus encode factors responsible for (CNF1) which can constitutively activate
hemoglobin binding and passage of haem- the Rho family GTPases [77]. Activation
bound iron from the cell wall to the cyto- of Rho GTPases affects many eukaryotic
plasm [65]. S. aureus does also express cellular functions, e.g. the formation of
the siderophore staphylobactin [66]. actin stress fibers, lamellipodia, filopodia,
C. albicans is able to utilize haemin and the induction of membrane ruffling, and
haemoglobin as iron sources. A conserved the modulation of inflammatory signaling
family of plasma membrane-anchored pathways [78]. In murine UTI model sys-
haem-binding proteins has been identified tems CNF1 has been demonstrated to be
also in other Candida species [67]. a UPEC virulence factor [79]. CNF1 may
facilitate the dissemination and persist-
ence of UPEC within the urinary tract as
6. TOXINS it promotes apoptosis of bladder epithelial
cells thus stimulating their exfoliation
Colonization by uropathogens frequently and enhancing bacterial access to the sub-
results in inflammatory processes, fever jacent tissue [80]. This toxin also inhibits
as well as damage of the urothelium and the phagocytic activity and chemotaxis of
the subjacent tissue. Toxins are involved neutrophils [81]. HlyA and CNF1 can be
in these processes. The α-hemolysin associated with outer membrane vesicles
(HlyA), is encoded by about 50% of UPEC (OMVs) that bleb from the bacterial sur-
isolates and its expression is associated face [82]. Both toxins seem to be delivered
with increased clinical severity in UTI to target host cells via OMVs [83–84].
patients [68]. In high concentrations, the Other uropathogens also express tox-
calcium-dependent pore-forming toxin ins. P. mirabilis expresses the hemo-
HlyA leads to cell lysis [69–70]. The func- lysin HpmA, as well as proteases
tion of HlyA was thus supposed to be [85–86]. Several toxins are expressed in
11
Ps. aeruginosa including elastase, pro- a variety of cytopathic effects in target

teases, phospholipase C, pyochelin and host cells. Sat expression has been shown
hemolysin. Renal colonization of mice to induce dramatic kidney damage in a
correlated with the expression level of mouse UTI model system [99–100].
hemolysin [87]. A well-described toxin The Proteus toxic agglutinin (Pta) has
is the hemolysin of Enterococcus faeca- been recently discovered in P. mirabilis
lis [88]. S. aureus also expresses a broad and represents a novel autotransporter
variety of toxins, but their impact on UTI cytotoxin that works optimally in the
is unclear [89]. C. albicans can secrete alkalinized urinary tract during P. mira-
phospholipases and aspartyl proteinases bilis infection [101]. The role(s) of several
that promote virulence and invasiveness. other autotransporter encoded by UPEC
At least nine members of the secreted and other Gram-negative uropathogens
aspartyl proteinase (SAP) family have awaits further investigation.
been detected in Candida species [46].
8. LIPOPOLYSACCHARIDE
7. AUTOTRANSPORTERS
The O antigen is a polysaccharide con-
The genomes of many Gram-negative sisting of ~10–25 repeating sugar subu-
pathogens comprise multiple genes cod- nits anchored in the outer core of the
ing for autotransporter proteins which lipopolysaccharide component of the bac-
may have various virulence-associated terial membrane [102]. There is a high
functions, such as adhesins and toxins frequency of the antigens O1, O2, O4,
[90]. Antigen 43 (Ag43) represents an O6, O7, O8, O16, O18, O25, O50 and O75
entire family of closely related autotrans- among UPEC, while specific K and H
porter proteins in E. coli and contributes antigens have a less defined pattern.[103]
in many ways to the phenotypic vari- While it is known that certain O and K
ability of E. coli as this autotransporter antigens provide a survival advantage for
mediates autoaggregation and biofilm for- some extraintestinal pathogenic E. coli
mation [91–92]. Ag43 contributes to the (ExPEC) strains, it is unclear how these
uptake and survival in macrophages and antigens specifically affect UPEC viru-
certain Ag43 variants may be associated lence. The LPS serotypes mentioned above
with long-term persistence of uropatho- seem to specifically interact with other
genic E. coli in the murine urinary tract. virulence factors (e.g. LPS-dependent tar-
[93–95] Ag43 also functions as a weak geting of HlyA to host cell membranes)
adhesin capable of binding to proteins and may also play a role in the protection
of the extracellular matrix as well as to against the human immune system. Other
T24 bladder epithelial cells [96]. Trimeric Gram-negative uropathogens express
autotransporters have also been recently specific LPS structures as well. Gram-
described in UPEC to mediate aggrega- positive microbes are characterized by a
tion, biofilm formation, and adhesion to multi-layered peptidoglycan. Fungi dis-
various ECM proteins [97]. play β-(1,3)-glucans as surface structures
In addition, UPEC also express different and whether they specifically contribute to
autotransporter toxins: i.e. the vacuolating uropathogenesis remains to be elucidated.
autotransporter toxin (Vat) and secreted
autotransporter toxin (Sat). Vat and Sat
belong to the SPATE (serine protease 9. CAPSULES
autotransporters of Enterobacteriaceae)
protein family [98]. and were initially Many uropathogens can produce polysac-
characterized by their ability to induce charide capsules which play an important
12
role during pathogenesis because the cap- 12. METABOLIC AND OTHER TRAITS
sule protects bacteria against the host
complement system and phagocytes thus Uropathogens are able to grow and multi-
contributing to serum resistance. In addi- ply in urine. Certain aspects of metabolic
tion, certain capsules (e.g. the K1 cap- properties that may promote growth in
sule) can mimic host structures thereby the bladder have been recently character-
reducing the immune response against ized mainly in E. coli.
invading bacteria. E. coli expresses more D-serine is one of the most prevalent
than 80 different capsule types. Group II amino acids excreted in mammalian
capsules are found in the vast majority urine. D-serine metabolism thus repre-
of UPEC, but there is no clear evidence sents a positive fitness trait during UTI.
for the involvement of specific K anti- High concentrations of D-serine, however,
gens in UPEC pathogenesis. The E. coli can also be bacteriostatic. In contrast to
K1 capsule is composed of 2,8-linked commensal and intestinal pathogenic
sialic acid residues (N-acetylneuraminic E. coli, the majority of UPEC carries at
acid) and mimics the neuronal cell adhe- least one operon for D-serine utilization
sion molecule (c-CAM). Also other Gram- [112]. The corresponding E. coli dsd-
negative and -positive bacteria express CXA locus permits growth on D-serine
capsules [104]. as a sole carbon and nitrogen source and
simultaneously represents a competitive
10. FLAGELLA advantage due to detoxification of this
growth inhibitor. It has been hypothe-
sized that D-serine plays role in signaling
The role of flagella in UPEC pathogen-
and virulence gene regulation [113–116].
esis becomes more and more defined. It
Zinc transport has been recently dem-
has been recently shown that they facili-
onstrated to be important for motility and
tate the ascension of UPEC from the
resistance to hydrogen peroxide of UPEC
bladder into the kidneys, dissemination
strain CFT073. Loss of the zinc transport
within the host and invasion into renal
systems Znu and ZupT has a cumulative
cells [105–109]. It is likely that flagella of
effect on fitness during UTI, which may
other Gram-negative uropathogens may
in part be due to a reduced motility and
have similar functions.
resistance to oxidative stress [117]. The
ability to resist oxidative stress has been
11. UREASE PRODUCTION shown to be required for full urovirulence
of UPEC [118].
One of the major virulence factors of C. albicans exhibits marked morpho-
P. mirabilis is the enzyme urease [110]. genetic plasticity; it can either grow in a
Urease hydrolyses urea into carbon yeast or in a hyphal form [119]. This vari-
dioxide and ammonia; the liberation of ability and the ability to switch from one
ammonia creates an alkaline environ- form to the other is linked to pathogenic-
ment that causes soluble ions to precipi- ity of C. albicans, but the importance of
tate from urine producing a urinary stone the morphogenetic variability for urovir-
[111]. Consequently, during P. mirabilis ulence has not yet been studied in detail.
infection, the urinary tract often becomes Niche-specific regulation of gene expres-
obstructed by urinary stones resulting sion and metabolic adaptation has also
from urease production. Urease expres- been shown to contribute to urovirulence
sion can also be frequently detected in of C. albicans [120–121].
K. pneumoniae and S. saprophyticus Subversion of the innate immune
isolates [40]. response is essential for survival during
13
the early stages of infection. UPEC can osmolarity are important for intravesical
directly inhibit TLR signaling by secret- growth [127–128].
ing a structural homolog of the signaling A family of bacterial transcription fac-
domain of human TLRs to prevent proin- tors (MarA, SoxS and Rob), which are
flammatory cytokine secretion. So-called not required for growth in vitro, has been
TIR domain containing–proteins (Tcps) shown to be necessary for persistence in a
directly bind to MyD88 and thus impede mouse model of UTI. Mutants did not show
TLR signaling through the myeloid dif- any statistically significant differences in
ferentiation factor 88 (MyD88) adap- growth rate, cytotoxicity, adherence and
tor protein ([122–123]; see also chapter internalization in cell culture, and induc-
“Host response induction in UTIs” by tion of cytokine expression [129]. These and
Wullt & Svanborg). The ability of UPEC other findings suggest that not only the
to actively suppress the innate immune presence of functional virulence-associated
response of bladder epithelial cells has genes [130], but also the ability to spatially
also been reported in other recent publi- and temporarily regulate their expression
cations [124–125]. is important for the establishment of UTI.
Known virulence factors of P. mirabilis
besides urease, are hemolysin, fimbriae,
13. INSIGHTS INTO THE VIRULENCE- metalloproteases, and flagella. Genome
ASSOCIATED GENE REPERTOIRE wide screening for urovirulence-related
OF UROPATHOGENS DUE TO genes by signature tagged mutagenesis
GENOMIC ANALYSES led to the identification of genes affecting
motility, iron acquisition, transcriptional
In the era of (patho-)genomics, the global regulation, phosphate transport, urease
analysis of gene expression together with activity, cell surface structure, and key
the access to complete genome sequences metabolic pathways as requirements for
of uropathogens enables the definition of P. mirabilis infection of the urinary tract
every coding sequence in the uropathogen [131–132]. Determination of the complete
and thus opens the door for a more thor- genome sequence of P. mirabilis isolate
ough analysis of their virulence traits. The HI4320 confirmed the presence of previ-
availability of (multiple) complete genome ously identified virulence determinants.
sequences of different non-pathogenic Interestingly, genes coding for 17 types
and uropathogenic variants of one spe- of fimbriae, a potential type III secretion
cies allows the global screen and survey system were identified as well as four
of specific virulence-associated genes of copies of the zapE metalloprotease gene,
uropathogens. This also enabled the sys- six putative autotransporter-encoding
tematic analysis of the contribution of genes, and genes coding for at least five
pathogenicity- and genomic islands (PAIs, iron uptake mechanisms, two potential
GEIs) of UPEC to urovirulence in general type IV secretion systems, and 16 two-
as well as the identification of previously component regulators [64].
unknown virulence-associated determi- Genomic comparison of S. saprophyti-
nants on these islands [28–30, 126]. cus and other staphylococci revealed spe-
Global transcriptome analyses of cific urovirulence traits including various
UPEC in vivo confirm the importance transport systems to facilitate adapta-
of type 1 fimbriae, iron uptake systems, tion to the varying pH and concentration
the capsule and LPS as important viru- of inorganic ions, urea and organic com-
lence factors in the bladder and indi- pounds in human urine as well as the
cate that genes required for protection presence of a cell wall-anchored hemag-
against NO, microaerobic growth under glutinin that promotes adhesion to blad-
iron and nitrogen limitation and at high der epithelial cells [40].
14
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22
|1.3|
Immunity, genetics and

susceptibility to urinary tract
infection
Björn Wullt1, 2, Bryndis Ragnarsdottir1, Hans Fischer1, Jenny Grönberg-Hernandez, Nataliya Lutay1,
Catharina Svanborg1, 3
1
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine
2
Department of Urology, Lund University, Lund, Sweden.
3
Singapore Immunology Network (SIgN), Biomedical Sciences Institutes, Agency for Science, Technology, and Research
(A*STAR), 8A Biomedical Grove, Immunos, BIOPOLIS, Singapore 138648.
Corresponding author: Björn Wullt, MD, PhD, bjorn.wullt@med.lu.se, Department of Microbiology, Immunology and
Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, 223 62 Lund
ABSTRACT low TLR4 immune response appears to be

protective, as the host develops asympto-
The urinary tract is normally kept ster- matic bacteriuria. Acute pyelonephritis
ile by the anti-microbial host defense, and urosepsis, in contrast, are caused by
through effectors of the innate immune an exaggerated innate immune response
system. In resistant hosts, bacteriuria is to infection, which may cause renal scar-
transient, and complete clearance of infec- ring. Chemokine receptor function is criti-
tion is achieved by the urine flow, mucosal cal to control tissue inflammation through
microbicidal molecules like defensins and neutrophil recruitment, and in the mouse,
recruited inflammatory cells. Persistent CXCR2 receptor dysfunctions cause acute
infections engage a more complex host pyelonephritis with bacteremia, as well
defense, with a gradual transition from as renal scarring. In clinical studies, the
innate to specific immunity. Immune acti- same genetic defects have been found in
vation is controlled by different receptors patients prone to asymptomatic bacteriu-
and signaling pathways. In experimental ria or acute pyelonephritis, respectively.
models, TOLL-like receptors (TLRs) are TLR4 expression was recently found to
critical for the innate immune response be reduced in children with asympto-
and to initiate the defense against viru- matic bacteriuria, suggesting that low
lent E. coli strains, but surprisingly, a TLR4 expression might protect against
symptomatic UTI. Pyelonephritis-prone (ABU) and children with ABU have

children instead have lower CXCR1 reduced TLR4 expression.
expression levels than controls, and new 7. This evidence of the genetic control
genetic polymorphisms have been iden- constitutes a rationale for alternative
tified, in this patient group. These stud- treatment and research studies.
ies illustrate that genetically controlled
immune mechanisms influence immunity
and UTI susceptibility. It might be useful 1. INTRODUCTION
to include such variables in future risk
assessment of UTI prone patients. Urinary tract infections (UTI) vary
in severity, depending on the balance
Key words: Urinary tract infection, Host
between the infecting bacterial strain
susceptibility, TLR4, CXCR1, Inflammation,
and the antibacterial host defense. The
Innate immunity
molecular determinants of bacterial viru-
lence have been extensively studied, and
the pathogenesis of infection is known to
KEY POINTS
proceed from adherence and initial tissue
contact through many, intricate steps,
In the human urinary tract ending either in resolution through bac-
1. Innate immunity is responsible for
terial clearance by the host defense or in
the defense against acute bacterial persistence and chronicity [1–5]. Crucial
infection virulence factors of uropathogenic E. coli
(UPEC) confer resistance to the effects
2. Inflammation is triggered by uropath- of the host defense and in addition, viru-
ogenic E. coli through virulence fac- lent bacterial are able to produce mol-
tors, including P and Type 1 fimbriae, ecules that actively inhibit the immune
which mediate adherence to the response of the host, thereby enhancing
uroepithelium bacterial persistence in the host. This is
3. Activation of the uroepithelial Toll exemplified by the TcpC protein, which
Receptor 4 (TLR4) signaling initiates acts by reducing TLR4 dependent inflam-
the innate immune response mation and by promoting pyelonephritis
4. Neutrophils, combating E. coli infec- [6–7]. Strains causing asymptomatic bac-
tion, are recruited and activated by teriuria (ABU), in contrast, often fail to
the CXCL8 chemokine family and activate the antibacterial host defense, as
their receptors, especially CXCR1 they lack critical virulence factors needed
for host defense activation [5, 8]. They
5. CXCR1/2 dysfunctions have a major establish bacteriuria and persist for long
impact on the individual susceptibil- periods of time in asymptomatic hosts
ity to UTI. Receptor deficient mice and many ABU strains undergo progres-
develop acute pyelonephritis with uro- sive attenuation, from a more virulent to
sepsis and renal scarring and patients an adapted phenotype [9–10].
susceptible to acute pyelonephritis Innate immune mechanisms control the
have low CXCR1 expression and a antimicrobial defense of the urinary tract.
high frequency of polymorphisms in Studies in cellular systems, animal mod-
the CXCR1 gene. els and patients with UTI have identified
6. TLR4 dysfunctions appear to be pro- critical steps in the activation of innate
tective, as they inhibit the inflamma- immunity by virulent bacteria as well as
tory response to infection and thus the critical effector functions that enhance or
symptoms of disease. TLR4 KO mice disrupt the host defense [2, 11]. This adds
develop asymptomatic bacteriuria an essential source of molecular variables
24
Immunity, genetics and susceptibility to urinary tract infection | 1.3 |
to the well-known structural defects In this way, these receptors control the
that render the urinary tract susceptible quality of inflammation and the arbitra-
to infection We have identified genetic tion of defense versus tissue damage.
defects that increase the susceptibility The urinary tract mucosa and the
to both symptomatic and asymptomatic uroepithelial cells respond actively to
UTI, in patients and animal models and infection in a two-step process involving
have shown that genetic variation influ- receptors for bacterial virulence factors
ences clinical UTI susceptibility [12–15]. for recognition and the TLRs for signal-
This review concerns two aspects of ing [11, 18] (Figure 1). Virulence factors,
the innate immune response to UTI. The expressed by the most pathogenic strains,
data has been generated in the Svanborg- function as ligands for epithelial receptors
Wullt UTI research-group, or by refer- and biochemical modifications of those
enced colleagues in the field. The first receptors alert the host to the danger of
aspect is how molecular interactions acti- infection [19–21]. Examples are P and
vate the innate defense against infection, type 1 fimbriae, which bind to host cells
including receptors for bacterial virulence through different saccharide recognition
factors and TOLL-Like receptors (TLRs). mechanisms and trigger TLR4 dependent
The second aspect deals with innate signaling [22–23]. For example, the cou-
immune mechanisms needed to elimi- pling of P fimbriae to glycosphingolipid
nate bacteria from the urinary tract. We receptors releases the membrane domain
review how chemokine receptors deter- of the receptor and this directly acti-
mine the quality of the innate defense vates TLR4 signaling, the transcription
and how tissue pathology may result from of specific innate immune response genes
inadequate chemokine receptor function. and the production of mediators like
We also summarise the results of deliber- IL-6, IL-8 and TNF [18]. The same cells
ate establishment of ABU, in the human respond poorly to asymptomatic carrier
inoculation model, and studies of host strains and proinflammatory pathways
immunity and protection by long-term are not activated but suppressed [24].
bacterial carriage in that model. This unresponsiveness is probably essen-
tial, to protect the host from constant
innate immune activation and to permit
2. MOLECULAR INTERACTIONS THAT the symbiotic relationship between bac-
ACTIVATE THE INNATE DEFENSE teria and host to develop into the com-
AGAINST INFECTION mensal like and protective state of ABU
(Figure 1).
Toll like receptors (TLRs) are critical
sensors of infection and control many
aspects of the host immune defense [16]. 3. INNATE IMMUNE RESPONSE
Different domains of these receptors con- VARIATION AND GENETICS OF
trol signaling, through a complex cas- SUSCEPTIBILITY
cade of so called adaptor proteins and
through transcription factors that deter- Against this background, it is under-
mine which inflammatory mediators will standable that TLR4 defects abrogate
be produced by the infected cell [17–18]. the inflammatory response to UTI. ABU
TLR-signaling elicits a pro-inflammatory may result from infection with a strain of
response, which controls the local activa- low virulence or from bacterial inhibition
tion of cells at the site of infection, as well of the host immune response. ABU has
as the recruitment of inflammatory cells also been shown to result from host sup-
to infected tissues, through the secretion pression of the innate immune response.
of cytokines, interferons and chemokines. Thus, mice lacking the TLR4 receptor or
25
Adhesion, signaling Chemokines

and activation
Chemokine
A receptors
Normal TLR4 Dysfunction of TLR 4

A Cytokines A No inflammation signal
Ceramide Ser/Thr PK Ceramide

TLR4
GSL GSL
P fimbriae P fimbriae
Inflammation is Inflammation is not

triggered triggered
Symptoms, pyuria, Asymptomatic
and activation
cleared infection A Bacteriuria Chemokine

receptors
Asymptomatic
Cleared infection
Adhesion, signaling
and activation Bacteriuria
Ceramide
Chemokines
Ser/Thr PK Ceramide
TLR4 Chemokine
Figure 1 Bacterial activation of the inflammatory response.

A receptors
GSL GSL
Bacterial adhesins (P-fimbriae, Type 1 fimbriae) bind to specific receptors on the surface of the uro-epithelial cells, and the
adhesin-receptor interaction activates different transmembrane signaling Inflammation
pathways.
Ceramide
TLR4
is
Uropathogenic
Ser/Thr PK
E. coli expressing P fimbriae
Ceramide
Inflammation is not
bind to specific glycosphingolipid receptors on the uroepithelial cells, and recruit the TLR4 receptor for signaling. A dysfunc-
GSL
triggered triggered
GSL
tional TLR4 receptor hinders this signaling cascade and prevents inflammation.
Symptoms, pyuria,
cleared infection
P fimbriae
Asymptomatic
Bacteriuria
P fimbriae
Inflammation is Inflammation is not Asymptomatic

In the experimental UTI-model, mice with a dysfunctional TLR4 ( ) have a infection Bacteriuriaresponse to E. coli challenge and
low inflammatory
Cleared triggered triggered
Symptoms, pyuria,
develop asymptomatic bacteriuria (11). Children with ABU ( ) have lower TLR4 expression than children without UTI (15).
Asymptomatic
cleared infection Bacteriuria
Asymptomatic
Cleared infection Bacteriuria
having a dysfunctional signalling domain developed ABU following a prior symp-

show a delayed in inflammation and tomatic infection had intermediate TLR4
bacterial clearance and do not develop expression levels. DNA sequencing did
symptoms or tissue damage [11, 18]. sug- not identify Tir domain mutations in the
gesting that unresponsiveness may be patients and there were no disease asso-
protective at the mucosal level. ciated structural TLR4 gene polymor-
Suppressed TLR4 function was recently phisms. The mechanism of reduced TLR4
detected also in children with primary expression in ABU thus remains unde-
ABU who also had lower RNA levels than fined but should be identified, as this
controls without UTI and children with appears to be highly relevant for human
acute pyelonephritis [15]. Children who disease (Figure 1).
26
4. CHEMOKINE RECEPTORS CONTROL and activation [25]. Infected uroepithe-

BACTERIAL CLEARANCE AND lial cells produce several chemokines
RENAL SCARRING and recruit inflammatory cells from the
blood to the mucosa within 30 min [26].
Chemokines and their receptors are Neutrophils then cross the epithelial
essential to direct the traffic of different barrier, into the urine and cause pyu-
cell types in the body, and specifically ria, a classical sign of UTI (Figure 2).
to recruit immune cells to sites of tis- This is supported by CXCR1, a recep-
sue damage [6]. CXCL8 (Interleukin-8) tor for CXCL8 on infected uroepithelial
is one of the prototype chemokines and cells and neutrophils, which supports the
is involved in neutrophil recruitment exit of neutrophils from the tissues, thus
Mediator release and

cell recruitment
Normal CXCR1 Dysfunction of CXCR1

B B
Blood Tissue
vessel damage
IL-8
IL-8R
Epithelium
Lumen Lumen
Neutrophils reach the Fewer neutrophils

lumen (pyuria) reach the lumen
and activation
Pyelonephritis heals Pyelonephritis

A
heals Chemokine
receptors
without sequele with scarring
Pyelonephritis heals Pyelonephritis causes

and activation
Ser/Thr PK
without sequele renal destruction
Ceramide Ceramide
TLR4
Chemokine
A receptors
Figure 2 Chemokine release and neutrophil recruitment. Normal TLR4 Dysfunction of TLR 4
GSL GSL
The activated uroepithelial cells create a chemotactic gradient by secreting members
Ceramide Ser/Thr PK
TLR4
Inflammation is
of the Interleukin
Ceramide
8 (IL-8) family of chem-
Inflammation is not
okines and the IL-8 receptor (CXCR1) is upregulated. Neutrophils are recruitedtriggered
GSL
to the site of infection,
GSL
triggered
migrate through the
tissue and cross the mucosal barrier into the urinary lumen aided by IL-8 and CXCR1.
Symptoms, pyuria,
cleared
P fimbriae
infection DuringAsymptomatic
this process, infection is cleared.
Bacteriuria
P fimbriae
Inflammation is Inflammation is not Asymptomatic

In the experimental UTI-model, mice with a dysfunctional CXCR1 ( ) have
triggered
massive
Cleared infection neutrophils
Bacteriuriaentrapment in the kidney
triggered
Symptoms, pyuria,
tissue leading to renal scarring (28). Children ( ) with recurrent pyelonephritis have lower CXCR1 expression than controls
Asymptomatic
cleared infection Bacteriuria
without UTI (27, 14).

Asymptomatic
Cleared infection Bacteriuria
27
creating pyuria in patients with sympto- it is still important to discuss in what

matic UTI. way this new information might be inte-
In the mouse UTI model, a chem- grated to improve the clinical assessment
okine receptor defect severely impairs of patients with UTI and their risk for
neutrophil migration into infected kid- infection and tissue damage. The results
neys and knock out mice develop acute predict that, the assessment of structural
pyelonephritis with bacteremia [27–28]. abnormalities and UTI history might be
Histology showed neutrophil accumulation complemented by genetic profiling. The
under the epithelium and surviving mice aim would be to identify individuals with
later developed renal scarring [27–28]. a dysregulated inflammatory response,
This double phenotype reflects the (CXCR1 low), who may run an increased
importance of neutrophils and chemok- risk of recurrent pyelonephritis and renal
ine receptors for the clearance of kidney scaring. Furthermore, in patients with
infection (Figure 2). ABU, TLR4 might be quantified to dis-
CXCR1 is also important for human criminate those patients who should be
disease susceptibility. In patients with left without antibiotic therapy, from those
symptomatic UTI, there is a strong cor- who might run a risk of progression.
relation between urinary CXCL8 levels Ideally, such analyses should also
and urinary neutrophil numbers [5, 29]. include virulence factor typing of the
CXCR1 levels vary in the population, and infecting strain using either single pheno-
pyelonephritis prone children have lower typic traits like P fimbriae or gene profil-
CXCR1 expression levels than controls ing. With such information, the physician
without UTI [12]. We have identified five may assess if the strain is virulent and if
polymorphisms/mutations in the CXCR1 the patient responds adequately to infec-
gene, suggesting a novel, genetically tion, according to a risk assessment table.
determined cause of UTI susceptibility. The use of such diagnostic markers needs
[14] In a three-generation family study, to be tested prospectively, in relevant
we observed that the frequency of APN patient populations, however.
was high in family members of pyelone-
phritis prone children. In addition,
5.2 Treatment by deliberate
CXCR1 expression was lower in the rela-
establishment of bacteriuria in
tives of the APN-prone children than in
UTI prone patients
paediatric and adult controls. The infec-
tion pattern in some families suggested a Several investigators have made the
dominant pattern of inheritance, while in observation that ABU protects against
others a recessive pattern was suggested. recurrent UTI. The presence of one bac-
The CXCR1 sequence variability and the terial strain in an infected host may
family study support the notion that APN thus protect against superinfection by a
susceptibility and low CXCR1 expression more virulent strain. This has motivated
are inherited [13–14]. attempts to deliberately establish pro-
tective bacteriuria with “apathogenic’’
E. coli in patients with therapy-resistant
recurrent UTI [30–33]. We have tested
5. IMPLICATIONS FOR FUTURE
this approach in several studies, and
DIAGNOSTIC/THERAPEUTIC USE
have analysed mechanism that control
the establishment of bacteriuria and the
5.1 Diagnostic approach
induction of innate immunity during
While current hospital policy in many the first few days after the inoculation.
countries aims to reduce cost by avoiding Our observations suggest that deliber-
new technology and scientific advance, ately established bacteriuria may be of
28
therapeutic value in therapy resistant These results suggested that there are
patients with recurrent UTI. important functional differences between
The prototype ABU strain E. coli 83972 P fimbriae and type 1 fimbriae in the
[30–31] was originally isolated from a girl human urinary tract. In addition, there
with ABU who had carried it for three appear to be major differences between
years without adverse effects [30, 34] the murine UTI model and the human
and has been shown to cause persistent urinary tract, in terms of type 1 fimbrial
ABU when deliberately inoculate into the function.
bladder of patients with recurrent UTI
83972 [30–31]. E. coli 83972 lacks func-
tional fimbriae and defined O and K sur- 6. CONCLUSIONS
face antigens and carries adhesin gene
clusters homologous to fim, pap, uca and This chapter presents new data suggest-
foc, but does not express fimbriae or func- ing that the susceptibility to UTI, and
tional adhesins after in vitro culture or especially of disease prone patients, is
when recovered from the human urinary influenced by genetic mechanisms that
tract [9, 30, 35]. control the innate immune response to
The human inoculation protocol has infection. Such genetic determinants
also been useful to prove in human include TLR4 and CXCR1; two important
patients that virulence factors influence molecules controlling different aspects
the establishment of bacteriuria and the of the innate immune defense. It is our
innate immune response in the urinary hope, that in the future, it may be possi-
tract. For example, patients were sub- ble to integrate such molecular informa-
jected to intravesical inoculation with the tion into the diagnostic and therapeutic
non-fimbriated ABU strain E. coli 83972 considerations needed to identify the UTI
or with P fimbriated transformants of prone individual and to select a proper
this strain [36–37]. The P-fimbriated therapeutic approach.
transformants invariably established bac-
teriuria more rapidly and caused higher
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31
|1.4|
Induction and modulation of

host responses by uropathogenic
Escherichia coli structures
David J. Klumpp*, Anthony J. Schaeffer
Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago,
Illinois 60611
*address all correspondence to: d-klumpp@northwestern.edu
312.908.1996 P, 312.908.7275 F
ABSTRACT secretion and is postulated to transiently

delay the innate immune response and
Acute urinary tract infection (UTI) has thus promote establishment of infection.
been characterized extensively in both UPEC have also recently been shown to
patients and rodent models and is associ- invade urothelium in murine UTI and
ated with local cytokine production by the establish intracellular reservoirs capable
urothelium, thereby leading to urinary of supporting recurrent infection. UPEC
cytokine accumulation, leukocytic influx, binding to the urothelial surface induces
and pyuria. Recent cellular and molecu- urothelial PI3 kinase activity that drives
lar studies that focus on uropathogenic cytoskeletal reorganization necessary
Escherichia coli (UPEC), however, reveal for bacterial invasion, but recent studies
strikingly complex host-pathogen interac- also point to additional signaling events.
tions. Keys to these interactions are sev- Binding of FimH adhesin to uroplakin
eral early effects upon urothelial signaling complexes on the urothelial surface trig-
pathways that are rapidly induced upon gers signals mediated by uroplakin III
UPEC binding. For example, although that are required for UPEC invasion.
acute UTI is associated with robust UPEC binding also triggers elevated
inflammation, UPEC have recently been cAMP levels that modulate both bacte-
shown to modulate urothelial inflamma- rial entry and fluxing out of urothelial
tory responses. This modulation includes cells. Finally, modulation of inflamma-
suppression of NFkB-dependent cytokine tory responses and UPEC invasion are
Induction and modulation of host responses | 1.4 |
coincident with FimH-induced urothelial 2. UPEC MODULATE UROTHELIAL

apoptosis. FimH-dependent urothelial INFLAMMATORY RESPONSES
apoptosis also requires uroplakin III, and
this apoptotic response leads to umbrella Canonical inflammatory responses to
cell exfoliation that is considered a host pathogens are initiated by receptors that
defense mechanism, acting in concert with recognize highly-conserved, pathogen-
inflammation to promote pathogen clear- associated molecular patterns, and
ance. Numerous gene expression changes toll-like receptors are the best studied
occur as the urothelium is remodeled fol- examples (PAMPs and TLRs, respec-
lowing UPEC infection and urothelial tively) [1–2]. TLR activation drives sig-
apoptosis, where bone morphogenetic pro- naling cascades that typically result in
tein 4 signaling is pivotal in this urothelial nuclear factor kB (NFkB) stimulation
renewal. Thus, in addition to inflamma- of transcription at promoters of inflam-
tion associated with acute infection, com- matory genes that contain kB binding
plex early interactions between bacteria sites. IL-6 and IL-8 are two such NFkB-
and the urothelium drive diverse host dependent genes, and UTI is character-
responses critical to UTI pathogenesis. ized by elevated urinary IL-8 and IL-6
Key words: LPS, calcium, uroplakin, due to local secretion of these factors by
invasion, apoptosis the urothelium in response to UPEC
[3–4]. Surprisingly, studies of urothelial
NFkB activity and cytokine secretion
1. INTRODUCTION revealed that UPEC modulate inflamma-
tory responses.
Urinary tract infection (UTI) is among The archetypal UPEC isolate, NU14,
the most common infectious diseases. was used in an in vitro model of early
Many clinical aspects of UTI are increas- events in UTI host-pathogen interac-
ingly well characterized and are described tions by assessing NFkB transcriptional
in detail elsewhere in this text, includ- activity [5–6]. Contrary to the robust
ing the causative pathogens, the physi- inflammation characteristic of acute UTI,
ologic and immune responses, effective we found that NU14 suppressed NFkB
therapeutic approaches, and epidemiol- induction in immortalized human urothe-
ogy. But recent data gleaned from ani- lial cell cultures, and this suppression
mal and human studies reveal previously occurred whether urothelial NFkB activ-
unappreciated complexity in UTI host- ity was stimulated with LPS or tumor
pathogen interactions. These findings necrosis factor α (TNF). Since a K12 labo-
identify multiple aspects of urothelial ratory strain did not inhibit NFkB, inhi-
cell signaling modulated during infec- bition appeared specific to select strains.
tion, often inducing host responses but Indeed, quantifying cytokine secretion
also inhibiting other signaling cascades in urothelial cultures infected with vari-
in a pathogen-specific manner. Here, we ous strains selected from the ECOR ref-
review the current understanding of host erence panel, modulation of TNF-induced
responses with an emphasis on those urothelial IL-8 was observed for 15 of 18
events triggered in the urothelium by ECOR clinical isolates including cysti-
uropathogenic Escherichia coli (UPEC). tis, pyelonephritis, and fecal strains [7].
We focus on initial signal transduction Some pathogens alter signaling cascades
events elicited by bacterial binding, the upstream of NFkB directly by deliver-
role of urothelial signaling in bacterial ing an inhibitory factor, such as YopJ of
internalization, and urothelial dynamics Y. pestis that is injected into host cells via
in response to infection. the type III secretion apparatus where
33
it then interacts with multiple kinases to specifically modify PAMPs in a way

[8]. To determine the molecular basis that evades normal host surveillance
of inflammatory modulation by UPEC, mechanisms (Figure 1A). In contrast, the
we and others employed genetic screens pyelonephritis isolate CFT073 encodes a
and targeted studies to identify mutants novel toxin, TcpC, a factor that contains a
defective for inflammatory modula-tion Toll/Interleukin-1 receptor (TIR) domain
in NU14 and the closely-related strain [12]. TcpC inhibits inflammatory signal-
UTI89. Surprisingly, instead of identifying directly through TIR-mediated inter-
ing genes for secreted factors, mutations actions with the critical TLR adaptor
that abolished inflammatory modulation MyD88 (Figure 1A). Although NU14 lacks
mapped to loci encoding biosyn-thetic a gene with significant homology to TcpC,
activities for bacterial surface struct-ures, it is unclear whether other UPEC encode
including genes of LPS biosynthesis and a similar toxin. Nonetheless, UPEC uti-
peptidoglycan biosynthesis [9–10]. The lize multiple mechanisms for modulating
outer membrane protein OmpA was simi- urothelial inflammatory responses.
larly found to be required for NFkB inhi-
bition by the neonatal meningitis E. coli
strain RS218, a strain that is highly 3. UPEC INDUCE CALCIUM RESPONSES
homologous to NU14 [5, 11]. These genes
are found in UPEC and laboratory E. coli Calcium is the most pervasive second
strains alike, suggesting that these gene messenger in biology, so it is not surpris-
products collaborate with other factors ing that urothelial responses to UPEC
A B
Figure 1 E. coli modulate multiple urothelial signaling cascades. A) TLR4 activation by E. coli LPS increases cytosolic calcium
and activation of adenylate cyclase 3 (AC3). AC3 in turn generates cAMP that activates protein kinase A (PKA), thereby
inducing PKA-mediated phosphorylation of CREB and enhanced transcription of IL-6. Uroplakin III (UPIII) and uroplakin Ia/Ib
act as a complex to also elevate cytosolic calcium. This calcium is induced by the FimH adhesin. B) TLR4 is the classic pattern
recognition receptor that mediates innate responses to gram-negative pathogens by virtue of its capacity to recognize LPS,
and MyD88-mediated signals then result in phosphorylation of IkB by IkB kinases (IKK) and subsequent transcription of NFkB-
dependent inflammatory genes. UPEC modulates TLR4 signaling pathway in at least two ways. UPEC strain CFT073 secretes
the TIR-domain protein TpcC that inhibits MyD88. UPEC strains that do not encode a TpcC-like factor may instead inhibit NFkB
activity at the level of TRL recognition.
34
include increased levels of cytosolic Ca2+. mediated signaling studies in the bladder
Elevated cytosolic Ca2+ was first reported is surprising given that recent studies in
in association with UPEC-induced Xenopus demonstrated a signaling role
urothelial apoptosis [13]. In that study, for uroplakin III during egg fertiliza-
we found that elevated calcium induction tion that required tyrosine phosphoryla-
occurred five hours after in vitro infection [19–21]. We found that application
tion of human immortalized urothelial of purified FimH protein to immortalized
cultures with NU14, and UPEC-induced urothelial cells induced a Ca2+ transient
calcium was strictly dependent upon that was dependent upon intracellular
the expression of FimH, the type 1 pilus and extracellular Ca2+ stores and decayed
adhesin. Another recent study from the within 150 seconds [22]. But instead of
laboratory of Dr. Soman Abraham iden- initiating at TLR4, FimH-induced Ca2+
tified elevated urothelial intracellular was strictly dependent upon uroplakin
resulting from TLR4 activation [14]. III, the only uroplakin with an appre-
Using a K12 laboratory strain encoding ciable intracellular domain potentially
type 1 pili on a plasmid in combination capable of transducing intracellular sig-
with urothelial carcinoma cells, TLR4 nals (Figure 1B). Threonine 244 (T244)
activation was shown to sequentially within the cytoplasmic tail of uroplakin
induce Ca2+, cAMP, and CREB-mediated III proved essential for FimH-induced
transcription that accelerates IL-6 secre- Ca2+, and T244 corresponded to a poten-
tion (Figure 1B). The transient Ca2+ tial phosphorylation site for casein
increase was mimicked in part by puri- kinase II (CK2). Consistent with this,
fied LPS, but delayed kinetics relative to FimH treatment resulted in uroplakin
intact bacteria suggest that additional phosphorylation, suggesting that FimH
host-pathogen interactions modulate induces CK2-dependent phosphorylation.
Ca2+ responses. Furthermore, given that Interestingly, mutation of a highly con-
many UPEC isolates modulate inflam- served tyrosine associated with fertiliza-
matory responses downstream of TLR4 tion-induced phosphorylation in Xenopus
[7], it would be interesting to determine had no effect on Ca2+ responses to FimH.
whether the same TLR4-dependent Ca2+ Understanding how uroplakin III phos-
responses occur in cultures treated with phorylation alters interactions with other
UPEC. urothelial proteins will be key to under-
A more recent study identified another standing FimH-induced signaling.
mechanism of UPEC-induced Ca2+
response and simultaneously identified
a novel signaling role for uroplakin III 4. UPEC-INDUCED UROTHELIAL
in UPEC pathogenesis. Uroplakin pro- RESPONSES DRIVE BACTERIAL
teins were identified by pioneering stud- INVASION
ies in the laboratory of Dr. Tung-Tien Sun
[15–16]. Uroplakins are highly expressed Uropathogen reservoirs have long been
as complexes in urothelial superficial understood to exist within the GI tract
umbrella cells and are so abundant that and the vagina, but seminal studies in the
they constitute the electronic density laboratory of Dr. Scott Hultgren demon-
characteristic of the asymmetric unit strate that the urothelium represents an
membrane. While uroplakin Ia (and pos- additional potential reservoir for bacteria.
sibly uroplakin Ib) was identified by Dr. UPEC have been shown to invade urothe-
Sun’s group as the bladder receptor for lial cells and form stable intracellular
FimH [17–18], a signaling role for uro- populations in vitro and in a murine UTI
plakins was previously unknown in model, and these drug-resistant intrac-
the bladder. The absence of uroplakin- ellular populations then drive recurrent
35
bacteriuria in mice [23–27]. Similar intra- [32]. Indeed, manipulating cAMP levels
cellular UPEC populations have been may offer clinical promise, for the ade-
observed in exfoliated human urothelial nylate cyclase activator forskolin pro-
cells, and K. pneumoniae is also capable moted UPEC exocytosis from urothelial
of forming intracellular communities, sug- cells in vitro and in vivo [33].
gesting that the urothelium is a potential Despite uroplakin complexes serving
reservoir that underlies recurrent UTI for as UPEC receptors via interactions with
multiple uropathogens [28–29]. A central FimH (see above), integrins appear to cen-
question, then, is what events are required tral mediators of invasion. Dr. Matthew
for bacterial invasion of urothelial cells? Mulvey recently reported that adhesion
Bacterial invasion has been widely of either UTI89 or a piliated laboratory
studied in other systems and typi- strain colocalized with integrins β1 and
cally involves cytoskeletal remodeling. α3 on carcinoma cells, and antibodies
Similarly, UPEC invasion of urothelial against these integrins inhibited inva-
cells was shown to require actin polym- sion [34]. Mutation of known β1 integrin
erization. Invasion was FimH-dependent phosphorylation sites resulted in signifi-
and associated with activation of phos- cantly reduced invasion in β1-deficient
phoinositide 3-kinase and focal adhesion fibroblasts, and inhibition of Src and focal
kinase as well as the involvement of the adhesion kinases also inhibited invasion.
Rho-GTPases RhoA, Cdc42, and Rac1, These data suggest that integrins are
all molecules that are critical media- important mediators of UPEC invasion
tors of cytoskeletal remodeling [30–31]. in vitro, but it is difficult to reconcile the
Interestingly, studies from the Abraham likely subcellular restriction of integrins
lab suggest that TLR4 signaling antag- to urothelial umbrella cell baso-lateral
onizes UPEC invasion (Figure 2). By surfaces in urothelium with images that
stimulating adenylate cyclase 3 and sub- demonstrate UPEC binding across the
sequent cAMP accumulation, cAMP-de- apical surface in the intact bladder [23].
pendent protein kinase A was shown to In addition to roles for integrins and
inhibit Rac1 and thereby reduce invasion TLR4 signaling in invasion, it now
Figure 2 Multiple factors mediate UPEC invasion of urothelial cells. UPEC entry requires actin remodeling that is dependent
upon phosphoinositde 3-kinase (PI3K) and Rho-like GTPases, such as Rac. TLR4 activation antagonizes this entry through inhi-
bition of Rac by TLR4-induced adenylate cyclase 3 activity (AC3) and subsequent protein kinase A (PKA) activation. PKA also
enhances UPEC exocytosis by promoting fusion of umbrella cell fusiform vesicles, containing UPEC, with the plasma membrane.
UPEC binding to integrins a3 and b1 promotes entry that is dependent upon phosphorylation of the b1 cytosolic tail. The UPEC
adhesin FimH also promotes entry that requires casein kinase 2 (CK2) and uroplakin III (UPIII).
36
appears that uroplakin III is also an to assess urothelial integrity in interstitial

important mediator of UPEC invasion cystitis patients [36].
(Figure 2). We recently found that expres- A biochemical understanding of UPEC-
sion of a uroplakin III variant, where T244 induced urothelial apoptosis was facili-
was modified to a glutamic acid residue tated by development of in vitro models
to mimic constitutive phosphorylation by of UPEC-pathogen interactions. We found
CK2, significantly decreased urothelial that immortalized urothelial cell cultures
invasion by NU14 [35]. Conversely, the underwent FimH-dependent apopto-
T244-to-alanine mutant that mimics con- sis in response to NU14 with the same
stitutive uroplakin III dephosphoryla- kinetics as the murine UTI model, thus
tion did not affect invasion, suggesting establishing the utility of in vitro models
that T245 phosphorylation plays distinct for studying this key early event in UTI
roles in UPEC-induced Ca2+ elevation pathogenesis [36]. This model revealed
and UPEC invasion. Nevertheless, CK2 that NU14 caused activation of multiple
appears important in UPEC invasion caspases, proteases pivotal to the ini-
for pharmacologic or genetic CK2 inhi- tiation and execution of apoptotic signal-
bition significantly reduced NU14 inva- ing cascades [13]. Indeed, NU14 induced
sion in vitro and in a murine UTI model. urothelial caspase 2, 3, and 8 activities
Thus, UPEC invasion of urothelial cells (Figure 3). Specific inhibitors confirmed
is emerging as a major component of UTI the involvement of these caspases and
pathogenesis, and these basic science also implicated caspase 9, an intermedi-
studies have identified multiple novel tar- ate caspase that couples mitochondrial
gets for therapeutic intervention. amplification of input apoptotic signals
with executioner caspases. Consistent
5. UROTHELIAL APOPTOSIS IS
A KEY EARLY EVENT IN UTI
PATHOGENESIS
In addition to UPEC invasion, EM analy-

ses in a murine UTI model by the Hultgren
laboratory revealed that NU14 caused
the formation of urothelial lesions devoid
of superficial umbrella cells [23]. Using
TUNEL staining to identify DNA fragmen-
tation characteristic of apoptosis, NU14-
induced urothelial lesions were found to
result from rapid induction of apopto-
sis that was dependent upon FimH and
caused umbrella cell exfoliation. Moreover,
co-instillation of an apoptosis inhibitor
increased NU14 colonization of the blad-
der, suggesting that urothelial apoptosis
is a host defense mechanism so that rapid, Figure 3. UPEC-induced urothelial apoptosis involves intrinsic
UPEC-induced apoptosis leads to shedding and extrinsic cascades. Both the extrinsic apoptotic cascade
(caspase 8) and the intrinsic apoptotic cascade (caspase 2) are
of the superficial urothelium and pathogen induced by FimH. Bid translocation to mitochondria is associ-
purging. Urothelial apoptosis likely also ated with a loss of mitochondrial membrane potential (DYm)
occurs in humans, for UTI patients are and accumulation of cytochrome C, ultimately resulting in
activation of caspase 3, an executioner caspase. Initiation of
highly sensitive to intravesical instillation apoptosis requires uroplakin III (UPIII) and casein kinase
of potassium chloride, a clinical assay used II (CK2).
37
with this potential role for mitochon- response to UPEC insult naturally
dria in UPEC-induced apoptosis, over- requires epithelial renewal to re-estab-
expression of Bcl-XL blocked caspase-3 lish the urothelial permeability barrier
activity, and NU14 induced translocation critical to normal bladder function. The
of Bid to mitochondria, accumulation of initial EM characterization of urothelial
cytosolic cytochrome c, and loss of mito- apoptosis in murine UTI showed compel-
chondrial membrane potential. These ling evidence for rapid urothelial differ-
findings together suggest an ordering of entiation [23]. In these images, urothelial
events that includes activation of extrin- lesions devoid of umbrella cells were
sic (caspase 8) and intrinsic (caspase 2) evident within 4 hours of infection, and
apoptotic cascades upstream of mito- lesions were progressively re-populated
chondrial destabilization and subsequent with less differentiated urothelial cells
activation of executioner caspases (cas- that then reconstituted a mature and
pase 3). Finally, all of these events were fully differentiated urothelium within
specifically initiated by NU14 bearing days. In subsequent studies, microarray
functional FimH or could be induced by analyses were then employed to identify
purified FimC·H. Therefore, in addition the changes in gene expression associ-
to the long-appreciated role for FimH as ated with urothelial renewal in mice
a key UPEC adhesin, FimH also medi- [37]. NU14 infection was associated with
ates UTI pathogenesis by functioning as suppression of the bone morphogenetic
a tethered toxin that promotes apoptosis. protein 4 (BMP-4) signaling pathway,
These findings illuminate the role of suppression that was strictly dependent
apoptosis in UTI, but the membrane-prox- upon NU14 expressing functional type 1
imal events that initiate urothelial apop- pili. BMP-4 suppression also correlated
tosis remained unclear until very recently. with decreased Wnt5a signaling and a
We observed that NU14-induced apoptosis consequent de-repression of urothelial
of immortalized urothelial cells was sig- markers of proliferation and differentia-
nificantly diminished by genetic abrogation. A key promoter of epithelial differ-
tion of uroplakin III expression [22]. Since entiation, Delta-like 1, was maximally
CK2 appears to be a critical mediator of expressed at 3.5 h following infection,
uroplakin III signaling, we next exam- consistent with the kinetics of apoptosis
ined the role of CK2 in apoptosis. Genetic in vitro and in vivo [13, 23, 36]. Delta-
knock-down of urothelial CK2 expression like 1 expression subsided entirely by 7
also blocked apoptosis induced by NU14. days following expression, by which time
Thus, uroplakin III signaling mediates UPEC-induced lesions were repaired.
both UPEC-induced apoptosis and urothe- These events are consistent with rapid
lial invasion by UPEC, and future studies induction of urothelial proliferation
that identify the repertoire of protein- and differentiation that accelerates the
protein interactions in uroplakin III com- otherwise slow turnover of urothelium
plexes should define the signaling events and thus restores normal urothelial
that drive these disparate – indeed mutu- integrity. Indeed, recent studies sug-
ally exclusive – cell fates. gest that UPEC-associated inflamma-
tory responses are critical to activation
of a urothelial stem cell population that
6. UPEC INDUCES UROTHELIAL mediates urothelial renewal, and BMP-4
TURNOVER is a key regulator of these processes [38].
Uroplakin III is a marker of termi-
Urothelium exhibits the slowest turno- nal differentiation in urothelium. Since
ver of any epithelium, several months in we identified a central role for uroplakin
mouse and man. The urothelial apoptotic III in UPEC-induced apoptosis, we also
38
examined the effects of uroplakin III on process will foster development of thera-
apoptosis during urothelial apoptosis pies that selectively target urothelial
in vitro and in murine UTI [39]. Serum- cells which harbor intracellular UPEC
induced differentiation of immortal- and may also have utility for treating
ized urothelial cultures was associated carcinoma. Therefore, understanding the
with increased expression of urothelial molecular details of the host responses
differentiation markers, including uro- to UPEC – and how these responses vary
plakins. Coincident with increased dif- between pathogenic and benign bacte-
ferentiation in vitro, urothelial cultures ria – will expand our arsenal for treating
became increasingly sensitive to NU14- bladder disease.
induced apoptosis. This enhanced apop-
totic response, promoted by urothelial
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41
|1.5|
Immunology of the urinary tract

Hartwig W. Bauer1, Wolfgang G. Bessler2
1
Prof. Dr. med. habil. H. W. Bauer. Facharzt für Urologie und Andrologie, Maximilianstr. 31. D-80539 München, Germany.
2
Institut für Molekulare Medizin und Zellforschung, Universitätsklinikum Freiburg, AK
Tumorimmunologie/Vakzine, Hermann-Herder-Str. 9, 79104 Freiburg, Germany.
ABSTRACT subsystems: 1) the cellular comprising

CD4 T cells (e.g. Th1, Th2) and the CD8
Infection of the urinary tract is gov- T killer cells, and 2) the humoral where
erned, as elsewhere, by the general B cells produce specific IgG, IgA, IgM,
principles of bacterial pathogenesis; the and IgE antibodies. IgA is the secre-
first encounter of bacteria with their tory immunoglobulin present in body
host involves attachment to a cell sur- secretions, including urine. The toll-like
face, which results in colonization of the receptor (TLR) family mediates immune
host. In such cases, induced antibody responses; there are ten known human
responses at the mucosal surface could TLRs. Gram-negative bacterial lipopoly-
prevent attachment and abrogate coloni- saccharide (LPS) activates antigen-pre-
zation. Recurrent urinary tract infection senting cells through TLR-4 whereas
represents a case of successful microbial lipopeptides and mycobacterial lipogly-
host evasion and poses a major medi- cans activate cells through TLR-2. TLRs
cal health problem. In this overview, can influence adaptive immune responses
after a review of the general character- and exert complex effects on Th1 and
istics of the immune system we describe Th2 polarization of CD4+ helper cell
the peculiarities of the immune system responses.
in the genitourinary tract. The line- In the urinary tract there is a well
age of macrophages, dendritic and other organised lymphoid tissue, resembling
antigen-presenting cells orchestrate the mucosa-associated lymphoid tissue,
the inflammatory and immune defences although in the lower urinary tract it
against the invader(s). They include the seems insufficient to generate common
innate immunity (macrophages, poly- mucosal immune responses. In the uri-
morphonuclear leukocytes, natural killer nary tract, the defence mechanism may
cells, complement system, etc.) and the be explained by the shedding of uropath-
adaptative immune system with two ogens with urethral cells, trapping of
Immunology of the urinary tract | 1.5 |
bacteria by mucus, intermittent wash- must first be able to colonize an appropri-

out by urine, local production of immu- ate target tissue of the host. This tropism
noglobulins, cytokines and defensins and and the ability of the bacterium to breach
mobilization of leukocytes in addition to mucosal barriers and invade the host,
the Tamm-Horsfall protein which is capa- distinguishes pathogenic from commen-
ble of both mediating direct antimicro- sal organisms. Colonization begins with
bial activity and alerting immune cells. the attachment of the bacterium to recep-
Locally synthesized sIgA immunoglobu- tors expressed by cells forming the lining
lins can be low or normal in the urine of of the mucosa. This attachment will give
individuals with recurrent (lower) uri- the opportunity to specialised cells to rec-
nary tract infections (UTIs). The bacte- ognise this bacterium as “non-self” and
rial extract OM-89, which binds to TLR-4, trigger the corresponding chain of events
generally activates the immune system, (see Figure 1). Recurrent urinary tract
and reduces the number of recurrences of infection represents a case of successful
UTIs. A better understanding of the com- microbial host evasion and poses a major
plex immunological factors involved in medical health problem. We shall not dis-
fighting UTIs will certainly lead to better cuss herein other, intimately related, sub-
medicines or improved usage of the exist- jects such as basic mechanisms of disease
ing ones. pathogenesis, host response induction,
and genetic variation in the innate host-
Key words: Urinary tract infections,
response or the epithelium-derived cathe-
Innate Immunity, Adaptive Immunity,
licidin (See chapters 1.3. Host response
TLR, toll like receptors, prevention of
induction in urinary tract infections by
infections, Uro-Vaxom
Björn Wullt, & Catharina Svanborg, and
1.4. Host reaction by Dave Klumpp &
Anthony Schaeffer) nor the role of bio-
1. INTRODUCTION film formation, which has a great impact
on the development or maintenance of
Infection of the urinary tract is governed, urological infections (See Chapter 1.6.
as elsewhere, by the general principles of The role of biofilm infection in urogeni-
bacterial pathogenesis. Proteins produced tal infections by Peter Tenke & Shinya
by the microbial agent during infection Uehara). In the overview presented
contribute to (i) colonization of the host, herein, we shall review the general char-
(ii) evasion of host defence, and (iii) dam- acteristics of the immune system and,
age of host tissue. The flushing mecha- thereafter, describe in greater detail the
nisms and the acidity of urine maintain peculiarities of the immune system in the
the bladder and most of the urethra genitourinary tract.
almost free of microorganisms most of the
time. For most bacteria and viruses, the
first encounter with their host involves 2. INNATE IMMUNITY
attachment to a eukaryotic cell surface,
which results in colonization of the host Innate and adaptive immunity have tra-
prior to disease. In such cases, induced ditionally been considered as largely sepa-
antibody responses at the mucosal sur- rate, though complimentary, mechanisms
face could prevent attachment and abro- of defence against microbial threats.
gate colonization. The ideal target for The adaptive system, being evolution-
such antibodies are bacterial surface ally newer and having the capacity for
proteins known as adhesins which medi- selectivity, adaptation, amplification, and
ate microbial attachment to host tissue. memory, has arguably been regarded as
To initiate infection, bacterial pathogens more sophisticated and potent. However,
43
Figure 1 Schematic chain of events In an immune reaction, Involving the Innate and the acquired, T’ and, B’ cell systems.
recent advances in our understand- Some macrophages are concentrated in

ing of the nature and functions of toll- the lungs, liver (Kupffer cells), lining
like receptors (TLRs) has sparked a new of the lymph nodes and spleen, as brain
appreciation of the extensive interde- microglia, kidney mesoangial cells, syno-
pendence and cross-talk between innate vial A cells, and osteoclasts. Once a mac-
and adaptive responses and has led to rophage phagocytes a cell, it displays
renewed interest and higher regard for some of its proteins, i.e. “epitopes”, on its
the contribution of the innate arm of the surface. These surface markers serve as
immune network. A phagocyte is a cell an alarm to other immune cells that then
that attracts (by chemotaxis), adheres infer the form of the invader. Dendritic
to, engulfs, and ingests foreign bodies. cells are covered with a maze of mem-
Promonocytes originate in the bone mar- branous processes reminding nerve cell
row, after which they are released into dendrites. Like the macrophages, most
the blood (circulating monocytes,) and of them are highly efficient antigen pre-
eventually mature into macrophages. senting cells (APCs). There are four basic
44
types: Langerhans cells, interstitial den- phagocytes. The neutrophils provide

dritic cells, interdigitating dendritic the major defence against pyogenic bac-
cells, and circulating dendritic cells. The teria and are the first on the scene to
Langerhans cells are specialized dendritic fight infection. Eosinophils are attracted
cells strategically located in stratified to cells coated with complement C3b,
epithelia, such as those of the skin, oral where they release major basic protein
cavity, pharynx, oesophagus, upper air- (MBP), cationic protein, perforins, and
ways, urethra, and female reproductive peroxides, all of which fight infection.
tract, which are exposed to a wide vari- Each of the cells in the innate immune
ety of microbial pathogens. Langerhans system binds to antigen using pattern-
cells play an essential role in the induc- recognition receptors. Over the course
tion of T-lymphocyte responses against of human development these receptors
viruses, bacteria, and parasites that gain for pathogen-associated molecular pat-
access to those epithelial surfaces, due to terns have evolved via natural selection
their high antigen capture and processing to be specific to certain characteristics
potential and their capacity to present of broad classes of infectious organ-
antigen peptides to T cells on migration isms. There are several hundred of these
to the lymph nodes [1]. receptors and they recognize patterns of
Further elements of the innate bacterial lipopolysaccharide, peptidogly-
immune system are the natural killer can, bacterial DNA, dsRNA, and other
cells which are found in blood and lymph substances.
and are known to lyse cancer cells and The complement system, which con-
virus-infected body cells. They are large sists of some 30 proteins circulating in
granular lymphocytes that attach to the blood plasma, is a major enzyme system
glycoproteins on the surfaces of infected which coats microbes with molecules that
cells and kill them. To discriminate make them more susceptible to engulf-
between “normal” and virus-infected, ment by phagocytes. Vascular permeabil-
tumour, or allogeneic cells, mammalian ity mediators increase the permeability
natural killer cells monitor MHC class of the capillaries to allow more plasma
I expression on target cells by means of and complement fluid to flow to the site
inhibitory natural killer cell receptors of infection and induce the neutrophils to
(NKRs). The receptors transmit an inhib- adhere to the walls of capillaries.
itory signal that cancels a program for
cytotoxic action previously triggered by
contact with the target cell. NKRs belong 3. ADAPTIVE IMMUNITY
to two distinct groups of molecules: immu-
noglobulin-like receptors and C-type lec- Lymphoid stem cells, which originate in
tin receptors such as CD94, NKG2, and the bone marrow, give rise to the vari-
NKR-P1 in humans and a group of Ly49 ous components of the acquired immune
receptors in rodents [2]. Several authors system. Secondary lymphoid tissue is
have shown that dendritic cells can acti- “peripheral” tissue that provides an
vate natural killer cells and are prob- environment for lymphocytes to encoun-
ably responsible for natural killer cell ter antigens and proliferate if neces-
activation prior to the initiation of adap- sary. Secondary lymphoid tissue consists
tive immunity. Furthermore, NK cells of spleen, lymph nodes, bone marrow
activated in this fashion can restrict B and mucosa-associated lymphoid tis-
cell transformation, e.g. by Epstein-Barr sue (MALT) in the tonsils, respiratory
virus [3–4]. tract, and gut. All of these structures
The polymorphonuclear neutrophil provide major portals for the entry of
leukocytes are non-dividing, short-lived foreign microorganisms into the body.
45
Once in secondary lymphoid tissues, Th17 (IL-17 producing cells) and induced
lymphocytes may migrate from one lym- regulatory T cells (iTreg; also of the CD8 T
phoid structure to another by vascular cell lineage) [6–7].
and lymphatic channel systems. Mucosa When a B cell is stimulated by a par-
associated lymphoid tissue (MALT) con- ticular antigen, it differentiates into a
sists of large numbers of lymphocytes, lymphoblast which further differentiates
plasma cells and macrophages in the lam- into a plasma cell. Plasma cells release
ina propria of digestive, respiratory and antibody until the antigen is destroyed.
nasal-associated lymphoid tissue in the Following exposure of a B cell to a specific
oropharyngeal cavity. After antigen expo- antigen, the antibody it produces may
sure activated lymphocytes and antigen combine with a toxic site on the antigen
presenting cells migrate to regional lymph molecule or cause its removal by phago-
nodes where immunologically active cells cytes. In addition, memory of the offend-
are produced. These effector T and B ing antigen is retained for at least several
cells, plasma cell precursors and mem- months.
ory cells are returned via the circulation Antibodies can be divided into 5 major
to the mucosa that is threatened. In the classifications: IgM, IgG, IgA, IgD, and
gut-associated lymphoid tissue (GALT) IgE. IgM is the main mediator of the pri-
some of the columnar epithelial cells over mary immune response; for IgM “natu-
lymph nodules are replaced by cells that ral” antibodies there is no known contact
are specialized for antigen processing. with the antigen that stimulated its pro-
Their surface has short irregular micro- duction [8]. Secreted IgM antibodies play
villous folds and their basal cytoplasmic important roles in the initial phases of
folds surround many lymphocytes. These humoral immune responses. Secreted
“M” cells present unprocessed antigens to IgM in combination with complement
the underlying lymphoid tissue [5]. promotes antigen trapping and follicular
Lymphocytes, the primary defenders of localization [9]. IgG is the principal medi-
the acquired immune system, play a cen- ator of the secondary immune response,
tral role in regulating immune responses which requires repeated exposure to the
to all antigens; they are the only cells that same antigen; it is the major antibody
have the intrinsic ability to recognize spe- against bacteria and viruses. IgA is the
cific antigens. Lymphocytes are the major secretory immunoglobulin present in
components of lymph nodes; 95% reside body secretions and offers natural protec-
in the lymph nodes and spleen. There are tion against nonspecific foreign antigens.
2 major populations of lymphocytes: T cells Secretory IgA (SIgA) is essential in pro-
have receptors for class I and class II anti- tecting mucosal surfaces. It is composed
gens, and B cells carry immunoglobulins of at least two monomeric IgA molecules,
on their surface. B cells produce antibodies covalently linked through the J chain,
and mediate what is called the “humoral” and secretory component (SC). The
immune response. T cells are involved in dimeric/polymeric IgA (IgA(d/p)) is more
immunologic regulation and mediate what efficient when bound to the secretory
is called the “cellular” immune response. component in murine respiratory infec-
During thymic development the recog- tion by anchoring the antibody to mucus
nition of MHC proteins by developing lining the epithelial surface [10]. The
thymocytes influences their lineage com- function of IgD is not known and the IgE
mitment, such that recognition of class antibodies present on basophils and mast
I MHC leads to CD8 T cell development cells play a significant role in inflamma-
(killer cells), whereas recognition of class tory and allergic reactions. Structurally,
II MHC leads to CD4 T cell development antibodies consist of four polypeptide
(with four known cell types: Th1, Th2, chains, two heavy and two light chains.
46
The light chains have an adaptor compo- homology with cytoplasmic sequences of
nent (Fab) that binds to antigen, and the the mammalian IL-1 receptor and plant
heavy chains have an adaptor component disease resistance genes. Ten human
(Fc) that activates complement. TLRs have been cloned as well as RP105,
T cells have molecules on their surfaces a protein similar to TLR-4 but lacking
called TcRs, which recognize peptide frag- the intracellular signalling domain [11].
ments presented with human leukocyte Recent progress has revealed a require-
antigen (HLA) class I and HLA class II ment for accessory molecules in micro-
molecules found on the surface of antigen bial recognition by Toll-like receptors.
presenting cells (APCs). The structure of Gram-negative bacterial lipopolysaccha-
the TcR is similar to the structure of an ride (LPS) activates cells through TLR-4
antibody and also varies in one region whereas lipopeptides and mycobacte-
so that each TcR is unique. T cells are rial lipoglycans activate cells through
divided into 4 functionally distinct, but TLR-2. Lipopolysaccharide (LPS) rec-
interactive, cell populations or subsets: ognition requires LPS binding protein
cytotoxic (CTL), memory (Tm), (helper) (LBP), CD14, and MD-2. MD-2 is directly
Th, and suppressor (Ts). Tc and Tm cells involved in ligand binding and subse-
are referred to as effector cells because quent receptor activation, whereas LBP
they are cytotoxic to antigen-bearing and CD14 control ligand presentation
cells. Th and Ts cells are referred to as to the receptor complex, Toll-like recep-
regulatory cells. The cellular immune tor (TLR-4)/MD-2. CD14 and LBP influ-
response is mediated by T cells which can ence the amplitude of LPS responses and
recognize antigen only in association with LPS-induced type I interferon production.
a class I MHC antigen displayed on the TLR-2 is also reported to require simi-
surfaces of macrophages or antigen pre- lar accessory molecules. Innate immune
senting cells (APCs). T cells are triggered responses to microbial products driven
by stimulation of antigen receptors on by TLRs are controlled by accessory mol-
their cell surfaces. Under the influence of ecules working upstream of TLRs [12].
alloantigen and Th1-derived IL-2, clones The 11 known TLR receptors in mam-
of alloantigen-responsive CTLs prolifer- mals (10 in humans) bind a restricted
ate and seek direct contact with alloanti- repertoire of ligands and recruit com-
gen-bearing cells. CTLs are programmed mon adaptor molecules to induce cell
to produce molecules such as perforin and signalling. Their description as “pattern
granzymes which pass from the T-cell recognition receptors” reflects their abil-
cytoplasm into the donor cell, where they ity to recognize exogenous ligands (lipid,
mediate the killing of the donor cell. nucleic acid, or protein) associated with
pathogenic microorganisms—the so-called
pathogen-associated molecular patterns
4. TOLL-LIKE RECEPTORS, A BRIDGE (PAMPs). Various classes of pathogens can
BETWEEN INNATE AND ADAPTIVE be recognized by the same pattern PAMPs
IMMUNITY [13]; that is, for example,TLR-4, which
recognizes uropathogenic Escherichia
Members of the toll-like receptor (TLR) coli, is a critical component of the lipopol-
family mediate dorsoventral pattern- ysaccharide (LPS) receptor complex,
ing and cellular adhesion in insects as which forms a detection system for Gram-
well as immune responses to microbial negative bacteria [14]. One further exam-
products in both insects and mammals. ple is the type VI toxin secretion pathway
TLRs are characterized by extracellular which is shared by Pseudomonas aerugi-
leucine-rich repeat domains and an intra- nosa, Vibrio cholerae, Salmonella enter-
cellular signalling domain that shares ica, Yersinia pestis, and Escherichia coli
47
[15]. Dendritic cells and macrophages infection of internal organs of the uro-
possess receptors for carbohydrates that genital system [18]. Pathogen recogni-
are not normally exposed on the cells of tion by TLRs promotes the production
vertebrates, such as mannose, and thereof proinflammatory cytokines and acute
fore can discriminate between “foreign” inflammation by recruitment of inflam-
and “self” molecules. These antigen pre- matory cells to the site of infection by
senting cells are particularly efficient at activation of local stromal cells and cir-
initiating (priming) immune responses culating leukocytes. TLR-2 can be found
for which immunologic memory has not on professional immune cells, including
been established; that is, they activate neutrophils, macrophages, and dendritic
so-called naive T cells. Activation causes cells, but also on stromal cells through-
dendritic cells to up-regulate the expres- out the body [11]. As epithelial surfaces
sion of B7 co-stimulatory molecules (also provide the first line of defence against
known as CD80 and CD86) on their sur- infection, it is not surprising that they
face. Co-stimulatory molecules are mol- prominently express TLRs. In the kid-
ecules that provide the signals necessary ney, TLRs (mainly TLR-2 and TLR-4) are
for lymphocyte activation in addition constitutively expressed on renal epithe-
to those provided through the antigen lial cells, including the cells of Bowman’s
receptor. These activated dendritic cells capsule, proximal and distal tubules, and
migrate to the local draining lymph node, the lower urinary tract and bladder. Their
where they present antigen to T cells expression is up-regulated in response to
[16]. It is apparent now that they also inflammation, and various potential roles
have the capacity to recognize ligands for TLRs have been proposed in renal
from non-pathogenic organisms as well inflammation. In inflammation, TLR-4
as various endogenous ligands, including on renal epithelia is required for protec-
components of necrotic cells that activate tion against Escherichia coli challenge
TLR-2, heat shock proteins, extracellular from within the urinary tract, although
matrix components, and Tamm-Horsfall in response to systemic E. coli lipopoly-
proteins in urine, which activate TLR-4. saccharide challenge, TLR-4 on intrinsic
In addition to their ability to augment renal cells makes only a minor contribu-
innate immune defence mechanisms tion to acute renal injury [17]. However,
(opsonization and phagocytosis of bacteria the TLR-2 ligand Pam3CysSK4 can modu-
and viruses, activation of the complement late the development of disease in acceler-
and coagulation cascades, and production ated nephrotoxic nephritis by influencing
of type 1 interferons), TLRs have been the development of adaptive immunity.
shown to play an important role in initia- This agent can increase profoundly the
tion and modulation of adaptive immune severity of disease, and mice that were
responses (via effects on dendritic cells), T given the lipopeptide Pam3CysSK4 at
helper subset differentiation, and immune immunization and had a more severe
tolerance [17]. Not present in humans disease and also had a greater amount of
is TLR-11, that displays a distinct pat- antigen-specific IgG1, IgG2b, and IgG3
tern of expression in macrophages and in the serum and more IgG2b and IgG3
liver, kidney, and bladder epithelial cells. deposited within the glomeruli [19]. TLRs
Cells expressing TLR-11 fail to respond to can influence adaptive immune responses
known TLR ligands but instead respond and exert complex effects on Th1 and
specifically to uropathogenic bacteria. Th2 polarization of CD4+ helper cell
Mice lacking TLR-11 are highly suscepti- responses [20]. Lipopolysaccharide from
ble to infection of the kidneys by uropath- Gram-negative bacteria stimulates TLR-4
ogenic bacteria, indicating a potentially to induce IL-12 and IFN-alpha produc-
important role for TLR-11 in preventing tion by mouse and human dendritic cells,
48
which drives Th1 responses [21], although pyelonephritis. Recent data show that
this effect can be modulated by the level Tamm-Horsfall protein links the innate
of LPS exposure or the route of adminis- immune response with specific THP-
tration which can determine the type of directed cell-mediated immunity. It has
inflammatory response generated [22]. been proposed that Tamm-Horsfall pro-
TLRs also may stimulate the production tein acts by two principle non-mutually
of humoral antibodies [23]. exclusive mechanisms involving the cap-
The TLR-4 signalling may initiate ture of potentially dangerous microbes
the symptomatic disease process. In the and the ability to induce robust pro-
absence of TLR-4 signalling the infected tective immune responses against
host instead develops an asymptomatic uropathogenic bacteria. Tamm-Horsfall
carrier state. The TLR-4 dependence glycoprotein not only binds to fimbri-
has been demonstrated in mice and the ated E. coli and activates complement
relevance of low TLR-4 function for pro- and dendritic cells, but also apparently
tection for human disease was recently shows an immunoregulatory function in
confirmed in children with asymptomatic UTI via a TLR-4-dependent mechanism
bacteriuria, who expressed less TLR-4 [28–29]. Animal studies have shown an
than age matched controls [24–25]. The anatomically well organised lymphoid
molecular machinery utilized by bladder tissue in the urinary tract, resembling
epithelial cells for the recognition of E. the mucosa-associated lymphoid tissue,
coli is very similar to that described for which is associated with the epithelium
traditional innate immune cells, such as of the renal pelvis and the ureter, respec-
macrophages [26]. It should be reminded tively. Immunocytochemistry revealed
that also the BCG-derived stimulus – a S-100-immunoreactive dendritic cells in
mainstay for treating superficial bladder both, structurally organised and structur-
carcinoma – could include TLR agonists; ally non-organised lymphoid tissues [30].
it has been suggested that TLRs-2 and Also humans have a well organised lym-
-4 and possibly -9, present in immune phoid tissue in the urinary tract, particu-
cells, mediate BCG-induced immune larly in the urinary bladder. The female
responses [27]. urethra has powerful antimicrobial
defence mechanisms, which appears to
differ in women with and without recur-
5. THE GENITOURINARY TRACT rent urinary tract infections. The female
urethra is lined by cells identical to those
Human genito-urinary tracts represent of the vagina that respond similarly to
components of the mucosal immune sys- estrogens (plus immature basal and
tem with unique features. One particu- parabasal cells in children) The defence
lar element in the urogenital tract is the mechanism may be explained by the
evolutionary conserved Tamm-Horsfall shedding of uropathogens bound to exfo-
protein (THP); capable of both mediating liating urethral cells, trapping of bacteria
direct antimicrobial activity and alerting by mucus secreted by the paraurethral
immune cells. Tamm-Horsfall protein is glands, intermittent washout by urine,
exclusively produced by the kidney in the local production of immunoglobulins,
distal loop of Henle; the evidence indi- cytokines and defensins and mobiliza-
cates that beyond a mere direct antimi- tion of leukocytes [31]. The human penile
crobial activity, Tamm-Horsfall protein urethra contains numerous IgA and J
exerts potent immunoregulatory activ- chain-positive plasma cells, and the epi-
ity. In animal experiments, the genetic thelium expresses secretory component,
ablation of the Tamm-Horsfall protein the transport molecule for polymeric IgA,
gene leads to severe infection and lethal indicating that this region is an active
49
site of secretory IgA-mediated immune of urinary IgG, IgM and IgA antibodies
defence. The mucosa contains intraepi- when compared to controls; sIgA level
thelial dendritic cells while T lym- was highest in symptomatic UTI. The
phocytes are abundant and ubiquitous in discrepancies may be explained by the
all regions of the urethra. Both CD8+ and fact that an antigen that does not reach
CD4+ subpopulations of T lymphocytes secondary lymphoid tissues in minimum
are present in lamina propria and epi- doses for a sufficiently long period of time
thelium, although CD8+ cells predomi- to be appropriately presented by antigen
nate. The majority of T lymphocytes are presenting cells or without sufficient posi-
positive for CD45RO (memory marker), tive co-stimulatory signalling by dendritic
and many are also positive for the alpha cells, is immunologically ignored [7].
E beta 7 integrin (mucosal-associated Studies concerning the origin of pre-
antigen). These data indicate that, in cursors of mucosal IgA plasma cells per-
addition to the bladder, the urethra is a formed in animal models revealed that
highly dynamic immunocompetent tissue the organized lymphoepithelial struc-
possessing all the necessary elements for tures found along the gastrointesti-
antigen presentation and both humoral nal and respiratory tracts are the main
and cellular mucosal immune responses. source of such cells. These precursors,
It is likely that this region plays a domi- which are committed to IgA synthesis,
nant role in protecting the urogenital mature in mesenteric lymph nodes and
tract against ascending infections [32]. enter the circulation through the thoracic
Although a typical mucosa-associated duct. Subsequently, they lodge in the
lymphoid tissue for generating common lamina propria of the intestinal, respira-
mucosal immune responses is absent, tory, and urogenital tracts, where termi-
secretory IgA and IgG are present in tis- nal differentiation into IgA plasma cells
sues and urine secretions of both females occurs under the influence of locally pro-
and males. It has been reported that duced cytokines [38]. Antibody responses
locally synthesized sIgA immunoglobu- to genital infections or to locally applied
lins are low or normal in the urine of bacteria or derived vaccines are usually
individuals with recurrent UTI with or modest, but alternative strategies for
without bacteriuria at the time of the eliciting genital tract antibodies are being
study. UTI per se does not interfere with developed [39]. Animal studies show that
sIgA secretion as shown by high sIgA in experimental UTIs by P. mirabilis yield
patients with upper UTI. It has been sug- little protection to mice from re-infection
gested that low urinary sIgA may repre- by a homologous strain. Despite produc-
sent one factor predisposing to recurrent tion of serum immunoglobulin G (IgG)
UTI [33–35]. These findings seems con- and IgM, vaccinated (infected and antibi-
troversial; an elevated s-IgA urinary otic-cured) mice did not show a decrease
excretion was found in all patient groups in mortality upon re-challenge; the survi-
studied: patients with bladder catheter, vors experienced only modest protection
cystotomy and urinary tract infection, from infection. There was no correlation
urosepsis, chronic glomerulonephritis, between serum IgG or IgM levels and pro-
including IgA-nephritis, in renal allo- tection from mortality or infection [40].
graft recipients, compared to healthy Studies with the FimH protein from
controls [36]. In a more recent study [37] uropathogenic Escherichia coli show that
all cases of UTI had significantly higher anti–adhesin antibodies can block micro-
concentrations of urinary IgG antibody to bial attachment and subsequent disease.
mixed coliform antigens. Asymptomatic Furthermore, the FimH animal studies
UTI cases had higher concentrations demonstrate that immunoglobulin IgG
50
antibodies alone, which transudate into of ester-bound fatty acids on the

secretions after parenteral vaccination glucosaminediphosphate which will lead
with the FimH adhesin, are sufficient to to partially deacylated LPS structures.
block colonization and infection [41]. The • RNA – Complete hydrolysis of RNA
intranasal vaccination with recombinant into individual ribonucleotide and
modification of the tip adhesin of MR/P rearrangement of phosphate groups.
fimbria or recombinant Lactococcus lactis
• Other modifications including
displaying Proteus mirabilis MrpA fim-
brial protein, were effective in preventing partial solubilization of cell wall
UTIs with P. mirabilis in mice [42–43]. polysaccharides.
A small first clinical study was promising; OM-89 is marketed as an immunos-
the response to P fimbria was stronger timulant for the prevention of recurrent
among patients with P+ pyelonephritis urinary tract infections. Although there
than among patients with pyelonephri- is a rich body clinical studies (see 4.3.
tis caused by non–P-fimbriated E. coli Immunoprophylaxis by Kurt G. Naber),
(P < 0.001) or patients with P+ lower only the developments of the latest years
UTIs (P < 0.001) [44]. have lead to a better understanding of its
OM-89 is an immunomodulator of bac- mechanism of action. OM-89 is adminis-
terial origin used for the prevention of tered per os and therefore its first site of
recurrent urinary tract infections. The action will be in the digestive MALT. The
active principle is prepared from lysates table provides an overview of the main
of 18 E. coli strains obtained by alkaline pharmacodynamic findings:
lysis, followed by a two-stage tangential Thus, OM-89 binds to TLR-4, gener-
flow filtration and then microfiltration to ally activates the immune system, and
remove larger insoluble cellular debris. reduces the number of recurrences of
The resulting extract is a mixture of mod- UTIs. The bacterial extract hereby causes
ified bacterial cell components includ- the expression of CD40 and CD86, a
ing proteins, peptides, free amino acids, priming of immune responses, activat-
polysaccharides, amphiphilic molecules, ing T-cells and the consequent cascade of
nucleotides and trace amounts of DNA. cytokine production (enhanced secretion
Lipopolysaccharide (LPS), a well known of TNF-alpha nd IL-12). The “in vitro”
amphiphilic component of the Gram- data suggest that OM-89 acts via activa-
negative bacterial cell wall, is also chemi- tion of antigen presenting cells, mono-
cally modified as part of the process. For cytes (IL-1, TNF-alpha), T-lymphocytes
the main bacterial components, the modi- (IL-2, IFN-gamma) and natural killer
fications are the following: cells (NK-cells). While the effects on
NK-cells and IL-1 are stronger at the
• Proteins – Partial cleavage of peptide lower OM-89 concentrations tested, thus
bonds generating smaller polypeptides, suggesting a bell-shaped dose/response
racemization of amino acids from the relation, the remaining effects stud-
naturally occurring L-amino acids to ied are clearly concentration-depend-
D-amino acids, and de-amination of ent. In human subjects, previously on
asparagine and glutamine residues short treatment courses, OM-89 stimu-
leading to acidic polypeptides (low pI) lated the blastogenic transformation of
containing aspartic acid and glutamic T-lymphocytes and the interferon pro-
acid residues. duction ‘ex vivo’. A duplication of urinary
• Amphiphilic Molecules – Modification s-IgA concentrations was observed in girls
of E. coli lipopolysaccharide (LPS) after three months of treatment with
due to the base catalyzed hydrolysis OM-89. After three additional months of
51
Table: Summary of the effects of OM-89
Non human data Human data
OM-89 is a selective TLR-4-agonist in bone marrow derived “In vitro” OM-89- activated human (monocyte derived)
macrophages (mice); this induced expression of CD40 and dendritic cells displayed a phenotype of mature DCs with
CD86, and an enhanced secretion (via MyD88) of TNF-alpha high levels of MHC molecules and increased levels of
and IL-12 [46]. co-stimulatory molecules (CD80, CD86) [48].
OM-89 stimulated the expression of the costimulatory
molecule CD40 on dendritic cells through TLR-4 but not
through [47].
Oral OM-89 inhibits bladder inflammation caused by instilled The changes in circulating Immunoglobulin levels (specific
LPS* (mice) [49]. IgAs & IgGs) in pts. with recurrent UTIs did not correlate
significantly with the clinically effective OM-89 treatment
(vs. placebo) although small increases in specific IgAs were
observed [50].
Increases specific IgG & IgA levels against human bacteria in

orally treated mice [51–53].
Different animal models have shown the capacity of OM-89 In healthy volunteers, there was a non-significant increase
to protect from both kidneys and bladder infections and of T & B-lymphocyte counts and no relevant changes in the
death after experimental infection by Salmonella t., E. coli, IgM, IgG, IgA levels after OM-89 treatment [57].
Klebsiella p., Pseudomonas a. or Myxovirus influenza (mice)
[54–56].
The Plaque-Forming Cells (PFC) Test** with splenocytes OM-89 increased the levels of secretory IgA in the urine of
of mice has shown a dose-dependent immunostimulating girls with recurrent UTIs [59].
effect of OM-89 after oral administration [56, 58].
Mitogenic properties towards murine spleen cell cultures,

independent of LPS*-response status. In macrophages it
induces the translocation of NF-B into the cell nucleus and
release of RNI *** [60].
Older studies indicated an increased antigen presentation

capacity of the macrophages [61–62].
* LPS binds to TLR-4. TLR-4 activates both MyD88- and TRIF-dependent pathways and, in the bladder, a c-AMP dependent
rapid IL-6 mediated response. Low TLR-4 expression levels have been described in children with asymptomatic bacteriuria.
** The PFC test measures the non-specific immunostimulation of B cells.
*** radical nitrogen intermediates.
follow up, this effect had worn off, thus 7. CONCLUSIONS

indicating a transitory stimulation of uri-
nary s-IgA production. One of the authors Immunology has gone through a tortu-
(Bessler) determined the circulating spe- ous evolution with many theories since
cific IgGs & IgAs in a sample of patients Paul Ehrlich forwarded the first coher-
with recurrent UTIs [45] and showed in ent “side chain theory” in 1900, later fol-
the OM-89 treated population a transi- lowed by the template model in the 1930s
tory increase in the Proteus mirabilis and and the clonal selection model described
OM-89 lyophilisate-specific IgA levels, not by Burnet in 1957. About the same time,
observed in the placebo treated patients. Robert A. Good discovered thymus medi-
These transitory increases in specific IgA ated cellular immunity as assessed by
levels are probably too small to explain skin graft rejection, delayed-type hyper-
the therapeutic effect. sensitivity and graft versus host assays,
52
independent of germinal centres, plasma 6. Paul WE, Th1 fate determination in CD4+
cells and circulating immunoglobulins. T cells: notice is served of the impor-
The discovery in the late 1990s of toll-like tance of IL-12! J Immunol, 2008. 181(7):
receptors as primary sensors of micro- 4435–6.
bial infection probably was just the latest 7. Adler HS and Steinbrink K, Tolerogenic
major discovery in this field. Hard work dendritic cells in health and disease:
friend and foe! Eur J Dermatol, 2007.
and serendipity will certainly increase
17(6): 476–91.
our understanding of immunological phe-
8. Brändlein S, Tumorimmunity: Specificity,
nomena both in general and in the uri-
Genetics and Function of natural IgM
nary tract in particular. This will also antibodies (http://www.opus-bayern.de/
affect how infections are treated or pre- uni-wuerzburg/volltexte/2003/666/),
vented. For example, it is only in recent in Pathologisches Institut, Fakultät für
years that it has become evident that Biologie. 2003, Universität Würzburg:
the bacterial OM-89 binds to TLR-4 and Würzburg.
causes a kick-off of the immune system, 9. Youd ME, Ferguson AR, and Corley RB,
hereby reducing the number of recur- Synergistic roles of IgM and comple-
rences of UTIs. Better understanding ment in antigen trapping and follicular
of the factors involved in fighting UTIs localization. Eur J Immunol, 2002. 32(8):
will certainly lead to better medicines or 2328–37.
improved usage of the existing ones. 10. Phalipon A, Cardona A, Kraehenbuhl
JP, Edelman L, Sansonetti PJ, and
Corthesy B, Secretory component: a new
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|1.6|
The role of biofilm infection in

urogenital infections
Peter Tenkea, Bela Kovesa, Shinya Ueharab, Hiromi Kumonb, Scott J. Hultgrenc, Chia Hungc
a
Department of Urology, South-Pest Hospital, 1 Koves Str., H-1204 Budapest, Hungary
b
Department of Urology, Okayama University, 2-5-1 Shikata-cho, Okayama city, 700-8558 Japan
c
Department of Molecular Microbiology, Washington University Medical School, St. Louis, MO 63011
ABSTRACT on their inner and outer surfaces once

they are inserted. Uropathogenic E. coli
In medicine biofilm infections have a possess mechanisms to overcome host
major impact on temporary and perma- defenses, and after bacterial binding and
nent implants or devices placed in the invasion into superficial bladder epithe-
human body. The formation of biofilm lial cells, they organize into biofilm-like
consists of several main steps: the depo- structures termed intracellular bacterial
sition of a conditioning film, followed by communities (IBCs). Bacteria in these
the attachment of microorganisms, and intracellular niches can create a chronic
the final stage is the formation of a bio- quiescent reservoir in the bladder, which
film structure. The biofilm is usually built can persist undetected for several months
up from three layers: the linking film, the without bacteria shedding in the urine.
base film and the surface film. Even in These bacteria are completely resistant
the presence of antibiotics bacteria can to 3- and 10-day courses of antibiotics.
adhere, colonize and survive on implanted Key words: biofilm, bacterial, urinary
medical devices, such as catheters, ure- tract, infection, catheter, encrustation,
teral stents, penile prostheses or artificial intracellular, UPEC, IBC
urinary sphincters. Antimicrobial agents
are effective against planktonic bacteria
and appear to clear mucosal surfaces of 1. INTRODUCTION
adherent bacterial microcolonies but fre-
quently fail to eradicate bacterial biofilms Bacterial adherence and the growth of
on urological devices. Urinary catheters bacteria on solid surfaces as biofilm are
are readily targets of biofilm development both naturally occurring phenomena. In
medicine, biofilm infections have a major 3. MECHANISM OF BIOFILM

impact on temporary and permanent FORMATION
implants or devices placed in the human
body. In the process of endourological The formation of biofilm generally con-
development, a great variety of foreign sists of several main steps: the first step is
bodies have been invented besides ure- always the deposition of a conditioning film
thral catheters such as ureteral and pro- produced by the host to the foreign body. It
static stents, percutaneous nephrostomy is followed by the attachment of microorgan-
tubes, penile and testicular implants isms. The microbial adhesion and anchor-
and artificial urinary sphincters. Biofilm age to the surface are made by exopolymer
can also build up under natural circum- production. After this process their growth,
stances, for instance on the urothelium multiplication and dissemination can be
or on prostate stones. Biofilms can have observed (LoE 2b) [3–7] (Figure 1).
a positive impact as well, namely lin- Immediately after insertion of the
ing healthy intestine and the female device into the body the material sur-
genitourinary tract. Biofilms have sig- face enters into contact with body fluids
nificant implications for clinical pharma- (such as blood, urine, saliva and mucus)
cology, in particular related to antibiotic around the implant. In the urinary tract
resistance, drug adsorption onto and off Tamm-Horsfall glycoprotein, various
devices, and minimum inhibitory concen- ions, polysaccharides and other compo-
trations of drugs required for effective nents diffuse within minutes toward the
therapy. implant surface from the bulk urine [8].
Macromolecular components from these
body fluids adsorb extremely fast onto the
2. METHODS material surfaces to form a conditioning
film, prior to the arrival of the first organ-
We surveyed the extensive literature isms. Many of the molecules are proteina-
regarding biofilm formation and the ceous, such as serum albumin, fibrinogen,
role of biofilms in urogenital infections. collagen and fibronectin [9]. Thus, the
Studies were identified through a PubMed
search. We systematically searched for
meta-analyses of randomised controlled
trials available in Medline by giving pref-
erence to the Cochrane Central Register
of Controlled Trials and also considered
other relevant publications from the last
25 years until March 2008. The search
was performed by using the following
items in different combinations: biofilm,
infection, catheter, encrustation, urinary.
The identified publications were screened
by title and abstract. After exclusion of
duplicates a total of 53 publication were
included in the analysis, however there
was no prospective comparative study on
this subject within the publications.
The studies were rated according to the
level of evidence (LoE) and the grade of
recommendation (GoR) using ICUD
standards (for details see Preface) [1–2]. Figure 1 Formation of biofilm.
58
The role of biofilm infection in urogenital infections | 1.6 |
creation of a conditioning film alters the which anchor the organisms to the sur-
surface characteristics of implants. It is face. Subsequently, colonization occurs
for this reason that many implants with by species specific factors, such as slow
altered surface characteristics (includ- migration and spreading, rolling, packing
ing hydrophilic gels and antmicrobial and adhesion of the progress. A developed
coatings) are ineffective as mechanisms biofilm consists of groups of microorgan-
of preventing microbial attachment. isms, sometimes in mushroom-like forms,
The role of the conditioning film is vital separated by interstitial spaces that are
as many pathogens do not have mecha- filled with the surrounding fluid [13]. The
nisms allowing them to adhere directly or growth rates of organisms on a surface as
strongly onto bare implant surfaces [10]. well as the strategies used by microorgan-
The next step in the development of a isms to spread over a surface are impor-
biofilm is the approach and attachment tant for colonization. These strategies are
of microorganisms. The ability of micro- species specific and can influence the dis-
organisms to adhere to surfaces is influ- tribution of a biofilm on a surface [14].
enced by electrostatic and hydrophobic The final stage of microbial coloni-
interactions, ionic strength, osmolality zation of a surface is the formation of a
and urinary pH [11–12]. Several theories biofilm structure. At this point the micro-
have been put forth to explain the com- organisms have created a microenvi-
plex interaction that occurs as a microbe ronment which protects against many
approaches and then attaches to a sur- antimicrobial agents and host immune
face. However, the precise mechanisms defense mechanisms. Biofilm has been
of attachment to biomaterials are still described as having a heterogeneous
under investigation. structure with a rough surface [15]. The
In order for bacteria to react to a sur- microcolony is actually the basic struc-
face or an interface like an air-water tural unit of the biofilm, similar to the
interface, these cells must be able to tissue which is the basic unit of growth
‘sense’ their proximity to these surfaces. of more complex organisms. Depending
The planktonic ‘free-floating’ bacterial on the species involved, the microcolony
cells release both protons and signaling may be composed of 10–25% cells and
molecules as they move through the bulk 75–90% exopolysaccharide (EPS) matrix.
fluid. These protons and signaling mol- The biofilm contains ‘water channels’
ecules must diffuse radially away from which allows the transport of essential
the floating cell if not adjacent to any nutrients and oxygen for the growth of
surface or interface. But a significantly the cells [16]. Microorganisms within the
higher concentration of either protons or biofilm also secrete chemical signals that
signaling molecules can develop on the mediate population density-dependent
side of the bacterial cell close to any sur- gene expression, which has an important
face. This allows the cell to sense that it role in biofilm development [17]. In sum-
is near a surface because diffusion is lim- mary, the biofilm is usually built up of
ited on this side [6]. After the planktonic three layers (LoE 2b) (Figure 2) [18]:
bacterial cell has sensed the surface, it 1. the linking film which attaches to the
may commit to the active process of adhe- surface of tissue or biomaterials
sion and biofilm formation.
There is no single process or theory 2. the base film of compact
which can completely describe microbial microorganisms
adhesion. The initial adhesion is reversible 3. the surface film as an outer layer,
and involves hydrophobic and electrostatic where planktonic organisms can be
forces. It is followed by irreversible attach- released free-floating and spreading
ment provided by bacterial polysaccharides over the surface.
59
Figure 2 Composition of biofilm.
4. ANTIMICROBIAL SUSCEPTIBILITY resistant to the effects of antimicrobial

OF BACTERIA LIVING IN BIOFILM agents, which require active growth.
• Bacteria within biofilm are phenotypi-
The use of antibiotics is currently one of cally so different from their planktonic
the possibilities for the prevention of bio- counterparts that antimicrobial agents
film formation. However, even in the pres- developed against the latter often fail
ence of antibiotics bacteria can adhere, to eradicate organisms in the biofilm.
colonize and survive on implanted medi- Bacteria within a biofilm activate many
cal devices as has been shown for urinary genes which alter the cell envelope, the
catheters and ureteral stent surfaces in molecular targets and the susceptibil-
vitro and in vivo [19–21]. In addition, ity to antimicrobial agents (intrinsic
resistance to antimicrobial agents and resistance). Current opinion is that
other chemicals is one of the greatest phenotypic changes caused by a genetic
problems in the age of widely used medi- switch, when approximately 65–80 pro-
cal devices. The problem in conventional teins change, play a more important
clinical microbiology is how to treat role in the protection from antimicrobial
patients in the best way when choosing agents than the external resistance pro-
antibiotics, the choice of which is based vided by the exopolysaccharide matrix.
on bacterial cultures derived from plank-
• Bacteria within a biofilm can sense the
tonic bacterial cells which differ very
external environment, communicate
much from bacteria in the biofilm mode.
with each other and transfer genetic
This can explain the clinical failure rate
information and plasmids within biofilm.
of treating chronic bacterial infection.
The failure of antimicrobial agents to • Bacteria in a biofilm can usually survive
treat biofilms has been associated with a the presence of antimicrobial agents at
variety of mechanisms (LoE 4) [20–26]. a concentration 1000–1500 times higher
One mechanism of biofilm resistance to than the concentration that kills plank-
antimicrobial agents is the failure of an tonic cells of the same species.
agent to penetrate the full depth of the
biofilm (extrinsic resistance). For instance, 5. ANTIBIOTICS AND BIOFILMS
the extracellular matrix may block the
penetration at the very beginning. Antimicrobial agents are effective against
• The organisms growing at a slower planktonic bacteria and appear to clear
rate within the biofilm are more mucosal surfaces of adherent bacterial
60
microcolonies but frequently fail to a

eradicate bacterial biofilms on urologi-
cal devices (LoE 2b). According to some
in vitro and in vivo studies beta-lactam
antibiotics and aminoglycosides can pre-
vent the formation and the extension of
‘young’ biofilms in growth. On the other
hand, fluoroquinolones, such as ofloxacin,
levofloxacin and ciprofloxacin, are effec-
tive in the case of both ‘young’ and ‘older’
biofilms because of their good penetrative
qualities. Moreover, they are present in
biofilms even one or two weeks after end-
ing antibiotic treatment [27–30].
b
Most researchers believe that antibiot-
ics only slow down the progress of biofilm
formation by eliminating unprotected
planktonic bacteria and stopping or
reducing the metabolic activity of bacte-
ria on the biofilm surface [25, 31–32].
6. BIOFILM ON INDWELLING
URETHRAL CATHETERS
Urinary catheters are ready targets for

biofilm development on their inner and
outer surfaces once they are inserted Figure 3 a, b Scanning electron microscopic picture of a
developing biofilm.
(LoE 2b) (Figure 3). The long-term use
of them leads to infection in most cases.
The surface of a catheter (depending on access to the internal lumen of the cath-
its material) provides sufficient circum- eter via failure of the closed drainage
stances for bacteria to adhere to and system or contamination of the collec-
spread along in two ways. tion bag. These organisms are usually
One route is when organisms ascend the introduced from exogenous sources,
catheter extraluminally by direct inocula- for instance cross-transmission from
tion at the time of the catheter insertion the hands of health care personnel [15,
or migrate in the mucous sheath that sur- 34–35, 37]. Adhesion of microorganisms
rounds the external aspect of the catheter. to catheter materials depends on the
Extraluminal organisms are primarily hydrophobicity of the organism and cath-
endogenous, originating from the gas- eter surface.
trointestinal tract. These organisms colo-
nize the patient’s perineum and ascend
the urethra after catheter insertion [15, 7. THE ROLE OF BIOFILMS IN THE
33–36]. Approximately 70% of bacteriuria ENCRUSTATION AND BLOCKAGE
in catheterized women is believed to occur OF CATHETERS
through extraluminal entry.
Microorganisms may also enter the An additional problem relating to the use
catheter by an intraluminal route, which of medical biomaterials in the urinary
occurs primarily when organisms gain tract environment is the development of
61
encrustation and consecutive obstruction. 8. BIOFILMS ON URETERAL STENTS

When the drained urinary tract becomes
infected by urease-producing bacteria Bacterial biofilm can even develop on
such as Proteus mirabilis, the bacterial ureteral stents that are lying completely
urease generates ammonia from urea and within the urinary tract (LoE 2a-b)
elevates the pH of the urine. The urease (Figure 4). Reid at al found that 90% of
derived from Proteus mirabilis hydro- indwelling silicone double J stents were
lyses urea six to ten times faster than colonized by adherent bacteria, however
the urease of other species (Morganella the incidence of urinary infection detected
morganii, Providencia stuartii, Klebsiella clinically was only 27% [40]. Further
pneumoniae, Proteus tettgeri, and Proteus remarkable data showed that 45% of
vulgaris). In the alkaline environment, adherent pathogens were present in low
crystals of magnesium ammonium phos- numbers (101–102 per 1 cm3) and 55%
phate (struvite) and calcium phosphate were in small and large microcolony bio-
(hydroxyapatite) are formed and trapped films (>2 × 102 – 107). The isolated organ-
in the organic matrix surrounding the isms were Gram-positive cocci (77%),
cells [22–23, 38–39]. Progression of these Gram-negative rods (15%) and Candida
encrustations eventually blocks the cath- sp. (8%) [41]. The difficulty in detecting
eter lumen (LoE 2b) (Figure 4). biofilm formation by using conventional
laboratory procedures was confirmed in
a large study where 237 ureteral stents
were tested. It was shown that 68% of
stents were actually colonized but only
30% of patients were found to have bac-
teriuria [41]. Therefore, a negative urine
culture does not rule out the possibil-
ity of stent colonization. The study testi-
fied correlation between the length of the
indwelling time and the development of
infection.
9. PENILE PROSTHESES
Prosthesis-associated chronic pain due

to subclinical infection is more common
than clinically apparent infection [5].
Staphylococcus epidermidis accounts for
35–56% of infections and usually becomes
manifest approximately six months after
implantation [42]. S. epidermidis was cul-
tured in 40% of penile prosthesis removed
for malfunction with no clinical evidence
of infection [43]. Staphylococcal species
were also found to enhance biofilm forma-
tion. These cases can be ‘silent’ for many
years before becoming clinically evident
[44] in contrast to Gram-negative bacte-
Figure 4 Developed encrustations and biofilms on rial infection (Pseudomonas aeruginosa,
stents, different sections and enlargements. E.coli, Serratia marcescens, and Proteus
62
mirabilis) which is responsible for 20% of 12. CHRONIC BACTERIAL

infections and which usually become man- PROSTATITIS
ifest in a month after implantation [43].
Antibiotic prophylaxis is desirable for Although the diagnosis and classification
the above-mentioned facts. Since the most of chronically inflamed prostate glands
common pathogen is Staphylococcus epi- have been standardized, great difficul-
dermidis, first-generation cephalosporins ties still exist in differentiating chronic
and broad-spectrum penicillin should be non-bacterial inflammation from bacte-
used [45]. In cases of chronic pain, long- rial inflammation. The prostatic ducts
term administration of quinolones eased and acini (being out of the sweeping effect
60% of symptoms. Failure involves the of streaming urine) provide safe circum-
necessity of implant removal. stances for planktonic bacteria to multi-
ply rapidly and induce a host response
10. ARTIFICIAL URINARY with infiltration of acute inflammatory
SPHINCTERS (AUS) cells into the ducts. The ducts become
engorged with infiltrate composed of dead
and living bacteria as well as living and
Around 3% of AUS become infected and
dying acute inflammatory cells, desqua-
symptoms are mainly associated with
mated epithelial cells and cellular debris.
the control pump device. Avoiding risk
At this point it is relatively easy to eradi-
factors such as infected urine, prolonged
cate all the offending organisms which
urinary retention and large bladder
are in a ‘planktonic state’ with appropri-
residuals can reduce this high occurrence
ate antibiotic therapy. If the bacteria per-
[43, 45]. Because parts of the sphincter
sist from either clinically acute or more
device form one continuous surface, the
likely, subacute inflammation, they can
AUS is suggested to be removed entirely
form sporadic bacterial microcolonies
as the first step to eliminate the infec-
or biofilms adherent to the epithelium
tion. Reimplantation must be preceded by
of the ductal system (LoE 2b) [47–48].
complete treatment of the infected area.
These bacteria also produce an exopoly-
This is not always achievable as many of
saccharide slime or glycocalyx that envel-
these patients are paraplegic or have a
ops these adherent microcolonies. The
neurogenic bladder with recurrent UTIs
bacteria persisting in the prostate gland
[43, 45].
within these focal biofilms can provoke
persistent immunological stimulation and
11. INFECTED URINARY CALCULI subsequent chronic inflammation [47].
The diagnosis of chronic bacterial prosta-
In the case of urease-producing bacteriu- titis can be difficult as colonized bacteria
ria, infection can be concurrent with the will not get into the prostatic secretion
formation of struvite and calcium phos- or urine sample. Antimicrobial therapy
phate calculi as described above. The eradicates the planktonic bacteria but
infected calculi grow rapidly and pro- not the adherent bacterial biofilms deep
vide a safe environment for the bacteria within the prostate gland. Another cause
adhered to the biofilm (LoE 3) [46]. The of unsuccessful treatment may be the
most effective treatment strategy involves fact that the bacteria within biofilms dif-
complete removal of all stone frag- fer significantly from their planktonic
ments during a stone operation (PCNL, counterparts in metabolic rate, molecular
URS, ±combined with ESWL), prolonged targets and expression of antimicrobial
administration of antibiotics (8–10 weeks binding proteins [5, 21]. The development
for destroying urease-producing bacteria) of diagnostic tools to recognize small
and metaphylaxis. adherent bacterial biofilms which exist
63
deep within the prostate gland in chronic epithelial exfoliation, UPEC are able to
bacterial prostatitis is needed. New treat- maintain high titers in the bladder for
ment regimens should be carried out in several days.
order to be able to deliver much higher A bacterial mechanism of FimH-
antibiotic concentrations to the biofilm mediated invasion into the superficial cells
within the prostatic duct. Theoretically apparently allows evasion of these innate
this should improve treatment success defenses. Initially, bacteria replicate rap-
rates. idly inside superficial cells as disorgan-
ized clusters. Subsequently, bacteria in
the clusters divide without much growth
13. INTRACELLULAR BACTERIAL in cell size, resulting in coccoid-shaped
BIOFILM-LIKE PODS IN THE bacteria, presumably due to changes in
RECURRENT CYSTITIS genetic programs. Furthermore, the bac-
terial clusters became highly compact
Entry of E. coli into the urinary tract is and organized into biofilm-like structures,
not well understood, although sexual termed intracellular bacterial commu-
intercourse is the most clearly defined nities (IBCs), inside bladder superficial
predisposing factor. Presumably, a small cells [49] (Figure 5). The IBCs push the
number of E. coli from the vaginal or bladder superficial cell membranes out-
enteric flora are introduced into the blad- ward to give a “pod” like appearance by
der during an average incident, and it scanning electron microscopy (Figure 6).
seems plausible that in most cases the Bacteria in the IBCs are held together
innate defenses in the bladder would by exopolymeric matrices, reminiscent of
be able to prevent infection. However, biofilm structures [50] (Figure 7–8). The
sometimes uropathogenic E. coli (UPEC) IBCs could still grow and expand in size.
clearly possess mechanisms to overcome At some point during this IBC develop-
these defenses and establish a foothold in mental process, bacteria on the edges of
the bladder. UPEC pathogenesis initiates IBCs become elongated again, become
with bacterial binding of superficial blad-
der epithelial cells via the adhesin FimH
at the tips of bacterially expressed type
1 pili. Initial colonization events activate
inflammatory and apoptotic cascades
in the epithelium, which is normally
inert and only turns over every 6 to 12
months. Bladder epithelial cells respond
to invading bacteria in part by recogniz-
ing bacterial lipopolysaccharide (LPS)
via the Toll-like receptor pathway, which
results in strong neutrophil influx into
the bladder. In addition, FimH-mediated
interactions with the bladder epithelium
stimulate exfoliation of superficial epithe-
lial cells, causing many of the pathogens
to be shed into the urine. Genetic pro-
Figure 5 Confocal laser scanning microscopic image
grams are activated that lead to differen- of an IBC at 16 hrs post-infection. Clinical UPEC isolate
tiation and proliferation of the underlying expressing green-fluorescence protein (green) form a compact
transitional cells in an effort to renew the and organized intracellular cluster inside a mouse bladder
superficial cell. The membrane of the bladder epithelial cells
exfoliated superficial epithelium. Despite are stained with Alexa Fluor 594-conjugated Wheat Germ
the robust inflammatory response and Agglutinin (red). A filamentous bacterium is also visible.
64
Figure 8 High-resolution freeze-fracture microscopy

image of bacteria inside and IBC. High-resolution
freeze-fracture microcopy shows bacteria embedded within
fibrous networks. Image courtesy of Dr. John Heuser.
motile and start to move away from

IBCs, similar to the detachment event
in abiotic biofilms. Bacteria can exit out
Figure 6 Scanning electron microscopic image of a UPEC
infected mouse bladder surface at 16 hrs post-infection. of infected bladder cells, probably due to
UPEC infection resulted in formation of IBCs, which pro- compromised membrane integrity. UPEC
trude bladder superficial cell membrane out into the bladder
lumen.
undergo such IBC cascade to increase in
numbers, resulting in high bacterial tit-
ers in the bladder. In addition, bacteria
in these intracellular niches can create a
chronic quiescent reservoir in the bladder,
which can persist undetected for several
months without bacteria shedding in the
urine [51–53]. These bacteria are com-
pletely resistant to 3- and 10-day courses
of antibiotics [54].
14. PYELONEPHRITIS AND BIOFILM
Once bacteria reach the kidney either

by ascending infection or vesicoureteral
reflux they are able to adhere to the
urothelium and papillae. Nickel et al
showed that bacteria could adhere in
thin biofilms to the urothelium before
invading the renal tissue with resultant
pyelonephritis (LoE 2b) [46]. These bac-
terial biofilms are more easily eradicated
by antimicrobial agents, in contrast to the
Figure 7 Scanning electron microscopic image of a
biofilms on catheter surfaces [50], which
broken UPEC infected mouse bladder cell. IBCs contain may be ascribed to the effective syner-
both bacteria and exopolymeric matrices. SEM image of an gistic actions of antimicrobial agents
infected cell with partial membrane lost reveals the biofilm-
like nature of the IBCs. Bacteria are seen embedded within and host defenses against the biofilms on
fibrous networks. urothelium [55].
65
15. FUTURE RESEARCH 2. Abrams P, Khoury S, and Grant A,

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Agents, 2001. 17(4): 305–10. Prevention. Nosocomial and Health Care
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68
Chapter |2|
Aetiology,
antimicrobial resistance of
uropathogens, antibiotic
therapy and policy
Chair: Gunnar Kahlmeter
CHAPTER OUTLINE
2.1 Introduction 70
2.2 Uncomplicated and community acquired urinary
tract infections: aetiology and resistance 72
2.3 Complicated and healthcare associated urinary
tract infections: aetiology and antimicrobial resistance 82
2.4 Methicillin-resistant staphylococcus aureus (MRSA)
in urology 92
2.5 ESBL and multi-resistance in urology 102
2.6 Antimicrobials in urogenital infections 111
2.7 Antibiotic policy 127
|2.1|
Introduction
Gunnar Kahlmeter
Corresponding author: Gunnar Kahlmeter, MD
Professor and Head of Clinical Microbiology, Central Hospital, S-35185 Växjö Sweden
Tel 0046-470-587477, Fax 0046-470-587455, E-mail: gunnar.kahlmeter@ltkronoberg.se
Uncomplicated (uUTI) and complicated and Enterobacteriaceae are occasionally

urinary tract infections (cUTI) share resistant to almost all therapeutic alter-
Escherichia coli as the most common natives. Irrespective of species, and also
etiology. In uUTI, E.coli is without in uUTI, associated resistance (e.g. an
comparison the dominating pathogen. organism resistant to one antibiotic is
S. saprophyticus, is the second most com- prone to be resistant to any other antibi-
mon pathogen. In temperate climates it otic) is now very common.
shows a pronounced seasonal variation, In uUTI, empirical therapy is still
with cases concentrated in late summer recommended, but in geographic areas
and early autumn. E.coli also dominates or in age groups where antimicrobial
cUTI, but here in competition with many resistance is high, pre-emptive cultur-
other Enterobacteriaceae (Klebsiella ing (a culture secured prior to instituting
spp, Proteus spp, Enterobacter spp) and empirical therapy) is recommended. In
Enterococcus species, Staphylococcus cUTI and HAUTI therapy, irrespective of
species and Streptococcus agalactiae. In whether empirical or not, should always
healthcare associated UTI (HAUTI), the be preceded by a culture. Special atten-
flora is supplemented with Pseudomonas tion should be given to the therapeutic
aeruginosa, Acinetobacter spp and dilemma caused by methicillin resistant
Candida spp. Staphylococcus aureus (MRSA) and
Antimicrobial resistance is a rapidly “ESBL-producing” Enterobacteriaceae in
increasing problem all over the world. HAUTI, especially in urology. Due to the
The problem is less pronounced in uUTI, nature of “complicated” and “healthcare
although ESBL-producing organisms are associated” UTI, eradication of causa-
increasingly common in the community. tive organisms is difficult at the best
In cUTI or HAUTI the situation will mir- of times, and even more so when mul-
ror that of the hospital or institution. tiresistant bacteria, not least MRSA or
Some Acinetobacter spp, Pseudomonas ESBL-producing organisms, are involved.
Infection control strategies to prevent UTI is a common reason for antimi-

dissemination of these organisms are crobial therapy and by addressing issues
necessary. related to the treatment and prophylaxis
Antibiotics used for the treatment of of UTI, antibiotic consumption can be
uUTI, cUTI and HAUTI are evaluated. reduced. Each institution should develop
For uUTI antibiotics which are used only an antibiotic policy to further the pru-
for UTI are recommended for first line dent and economical use of antibiotics.
therapy. By doing this, the selection pres- Antibiotic policies address prescribing
sure on other classes of antibiotics, with strategies, dosing, route of administra-
more general use, is removed or dimin- tion, duration and timing of antibiotic
ished. For cUTI and HAUTI, antibiot- therapy to maximize clinical cure or pre-
ics with broader spectrum and a more vention of infection while limiting the
“systemic” set of pharmacokinetic and unintended consequences of antibiotic
pharmacodynamic properties are often use, including toxicity and selection of
needed. resistant microorganisms.
71
|2.2|
Uncomplicated and community

acquired urinary tract infections:
aetiology and resistance
Martin Sundqvist1,2, Gunnar Kahlmeter1,3
1
Dept of Clin Microbiology, Central Hospital, Växjö Sweden
2
Dept of Medical Sciences, Div of Infectious diseases, Uppsala University, Uppsala, Sweden
3
Dept of Medical Sciences, Div of Clinical Bacteriology, Uppsala University, Uppsala, Sweden
Corresponding author: Gunnar Kahlmeter, MD, Professor, Dept of Clin Microbiology, Central Hospital
S-35185 Växjö, Sweden
Tel +46-470-588.000, Fax +46-470-587.455, gunnar.kahlmeter@ltkronoberg.se
ABSTRACT low-resistance alternatives: pivmecil-

linam, nitrofurantoin and fosfomycin.
E. coli and S. saprophyticus are the two These have not been thoroughly evalu-
dominating pathogens in uncompli- ated in men but are thought to be insuf-
cated community acquired urinary tract ficiently active; something that needs
infections. In E. coli the level of anti- further investigation.
biotic resistance is accelerating at an Key words: resistance development,
amazing speed. This is especially true Escherichia coli, Staphylococcus sapro-
for trimethoprim (alone and in combi- phyticus
nation with sulfamethoxazole) and for
fluoroquinolones with resistance rates
of 15–45% and 10–20% respectively. An
additional problem is that trimethoprim SUMMARY OF RECOMMENDATIONS
resistance in fluoroquinolone resistant
E. coli is at least 48% and that fluoroqui- A prerequisite for successful antibiotic
nolone resistance in trimethoprim resist- therapy is the good understanding of aeti-
ant E. coli is at least 25%. This means ology and antimicrobial resistance. E. coli
that in a man presenting with UTI there dominates the aetiology of both uncom-
is little choice and empirical therapy plicated urinary tract infections (UTI)
may well fail. In women there are three and complicated UTI (cUTI). However, the
Uncomplicated and community acquired urinary tract infections | 2.2 |
latter, and especially healthcare associ- 1. INTRODUCTION

ated UTI (HAUTI), sprouts a much larger
spectrum of microorganisms than UTI. In order to recommend optimal empiric
Successful empirical therapy rests on the therapy for each kind of infection we
absolute majority of microorganisms being should be aware of the most common
susceptible to the drugs chosen. A rapid pathogens and their antibiotic suscepti-
worldwide increase in antimicrobial resist- bility in the local area. This review was
ance in pathogens causing UTI and espe- undertaken to describe the basics of
cially cUTI threatens to jeopardize our resistance development in Escherichia
empiric traditions. Regional surveillance coli and the worldwide trends in the aeti-
studies should be performed regularly to ology and antibiotic resistance of uncom-
guide the choice of empiric antimicrobial plicated UTI. This cannot replace local
therapy (GoR A). epidemiological studies which should be
In uncomplicated UTI it is often justifi- available.
able to initiate antibiotic therapy without
performing a urine culture, provided that
the local epidemiology of antimicrobial
2. METHODS
resistance in E. coli is known. A urine
culture should be performed prior to or
The PubMed database was searched for
in conjunction with treatment in the
the terms uncomplicated UTI and cysti-
following situations:
tis in combination with antibiotic resist-
1. When the patient has received anti- ance. Articles in English regarding UTI in
biotic treatment in the last three adults and judged by the authors of this
months (GoR B). review as being of sufficient quality were
included and these formed the basis for
2. When planning to give empiric ther-
the recommendations in this chapter. In
apy with amoxicillin, sulfamethoxa- addition, articles from the last 10 years
zole, trimethoprim or co-trimoxazole, describing the antimicrobial resistance
to all of which resistance rates are of UTI pathogens were retrieved. Despite
high and co-resistance to other drugs the fact that the rating system is not
common (GoR B). optimal for this purpose, the studies were
3. When planning to give empiric rated according to the level of evidence
treatment with a fluoroquinolone or (LoE) and the grade of recommendation
a cephalosporin in areas where local (GoR) using ICUD standards (for details
resistance rates are high (>10%), see Preface) [1–2].
i.e. in areas where ESBL-producing
Enterobacteriaceae are increasingly
common (GoR B).
3. AETIOLOGY OF UNCOMPLICATED
4. When antimicrobial treatment has UTI
recently failed (GoR B).
5. When there are signs of pyelonephritis. Virtually any bacteria can occasionally
(GoR A) cause a UTI. Although the definition of
6. When the patient is a man (GoR B).
uncomplicated UTI is under debate, we
here use: that the bacterium can infect the
7. When the patient is a woman with (anatomically and physiologically) nor-
complicated and/or recurrent UTI and/or mal urinary tract of a woman [3–4] leav-
is over the age of 65 (GoR B). ing only E. coli and S. saprophyticus [5]
8. When the patient has a healthcare as primary pathogens (Table 1) (LoE 2a).
associated UTI (GoR A). These two pathogens dominate the picture
73
Chapter |2| Aetiology, antimicrobial resistance of uropathogens
Table 1 Pathogens causing urinary tract infections.
Primary pathogens
E. coli and S. saprophyticus LoE 2a
Secondary pathogens
Bacteria not normally present in the periurethral flora and which only rarely cause uncomplicated UTI eg. K. pneumoniae
(and occasionally other Enterobacteriaceae), E. faecalis and S. agalactiae. LoE 2a
Doubtful pathogens
Bacteria belonging to the normal skin flora/periurethral flora eg. Coagulase Negative Staphylococci (CNS other than
S. saprophyticus), coryneform bacteria and viridans streptococci. LoE 2a
Significant bacteriuria in women with specific UTI symtoms: LoG 2a
Primary pathogens: ≥106 cfu/l
Secondary pathogens in pure culture: ≥107 cfu/l
Doubtful pathogens in pure culture: ≥108 cfu/l
particularly in women under the age of reported to be 2–10% [19] and 2.3–4.8% in
50 [6–8] (LoE 2a). In older women the eti- the ECO-SENS study on uncomplicated
ological spectrum is more complex [9–10] UTI in Europe [11] (LoE 2a). This level
(LoE 2b). One can argue that infections seems to be true not only in Europe and
in women over 50 are not truly uncompli- the USA as, although reported uncom-
cated, as the number of predisposing fac- mon in Israel [20], a recent study showed
tors (such as incontinence) increase with S. saprophyticus to be the third most
age [9–10] (LoE 2b). Secondary pathogens common (6.4%) UTI-pathogen in north-
(Table 1) play an increasing role while the ern Iran [12] (LoE 2b). S. saprophyticus
importance of S. saprophyticus decreases. is more common in younger women [18]
Irrespective of age and geography, E. coli and is reported to colonize the rectum
is by far the most common pathogen and, to a lesser extent, the cervix and
[11–14] (LoE 2a). This also holds true urethra in a relatively small proportion
when we broaden the definition to include of women [17] (LoE 2b). Other bacteria
all community acquired UTI in men and occur, including E. faecalis, S. agalactiae,
women with recurrent infections. The P. mirabilis and K. pneumoniae, but are
special features of UTI in children will more frequent in men and in the elderly.
not be discussed here, although E. coli Some of these bacteria will be described
also dominates the aetiology in children more thoroughly in the next chapter and
[15] (LoE 2a). are therefore only listed here (Table 1).
Escherichia coli is held responsible for
at least 80% of all uncomplicated UTI
[11, 13] (LoE 2a) in women under the 4. ESCHERICHIA COLI
age of 65 and at least 50% of community
acquired UTI in other groups [7] (LoE Escherichia coli is a Gram-negative
2a). During the late summer/early fall rod belonging to the genera of Entero-
in the northern hemisphere [16–17], and bacteriacae. It is a commensal bacte-
with typical seasonal variation (Fig 1), rium and is common not only in the
as many as 20% of uncomplicated UTI human gut, but also in animals. It is the
are caused by S. saprophyticus [18] (LoE most frequent facultative aerobic found
2b). The prevalence of S. saprophyticus is in the intestinal tract [21] (LoE 2a).
74
This, however, corresponds only to a modified dfr-genes encoding trimethoprim

small proportion of the total flora in resistance). However, this will only be suc-
the distal colon, as most of the flora in cessful when the changes encoded for by
this part of the intestine are anaerobic the new gene/mutation, are favoured by
bacteria (Bacteroides spp and bifidobac- the presence of antibiotics in the environ-
teria) [21] (LoE 2a). The dominating E. ment or if the mutation is combined with
coli strain in the faecal flora will be the other new traits such as an increased
strain most likely to colonize the periu- spreading capacity or ability to survive
rethral space and to infect the urinary [24] (LoE 3). The most important form of
tract [22] (LoE 2b). acquisition and spread of resistance in
E. coli and other Enterobacteriacae as well
as in enterococci is horizontal gene trans-
5. ANTIMICROBIAL RESISTANCE fer (HGT). This way of spreading antibi-
otic resistance genes is very efficient since
Antimicrobial resistance is increasing many resistance genes can be spread on
worldwide in almost all pathogenic bac- the same mobile genetic elements (usually
teria and fungi. This is certainly true for conjugative plasmids) [25–26] (LoE 3). In
E. coli in which resistance to ampicillin, this way the different genetic mechanisms
sulphonamides and trimethoprim, alone will hitchhike on one another and thus be
or combined, has gradually increased over spread as whole packages of resistance,
more than 50 years. The recent dramatic converting fully susceptible bacteria into
increase in resistance to fluoroquinlones, multiresistant organisms in one trans-
cephalosporines (due to the rapid increase fer event [27–28] (LoE 3). The antibiotic
in and spread of extended spectrum beta- resistance genes can then, at the same
lactamases (ESBLs)) and aminoglycosides time, be spread vertically in an epidemic
is especially problematic [23] (LoE 3). strain [29] and horizontally to other mem-
Paradoxically, this increase in resist- bers of the same species [26] and to other
ance will cause more therapeutic prob- species [28] (LoE 3). It is important to
lems in complicated and febrile UTI than stress the importance of the dissemina-
in uncomplicated UTI, since three drugs tion of antibiotic resistance by successful
to which resistance is still uncommon, lineages of bacteria (as exemplified by the
fosfomycin, nitrofurantoin and pivmecil- spread of ST 131) containing several resist-
linam, can be used in the latter but not in ance genes (including ctxM-15), which are
the former. However, on occasion, intrave- spreading over the world [30–31] (LoE 3).
nous carbapenems are the only antibiot- In the same way, the E. coli co-trimoxazole
ics to which the isolate is susceptible. The resistant Clonal group A (CgA) causing
magnitude of the problem is best realised UTI in young college women, behaves as
when the following is understood about an epidemic strain [29] (LoE 3). It is how-
resistance development. ever important to point out that these line-
ages or clones are quite heterogeneous and
5.1 Development of antibiotic clonal outbreaks within the clones have
resistance been reported [32] (LoE 3).
There is evidence to suggest that
A prerequisite for antibiotic resistance is bacteria already carrying one or more
the occurrence of de novo mutations (as resistances are better suited to acquire
exemplified by point mutations in the gyrA additional resistance mechanisms than
gene leading to quinolone resistance) and wild type lineages. Data from Sweden
the ability of bacteria to incorporate new shows that the rate of E. coli without any
genetic material into their genome via hor- resistance only decreased from 76.4% in
izontal gene transfer (exemplified by the 1993 to 76.1% in 2003 while resistance to
75
S. saprophyticus, Kronoberg county 1990–2008

60
0–30 years total
50
40
30
20
10
0
jan-90
jan-91
jan-92
jan-93
jan-94
jan-95
jan-96
jan-97
jan-98
jan-99
jan-00
jan-01
jan-02
jan-03
jan-04
jan-05
jan-06
jan-07
jan-08
jul-90
jul-91
jul-92
jul-93
jul-94
jul-95
jul-96
jul-97
jul-98
jul-99
jul-00
jul-01
jul-02
jul-03
jul-04
jul-05
jul-06
jul-07
jul-08
Figure 1 A distinct seasonal variation in the number of S. saprophyticus isolated from urinary specimens, County Kronoberg in
southern Sweden, 1990–2008.
several antibiotics [33–34] (LoE 3), such UTI, but not for a patient suffering from
as ampicillin (19–26%) and trimethoprim septic shock with the same organism.
(8–12 %) increased. The ECO-SENS study Antibiotic choice is becoming increasingly
on E. coli causing non-complicated UTI difficult as resistance rates may vary sig-
in 17 European countries in 2000 showed nificantly between different areas within
that the corresponding figure in Spain the same country. In Sweden resistance
was 50% [34] (LoE 3). These figures are to nalidixic acid (as a sensitive marker
especially important when discussing for fluoroquinolone resistance) by E. coli
empirical treatment. in urinary tract infections ranged from
9–21% (Swedres 2008, www.strama.se)
5.2 Antibiotic resistance in E. coli and ciprofloxacin resistance by E. coli in
blood stream infections in Europe 2007
The majority of uncomplicated UTIs are
varied from 7–30% (www.rivm.nl/earss/)
treated with empirical antibiotic ther-
This is further exemplified in Table 2,
apy and cultures are almost never taken
which shows the susceptibility of E. coli
unless the patient fails to respond. For
in uncomplicated UTI in different parts
empirical therapy to be successful, it
of the world.
must be based on knowledge of local aeti-
ology, resistance trends and resistance
5.3 Antibiotic resistance in E. coli –
patterns. The acceptable resistance rate
a global perspective
will be different in uncomplicated UTI
and in septicaemia but in both, resist- Studies on antibiotic resistance in unse-
ance will have an impact on the choice lected uncomplicated UTI are quite
of empirical therapy chosen in order to sparse, but some studies have been per-
avoid failure [35–36] (LoE 2b). A cipro- formed in the past few years. Some of
floxacin resistance of 10% would be con- these studies will be discussed in the fol-
sidered by most to be an acceptable level lowing section. The ECO-SENS project
for empirical treatment of uncomplicated studied antibiotic resistance by E. coli
76
Table 2 Antimicrobial resistance in Escherichia coli isolated from lower urinary tract infections in women 1998–2008. For some of the antibiotics, resistance rates are heavily influenced
by which breakpoints (BP) were used. In some instances breakpoints artificially divide isolates devoid of any resistance mechanisms into more than one susceptibility category.
NIT: nitrofurantoin, MEC: mecillinam, FOS:fosfomycin, Oral ceph: marker for oral cephalosporines (cefadroxil, cefalexin etc), AMP:ampicillin, AMC: amoxicillin + clavulanic acid,
SUL: sulfamethoxazole, TMP: trimethoprim, SXT: trimethoprim-sulfamethoxazole, NAL: nalidixic acid, CIP: ciprofloxacin, PTZ: piperacillin-tazobactam, 2:nd gen ceph: cefuroxim,
3:rd gen ceph: cefotaxome or ceftriaxone, GEN: gentamicin
Country/ Isolates E.coli Oral 2:nd gen 3:rd gen

Study Region year (n) (n) BP NIT MEC FOS ceph AMP AMC SUL TMP SXT NAL CIP PTZ ceph ceph GEN
Kahlmeter [6] Europe 2001 4734 2478 SRGA 98.8 98.8 99.3 87.9 70.2 96.6 70.9 85.2 85.9 97.7 - - - 99.0
Grude [4] Norway 2001 184 112 NWGA 97 94 - - 72 - 81 88 - - - - - - -
Stratchounski [44] Russia 456 423 CLSI 95.7 - - - 62.9 84.4 - 77.1 79.0 93.1 95.5 - 96.4 - -
1998–2001
Christiaens [45] Belgium 1996 166 138 CLSI 99.3 - - - 73.2 - - - 83.3 - 99.3* - - - -
De Backer [46] Belgium 2006 279 86 CLSI 100 - - - 62.8 - - - 86.0 - 100* - - - -
Naber [13] Europe+Brazil 3980 2315 CLSI 87.0 95.9 96.4 - - - - - 71.5 81.3 90.3 - 82.4 - -
2003
Ho P-I [47] Hong Kong 592 271 CLSI 92.3 - 98.2 36.2 40.6 84.9 - - 69.4 52.8 87.1 - 88.2 81.9 81.9
2006–2008
* fluoroquinolone tested: ofloxacin

Uncomplicated and community acquired urinary tract infections
77
| 2.2 |
in uncomplicated UTI in 16 European These agents are all excreted mainly in

countries and Canada in 1999. It pointed urine and the impact on the normal gut
to pronounced variation in antibiotic flora is thus limited [39] (LoE 3). A shift
resistance with the highest figures being from intense use of fluoroquinolones
in the Mediterranean countries and the and trimethoprim/cotrimoxazole to an
lowest in Scandinavia. The proportion increased use of these agents in uncom-
of isolates without resistance to any of plicated UTI is thwarted by the fact that
12 antibiotics tested varied from ~50% in many countries only one or two of the
(Spain and Portugal) to ~75% (Sweden, drugs are available.
Finland) [6]. The Sentry project is a lon-
gitudinal project but designed differ- 5.4 Antibiotic resistance in
ently as it utilises the specimens that S. Saprophyticus
are sent for culture to the local micro-
biology lab. Thus differences in cultur- Acquired antibiotic resistance is uncom-
ing practice may influence the result. mon in S. saprophyticus and suscep-
However, the Sentry program uses the tibility rates of >97% are reported for
same method for susceptibility testing nitrofurantoin, sulphonamides, trimetho-
and the same set of breakpoints every prim, amoxicillin, oral cephalosporines
year. The results from all over the globe and ciprofloxacin [16, 19, 40] (LoE 2b).
are interesting, indicating high resist- Methicillin resistance has been reported,
ance rates in South America and Asia but is still rare, in S. Saprophyticus [41]
while levels are more modest in Europe (LoE 3). Pivmecillinam is insufficiently
and North America [37–38]. In the most active against Gram-positives in vitro and
recent study, published by Naber and susceptibility testing of this antibiotic
co-workers, which looked at uncompli- is not advocated. However, in a Swedish
cated cystitis in females in Europe and study, the clinical cure rate of pivmecil-
Brazil [13], some countries in Europe linam was acceptable despite the intrin-
reported almost as high resistance sic resistance in vitro [42] (LoE 3). This is
rates as Brazil. There are some common probably due to the high concentrations
traits all over the world in these stud- of mecillinam reached in the urine [39].
ies. Increasing resistance to ampicillin,
trimethoprim, sulfamethoxazole, co-tri-
moxazole, fluoroquinolones and, over the 6. FURTHER RESEARCH
last few years, to third generation cepha-
losporines and aminoglycosides [6, 13, 38] The aetiology of uncomplicated UTI has
(LoE 2a). An additional problem is the been amazingly stable over the years
pronounced associated resistance lead- and further studies should now focus
ing to trimethoprim resistance in fluoro- on issues of antibiotic resistance: These
quinolone resistant E. coli being at least studies must meet some standard criteria
48% [34] and fluoroquinolone resistance in order to be useful in decision making
in trimethoprim resistant E. coli being at regarding empiric antibiotic use:
least 25% (LoE 2b). The resistance rates 1. The cohort followed should be
to several of these agents are now so high described (i.e. women of the age of so
across the world that empirical treatment and so)
will fail increasingly often. Three anti-
2. The number of negative cultures and
bacterial agents have so far fared better
than the others: resistance to fosfomy- the species distribution should always
cin, nitrofurantoin and pivmecillinam is be reported
still very low (1–5%) and this is in spite 3. The algorithms used for when to per-
of quite intense use in some countries. form a urinary culture and for how
78
duplicate isolates were excluded [43] 5. Jellheden B, Norrby RS, and Sandberg
should be stated T, Symptomatic urinary tract infec-
tion in women in primary health care.
4. A description of the methodology for
Bacteriological, clinical and diagnostic
susceptibility testing and the break- aspects in relation to host response to
points for SIR categorization should infection. Scand J Prim Health Care,
be stated 1996. 14(2): 122–8.
5. When these studies are performed, a 6. Kahlmeter G, Prevalence and antimicro-
sufficient number of isolates and anti- bial susceptibility of pathogens in uncom-
biotics should be included plicated cystitis in Europe. The ECO.
SENS study. Int J Antimicrob Agents,
For more information about how to per- 2003. 22 Suppl 2: 49–52.
form antibiotic resistance surveillance 7. Ronald A, The etiology of urinary tract
please see the reports by G. Cornaglia et al infection: traditional and emerging patho-
[44] and R. Jones and R. Masterton [43]. gens. Dis Mon, 2003. 49(2): 71–82.
8. Hummers-Pradier E and Kochen MM,
Urinary tract infections in adult general
7. CONCLUSIONS practice patients. Br J Gen Pract, 2002.
52(482): 752–61.
This review highlights the importance 9. Ruben FL, Dearwater SR, Norden
of E. coli as the most important bacteria CW, Kuller LH, Gartner K, Shalley A,
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role of several first line agents. However, in the noninstitutionalized geriatric age
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Well-performed antibiotic resistance sur- Study. Am J Epidemiol, 1995. 141(2):
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and Sandberg T, A longitudinal cohort
treatment.
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81
|2.3|
Complicated and healthcare

associated urinary tract infections:
aetiology and antimicrobial
resistance
Martin Sundqvist1,2, Gunnar Kahlmeter1,3
1
Dept of Clin Microbiology, Central Hospital, Växjö Sweden
2
Dept of Medical Sciences, Div of Infectious diseases, Uppsala University, Uppsala, Sweden
3
Dept of Medical Sciences, Div of Clinical Bacteriology, Uppsala University, Uppsala, Sweden
Corresponding author: Gunnar Kahlmeter, MD, Professor, Dept of Clin Microbiology, Central Hospital, S-35185 Växjö, Sweden,
Tel +46-470-588 000, Fax +46-470-587 455, gunnar.kahlmeter@ltkronoberg.se
ABSTRACT considered significant should be performed.

The finding of bacteriuria in these patients
Several species are important in compli- should, as always, be related to symptoms
cated (cUTI) and healthcare associated uri- and treated only if necessary.
nary tract infections (HAUTI). Importantly Key words: Enterobacteriacae, Candida
Escherichia coli still dominates the aetiol- spp, Pseudomonas spp
ogy, however, it is found more often to be
resistant to several antibiotics in cUTI and
HAUTI than in uncomplicated UTI. Other
bacteria like Enterococcus spp, P. aerugi- SUMMARY OF RECOMMENDATIONS
nosa and Candida spp. are more common
with the use of urinary catheters and the A prerequisite for successful antibiotic
high use of broad spectrum antibiotics. therapy is the good understanding of aeti-
Culture is always advocated in the diagno- ology and antimicrobial resistance. E.coli
sis of cUTI and HAUTI, and as resistance dominates the aetiology of both uncompli-
rates in these situations are unpredictable cated urinary tract infections (UTI) and
and may be very local within the hospital, complicated UTI (cUTI). However, the lat-
susceptibility testing of all bacterial isolates ter, and especially healthcare associated
Complicated and healthcare associated urinary tract infections | 2.3 |
UTI (HAUTI), sprouts a much larger 1. INTRODUCTION

spectrum of microorganisms than UTI.
Successful empirical therapy rests on Patients diagnosed with a complicated
the absolute majority of microorganisms UTI (cUTI) or a health care associated
being susceptible to the drugs chosen. A UTI (HAUTI) are often elderly, have
rapid worldwide increase in antimicro- devices like urinary catheters and/or
bial resistance in pathogens causing UTI have neurological or anatomical disor-
and especially cUTI threatens to jeop- ders resulting in voiding problems and/
ardize our empiric traditions. Regional or bladder retention [1–3] (LoE 2b).
surveillance studies should be performed Although Escherichia coli is the most
regularly to guide the choice of empiric common pathogen [1, 4], the above men-
antimicrobial therapy (GoR A). tioned conditions together with the fact
In uncomplicated UTI it is often justifi- that these patients often are treated with
able to initiate antibiotic therapy without antibiotics will increase the frequency of
performing a urine culture, provided that secondary pathogens like Pseudomonas
the epidemiology of antimicrobial resist- aeruginosa, Enterococcus faecalis and
ance in E. coli is known. A urine culture Enterococcus faecium, Proteus mirabi-
should be performed prior to or in con- lis, Staphylococcus spp and Candida spp
junction with treatment in the follow- (Table 1) [5–6] (LoE 2b).
ing situations: It is advocated that urine cultures
should be taken in these patients and
1. When the patient has received that antimicrobial susceptibility testing
antibiotic treatment in the last three should steer therapy (GoR B). The diver-
months (GoR B). sity of pathogens and the rapidly increas-
2. When planning to give empiric therapy ing levels of antimicrobial resistance
with amoxicillin, sulfamethoxazole, make empirical therapy a lottery with
trimethoprim or co-trimoxazole, to all ever worsening odds. At the same time it
of which resistance rates are high and is important to stress that not all bacte-
co-resistance to other drugs common riuria noticed after 48 hours of hospitali-
(GoR B). zation should be considered as indicative
of complicated UTI or health care associ-
3. When planning to give empiric treat-
ated UTI (HAUTI) since up to 40% of the
ment with a fluoroquinolone or a
elderly in nursing homes have asympto-
cephalosporin in areas where local
matic bacteriuria (ABU) [7–8] (LoE 2b).
resistance rates are high (>10%),
When admitted to hospital, these
i.e. in areas where ESBL-producing
patients should not be treated unless
Enterobacteriaceae are increasingly
they have symptoms of UTI and if so, cul-
common (GoR B).
tures should always be obtained. Despite
4. When antimicrobial treatment has the location of the onset of the infection,
recently failed (GoR B). there is no reason to consider other bacte-
5. When there are signs of pyelone- ria or more resistant bacteria than those
phritis (GoR A). outside the hospital environment and
6. When the patient is a man (GoR B). the same antibiotics thus apply (LoE 4).
However, local epidemiology (commonly
7. When the patient is a woman with occurring pathogens and resistance lev-
complicated and/or recurrent UTI and/ els), time after admission, presence of
or is over the age of 65 (GoR B). catheters, recent surgery and recent anti-
8. When the patient has a healthcare biotic use as well as previous cultures
associated UTI (GoR A). must be taken into consideration when
83
Table 1 Spectrum of nosocomial uropathogens of urological patients (species <2% are not considered).
Adopted from Wagenlehner et al [6]
Pathoaen 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
E. coli 27.9% 26.6% 30.2% 31.7% 28.0% 35.1% 31.3% 31.6% 41.3% 41.4% 38.3% 37.2%
Klebsiella spp. 6.0% 6.7% 9.1% 8.1% 8.7% 7.7% 9.6% 8.0% 5.5% 6.5% 7.6% 7.3%
Proteus spp. 8.0% 5.6% 7.5% 7.9% 5.9% 6.4% 7.5% 8.7% 6.5% 8.8% 7.6% 5.4%
Enterobacter 5.4% 6.0% 4.0% 4.9% 5.4% 4.0% 6.4% 5.5% 4.9% 3.3% 4.0% 3.3%
spp.
Citrobacter spp. 4.0% 3.3% 1.3% 3.7% 2.6% 2.7% 1.3% 3.3% 2.6% 3.3% 3.1% 5.0%
P. aeruginosa 12.7% 13.8% 11.5% 11.5% 12.3% 10.1% 10.8% 6.9% 7.7% 5.6% 6.9% 7.4%
Enterococcus 20.5% 20.8% 22.2% 16.5% 20.1% 19.8% 23.0% 21.8% 18.7% 17.5% 18.0% 17.1%
spp.
CNS 10.9% 14.1% 10.7% 13.3% 13.4% 11.1% 8.0% 10.0% 9.7% 7.7% 9.6% 10.2%
S. aureus 4.5% 3.1% 3.5% 2.5% 3.6% 3.2% 2.1% 4.2% 3.1% 5.9% 4.9% 7.1%
total (n = 100%) 448 448 374 407 389 405 623 550 508 479 447 462
choosing empirical therapy for HAUTI. of urease which hydrolyses urea to ammo-
The importance of urinary catheters as the nium and hydroxyl ions. These are not
main risk factor of HAUTI [9–10] and the only involved in the pathogenesis of uro-
treatment of these infections will be dis- lithiasis [13] but also in recurrent UTI
cussed in more detail in other chapters in as the treatment given does not penetrate
this book. the biofilm formed around and within the
infectious stone [14] (LoE 3). These bac-
teria are, in many cases, the same that
2. METHODS can be found associated with catheters
but in catheter related infections Gram-
The PubMed database was searched for positive bacteria like staphylococci are
the terms complicated UTI and Hospital more common. Enterococci are mainly a
acquired UTI in combination with anti- concern in patients with recurrent UTI,
biotic resistance. Articles on cUTI and and often in patients with urinary reten-
HAUTI in adults that were in English tion [15] (LoE 3).
and of appropriate quality were included.
In addition, articles from the last 10 years
describing antimicrobial resistance in 4. ANTIBIOTIC RESISTANCE
UTI pathogens were retrieved. Despite
the fact that the rating system is not opti- In the following section the special fea-
mal for our purposes, the studies were tures regarding antibiotic resistance
rated according to the level of evidence in several of the species important in
(LoE) and the grade†of recommendation HAUTI are described. The features of
(GoR) using ICUD standards (for details E. coli, although still the most common
see Preface) [11–12]. bacteria causing HAUTI, is covered in the
previous chapter. Resistance rates in E.
coli from a number of studies on HAUTI
3. COMMON PATHOGENS IN
are presented in Table 2.
COMPLICATED AND HEALTHCARE
Multiresistant bacteria are encountered
ASSOCIATED UTI
increasingly often in the treatment of
cUTI and HAUTI. With exceptions (most
As mentioned in the previous chapter, notably rare instances of pan resistant
almost any bacterium and yeast could Acinetobacter spp.and Stenotrophomonas
be responsible for, or at least found in, spp.) one or two antibiotics are still left to
cultures obtained from patients with choose between. In some cases multire-
HAUTI. An example of the presence of sistant E. coli in UTI may still be suscep-
different pathogens in urinary samples tible to pivmecillinam, fosfomycin and/
from a urology department over time is or nitrofurantoin (LoE 4). In all these
reported in Table 1. Most of these organ- cases, one should consult the clinical
isms have certain features which render microbiologist.
them eminently suitable for colonisa-
tion of the urinary tract of hospitalized
4.1 Enterobacteriacae (not E. coli)
patients and or patients with compli-
cated UTI. Some bacteria are prone to As mentioned and shown in Table 1,
reside in and promote growth of stones Klebsiella pneumoniae, Klebsiella oxy-
in the urinary tract (Proteus spp (most toca, Proteus mirabilis, Citrobacter spp,
common), Corynebacterium urealyticum, Enterobacter spp and Morganella mor-
Staphylococcus spp, Klebsiella spp, ganii are the most common aetiology in
Providencia spp, and Pseudomonas spp). complicated infections [5–6]. The resist-
Their common trait is a prolific production ance rates in these species are in many
85
Table 2 Resistance rates in Escherichia coli isolates from HAUTI and/or routine resistance surveillance utilizing clinical databases. For some of the antibiotics, resistance rates are heavily influenced
by which breakpoints (BP) were used. In some instances breakpoints artificially divide isolates devoid of any resistance mechanisms into more than one susceptibility category. The numbers gives an
impression on the importance of knowing the local epidemiology.
NIT: nitrofurantoin, MEC: mecillinam, FOS: fosfomycin, Oral ceph: marker for oral cephalosporines (cefadroxil, cefalexin etc), AMP: ampicillin, AMC: amoxicillin + clavulanic acid, SUL:
sulfamethoxazole, TMP: trimethoprim, SXT: trimethoprim-sulfamethoxazole, NAL: nalidixic acid, CIP: ciprofloxacin, PTZ: piperacillin-tazobactam, 2:nd gen ceph: cefuroxim, 3:rd gen ceph:
cefotaxime or ceftriaxone, IMI: imipenem, GEN: gentamicin
3:rd
Country/ Isolates E.coli Oral gen
study Region year (n) (n) BP NIT MEC FOS Ceph AMP AMC SUL TMP SXT CIP PTZ ceph IMI GEN
Gales [43] Latin America 1997–1999 1961 801 CLSI 87.0 - - 82.4 41.6 74.2 - - 52.3 81.1 91.0 96.4 100 89.1
Soraya [44] Latin America 2003 403 CLSI 93.1 - - 76.4 43.2 83.6 - - 59.6 77.4 97.3 98.5 100 90.1
Karlowsky USA 1999 5739 3505 CLSI 99.1 - - 71.0 - - - - 83.2 98.3 - - - -
[45]
Johansen [5] Europe 2003/2004 569 175 DIN/CLSI - - - - - 53 - - 48 59 - 77 - -
Akram [46] India 2004–2005 100 61 CLSI 20 - - 31 - - - - 24 31 - 45 100 36
Olson [47] USA 2005–2007 176 176 NS 100 - - - - - - - 70.3 93.2 - - - -
Khameneh Iran 2005–2006 803 631 NS 69.8 - - - - - - - - 83.2 - ?89.5 - 83.9

[48]
Karou [49] Burkina Faso 709 260 NS - - - - 23.4 75.0 - - 25.3 10.0 - - - -
Wagenlehner Germany 1994 448 125 NS 100 71.2 77.6 85.2 95.6 100 100 MIC 96.7
[6] >=16
Wagenlehner Germany 2005 462 172 NS 98.1 65.7 74.4 77.4 84.9 100 100 94.3
[6]
Farajnia [50] Iran 2009 676 504 NS 87.1 76.0 6.9 48.2 94.0 97.0
cases a reflection of those found in E. coli 4.3 Pseudomonas aeruginosa

(see Table 2). There are however some Pseudomonas aeruginosa is a Gram-
important differences to be pointed out. negative rod, easily distinguished in
Firstly, treatment with cephalosporins the microbiology lab from other Gram-
is not advocated in infections caused by negatives by its production of pigment
Enterobacter spp, Citrobacter freundii, and oxidase. P. aeruginosa is intrin-
Serratia spp and Morganella morganii. sically resistant to all oral antibiot-
This is due to a chromosomally located ics except fluoroquinolones, of which
AmpC enzyme that might be derepressed ciprofloxacin has the highest activity [29]
by the cephalosporin given and resistance (LoE 2b). However in many parts of the
can thus display under ongoing therapy world resistance rates to ciprofloxacin
[16–17] (LoE 3). Secondly, an important now exceed 20% and in some countries
emerging resistance within this group is even higher [30], leaving no oral treat-
the carbapenemases first reported in K. ment options in these patients (LoE 3).
pneumoniae (KPC) that have now caused In addition an increasing number of P.
major outbreaks in the USA, Greece and aeruginosa have adapted to the constant
Israel [18–20]. These multiresistant bac- selective pressure of antibiotics in hos-
teria will be more and more common pitals by down-regulating their perme-
and the importance of well-performed ability and up-regulating efflux pumps,
Infection Control Bundles to minimize pumping out several antibiotics, among
their spread cannot be emphasized these β-lactam antibiotics [31] (LoE 3)
enough. resulting in resistance to ceftazidime,
piperacillin/tazobactam and increasingly
4.2 Enterococcus spp also to carbapenems. Isolates produc-
ing metallo-fl-lactamases (MBL) usually
Enterococcus spp are Gram-positive cocci
express higher levels of resistance to
normally residing in the gut flora [21].
carbapenems and other betalactams
They frequently colonise the urinary
[32] (LoE 3). The prevalence of these
tract and occasionally cause UTI, in both
fl-lactamases are increasing in most parts
cUTI and HAUTI [5, 22]. Antibiotics
of the world. Such isolates are usually
active against Gram-negative bacteria
multi drug resistant and the MBL encod-
are often poorly active against entero-
ing genes may co-exist with aminoglyco-
cocci. This is true for fluoroquinolones
side resistance genes [33] leaving only
[23], cephalosporines [24] and enterococci
the “old kids on the block” like colistin as
are considered indeterminant suscepti-
possible treatment (LoE 3).
ble to trimethoprim and co-trimoxazole
[25]. Ampicillin is basically always active
against Enterococcus faecalis but only 4.4 Acinetobacter spp
rarely against Enterococcus faecium (LoE In this non-fermentative group of Gram-
2b). Cultures taken after some days of negative bacteria the Acinetobacter bau-
antibiotic treatment will often yield ente- manii is the most frequently described in
rococci. It is then important to weigh the hospital acquired infections [34] (LoE 3).
relevance of the finding against the clini- It is not mainly a UTI pathogen but
cal course of the patient. E. faecium is rather a colonizer and can be found in the
intrinsically, or by acquisition, resistant urine from patients with CAD. In these
to almost any antibiotic appropriate for cases the resistance pattern is almost
treatment of UTI, except for nitrofuran- always a depressing sight as resistance to
toin. In addition vancomycin resistance a large number of antibiotics is manda-
is a major nosocomial problem in many tory and several outbreaks of Extremely
parts of the world [26–28] (LoE 2a). Drug Resistant (XDR) A. baumanii have
87
been reported [35] (LoE 3). In some cases problematic/antibiotic resistant bacteria
susceptibility testing to colistin and other in relation to the time from admission are
not so frequently used antibiotics is advo- also needed, to avoid unnecessary broad
cated to support clinicians in selecting a spectrum antibiotic treatments.
treatment option.
6. CONCLUSIONS
4.5 Candida spp
The growth of Candida spp. in urine In contrast to the aetiology of uncom-
is found with increasing frequency in plicated UTI, the aetiology of HAUTI is
severely ill patients [1] (LoE 2b) and the very much influenced by local epidemi-
wide use of broad spectrum antibiotics in ology. However, E. coli is still the most
ICUs further promotes this. Usually the important pathogen in these infections
finding of Candida spp. reflects a coloni- as well as in cUTI. The diverse aetiol-
zation rather than infection, especially if ogy and increased resistance rates in
the patient has a urinary catheter (LoE these infections call for urinary cul-
3). Treatment of this condition does not tures to be obtained and analysed in all
give any beneficial effects [36] (LoE 3). these patients prior to or in conjunction
However, yeasts in urine might reflect a with the start of treatment. One should
concomitant candidemia and candiduria always keep in mind the possibility of
may be found prior to finding the can- asymptomatic bacteriuria when inter-
didemia in blood cultures [37] (LoE 3). preting the microbiological report in
If treatment is initiated, it is important these patients.
to decide what species are responsible
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91
|2.4|
Methicillin-resistant Staphylococcus
aureus (MRSA) in urology
Satoshi Takahashi
Corresponding author: Satoshi Takahashi, MD, Department of Urology, Sapporo Medical University, School of Medicine,
S1, W16, Chuo-ku, Sapporo, 060-8543, Japan, stakahas@sapmed.ac.jp
ABSTRACT in the community. Therefore, we should

know how to diagnose and treat such
Methicillin-resistant Staphylococcus aur- skin and soft-tissue infections caused by
eus (MRSA) is the main nosocomial patho- community-associated MRSA, although
gen worldwide, especially in hospitals and they have been rare in the field of urology.
long-term care facilities. In the field of Key words: methicillin-resistant S.
urology, there has been a lack of compre- aureus (MRSA), urology, urinary tract
hensive study of MRSA infection. Indeed, infection, surgical site infection
it is necessary that MRSA infection be
examined comprehensively in clinical tri-
als. We should note that urinary tract SUMMARY OF RECOMMENDATIONS
infection caused by MRSA has been an
important origin of healthcare-associated Epidemology
infection, and surgical site infection
caused by MRSA has been the principal 1. If the rate of MRSA infection is high
issue in contaminated operations in uro- or increasing, active surveillance
logical surgery. Treatment for MRSA infec- might be effective for prevention of
tion has been uncommonly empirical and outbreaks (GoR B).
the complicated origin of the urinary tract
makes complete eradication of MRSA dif- Pathogenesis of UTI caused by MRSA
ficult. There have been no randomized
clinical trials of the treatments for various 2. In the point of pathogenesis of urinary
MRSA infections in urological diseases. In MRSA, the multifactorial conditions of
recent years, community-acquired MRSA UTI caused by MRSA and especially
has been noted as an emerging pathogen the toxins of MRSA involved need fur-
causing skin and soft-tissue infections ther research (GoR C).
MRSA in urology | 2.4 |
3. We should have common cognizance Treatment

that urinary MRSA could be a poten-
tial reservoir for healthcare-associated 10. In the clinical field, glycopeptides
infection (GoR B). could be used as treatment for MRSA
urinary tract infection, although
there is a lack of data on the treat-
Biofilm ment outcomes for glycopeptides for
urinary tract infection caused by
4. Two virulence factors, beta-hemolysin
MRSA and not enough data on their
and fibronectin-binding protein A,
cost, toxicity and the availability of
should be recognized as biofilm for-
other agents (GoR C).
mation, because they are suggested
to be associated with MRSA coloniza- 11. Daptomycin, a new lipopeptide anti-
tion and infection of the urinary tract microbial agent, could be used as an
(GoR C). alternative treatment option, because
it is considered to be as effective as
5. Clarithromycin could be considered for
linezolid or vancomycin (GoR C).
combination because it has an inhibi-
tory action on the glycocalyx and bio- 12. In an in vitro study, treatment with
film of MRSA (GoR C). vancomycin or rifampicin for the
purpose of reducing biofilm growth
was ineffective and combined with
MRSA in surgical site infection linezolid was also ineffective
(GoR C).
6. The clinical relevance of SSIs caused
by MRSA should be perceived, because 13. Clarithromycin could be an alterna-
the isolation rate of MRSA from SSIs tive treatment for MRSA biofilm
was unchanged without regard to the infection because it had an inhibitory
duration and type of antimicrobial action on the glycocalyx and biofilm
prophylaxis (GoR B). of MRSA (GoR C).
7. Preoperative urine culture for the 14. Combination therapy with vancomy-
surveillance of MRSA could be a criti- cin and clarithromycin might be an
cal point in some situations, because alternative treatment option because
MRSA isolated from wounds tends of their efficacy in urinary tract
to correspond to that in preoperative infection caused by MRSA (GoR C).
infected urine (GoR B).
Community- versus healthcare-
8. Preoperative urine culture for the acquired MRSA (CA- versus HAMRSA)
surveillance of MRSA could be a
critical point in some situations, 15. Genetic marker can be an important
because MRSA is frequently asso- diagnostic tool, because use of genetic
ciated with SSI of open urological markers may make it possible to
surgery and preoperative UTI is the discriminate between CAMRSA and
most important risk factor for SSI HAMRSA (GoR A).
(GoR B). 16. Daptomycin and tigecycline can
9. Preoperative urine culture for the be used for skin and soft-tissue
surveillance of MRSA could be a criti- infections by CAMRSA, because
cal point in some situations, because double-blinded clinical trials reveal
preoperative MRSA bacteriuria is that daptomycin and tigecycline
considered to be one of the risk fac- were equally effective for skin and
tors for SSIs in urological surgery soft-tissue infections by CAMRSA
(GoR B). (GoR A).
93
Prevention 2. METHODS
17. For the purpose of prevention of A systematic literature search was

UTI and SSI caused by MRSA, we performed in PubMed with the follow-
should exploit useful and practi- ing keywords: MRSA and urinary tract
cal recommendations because there infection, MRSA and biofilm, MRSA
are several educational guidelines and surgical site infection, MRSA and
for the prevention of UTI and SSI genital infection, community-associated
(GoR A). MRSA and genital infection, MRSA
and skin and soft tissue infection,
MRSA and balanoposthitis and MRSA
1. INTRODUCTION and treatment. Only English publica-
tions with abstracts available were
Staphylococcus aureus (S.aureus) is one considered. Publications on infections
of the normal floras on the human skin irrelevant to the urological field, such
and in the nasal cavity. To date, various as pneumonia, sepsis and blood stream
multi drug resistant bacterial pathogens infection were excluded from the anal-
have been noted and methicillin-resistant ysis. A total of 8227 publications were
S.aureus (MRSA) is one of the most found, which were screened by title and
important. Multi drug resistant bacterial abstract, and finally 30 were included
organisms have been mostly isolated in in the analysis.
hospitals or long-term care facilities and The studies were rated according
that has led to clinical issues, such as to the level of evidence (LoE) and the
healthcare-associated infections. MRSA grade of recommendation (GoR) using
was first isolated in the United Kingdom ICUD standards (for details see Preface)
in 1961 [1–2] and has become wide- [5–6].
spread worldwide since then. In Japan,
healthcare-associated MRSA infection,
including urinary tract infection (UTI) 3. DEFINITION
and surgical site infection (SSI), became
an issue of clinical importance especially MRSA is defined as strains of Staphy-
during the period 1980 to 1990. At that lococcus aureus resistant to isoxaszoyl
time, there were occasional outbreaks penicillins, such as methicillin and oxa-
of healthcare-associated MRSA not only cillin. Additionally, at present, the defini-
in the intensive care unit but also in the tion of MRSA should be made according
urology ward. Although frequent out- to clinical background at isolation and
breaks of healthcare-associated MRSA in microbiological characteristic findings. In
the urology field in Japan have occurred this chapter, MRSA is defined according
rarely in recent years, the isolation rate to the clinical background or situation at
of MRSA in the urological field has been isolation because we focused on clinical
either unchanged or increasing [3–4] MRSA infection. We define both health-
despite the enactment of the standard care-associated MRSA (HAMRSA) and
precautions advocated by the Centers for community-associated MRSA (CAMRSA)
Disease Control and Prevention (CDC) of mostly according to the guidelines
the United States. In this chapter, reports developed by the British Society for
on the mainly healthcare-associated Antimicrobial Chemotherapy [7] because
MRSA isolated from urine or surgical of its specific content. We mainly focus on
sites in the urology field are reviewed and HAMRSA throughout, except the section
discussed. on CAMRSA.
94
4. HEALTHCARE-ASSOCIATED MRSA infection and pneumonia due to MRSA

(HAMRSA) have been frequently observed [10].
In a report on the isolation rate of UTI
The pattern of transmission is dissemi- bacterial pathogens for urology inpa-
nation within healthcare settings. Most tients in Kobe, Japan [4], the preva-
HAMRSA strains are diagnosed in inpa- lence rates of isolated urinary S.aureus
tient settings. In general, the medical were 1.9% from 1983 to 1987, 4.6% from
history shows the history of MRSA colo- 1988 to 1992, 5.3% from 1993 to 1997,
nization, infection, recent surgery, anti- and 6.6% from 1998 to 2002. The rate
biotic use and admission to a hospital or showed an increasing trend in the past
nursing home. When infection occurs in years. The authors note that the rate of
hospitals or healthcare settings, it is hos- MRSA showed a similar increasing trend
pital or healthcare onset. When it occurs and accounted for 82.2% of the entire
in the community after hospital dis- S. aureus population in 2002 (LoE 3,
charge, it is community onset [7]. GoR B).
In a report examining how to deter-
mine the number of newly diagnosed
5. COMMUNITY-ASSOCIATED MRSA cases of MRSA detected in a urology ward
(CAMRSA) in Portsmouth, UK [11], the ratios of the
number of newly diagnosed MRSA cases
The transmission pattern is just commu- to total urological admissions were 0.82
nity-acquired. Diagnosis is done in out- in 2000, 0.89 in 2001, 1.00 in 2002, 0.67
patient or community settings. Medical in 2003, and 0.79 in 2004. The origins of
history shows no significant history or isolates were urinary indwelling devices
healthcare contact. When infection occurs and urine, including three catheters, six
in an outpatient or community setting, it nephrostomy tips, 19 suprapubic cath-
means community onset. When it occurs eter tips, six cases of urine from cath-
within 48 hours of hospital admission, eter samples, and 11 midstream urine
it means hospital onset. Medical history samples. Other origins were wounds, the
shows no history of MRSA and patients nose, genitalia, groin, blood cultures, leg
have the absence of indwelling catheters ulcers, sputum, and bronchoscopic lavage
[7] (LoE 4, GoR A). However, because fluid. The proportion of MRSA isolates
S.aureus can persist for a longer duration, of urinary origin was 38.8% (45 of 116).
community-onset infections with pos- They concluded that the number of new
sible community-associated MRSA may cases of MRSA remained constant and
indeed be caused by healthcare-associ- low acquisition rates were found (LoE 3,
ated MRSA. GoR B).
The isolation rates of urinary MRSA
could be variable and depend on each
hospital and facility. We should track
6. MRSA IN URINARY TRACT
the isolation rates of urinary MRSA by
INFECTION
surveillance of urinary pathogens and
undertake the prevention of MRSA out-
6.1 Epidemiology
breaks according to standard precau-
The frequency of S. aureus infections, tions. If the rate of MRSA infection is
mostly MRSA, has been gradually grow- relatively high or increasing, active sur-
ing and it is a clinically important issue veillance cultures might be effective for
for healthcare-associated infection world- prevention of outbreaks [12] (LoE 1a,
wide [8–9]. In particular, bloodstream GoR B).
95
6.2 Virulence in urinary tract molecules such as collagen, fibronectin,

S.aureus strains, including MRSA (57%), and fibrinogen. MSCRAMMs might initi-
isolated from patients with UTI were ate catheter infections as well as endocar-
analyzed, and the prevalence of toxins ditis, osteomyelitis, septic arthritis and
and adhesion factors were determined prosthetic-device infections. One theory
[13]. Staphylococcal enterotoxin (SE) A showed that no virulence factors were
(63%), SE D (20%), toxic shock syndrome suggested for urinary tract infection with-
toxin-1 (8.5%) and staphylococcal bicom- out any urinary catheter or instrument
ponent leukotoxin LukE/LukD (60%) (LoE 1a, GoR B). The virulence of MRSA
were produced by the isolates. In addi- in the urinary tract depends on urinary
tion, S.aureus urinary tract infections catheters or instruments and it leads to
have been associated with implanted complicated urinary tract infection. There
catheters and biomaterials. Adhesin fac- are no definite virulence factors of MRSA
tors, included clumping factor B (clfb), reported for uncomplicated urinary tract
elastin-binding protein (ebp) and lam- infection to date.
inin-binding protein (lbp) are possibly
6.3 Biofilm
involved in colonization on urinary cath-
eters. In general, the pathogenesis of Although there are relatively many
urinary MRSA is multifactorial and tox- patients with asymptomatic urinary
ins causing urinary tract infections have MRSA, it rarely leads to severe sys-
not been clearly determined yet (LoE 3, temic infection or febrile UTI in most.
GoR C). However, on occasion, it can lead to
In a cohort study at a long-term care serious bacteremia. One of the factors
Veterans Affairs facility [14], 82% of 102 or background causes of asymptomatic
patients had urinary tract catheteriza- infection is considered to be biofilm for-
tion. In addition, 33% of the patients had mation in the urinary tract or on a uri-
symptomatic UTI at initial isolation of nary indwelling device. The mechanisms
S.aureus and 13% were bacteremic. In of biofilm formation in the urinary tract
this study, 86% of the initial urine cul- or on the urinary indwelling device [16]
tures were MRSA-positive. Persistent are as follows: once bacterial adhesion
carriers of urinary MRSA colonization is completed on the surface of a foreign
were determined to be at high risk of body such as a urinary catheter, a gly-
subsequent urinary tract infection and cocalyx consisting of polysaccharides
bacteremia. Therefore, the pathogenesis is produced outside the bacterial cells.
of urinary MRSA might be associated Finally, the condition results in biofilm
with urinary indwelling catheters and formation. The biofilm is considered to
there was a relatively high prevalence be antimicrobial-resistant, allowing bac-
of asymptomatic patients with urinary teria to escape the host defense against
MRSA. In the patients with asympto- infection and to escape the actions of
matic urinary MRSA, we should be aware antimicrobials. In this condition, two
of urinary MRSA being a potential reser- virulence factors, beta-hemolysin and
voir for healthcare-associated infection fibronectin-binding protein A, were sug-
(LoE 2, GoR B). gested to be associated with MRSA colo-
In a recent review of the pathogenesis nization and infection of the urinary
of MRSA [15], selected virulence factors tract [17] (LoE 2b, GoR C). In an experi-
of S.aureus were presented. Microbial mental study [16], the results suggested
surface components recognizing adhe- that clarithromycin had an inhibitory
sive matrix molecules (MSCRAMMs) are action on the glycocalyx and biofilm of
important surface proteins that can bind MRSA (LoE 2b, GoR C).
96
7. MRSA IN SURGICAL SITE MRSA bacteriuria is considered to be one

INFECTIONS of the risk factors for SSIs in urological
surgery (LoE 3, GoR B). As we know, the
SSIs are strongly associated with morbid- rate of SSI in clean or clean-contaminated
ity and mortality for inpatients as health- surgery is much lower than that in con-
care-associated infections that occur taminated surgery [3, 20]. Therefore, SSIs
despite standard precautions. SSIs caused of urological surgeries caused by MRSA
by MRSA are common in urology wards are mainly related to contaminated sur-
[3, 18]. Two transmission manners are gery such as radical cystectomy with
hypothesized. One is preoperative dis- urinary diversion as described in previ-
semination from MRSA bacteriuria, with ous reports [3, 18–19]. Unfortunately, no
MRSA endogenously transmitted from effective antimicrobial prophylaxis regi-
the urinary tract to the wound. The other men against SSI caused by MRSA has
is exogenous contact transmission from been established yet. Because MRSA iso-
hand to hand by the medical staff. lation rates in each medical center are
In a study [3] on SSIs of open urologi- highly variable, every urologist may not
cal operations, the results showed that have trouble about SSI caused by MRSA.
the most frequently isolated bacterium However, MRSA has been the princi-
was MRSA. The isolation rate of MRSA pal nosocomial pathogen in healthcare-
from SSIs was unchanged without regard associated infections and we should
to the duration and type of antimicrobial establish an effective regimen as well as
prophylaxis. The frequencies of MRSA iso- standard precautions.
lation from SSI were 73.3% in an uncon-
trolled antimicrobial prophylaxis group
and 93.3% in a controlled antimicrobial 8. TREATMENT
prophylaxis group (LoE 2b, GoR B). In
addition, SSIs for radical cystectomy with Surprisingly few studies of antimicrobial
urinary diversion using the small intes- treatment for urinary MRSA have been per-
tine, considered a contaminated opera- formed to date. Applicable anti-MRSA drugs
tion by the CDC guideline, were surveyed are generally likely to vary in each coun-
and reported [18]. The results showed try or region. In addition, the frequency of
that the overall incidence of SSIs was uncomplicated UTI caused by MRSA is not
33% and MRSA was the most frequently high enough to establish a standard treat-
isolated bacterium, accounting for 38% ment regimen. In Japan, there are four
of the isolated pathogens. This study applicable antimicrobial agents for MRSA
showed that MRSA isolated from wounds infection, including urinary tract infection:
tended to correspond to that in preop- vancomycin, teicoplanin, arbekacin, and
erative infected urine (LoE 3, GoR B). linezolid. Regrettably, there have been no
Another report [19] also showed that randomized controlled studies with these
MRSA was frequently associated with antimicrobial agents [21] although such
SSI of open urological surgery and preop- studies might lead to favorable treatment
erative UTI was the most important risk outcomes.
factor for SSI (LoE 3, GoR B). In the guidelines of the United Kingdom
There have been a few reports about [22], tetracycline is recommended as the
SSIs of urological surgeries according to first-line treatment regimen for urinary
the classification of the CDC guideline; tract infection caused by susceptible
however, those reports indicated that MRSA. The guidelines state that there
MRSA was the organism most frequently is a lack of data on the treatment out-
isolated from wound SSIs. Preoperative comes for glycopeptides for urinary tract
97
infection caused by MRSA and not enough 9. CAMRSA

data on their cost, toxicity and the avail-
ability of other agents. This remark is cat- CAMRSA has been especially noted as
egorized as suggestive for implementation a pathogen causing skin and soft-tissue
and supported by suggestive clinical and infections in the community. In the field of
epidemiological studies as well as a theo- urology, a few special genital or perineal
retical rationale (LoE 4, GoR C). However, infections might be related to CAMRSA.
for patients with MRSA bacteremia such However, there has been an epidemic of
as severe febrile urinary tract infection, CAMRSA in recent years. Therefore, we
a minimum treatment duration by glyco- should know how to diagnose and treat
peptides or linezolid of 14 days is recom- the skin and soft-tissue infections caused
mended in the guidelines. Therefore, it by this pathogen.
is possible to apply glycopeptides or lin-
ezolid according to the patients’ condition
or severity.
10. DEFINITION USING BY GENETIC
In an in vitro study of daptomy-
MARKER
cin, a new lipopeptide antibiotic [23], it
was considered to be as effective as lin-
Use of genetic markers may make it pos-
ezolid or vancomycin (LoE 2b, GoR C).
sible to discriminate between commu-
Unfortunately, there has been no clini-
nity- and hospital-acquired MRSA [26]
cal study with daptomycin so it should be
(LoE 4, GoR A). In the United States,
studied in clinical trials in the future.
community-acquired MRSA has the sta-
In the clinical situation, urinary MRSA
phylococcal cassette chromosome (SCC)
is mostly impossible to eradicate per-
mec type IV and the gene for Panton-
fectly from the catheterized urinary tract.
Valentine leukocidin (PVL) [26] (LoE 4,
Exchange of the urinary catheter is one
GoR A).
possible procedure to eradicate urinary
MRSA; however, the complicated urinary
tract condition generally makes eradica-
tion of MRSA difficult. It is closely asso- 11. BALANOPOSTHITIS CAUSED BY
ciated with biofilm formation on the CAMRSA
urinary catheter. An in vitro study [24]
revealed that treatment with vancomy- There has been just 1 case clearly
cin or rifampicin to reduce biofilm growth caused by MRSA to date [27]. The his-
was ineffective and that with linezolid tory of that case revealed that it was
was also ineffective [25] (LoE 2b, GoR C). caused by HAMRSA. Indeed, we treated
Another study [16] revealed that clari- one case with balanoposthitis caused by
thromycin had an inhibitory action on CAMRSA determined by clinical history
the glycocalyx and biofilm of MRSA and with no inpatient or outpatient history,
that combination therapy with vancomy- although SCC mec type IV and the gene
cin and clarithromycin might be effica- for PVL could not be examined (LoE 3,
cious for UTI caused by MRSA (LoE 2b, GoR C).
GoR C). To date, skin infections caused by
To date, there have been no definitive CAMRSA have not been a critical issue
clinical trials for the treatment of UTI in the field of urology. However, impetigo,
caused by HAMRSA or for the inhibition folliculitis, furuncles and abscesses caused
of MRSA biofilm formation on urinary by CAMRSA are epidemic worldwide.
catheters. Current treatments for these We should be aware that such infections
conditions tend to be highly empirical. could occur in our field in the future.
98
12. TREATMENT FOR COMMUNITY- 14. FURTHER RESEARCH

ACQUIRED MRSA SKIN AND
SOFT-TISSUE INFECTIONS There is a lack of comprehensive stud-
ies of MRSA infection in the field of
There are four US Food and Drug urology, although UTI caused by MRSA
Administration (FDA)-approved anti- is an important origin of healthcare-
MRSA drugs: vancomycin, linezolid, dap- associated infections and surgical site
tomycin, and tigecycline. Vancomycin is infections.
a standard drug for skin and soft-tissue
infections by CAMRSA [26]. Therefore,
clinical trials were carried out by com- 15. CONCLUSIONS
paring the other drugs with vancomycin.
An open-label clinical trial revealed that Urinary MRSA is a potential reservoir
the cure rate for CAMRSA infections was for healthcare-associated infection. If
higher in the group treated with linezolid the rate of MRSA infection is high or
(88.6%) than in that with vancomycin increasing, active surveillance might be
(66.9%) [28]. Double-blinded clinical tri- effective for prevention of outbreaks. The
als revealed that daptomycin and tigecy- pathogenesis of urinary MRSA is mul-
cline were equally effective for skin and tifactorial and toxins causing urinary
soft-tissue infections by CAMRSA [29–30] tract infections have not been clearly
(LoE 1b, GoR A). In addition, oral antimi- determined yet. MRSA is frequently
crobial agents such as trimethoprim-sul- associated with SSI of open urological
famethoxazole, doxycycline, minocycline, surgery and preoperative MRSA bacte-
rifampin, clindamycin, and fusidic acid riuria is considered to be one of the risk
are also recommended; however, clinical factors for SSIs in urological surgery.
trials in the field of urology are lacking. There is a lack of data on the treat-
ment of UTI caused by MRSA with glyc-
opeptides, e.g. vancomycin, and with
13. PREVENTION other agents, such as linezolid and dap-
tomycin. In an in vitro study, treatment
Prevention of both MRSA UTI and surgi- with vancomycin or rifampicin to reduce
cal site infection is the most important biofilm growth was ineffective and that
issue especially in the urology ward of with linezolid was also ineffective.
healthcare settings. There are several Clarithromycin had an inhibitory effect
educational guidelines for prevention of on the glycocalyx and biofilm of MRSA
UTI and surgical site infection [31–32] in contrast to the agents mentioned.
(LoE 1a, GoR A). These guidelines are Therefore a combination therapy with
commonly available for almost all noso- vancomycin and clarithromycin might
comial pathogens including HAMRSA. be efficacious for the treatment of UTI
Although those are not the guidelines for caused by MRSA. Daptomycin and tige-
the prevention of particular MRSA trans- cycline were equally effective for skin
mission, the intimate content can cover and soft-tissue infections by CAMRSA.
the field of urology. I strongly recommend There are several educational guide-
that urologists peruse these guidelines. lines for prevention of UTI and SSI.
99
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101
|2.5|
ESBL and multi-resistance

in urology
Tetsuro Muratani
Corresponding author: Tetsuro Muratani, PhD, The Head of Department, Department of Clinical Laboratory, Kyurin
Corporation and Assistant Professor, Department of Urology, School of Medicine, University of Occupational and
Environmental Health 27-25, Morishita-machi, Yathatanishi-ku, Kitakyushu, 806-0046, Japan
Tel 0081-93-642.3911, Fax 0081-93-642.3967, tetsuro_muratani@ybb.ne.jp
ABSTRACT penicillins, all cephalosporins or mono-

bactams may result in treatment fail-
β-lactamases are bacterial enzymes that ure even when the causative organisms
are encoded by chromosomal or by plasmid- appear to be susceptible to these anti-
mediated genes, the enzymes protecting microbial agents by routine susceptibil-
the microorganisms against the lethal ity testing. Regarding patients colonized
effects of β-lactam antibiotics by hydrolyz- or infected with ESBL-producers, it is
ing the β-lactam ring. The production of important to pay attention and perform
β-lactamases is the most important resist- contact precautions to avoid hospital
ant mechanism to β-lactam antibiotics, transmission. These benefits warrant
especially for Gram-negative bacteria. the detection of ESBL-producing organ-
Since the first description of plasmid- isms in clinical laboratories. All ESBL-
mediated extended-spectrum β-lactamases detection methods by only phenotype
(ESBL) in 1983, ESBL-producing Gram- utilize the characteristics of ESBLs:
negative organisms have posed a sig- conferring a reduced susceptibility to
nificant threat to hospitalized patients expanded-spectrum cephalosporins and
due to their hydrolyzing activity against inhibition by clavulanic acid. ESBL-
expanded-spectrum cephalosporins, which producers showed a significant reduction
are often employed in the treatment of in the susceptibility to most antimicro-
hospital-acquired infections. Detection of bials, such as aminoglycosides, quinolo-
ESBL producers provides clinicians with nes and trimethoprim-sulfamethoxazole.
helpful information. Treatment of infec- Moreover, community acquired infec-
tions caused by ESBL-producers with tions due to ESBL-producing organisms
ESBL and multi-resistance in urology | 2.5 |
pose a serious challenge to clinicians in into three different groups Class A, Class
choosing appropriate empiric therapy. C [2], and Class D [3]. Class B has been
The incidence of such infections is cur- divided into three subgroups, B1, B2,
rently not so high, but we have to pay and B3, on the basis of sequence similar-
attention to the trend. Furthermore, if ity [4], but phylogenetic analysis [5] has
multi-drug resistant Enterobacteriaceae shown that subgroup B3 lacks detectable
isolates with carbapenem hydrolyzing sequence homology with subgroups B1 &
activity such as KPC type β-lactamase B2 (Figure 1).
increase, they will pose a serious threat Plasmid-mediated β-lactamases have
that will limit choice of antibiotic become prevalent among Gram-negative
treatment. bacteria. The first plasmid-mediated
β-lactamase in Gram-negative bacteria,
Key words: Extended-spectrum β-
TEM-1, was described in the early 1960s
lactamase (ESBL), urinary tract infection,
[6]. Carried by transposons on plasmids,
antimicrobial therapy, plasmid-mediated
the TEM-1 genes have spread to several
broad spectrum β-lactamase
bacterial species and are now distributed
around the world. SHV-1 is another fre-
quently encountered plasmid-mediated
1. INTRODUCTION β-lactamase among Gram-negative bac-
teria. Extended-spectrum β-lactamases
β-lactamases are bacterial enzymes (ESBLs) have been increasingly reported
that are encoded by chromosomal or by in Europe since their first description in
plasmid-mediated genes, and are the 1983 in Germany [7–8] During the 1990s,
enzymes that protect microorganisms they were described mainly as members
against the lethal effects of β-lactam anti- of the TEM- and SHV-β-lactamase fami-
biotics by hydrolyzing the β-lactam ring. lies in Klebsiella pneumoniae causing
The production of β-lactamases is the nosocomial outbreaks. Nowadays, they
most important resistant mechanism to are mostly found in Escherichia coli that
β-lactam antibiotics, especially for Gram- cause community-acquired infections and
negative bacteria. Based on their struc- with increasing frequency contain CTX-M
tures, β-lactamases can be classified into enzymes. The increase in most of the
two different groups, serine β-lactamases widespread ESBLs belonging to the
and Metallo-β-lactamases (Class B) [1]. TEM, SHV and CTX-M families across
Serine β-lactamases can then be classified the world has occurred in community and
Amino acid homology

Basic structure Class A
Serine �-lactamase
Class C
�-lactam bond
hydrolyzing enzyme
Class D Sequence homology
�-lactamase
Class B1
ClassB
Metallo-�-lactamase
Class B3 Class B2
(Class E)
Figure 1 Classification of β-lactamases based on molecular structure Bellingham Research Institute website (http://homepage
.mac.com/barryghall/BRIHome.html).
Rasmussen and Bush. Carbapenem-hydrolyzing beta-lactamases. Antimicrob. Agents Chemother. 41:223–232, 1997. Hall BG,
Salipante SJ, Barlow M. The metallo-beta-lactamases fall into two distinct phylogenetic groups. J Mol Evol. 2003;57:249–54.
103
nosocomial settings due to clonal spread. Bush. It should be considered that some
Multi-resistances, especially to fluoro- groups active in hydrolyzing cephamy-
quinolones, aminoglycosides and sulfam- cins and/or carbapenems, such as GES
ethoxazole/trimethoprime, seem to have type or KPC type, are not in the same
contributed to the problem. Moreover, the ESBL group in terms of method of treat-
emergence of epidemic clones harbour- ment and method of preventing nosoco-
ing several β-lactamases simultaneously mial infection.
(ESBLs, metallo-β-lactamases or Class C
β-lactamases) and of new plasmid-
mediated mechanisms of resistance to 3. DETECTION OF ESBLS IN CLINICAL
fluoroquinolones (qnr) and aminogly- BY CLSI [10]
cosides (ribosome methylase) warrants
future surveillance studies. The Clinical and Laboratory Standards
Institute (CLSI) recommends performing
an ESBL screening test and ESBL confir-
2. DEFINITION OF ESBL mation test as follows. Strains of Klebsiella
spp., E. coli, and P. mirabilis that produce
The first plasmid-mediated β-lactamase ESBLs may be clinically resistant to ther-
capable of hydrolyzing all cepha- apy with penicillins, cephalosporins, or
losporins, now known as SHV-2, was aztreonam, despite apparent in vitro sus-
reported in 1983 [7] and a number ceptibility to some of these agents. Some
of other groups of β-lactamases with of these strains will show MICs above
expanded hydrolytic activity were the normal susceptible population but
reported thereafter. The term ‘extended- below the standard breakpoints for cer-
spectrum β-lactamases (ESBLs)’ was tain extended-spectrum cephalosporins or
applied to denote these enzymes, which aztreonam; such strains may be screened
are plasmid-mediated Class A or Class for potential ESBL production by using
D β-lactamases, with activity against the screening breakpoints (the screening
penicillin, all cephalosporins including positive results of broth microdilution for
expanded-spectrum ones (3rd and 4th E. coli, K. pneumoniae, and K. oxytoca are
generation cephalosporin), and mono- MIC ≥ 8 µg/ml for cefpodoxime or MIC ≥ 2
bactams (aztereonam and carmonam). µg/ml cefotaxime, ceftazidime, ceftriaxone,
ESBLs basically cannot hydrolyze or aztreonam; and for P. mirabilis MIC ≥ 2
cephamycins (such as cefoxitin, cefmeta- µg/ml for cefpodoxime, ceftazidime, or cefo-
zole, moxalactam, etc.), penems (such taxime). The screening positive diameters
as faropenem, ritipenem), and carbap- of the disk diffusion test to screen ESBL
enems (such as imipenem, meropenem) also are defined, as is an initial screen test
except some groups with a super broad according to routine susceptibility results.
spectrum (such as GES type, KPC type). Other strains may test intermediate or
ESBLs are generally inhibited by clavu- resistant by standard breakpoints to one
lanic acid. Therefore, ESBLs include not or more of these agents. In all strains with
only TEM-, and SHV-variants but also ESBLs, the MICs for ceftazidime or cefo-
CTX-M derivatives. This definition is taxime should decrease in the presence of
practical enough to allow detection in the clavulanic acid (A ≥ 3 twofold concentra-
hospital laboratory by only phenotype. tion decrease in an MIC for either antimi-
Amino acid sequences of TEM, SHV, and crobial agent tested in combination with
CTX-M enzymes are listed on the Lahey clavulanic acid vs its MIC when tested
clinic website [9] which is dedicated to alone. The diameter of disk diffusion test:
the nomenclature of β-lactamases and A ≥ 5-mm increase in a zone diameter
is hosted by George Jacoby and Karen for either antimicrobial agent tested in
104
A B C D
CAZ CAZ
/CVA
CTX CTX
/CVA
E F G H
Figure 2 The results of ESBL confirmatory test according to CLSI. CAZ: ceftazidime 30µg, CVA: clavulanic acid 10µg, CTX:
cefotaxime 30µg A: Position of disk, B: ESBL non-producing E. coli, C: SHV-12 producing E. coli, D: TEM-6 producing E. coli,
E: ESBL non-producing K. pneumoniae, F: CTX-M-14 producing E. coli, G: CTX-M-2 producing K. pneumoniae, H: CTX-M-2
producing P. mirabilis.
combination with clavulanic acid vs its does AmpC β-lactamase resist inhibition
zone when tested alone) on a phenotypic by clavulanic acid but also clavulanic acid
confirmatory test (Figure 2). For all con- may act as a good inducer of the AmpC
firmed ESBL-producing strains, the test β-lactamases of these organisms.
interpretation should be reported as resist-
ant for all penicillins, cephalosporins, and
aztreonam. 4. ESBL PRODUCERS IN UROLOGY
Detection of ESBL producers pro-
vides clinicians with helpful information. It is well known that the prevalence
Treatment of infections caused by ESBL- of ESBL producing microorganisms in
producers with penicillins, all cepha- high-risk areas of the hospital, such as
losporins or monobactams may result in intensive care units, has increased dra-
treatment failure even when the causa- matically from 3.6% in 1990 to 21.8% in
tive organisms appear to be susceptible 1993, in U.S. hospitals [12–13]. However,
to these antimicrobial agents by routine greater concern has resulted from reports
susceptibility testing [11]. Regarding of the increasing frequency of ESBL-
patients colonized or infected with ESBL- producing organisms causing infections
producers, it is important to pay attention in outpatients. Yumuk et al [14] reported
and perform contact precautions to avoid that among the 3108 UTIs diagnosed,
hospital transmission. These benefits 82 (2.6%) were due to community E. coli
warrant the detection of ESBL-producing isolates and followed the strict inclusion
organisms in clinical laboratories. All criteria. Seventeen of them (21%) pro-
ESBL-detection methods by phenotype duced an ESBL, of which CTX-M-15 was
only utilize the characteristics of ESBLs: predominant (53%). These ESBL-positive
conferring a reduced susceptibility to isolates, distributed equally into three
expanded-spectrum cephalosporins and phylogenetic groups, displayed 13 PFGE
inhibition by clavulanic acid. Detection profiles and three clusters. A Turkish
of ESBL production by organisms with CTX-M-15-producing isolate as a mem-
inducible chromosomal and plasmid- ber of the clone ST131 was suggested
mediated AmpC β-lactamases is difficult by a high similarity of its PFGE profile
using these methods because not only to that of the clone representative and
105
was confirmed by O serotyping, AmpC showed a significantly better clinical

typing and MLST. Ena et al [15] has outcome than that with other antibiot-
reported that ESBL-producing E. coli ics in a prospective observational study
significantly increased from two (0.20%) involving 85 episodes of ESBL-producing
to 89 (5.52%) isolates per year (P value K. pneumoniae bacteremia in 12 hospitals
for trend = 0.000). ESBL-producing in seven countries [11]. As noted above,
E. coli showed a significant reduction treatment of infections due to ESBL pro-
in susceptibility to most antimicrobials ducing organisms with cephalosporins is
(gentamicin, quinolones, trimethoprim- not generally recommended irrespective
sulfamethoxazole), although carbapen- of the result of MIC. Cephamycins (e.g.,
ems and fosfomycin retained significant cefoxitin, cefmetazole, moxalactam, flo-
activity. Muratani et al [16] also reported moxef ) are stable to the hydrolytic activ-
that ESBL-producing E. coli isolates in ity of ESBLs. However, a decrease in the
Japan showed a significant reduction in expression of outer membrane protein
the susceptibility to gentamicin, levo- [18] and inducible or constitutive produc-
floxacin, tetracycline, and trimethoprim- tion of AmpC β-lactamase [19–20] leads
sulfamethoxazole. to resistance to cephamycins. β-Lactam/
β-lactamase inhibitor combinations (e.g.,
amoxicillin/clavulanate and piperacillin/
5. TREATMENT OF INFECTIONS tazobactam) often remain active against
CAUSED BY ESBL-PRODUCERS ESBL-producers, but coexistence of other
resistance mechanisms such as decrease
CLSI established breakpoints for vari- of outer membrane protein or AmpC
ous antibiotics soon after the clinical production may lead to the resistance
release of them. Correlations of MICs of to these drugs. Moreover, the inoculum
expanded spectrum cephems to clinical effect with piperacillin/tazobactam was
outcome were excellent; indeed, an MIC observed among ESBL producing isolates
of less than 8 µg/ml correlated with more [21–22]. Due to these reasons, although
than 92% clinical success for all relevant cephamycins and piperacillin/tazobactam
species [11]. But in treatment of infec- have potent activity to most ESBL pro-
tions caused by an ESBL producer, cepha- ducers, these antibiotics alone are not rec-
losporins have been associated with poor ommended as first-line therapy for serious
clinical outcome, even with lower MICs infections caused by ESBL producers.
than breakpoint. So CLSI recommends Howver, these antibiotics alone or with
that organisms revealed as having ESBL the other antibiotics such as aminoglyco-
should be reported as resistant for all pen- sides may be effective against moderate
icillins, cephalosporins and monobactams. infection caused by ESBL producers [23].
Non-β-lactam antibiotics, such as fluoro- The appropriate use of these antibiotics
quinolones, may be useful for the therapy is important in avoiding the over use of
for mild infections caused by susceptible carbapenems.
organisms [17]. However, ESBL-producing
isolates tend to show a high rate of resist-
ance to various non-β-lactam antibiotics 6. PLASMID-MEDIATED CLASS A
such as fluoroquinolones and aminoglyco- β-LACTAMASE CAPABLE OF
sides. Carbapenems (e.g., imipenem and CARBAPENEM HYDROLYZING
meropenem) are regarded as the drug ACTIVITY
of choice in treating serious infections
caused by ESBL-producers. Carbapenems Resistance to carbapenems in Entero-
are stable against hydrolytic activity of bacteriaceae can be caused by over-
ESBLs and treatment with carbapenems production of AmpC β-lactamases or
106
carbapenem hydrolyzing β-lactamases 7. CONCLUSIONS

associated with loss of outer mem-
brane porins and/or overexpression of Since the first description of plasmid-
efflux pumps [24]. Carbapenemases mediated ESBL in 1983, ESBL-producing
can be divided into the metallo- Gram-negative organisms have posed
β-lactamases and serine carbapene- a significant threat to hospitalized
mases. Carbapenem-hydrolyzing KPC patients due to their hydrolyzing activ-
β-lactamases are a group of recently ity against expanded-spectrum cepha-
identified carbapenemases which belong losporins, which are often employed in
to Bush group 2f, molecular class A. the treatment of hospital acquired infec-
KPCs are capable of hydrolyzing car- tions. In the past decade CTX-M-type
bapenems, penicillins, cephems, and ESBLs have become prevalent globally
aztreonam. The initial report on KPC-1 and their distribution involves not only
β-lactamase was from carbapenem- healthcare environments but also the
resistant Klebsiella pneumoniae isolates community. Community acquired infec-
in the USA in 2001 [25]. KPC-2, the iden- tions due to ESBL-producing organisms
tical correct sequence of KPC-1 [26], was pose a serious challenge to clinicians in
then found in isolates of K. pneumoniae, choosing appropriate empiric therapy.
Salmonella enterica, Klebsiella oxytoca, The incidence of such infections is cur-
Serratia marcescens, and an Enterobacter rently not so high, but we have to pay
sp. [27–31]. KPC-3 was found in K. pneu- attention to the trend. Furthermore, if
moniae and Enterobacter cloacae iso- multi-drug resistant Enterobacteriaceae
lates in the USA [32–33]. Recently, KPCs isolates with carbapenem hydrolyzing
were found in various countries such as activity such as KPC type β-lactamase
France [34], South America [35], Israel increase, they will pose a serious threat
[36], and China [37]. Furthermore, which will limit choice of antibiotic
KPC-2 was identified for the first time treatment.
in Pseudomonas aeruginosa isolates
[38], that is, non-Enterobacteriaceae.
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110
|2.6|
Antimicrobials in urogenital
infections
Florian M.E. Wagenlehner1*, Björn Wullt2, Gianpaolo Perletti3
1
Department of Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany
2
Department of Urology, Skåne University Hospital, Malmö, Sweden
3
Dipartimento di Biologia Strutturale e Funzionale, Laboratorio di Tossicologia e Farmacologia, Universita’ degli Studi
dell’Insubria –Busto Arsizio/Varese, Italy
Corresponding author: Priv.-Doz. Dr. med. Florian Martin Erich Wagenlehner, MD, PhD, Department of Urology, Pediatric
Urology and Andrology, Justus-Liebig-University of Giessen, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany,
Phone +49-641-99-44518, Fax +49-641-99-44509, E-mail Wagenlehner@AOL.com
ABSTRACT to be considered. Different antibiotic sub-

stances should be used for treatment, such
Urinary tract infections (UTI) and male as penicillins, with β-lactamase inhibitors,
genital infections are amongst the most cephalosporins or carbapenems, fluoroqui-
prevalent infections. A prudent antibiotic nolones, aminoglycosides or cotrimoxazole,
policy therefore has a large impact on the if tested susceptible. For genital infections
society. The clinical classification in uncom- the pharmacokinetic properties of the anti-
plicated cystitis, uncomplicated pyelone- biotics should especially be considered,
phritis, complicated UTI and genital such as in prostatitis, where mainly fluoro-
infections is useful, also for the right choice quinolones and macrolides show sufficient
of antibiotic treatment. In this regard pharmacokinetic parameters for treatment
pharmacokinetic and pharmacodynamic of bacterial infections. Furthermore in gen-
aspects have to be considered. Nowadays ital infections fastidious organisms, such
in uncomplicated cystitis antibiotics exclu-
as chlamydia or mycoplasma spp. have to
sively reserved for this indication are
be considered with respect to their antimi-
preferred, such as fosfomycin trometa-
crobial susceptibility.
mol, nitrofuratnoin and pivmecillinam,
in order to reduce antibiotic pressure in Key words: Urinary tract infection;
this extremely frequent entity. In compli- male genital infection; antibiotic treat-
cated UTI a broad bacterial spectrum has ment; antimicrobial substances
1. INTRODUCTION ARESC study showed that antibiotic sub-

stances classically used for the treatment
Urinary tract infections (UTIs) and geni- of uncomplicated UTIs, such as co-trimox-
tal bacterial infections are among the azole (TMP/SMX), fluoroquinolones or
most prevalent microbial diseases, and aminopenicillines, lose their effectiveness
their financial burden on society is sub- due to increasing resistance. Therefore,
stantial. A large part of antibacterial ideal substances are those with high sus-
treatment is therefore allotted to these ceptibility rates, exclusively used for this
conditions. The bacterial spectrum, anti- indication, such as fosfomycin trometh-
microbial resistance patterns and the amine, nitrofurantoin or pivmecillinam.
activity of the antibiotic at the site of
infection are critical for an effective anti-
2.1 Fosfomycin
microbial chemotherapy. When treating
pyelonephritis, different antibiotics have Fosfomycin tromethamine is the oral
to be chosen to those for uncomplicated applicable salt of fosfomycin, an oxirane
female UTI and for bacterial prostati- antibiotic unrelated to other substances
tis, because the kinetics of the antibiotic [8], produced as a secondary metabolite
in the various organs will be completely by Streptomyces and Pseudomonas spp.
different. In addition, the increasing Fosfomycin acts as an analogue of phos-
microbial resistance, especially in Gram- phoenolpyruvate and forms a covalent
negative uropathogens, require knowl- bond with the active site cysteine residue
edge about the ecological side effects or (Cys 115) of UDP-N-acetylglucosamine
“collateral damage” [1] exerted by the dif- enolpyruvyltransferase (MurA), which is a
ferent antimicrobial drugs. key enzyme of peptidoglycan synthesis [8].
It thus inhibits cell-wall synthesis with
a different mechanism than β-lactam
2. UNCOMPLICATED UTI antibiotics. Fosfomycin tromethamine
has approximately 40% oral bioavailabil-
In uncomplicated UTI E. coli is the most ity and is primarily excreted unchanged
common pathogen, typically being iso- in the urine (approximately 90%) [9].
lated from approximately 80% of outpa- The substance is active against Gram-
tients with acute uncomplicated cystitis positive and Gram-negative bacteria,
across the various regions of the world but shows decreased activity against
[2–5]. In clinical practice, urine culture M. morganii, P. vulgaris, P. aerugi-
is usually not performed in the setting of nosa and E. faecium. Despite many
community acquired, uncomplicated cysti- years of usage, fosfomycin continues to
tis. Antibiotic therapy is therefore mostly have a low incidence of E. coli resist-
empiric and more or less based upon ant strains (1% to 3%) worldwide [10].
knowledge of national or international Fosfomycin has retained its activity
surveillance studies. The local resist- against quinolone-resistant strains of
ance levels of E. coli therefore determine E. coli and cross-resistance with other
the empiric antibiotic treatment. The classes of antimicrobial agents is pres-
range of pathogens associated with acute ently not a problem [11]. It is less active
uncomplicated pyelonephritis is similar against coagulase-negative staphylococci.
to that seen in acute uncomplicated cysti- The effect on the intestinal flora after
tis [6]. The most recent surveillance study intake of a single 3g dose of Fosfomycin
in Europe investigating uncomplicated has not been well studied. However, due to
cystitis is the ARESC (Antimicrobial the limited exposition, the effect is proba-
Resistance Epidemiology Survey on bly minor. This statement is supported by
Cystitis) project [7]. The results of the the high rate of E. coli susceptibility also
112
Antimicrobials in urogenital infections | 2.6 |
in regions with frequent use of Fosfomycin hydrolyzed into the active drug after
in uncomplicated female UTI [12]. Longer absorption [21]. Mecillinam is an amidine
peroral treatment (5 g twice daily for five derivative of the penicillin group. The
days) affects the intestinal flora signifi- mechanism of action differs slightly from
cantly, mainly with a reduction of entero- other β-lactams, because the drug inter-
bacteriaceae [13]. acts with the penicillin-binding protein 2
[22]. With a bioavailability of 60–75% it
is well absorbed orally; 45% of the drug
2.2 Nitrofurantoin
is excreted in the urine [21]. Mecillinam
Nitrofurantoin (NF) belongs to the class has high activity against Gram-negative
of nitroheterocyclic compounds. The nitro- organisms such as E. coli and other
group coupled onto the heterocyclic furan enterobacteriaceae. The level of resistance
ring represents the specific active site of has remained low, as approximately less
the drug and has to be activated by micro- than 2% of E. coli community isolates are
bial nitroreductases to interfere with resistant to mecillinam [23]. The in vitro
protein and DNA synthesis, energy metab- MIC for S. saprophyticus is 8–64 mg/L, so
olism, cell wall and carbohydrate synthe- these bacteria are considered resistant.
sis [14]. Nitrofurantoin interferes with The favorable situation regarding
the carbohydrate metabolism. The bio- E. coli susceptibility is also observed in
availability is about 90% and the urinary the Scandinavian countries, in which
excretion is 40% [15]. Activity against pivmecillinam is one of the most fre-
E. coli is excellent. In a recent study, the quently used drugs in female uncompli-
susceptibility for E. coli was 99.5%. High cated UTI. This is thought to be due to the
susceptibility of E. coli clinical isolates minor effect of Pivmecillinam on the nor-
to nitrofurantoine (2.3% resistance rate), mal flora [23], however a moderate reduc-
compared to TMP/SMX (29%) or cipro- tion of gram- negative enterobacteriaceae
floxacin (24.2%) was recently confirmed in the intestinal flora is observed [24].
[16]. However, nitrofurantoin is less sus-
ceptible against Gram-negative patho-
gens other than E. coli, such as Klebsiella 3. COMPLICATED UTI AND MALE
spp. (69.2%) or Enterobacter spp. (63%). GENITAL, BACTERIAL INFECTIONS
There is no activity against Proteus spp.
or P. aeruginosa [17]. Nitrofurantoin is Gram-negative species account for approx-
mainly used in preventing recurrent UTI imately 60 to 80% of the bacterial spec-
in children and women [18]. Potential trum of complicated and nosocomially
severe side effects with nitrofurantoin acquired UTI, and comprise E. coli, fol-
were reported, such as lung- and hepa- lowed by Klebsiella spp., Pseudomonas
totoxicity, especially in long-term usage spp., Proteus spp., Enterobacter spp. and
[19]. Due to the effective gastro-intestinal Citrobacter spp. Gram-positive pathogens
absorption of nitrofurantoin the effect on account for about 20 to 40% of the spec-
the intestinal flora is minimal [20]. trum and comprise enterococci and sta-
phylococci [25–30]. Male genital bacterial
infections can be caused by the same bac-
2.3 Pivmecillinam
terial spectrum as complicated UTI or by
Pivmecillinam is a β-lactam antimicro- sexually transmitted bacterial pathogens,
bial that has been used for the treatment such as N. gonorrhoeae, C. trachomatis or
of acute uncomplicated urinary infections Mycoplasmata.
for more than 20 years. Pivmecillinam For treatment of urogenital infections
is the pro-drug (ester) of mecillinam and a suitable pharmacokinetic/pharmaco-
shows no antibacterial activity until dynamic profile, i.e. high concentration
113
and activity in the urogenital tract, is The aminopenicillins ampicillin and

important. A wide array of different anti- amoxicillin are active against E. coli and
microbial agents is available. In order to P. mirabilis, but almost inactive against
decrease the antimicrobial pressure the other enterobacteria and totally inac-
full spectrum of agents available for these tive against Pseudomonas spp. However,
indications should be used. Enterocccus faecalis is susceptible. The
aminopenicillins are not stable against
the β-lactamases frequently found in
3.1 β-lactam-antibiotics
S. aureus and in many enterobacteria.
β-lactam antibiotics are chemically charac- Combination with a β-lactamase-inhibitor
terized by the presence of the β-lactam-ring such as clavulanic acid or sulbactam
in the molecule, i.e. by a cyclic amide form- enhances the anti-Gram-negative activ-
ing a four-atom ring. All β-lactam antibiot- ity to a certain extent, but not against
ics inhibit the bacterial cell wall synthesis bacteria producing AmpC β-lactamases,
by irreversible inhibition of the penicillin such as Enterobacter spp. or Citrobacter
binding proteins known as transpepti- spp. [32]. N. gonorrhoeae nowadays
dases. The β-lactam group includes three exhibits high levels of resistance against
important families of antibiotics, which penicillin [33]. The effect of ampicillin
differ in the moiety fused to the β-lactam and amoxicillin (including the amoxicil-
ring. The penicillins harbour a five-atom lin combination with clavulanic acid)
ring, a thiazolidine, the cephalosporins on the gastro-intestinal flora has been
have a six-atom ring, a dihydrothiazine, well characterized; in summary suppres-
and the carbapenems harbour a five-atom sion of Gram-positive aerobic cocci and
ring, in which the sulphur atom in position an increase of resistant Gram-negative
1 of the structure has been replaced with a enterobacteriaceae is demonstrated [34].
carbon atom [31]. The acylamino (ureido)-penicillins,
such as piperacillin, own stronger polar
groups on the amino-group. However,
3.1.1 Penicillins
this compound is not stable against the
Penicillins are classified mainly according β-lactamases of S. aureus and some
to the different chemical structures of the strains of Enterobacter spp. and Serratia
substituents at position 6 of the β-lactam spp. Combination of piperacillin with
molecule. the β-lactamase inhibitor tazobactam
The first penicillin introduced in clini- can counteract the activity of some of
cal practice was penicillin G. After intra- the β-lactamases increasingly produced
venous injection 95% of the substance is by Gram-negative bacteria. Piperacillin/
eliminated by renal excretion. Penicillins tazobactam also exhibits activity against
are primarily active against Gram-positive E. faecalis, but not against E. faecium.
pathogens, if no resistance mechanisms Urinary excretion of both piperacillin
have been acquired [31]. and tazobactam is approximately 70%.
The aminopenicillins ampicillin and Piperacillin exhibits activity against
amoxicillin feature an amino group, Pseudomonas spp. and P. vulgaris and
which confers stability against amidase, is therefore frequently used for empiric
an enzyme produced by some Gram- treatment of complicated nosocomial
negative bacteria that hydrolyzes the UTIs [35].
penicillin side chain, and stability against
gastric acid. Oral absorption of ampicillin
3.1.2 Cephalosporins
is approximately 50%, whereas amoxicil-
lin is absorbed by 90%. Urinary excre- The cephalosporins are classified according
tion of both antibiotics is about 70%. to their primary route of administration
114
(parenteral vs. oral), and in groups accord- spp. and P. aeruginosa. Cefotiam is more
ing to their antibacterial spectrum. For active against E. coli, Klebsiella spp. and
structure-activity relationships, com- P. mirabilis than cefuroxime.
parable characteristics can be seen as Group 3a cephalosporins, such as cefo-
with penicillins. Substitutions at the side taxime and ceftriaxone, and the orally
chain mainly influence activity, whereas active substances cefpodoxime-proxetil
modifications in position 3 of the nucleus and ceftibuten, exhibit a further increased
influence mainly pharmacokinetic and activity against Gram-negative organ-
metabolic properties of these drugs. The isms, because the side chain protects the
various groups of cephalosporins differ molecule from cephalosporinases by steric
from one another in the spectrum of activ- hindrance [41]. Cefotaxime is metabolized
ity and in potency against Gram-negative in about 30% to desacetyl-cefotaxime,
bacteria [36]. All cephalosporins are not which shows inferior antimicrobiologi-
active against enterococci. Novel cepha- cal activitiy [42]. Ceftriaxone undergoes
losporins are designed to treat multidrug- a partial biliary excretion of about 45%
resistant pathogens including MRSA, [43]. The bioavailability of cefpodoxime-
where current cephalosporins are not proxetil is about 40% [44], while the bio-
effective. availability of ceftibuten is about 90%
The first group cephalosporin, [45]. The renal excretion rates are about
cephalexin, harbours the phenylglycine 80%, 55%, 90% and 90% for cefotaxime,
side chain that is also encountered in ceftriaxone, cefpodoxime and ceftibuten,
the aminopenicillins. Cephalexin is pri- respectively [42–47]. Group 3 cepha-
marily active against staphylococci, but losporins are approximately ten times
less active against many Gram-negative more active against enterobacteria than
bacteria, because it is hydrolyzed by group 2 compounds. Group 3a cepha-
their β-lactamases. The bioavailability of losporins are currently recommended as
cephalexin is about 90%, and the renal empiric treatment of gonorrhoeae by the
excretion is about 90% as well [37]. First Centers for Disease Control of America
group cephalosporins should however (CDC), because of the high resistance lev-
not be used for the treatment of UTI, but els of other antibiotics [33].
only for prophylaxis, because of the over- Group 3b comprises the intravenously
all lower activities compared with second administered cephalosporin ceftazidime.
group cephalosporins. The propylcarboxy moiety at the side
Second group cephalosporins, such as chain is responsible for increased affinity
cefuroxime and cefotiam, show increased to penicillin-binding-proteins of Gram-
β-lactamase stability. This is mainly due negative bacilli and for high stability
to the oxime-group in cefuroxime and the to β-lactamases. The pyridine group is
thiazole-amino group in cefotiam. After responsible for rapid intrabacterial pen-
intravenous injection the renal excre- etration and favourable pharmacokinetic
tion is 90% in cefuroxime [38] and 70% in properties. Ceftazidime undergoes no rel-
cefotiam [39]. In contrast to cefuroxime, evant metabolism and the unchanged uri-
the prodrug cefuroxime axetil is absorbed nary excretion averages 90%. Compared
with a total bioavailability of 40% after to cefotaxime, ceftazidime exhibits
rapid hydrolysis to the active parent a 10-fold increased activity against
compound, cefuroxime [40]. Against sus- P. aeruginosa [48].
ceptible Gram-negative bacteria, second Group 4 cephalosporins comprise the
group cephalosporins are four to eight intravenously administered cefepime. It
times more potent than first group com- contains a thiazole-amino group and an
pounds. There is no activity against oxime group at position 7 and a quater-
P. vulgaris, Morganella spp., Serratia nary ammonium substituent at position 3.
115
The quaternary nitrogen imparts organisms. This stability against serine-

β-lactamase stability and improves both β-lactamases is due to the trans-1-hy-
the cell penetration and the pharmacoki- droxyethyl substituent and its unique
netic properties. The urinary excretion of juxtaposition to the β-lactam carbonyl
the unchanged drug accounts for about group [53]. The stability encompasses
85%. Cefepime shows excellent activity extended spectrum-β-lactamases and
against P. aeruginosa and good stability AmpC β-lactamases, but not to metallo-
against β-lactamases [49]. β-lactamases. The available carbapen-
Ceftobiprole is a novel β-lactam. Upon ems are currently classified by different
infusion, the prodrug ceftobiprole medo- criteria. The classification by groups can
caril is converted rapidly and almost com- follow the bacterial spectrum as in other
pletely by type A esterases to the active antibiotic classes [54].
drug, ceftobiprole. The predominant Ertapenem is the sole representative
mechanism responsible for elimination is of the first group. It contains a 1β-methyl
glomerular filtration (90%). Ceftobiprole substituent which reduces hydrolysis
exhibits a high activity against methi- of the β-lactam ring by the renal dihy-
cillin-resistant Staphylococcus aureus dropeptidase I. It further contains a meta-
(MRSA) in addition to broad-spectrum substituted benzoic acid substituent,
bactericidal activity against other Gram- which increases the molecular weight and
positive and Gram-negative pathogens lipophilicity of the substance, and a carbox-
[50]. Until now, Ceftobiprole has not been ylic acid moiety resulting in a net negative
investigated in urinary tract infections, charge. This results in a high protein bind-
but seems to be promising for empiric ing, which leads to a longer serum half-life
treatment of UTI due to the coverage [53]. Urinary excretion is 80%. Ertapenem
extended to MRSA and P. aeruginosa. exhibits a broad-spectrum activity against
The cephalosporine impact on the Gram-negative and Gram-positive patho-
gastro-intestinal flora is significant and gens, with only limited activity against
has been well studied [34]. The gen- non-fermenting Gram-negative bacteria.
eral pattern is a marked reduction of It is also not active against P. aeruginosa,
enterobacteriaceae, an increase of aero- MRSA and enterococci [53–54].
bic gram-positive cocci and commonly Imipenem and meropenem are the
an overgrowth of Cl. difficile. The recent representatives of the second group.
emergence of multiresistant E. coli Imipenem is hydrolysed by the renal
strains have become a major concern, dihydropeptidase I and is therefore
which threatens to disarm effective anti- combined with the specific inhibitor cil-
biotic therapy to common infections such astatin. Meropenem contains a 1β-methyl-
as UTI [51]. Importantly, cephalasporines substituent and is therefore stable against
have been suggested to be one of the driv- the renal dihydropeptidase I. Urinary
ing agents in the selection of multidrug excretion of imipenem (if combined with
resistant E. coli [1]. cilastatin) and meropenem is 70%. They
feature an additional broad-spectrum
activity against non-fermenting Gram-
3.1.3 Carbapenems negative bacteria. They are active against
Most carbapenems are available only many Gram-positive and Gram-negative
intravenously up to now, because they uropathogens excluding MRSA, E. fae-
are unstable, especially in gastric juice, cium and vancomycin-resistant entero-
but also in more alkaline intestinal pH cocci (VRE). Compared with imipenem,
conditions [52]. Carbapenems main- meropenem is somewhat more active
tain antibacterial efficacy against the against P. aeruginosa, but less active
vast majority of β-lactamase-producing against Gram-positive uropathogens [55].
116
Doripenem is a new parenteral car- this group is related to the number and
bapenem and offers slightly more activ- location of amino groups in the hexose
ity than meropenem against selected moiety linked to the deoxystreptamine
pathogens including some strains of as follows in decreasing order: 2´,6´-
P. aeruginosa not susceptible to imipenem diamino > 6´-amino > 2´-amino > no
or meropenem. Doripenem is also active amino group. The activity is enhanced if
against Gram-positive pathogens except the same primed sugar is not hydroxy-
MRSA, E. faecium and VRE. Urinary lated, thus gentamicins are generally
excretion is 75% [56]. more potent than kanamycins [57]. In
The faecal elimination of carbapen- parallel the more active substances how-
ems is very small and consequently the ever are better substrates for inactivating
intestinal flora is only slightly changed, nucleotidyltransferases. Because of the
mainly with decreased numbers of entero- aminocyclitol ring the aminoglycosides
bacteriaceae, increase in gram-positive are weak bases and have a high degree of
cocci, and a decrease in anaerobes [34]. solubility in water and poor solubility in
lipids. They are therefore poorly absorbed
and distributed in the tissues and must
3.2 Aminoglycosides
be actively transported across bacterial
Aminoglycosides are multifunctional cell membranes. Aminoglycosides are
hydrophilic sugars that possess sev- almost exclusively excreted in the urine
eral amino and hydroxy functionalities. by glomerular filtration, but approxi-
Aminoglycosides act primarily by alter- mately 5% of the administered doses
ing bacterial protein synthesis through are retained in the epithelial cells lining
binding to the 16S ribosomal RNA within the S1 and S2 segments of the proximal
procaryotic ribosomes [57]. There is no tubules [59]. Aminoglycosides thus are
generally agreed clinical classification ion-trapped in the lysosomes of the tubu-
of aminoglycosides. Therefore classifica- lar cells, which eventually causes them to
tion mainly follows the different chemi- rupture above a certain cut-off concentra-
cal structures. Aminoglycoside antibiotics tion. The highly concentrated aminogly-
can be divided according to the nature coside together with lysosomal enzymes,
of the core aminocyclitol ring into strep- are then released into the cytosol and
tidine, bluensidine, 2-deoxystreptamine eventually lead to cell damage. Single
and actinamine antibiotics. Clinically the short-term infusion shows significantly
2-deoxystreptamine-containing aminogly- lower renal drug levels than continuous
cosides are most important, which are infusion of the same dose [60]. This accu-
subdivided into the 4,6-disubstituted, and mulation in renal tubular cells renders
the 4,5-disubstituted deoxystreptamines aminoglycosides suitable for treatment of
[57–59]. The 4,6-disubstituted deoxys- pyelonephritis.
treptamine group comprises the agents Ototoxicity has always hampered the
kanamycin, gentamicin, tobramy- extensive use of aminoglycosides in anti-
cin, netilmicin and amikacin. The 4,5- bacterial chemotherapy. The extent of
disubstituted deoxystreptamine group inner ear toxicity can vary, ranging from
comprises agents such as neomycin, mild high-frequency impairment to pro-
which are the more potent antibiotics, found hearing loss, to vestibular dis-
but show a high degree of nephrotoxicity turbances. Vestibular toxicity is more
and ototoxicity, which almost exclusively frequently observed upon administration
prevents their systemic use [58–59]. of gentamicin and streptomycin, whereas
For treatment of UTI therefore only kanamicin, and amikacin are prevalently
the 4,6-disubstituted deoxystreptamine cochleotoxic. Damage caused by reac-
group is indicated. Antibiotic activity in tive oxygen species is believed to be a
117
common feature of inner ear hair cell tox- Fluoroquinolones form ternary com-
icity evoked by aminoglycosides [61]. In plexes between DNA and the bacterial
genetically predisposed individuals, car- topoisomerases II and IV, which play a
rying the A1555G and other mutations critical role in the organisation of the bac-
targeting the mitochondrial 12S ribos- terial DNA. Quinolones exert their toxic-
omal RNA, profound sensorineural deaf- ity on the bacterial cell by stabilizing the
ness occurs almost in all cases because double-stranded break in DNA created
aminoglycosides disrupt mitochondria by by gyrase so that relegation becomes
affecting translation in a fashion resem- unfavourable and consequently apopto-
bling their bactericidal activity [62]. sis of the bacterial cell is induced [65].
Spectinomycin is a structural relative of The structure-property relationships of
the aminoglycosides containing the ami- the different substituents corresponding
nocyclitol actinamine. It also binds the to the pharmacophore show the follow-
16SrRNA, albeit in a different location ing aspects [65]: Elements that enhance
from aminoglycosides. Unlike aminogly- activity and reduce resistance selec-
cosides, spectinomycin does not induce tion include a cyclopropyl at position 1,
codon misreading, nor is it bactericidal; a methoxy at position 8, a pyrrolidine
its indication is mainly the treatment of or substituted piperazine at position 7,
N. gonorrhoeae and U. urealyticum infec- and a fluorine substituent at position 6
tions. Urinary recovery after 2 g i.m. injec- [65]. Moieties or elements that enhance
tion is higher than 80%. the volume of distribution are a cyclopro-
Since aminoglycosides are adminis- pyl at position 1, and those that enhance
trated systemically and are completely half-life and central nervous system
excreted by glomerular filtration, the effect penetration are a bulky side chain at
on the intestinal flora is insignificant. position 7 [65]. Fluoroquinolones work
mainly in a concentration dependent
manner and exert a marked post-antibi-
3.3 Fluoroqinolones
otic effect. The antibacterial activity in
Fluoroquinolones can be classified accord- urine however is reduced, because fluor-
ing to antibacterial spectrum and activ- oqinolones form antibacterially inactive/
ity and the main indications into four less active complexes with divalent cati-
groups [63]. The first group comprises ons [66].
agents such as norfloxacin, with indica- Most fluoroquinolones show excellent
tions essentially limited to UTI. The sec- bioavailability (60–100%) and a high vol-
ond group encompasses agents such as ume of distribution. Penetration into the
ofloxacin and ciprofloxacin, with broad prostate tissue is better than any other
indications for systemic use and pre- antibiotic substance, with the excep-
dominant Gram-negative activity. The tion of macrolides. The serum levels are
third group comprises agents such as usually low [65]. All gyrase inhibitors
levofloxacin, with good Gram-negative undergo tubular secretion as either acids
activity and in addition improved activity or bases. Reabsorption then affects tubu-
against Gram-positive and atypical path- lar concentrations. The N4’-methylated
ogens. The fourth group comprises agents derivatives are the most lipophilic, and
with good Gram-negative activity and in addition or removal of the methyl group
addition further improved activity against can, but does not always, affect reab-
Gram-positive and atypical and anaero- sorption [67]. The urinary excretion of
bic bacteria, such as moxifloxacin and fluoroquinolones however, differs widely
gatifloxacin. However, gatifloxacin has between substances. A high urinary
been removed from the market because of excretion (≥ 75%) can be observed with
severe dysglycemia in some patients [64]. levofloxacin (84%), lomefloxacin (75%)
118
and ofloxacin (81%). An intermediate suppression of enterobacteriaceae, includ-

excretion rate (40–74%) is seen with cip- ing emergence of resistant strains. The
rofloxacin (43%), enoxacin (53%), fler- colonization of aerobic Gram-positive cocci
oxacin (67%), and a low excretion rate is less influenced [34]. Fluoroquinolones
(< 40%) is seen with moxifloxacin (20%) are considered to be driving agents in the
and norfloxacin (20%) [68]. Whereas selection of multidrug resistant entero-
most of the drugs with high or interme- bacteriaceae [1].
diate excretion achieved the clinical indi-
cation for the treatment of UTI, of the
3.4 Trimethoprim, Cotrimoxazole
drugs with low excretion only the older
substance norfloxacin achieved this indi- Cotrimoxazole is the combination of tri-
cation, possibly because of the lack of methoprim (TMP) and sulfamethoxa-
comparator substances these days. zole (SMX) in the ratio of 1 to 5. Both
Fluoroquinolones also play an impor- substances inhibit different steps in the
tant role in the treatment of bacterial folic acid biosynthetic pathway. SMX is
prostatitis. This is mainly because of a structural analogue of p-aminobenzoic
their favourable pharmacokinetic proper- acid, the basic building block used by
ties within the prostate fluid. bacteria to synthesize dihydrofolic acid,
Drug penetration into prostatic fluid the first step in the reaction leading to
is considered to consist mainly of pas- folic acid. SMX competitively inhibits
sive diffusion [69–70]. Amongst the drug this step. TMP competitively prevents
characteristics that determine simple dif- the conversion of dihydrofolic acid to tet-
fusion are concentration gradient, lipid rahydrofolic acid, the metabolically active
solubility, degree of ionization, degree of cofactor for synthesis of purines [73].
protein binding, and the size of the mol- Of all sulfonamides, SMX was paired
ecule. The highest concentrations in pros- with TMP because of similar absorptive
tatic secretion are seen with moxifloxacin, and pharmacodynamic properties. Each
followed by gatifloxacin, lomefloxacin, drug is well absorbed. Approximately
enoxacin, ofloxacin, levofloxacin, fler- 85% of total SMX is recovered in the
oxacin, ciprofloxacin, norfloxacin [71]. urine, 30% as free drug and the rest as
Fluoroquinolones have been excessively acetylated metabolite. In contrast, most
used for the treatment of N. gonorrhoeae of TMP is not metabolized and is excreted
and C. trachomatis induced genital infec- unchanged in the urine [73]. For more
tions. In many countries, resistance of N. than 30 years TMP/SMX has been used
gonorrhoeae to fluoroquinolones currently for the treatment of UTIs. Many aerobic
approaches levels to an extent where Gram-positive and Gram-negative bac-
empiric usage for treatment seems not teria are inhibited or killed including E.
to be advisory any more [33]. Minimal coli, Proteus mirabilis, Klebsiella spp.
inhibitory concentrations (MIC) of anti- and Enterobacter spp. There is no effect
biotic substances against C. trachomatis on Pseudomonas spp. In different sur-
are generally difficult to assess. In one veillance studies in Europe and North-
attempt using an RT-PCR method, MIC America, investigating resistance in
ranges of moxifloxacin were 0.015 to 0.25 uncomplicated UTI, the resistance rates
mg/L, and were remarkably lower than of the involved uropathogens approached
those of ofloxacin 0.25 to 8 mg/L and cip- or exceeded 20% [74–77]. In complicated
rofloxacin 0.5 to 8 mg/L [72]. UTIs TMP/SMX should only be used
Fluoroquinolones reach high concen- in accordance with sensitivity testing
trations in the gastro-intestinal tract because of the high resistance rates.
and have a significant impact on the TMP/SMX has been used as first line
gastro-intestinal flora. There is a strong agent in the treatment of chronic bacterial
119
prostatitis in the past, until the fluoroqui- agents that inhibit bacterial protein syn-
nolones emerged. Concentrations of TMP/ thesis through a unique mechanism. In
SMX in prostatic fluid in patients with contrast to other inhibitors of protein syn-
chronic bacterial prostatitis were meas- thesis, linezolid acts early in translation
ured and achieved approximately one third by preventing the formation of a func-
of plasma concentrations [78]. The secre- tional initiation complex [84]. Linezolid
tory dysfunction of the prostate accompa- is rapidly absorbed after oral dosing with
nying bacterial prostatitis results in an an absolute bioavailability of about 100%.
increased alkalinity of solute-poor secre- Serum half life is about 5.5 hours, and pro-
tions and adversely affects the accumula- tein binding approximately 31% [85–86].
tion of trimethoprim in the prostatic fluid Approximately 35% is excreted in urine as
[79]. Clinical cure of patients with chronic the parent drug and 50% as the two major
bacterial prostatitis treated with TMP/ metabolites. Linezolid is active exclusively
SMX has been seen in only approximately against Gram-positive uropathogens, such
40% of patients [80]. TMP/SMX has a role as enterococci and methicillin susceptible-
in the treatment of chronic bacterial pros- and resistant staphylococci. Linezolid can
tatitis only in fluoroquinolone-resistant be used for the treatment of UTI caused
isolates. Prolonged treatment over three by multi-resistant Gram-positive bacteria
months is then recommended [81]. like MRSA or vancomycin resistant ente-
TMP/SMX has a significant impact on rococci (VRE). However, both MRSA and
the intestinal flora with a strong suppres- VRE isolates resistant to Linezolid have
sion of enterobacteriaceae. The aerobic been reported [87].
Gram-positive flora is not affected [20]. Linezolid can induce mitochondrial
toxicity, manifesting as perihperal/optic
neuropathy and lactic acidosis, the latter
3.5 Glycopeptides
being hypothesized to occur in carriers
The glycopeptides (vancomycin, teico- of specific mutations in the mitochon-
planin) inhibit the synthesis of cell walls drial DNA [88]. Linezolide adverse effect
in susceptible microbes by inhibiting pep- appear to be evoked when extended
tidoglycan synthesis. Vancomycin and courses of antimicrobial therapy are pre-
teicoplanin are related but Teicoplanin scribed [89].
is more lipophilic. Both substances are Linezolid administered perorally
administered intravenously. Teicoplanin decreases the numbers of aerobe and
has a longer half life also due to increased anaerobe gram positive cocci in the intes-
plasma protein binding, compared to van- tinal flora, but enterobacteriaceae are un-
comycin, as well as a better tissue pen- affected [90].
etration. The urinary excretion of both
substances is 90%. They are active exclu-
3.7 Daptomycin
sively against Gram-positive uropatho-
gens, such as enterococci and methicillin Daptomycin is a semisynthetic lipopeptide
susceptible and resistant staphylococci antibiotic with a high specificity for Gram-
[82]. Ototoxicity and nephrotoxicity have positive bacteria [91–92]. Daptomycin
been observed upon administration of apparently acts via the dissipation of the
glycopeptides, with teicoplanin less likely bacterial membrane potential and has
to be associated with adverse events [83]. a rapid concentration-dependent bacte-
ricidal activity [92]. Daptomycin exhib-
its bactericidal activity against a broad
3.6 Linezolid
range of Gram-positive pathogens, includ-
Linezolid is a member of the oxazolidinone ing organisms resistant to methicillin,
class, comprising synthetic antibacterial vancomycin or other currently available
120
agents. Daptomycin is administered intra- and pharmacodynamic properties. Tetra-

venously, serum half-life averaged 8.5 cyclines inhibit cell growth by inhibiting
hours, protein binding is approximately the translation process via interaction
90%, urinary excretion is 80%, 66% as with the bacterial 30S ribosomal subu-
active drug. Clinically relevant toxicities nit. Group 1 consists of older agents with
are limited to skeletal muscle effects and reduced GI absorption and less lipophilic-
at higher dose levels, peripheral nerve ity, such as tetracycline.
effects. One study evaluated daptomycin Group 2 substances are almost com-
versus ciprofloxacin in 68 patients with pletely absorbed and are more lipophilic
complicated UTI, concluding equivalent than group 1 substances [95]. Doxycycline
efficacy in a patient cohort with predomi- belongs to group 2 and is the best
nantly Gram-positive pathogens [93]. absorbed tetracycline upon oral adminis-
tration (95%). About 35–60% of the drug
is excreted in urine and the remainder
3.8 Macrolides
in faeces [95]. Doxycycline exhibits good
Macrolides are antibiotics containing activity against most Gram-positive bac-
aliphatic lactones and are divided in two teria, variable activity against Gram-
classes: antibacterial macrolides and anti- negative pathogens and no activity
fungal macrolides (polyene macrolides). The against P. aeruginosa and Proteus spp.
antibacterial macrolides have generally low Tetracycline is also effective against C.
urinary recovery rates, clarithromycin 20%, trachomatis. MIC ranges by a RT-PCR
roxithromycin 7%, azithromycin 5% and method were 0.03 to 1 mg/L [72].
erythromycin 5%, and are therefore not Group 3 is composed of the glycylcy-
indicated for the treatment of UTI. Because clines. There is currently one compound
of their efficient distribution into urethral in clinical use named tigecycline. After
cells, macrolides are useful for treatment of intravenous injection the renal elimi-
non-specific urethritis by very susceptible nation accounts for 33%, while 59% are
C. trachomatis and U. urealyticum. excreted with the faeces [95]. The bacte-
Whereas N. gonorrhoeae shows increas- rial spectrum of tigecycline shows good
ing acquired resistance to macrolides, activity against Gram-positive pathogens
M. hominis displays intrinsic resistance including MRSA and VRE, and against
to these drugs. Thus, macrolides are fre- E. coli, Klebsiella spp., Enterobacter spp.
quently used for the treatment of genital and C. freundii, including ESBL produc-
infections caused by C. trachomatis and ing organisms. Tigecycline is less active
U. urealyticum. against P. aeruginosa, Proteus spp.,
In a recent report, highlighting the M. morganii and S. marcescens because
results of a meeting on prostatitis and of efflux-mechanisms [95]. There are no
chronic pelvic pain, macrolides have data of all three classes on the treatment
been recommended as second-line agents of UTI.
for the treatment of chronic prostatitis,
due to the excellent penetration of these
drugs in the prostate gland, the activity 4. FURTHER RESEARCH
against Chlamydia, and the penetration
in- and the inhibitory activity against Antimicrobial treatment will remain
bacterial biofilms [94]. one of the main cornerstones of therapy
in urinary and male genital infections.
Therefore it is of paramount importance
3.9 Tetracyclines
to preserve efficacy of antimicrobial sub-
The tetracyclines can be divided into three stances. Several concepts may be followed
groups based on their pharmacokinetic to perceive such a goal. Besides infection
121
control, implementation strategies for 4. Kahlmeter G, An international survey

prudent antibiotic use are most manda- of the antimicrobial susceptibility of
tory. Novel mechanisms of antibacte- pathogens from uncomplicated urinary
rial actions are of course most welcome. tract infections: the ECO.SENS Project.
However other novel strategies, such as J Antimicrob Chemother, 2003. 51(1):
69–76.
site directed substances, lacking major
collateral damage, or phage enzymes in 5. Warren JW, Abrutyn E, Hebel JR,
Johnson JR, Schaeffer AJ, and Stamm
various ways should be exploited further.
WE, Guidelines for antimicrobial treat-
ment of uncomplicated acute bacterial cys-
titis and acute pyelonephritis in women.
5. CONCLUSIONS Infectious Diseases Society of America
(IDSA). Clin Infect Dis, 1999. 29(4):
The developmental process of new anti- 745–58.
microbial substances has markedly 6. Talan DA, Stamm WE, Hooton TM,
slowed down because of a variety of rea- Moran GJ, Burke T, Iravani A, Reuning-
sons. On the other hand, antimicrobial Scherer J, and Church DA, Comparison of
resistance is continuously increasing in ciprofloxacin (7 days) and trimethoprim-
uncomplicated as well as complicated sulfamethoxazole (14 days) for acute
UTI and genital infections. Therefore the uncomplicated pyelonephritis pyelonephri-
management of infectious diseases must tis in women: a randomized trial. Jama,
2000. 283(12): 1583–90.
be highly responsible. The action of cur-
rently available antimicrobial substances 7. Naber KG, Schito, G.C., Botto, H., Palou,
J., Mazzei, T., Surveillance study in
and their structure-property relationships
Europe and Brazil on clinical aspects
have to be understood for the prudent
and antimicrobial resistance epidemiol-
use of antibiotics. Pharmacokinetic and ogy in females with cystitis (ARESC):
pharmacodynamic parameters need to be Implications for empiric therapy.
taken in greater consideration to improve European Urology, 2008. in press.
dosing strategies. Models that are able to 8. McLuskey K, Cameron S,
predict efficacy in patients and the degree Hammerschmidt F, and Hunter WN,
of emergence of resistance are needed in Structure and reactivity of hydroxypropyl-
that respect. phosphonic acid epoxidase in fosfomycin
biosynthesis by a cation- and flavin-de-
pendent mechanism. Proc Natl Acad Sci U
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126
|2.7|
Antibiotic policy
Inge C. Gyssens1,2,3
1
Nijmegen Institute for Infection, Inflammation, and Immunity (N4i) and Department of Medicine, Radboud University
Nijmegen Medical Centre and
2
Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
3
Hasselt University, Diepenbeek, Belgium
Tel secr +31 24 3657514, Fax +32 11 309488, Email i.gyssens@aig.umcn.nl
ABSTRACT The purpose of this chapter is to provide

the evidence base of prudent antibiotic
There is a clear association between policy. Special emphasis is placed on uri-
antibiotic use and resistance both on nary tract infections. The value and sup-
individual and population levels. In the port of antibiotic committees, guidelines,
European Union, countries with large ID consultants and/or antimicrobial stew-
antibiotic consumption have higher ardship teams to prolong the efficacy of
resistance rates. Antibiotic resistance available antibiotics will be discussed.
leads to failed treatments, prolonged hos- Key words: Antibiotic policy, antimicro-
pitalizations, increased costs and deaths. bial stewardship, antimicrobial resistance,
With few new antibiotics in the Research guidelines, pharmacokinetics, pharmaco-
& Development pipeline, prudent anti- dynamics, urinary tract infections
biotic use is the only option to delay the
development of resistance.
Antibiotic policy consists of prescrib- SUMMARY OF RECOMMENDATIONS
ing strategies to optimize the indication,
selection, dosing, route of administration, Indication – therapy
duration and timing of antibiotic therapy
to maximize clinical cure or prevention of 1. Asymptomatic bacteriuria with and
infection while limiting the unintended without the presence of urinary cath-
consequences of antibiotic use, including eters should not be treated except
toxicity and selection of resistant micro- in special circumstances (e.g. preg-
organisms. A secondary goal is to reduce nancy) (GoR A).
healthcare costs without adversely affect- 2. Perform timely imaging to document
ing the quality of care. focus, extent of the infection,
obstruction and presence of abscesses resistance patterns and local pathol-

(GoR A). ogy (GoR B).
3. Prompt removal of the focus of 11. The local antibiotic guide should
infection, relieving obstruction, cite empirical regimens with a
and drainage of abscesses improve spectrum that is broad enough to
the efficacy of antibiotic treatment cover the most frequently encoun-
(GoR A). tered pathogens for UTIs in specific
patient groups, in the community
Indication – prophylaxis and hospital respectively (GoR A).
12. If local fluoroquinolone resistance of
4. Use evidence based alternatives
E. coli exceeds 15%, fluoroquinolo-
for antibiotics where available
nes should not be used for empirical
(cranberry – estrogen topical creams)
therapy of UTIs (GoR B).
(GoR B).
13. Consider prior use of antibiotics
5. The benefit of antibiotics should be
(within three to six months prior to
balanced against side effects such as
presentation) when selecting an anti-
allergy, resistance and costs (GoR A).
biotic for empiric therapy (GoR B).
The number to treat to avoid a par-
ticular complication is useful for the
Pathogen-directed therapy
decision (GoR B).
6. In the absence of evidence, refrain 14. De-escalate or streamline to a nar-
from surgical antibiotic prophylaxis rower spectrum, less toxic, oral –
(GoR B). this strategy invariably results in
cost containment (GoR A).
Collecting the microbiological 15. A switch to oral agents with high
samples bioavailability can be made after 48h
of clinical improvement and when
7. Because urologists most often treat the identity and susceptibility of the
complicated UTIs, it is of para- causative micro-organism are known
mount importance to obtain urine (GoR A).
for culture before starting an empiric
antibiotic regimen (GoR A). 16. In patients with severe renal failure,
aminoglycosides are probably best
8. The determination of a causative avoided in long term therapy (GoR A).
organism and susceptibility is a
prerequisite for targeted therapy, Dosing regimens
including streamlining and the
switch to effective oral antibiotic 17. Antibiotics should be administered
therapy (GoR A). according to pharmacokinetic/phar-
macodynamic principles (GoR A).
Selection of antimicrobial agents 18. Low doses can not only lead to treat-
Empirical therapy ment failure, but also to increased
9. Build a local hospital or regional selection of resistance (GoR B).
formulary (list) of antibiotics to
Timing
treat UTI, according to local suscep-
tibility patterns (GoR A). 19. Starting with intravenous antimi-
10. The formulary should contain one crobial therapy within one hour in
drug of each major class, previously patients with severe (uro)sepsis is
determined on the basis of local recommended (GoR A).
128
Antibiotic policy | 2.7 |
20. Timely start of antibiotics for same countries. Thus, big consumers have
patients with UTI is < 4 hours after higher resistance rates. Another major
admission (GoR A). factor that drives resistance is the spread
21. The optimal administration of iv first of resistant bacteria among individuals in
or second generation cephalosporins healthcare institutions by poor infection
for surgical prophylaxis is within 30 control practices. A significant proportion
min before incision (GoR B). of heathcare-associated infections (HCAI)
is caused by multiresistant bacteria such
as methicillin-resistant Staphylococcus
Antimicrobial stewardship aureus (MRSA) and Clostridium dif-
ficile. The health burden associated
22. The societies for urology should par-
with HCAI is considerable and there is
ticipate in national UTI guideline
increased awareness of the fact that the
development and urology depart-
use of antimicrobials in hospitals is a key
ments should participate in the
determinant of HCAI rates due to these
update of their hospital antibiotic
hospital-acquired pathogens. Numerous
guide (GoR B).
reports in the literature [1–3] provide
23. Urology ward-specific surveillance evidence that the frequency of infections
data and inpatient versus outpatient caused by multidrug-resistant bacteria
data should be available to the anti- is escalating in many countries. Several
biotic committee to select appropri- highly resistant gram-negative pathogens
ate antibiotics for UTI treatment such as Acinetobacter species, multidrug-
guidelines in urological patients resistant (MDR) Pseudomonas aeruginosa,
(GoR B). carbapenem-resistant Klebsiella species
24. One urologist should have the man- and Escherichia coli are emerging as sig-
date on behalf of his department to nificant pathogens in hospitals. Acquired
support the implementation (GoR B). resistance to three or more classes of anti-
25. Implementation of guidelines: use biotics is commonly reported for some
quality indicators for UTI (GoR B). Gram-negative bacterial species [2, 4].
Antibiotic resistance leads to failed
26. Good communication with the micro- treatments, prolonged hospitalizations,
biologist will facilitate pathogen - increased costs and deaths. Mortality
directed therapy (GoR B). has since long been known to be higher
27. Infectious diseases specialist consul- in patients with bacteraemia treated
tations can optimize the antibiotic with inappropriate antibiotics (i.e. when
management of individual complex the micro-organism is not susceptible).
cases (GoR B). Increasingly, limited access to effec-
tive antibiotics is contributing to high
mortality from these resistant bacterial
1. INTRODUCTION infections. ESBL producing E. coli and
Klebsiella spp. causing bloodstream infec-
There is a clear association between tions are associated with severe adverse
antibiotic use and resistance both on outcomes, including higher overall and
individual and population levels. The infection-related mortality, length of hos-
surveillance project EARSS has shown pital stay, delay in appropriate therapy
considerable differences in resistance and higher costs [5] (LoE 3).
of key uropathogens (E. coli) between For approximately 40 years the phar-
European countries (Figure 1). In paral- maceutical industry has provided a steady
lel, the ESAC project has shown remark- flow of new antibiotics, including several
able differences of antibiotic use in the with new mechanisms of action that were
129
Figure 1 Proportion of invasive isolates with resistance to fluoroquinolones in 2007.
effective against bacteria that became on the characteristics of a patient and a

resistant to earlier antibiotics. However, drug, but also on the characteristics of
over the last decade several companies the microorganisms causing an infection
have abandoned antibacterial research and the colonising flora. The complex
due partly to scientific challenges of dis- interrelationship between man, micro-
covery, but also alleged lack of incentives. organisms and antimicrobial drugs is
Recently, companies have directed their best depicted in the pyramid of infectious
research to multidrug-resistant Gram- diseases (Figure 2).
positive bacteria; three systemically- The pyramid shows multiple interac-
administered antibiotics, including only tions between the patient, the drug, the
two from new classes, have been marketed. pathogen(s) and colonising microflora.
However, for Gram-negative bacteria, only Activity of the antimicrobial drug is coun-
a few antibiotics are in late stage devel- teracted by the development of resistance
opment. Already back in 2004, a WHO by the pathogen, but also by exposed col-
report identified antimicrobial resistance onising flora. Resistance to antibiotics,
as a public health problem with “a phar- either by mutation or after acquisition of
maceutical gap” , i.e. where existing treat- foreign genetic information, will continue
ments or preventive measures were likely to pose problems. Ideally, maximal efficacy
to become ineffective in the future [6]. should be combined with minimal toxicity
To understand the association of anti- at the lowest cost. As is illustrated in the
biotic use with resistance, one should pyramid (Figure 2), appropriate therapy
realise that antibiotic therapy is differ- is dependent on knowledge of many dif-
ent from other forms of pharmacotherapy. ferent aspects of infectious diseases. Host
Antimicrobial therapy is not only based factors, virulence of micro-organisms,
130
The pyramid of infectious diseases
Therapy
ity
Ac
xic
tiv
To
ity
Activity
ics
Re
et
sis
in
ok
ta
ac
nc
m
e
ar
Ph
Resistance
Host Commensals
n
res Host atio
ista l o niz nce
nce Co sista
Vir tion re
ule
nce niza
C olo
Pathogens
Figure 2 The pyramid of infectious diseases.
Table 1 Reasons for misuse of antibiotics.

By providers of health care
• Lack of education in infectious diseases
• Uncertainty about the diagnosis
• Lack of good microbiology laboratory support
• L ack of update of syndromic management of infectious diseases
• Belief that patients expect antibiotics
• Compensation for failing technique (prophylaxis)
By the public
• Insufficient knowledge (of viral vs bacterial infection)
• Former experience of beneficial effect of antibiotics
• Belief that some conditions require antibiotic treatment
• Pressure to return to work
• Fear
pharmacokinetics and dynamics of drugs dissemination of resistance is closely

have to be considered. linked to the magnitude of the selective
Avoiding overuse is an issue that will antimicrobial pressure, a major strategy is
need increasing attention. Overuse of to delay this dissemination. Unnecessary
antibiotics has many causes (Table 1). use of antibiotics as well as irrational use
Antimicrobial drugs have a unique including inadequate dosing and long
feature. Invariably, their use leads to duration are equally important for selec-
antimicrobial resistance, which in turn tion. Therefore, prudent prescribing poli-
leads to loss of their future value. As the cies to preserve the available antibiotics
131
are mandatory. Antibiotic policy (recently a US hospital [9] (LoE 2b). On the other
renamed antimicrobial stewardship), hand, the marketing strategies of antimi-
includes optimizing the indication, selec- crobial drug developers are pushing sales
tion, dosing, route of administration, and because profit and return to sharehold-
duration of antimicrobial therapy to maxi- ers are directly linked to volume sales of
mize clinical cure or prevention of infec- their products. This system has created
tion while limiting the collateral damage of a paradoxical situation, both for policy
antimicrobial use, including toxicity, selec- makers and drug developers [10].
tion of pathogenic organisms (such as C. In this chapter the evidence base of pru-
difficile), and emergence of resistance [7]. dent antibiotic policy is reviewed. A
Good microbiology laboratory facilities are number of publications provide a thor-
cornerstones of prudent antibiotic policies. ough understanding of the benefits of
Laboratoriesí multiple tasks consist of sur- antimicrobial stewardship [7, 11] (LoE 4).
veillance of resistance, determination of the A frequently observed effect of antibiotic
causative agent and its susceptibility pat- policy programs is a reduction of health-
tern in individual patients and monitoring care costs without adversely affecting the
of potentially toxic drug concentrations. quality of care [12–13] (LoE 2b). Recently,
Antibiotic resistance is reversible to antimicrobial stewardship, together with
some extent. In general, the reversal of infection control, has been identified as a
resistance after removal of selection pres- patient safety issue [14], and some suc-
sure is slower than its increase due to the cesses have been obtained by strategies
same antibiotic pressure. These observa- which are described in this chapter.
tions emphasize the urgency of applying
the principles of prudent antibiotic use in
hospitals. Recent successes of antibiotic 2. METHODS
policies in concert with infection control
to reduce resistance have been reported 2.1 Definitions
in European countries e.g. the reduc- Useful definitions on the field of antibi-
tion of MRSA in high consuming France otic policy are listed in table 2.
[8] (LoE 3), and control of C. difficile in
Table 2 Definitions for understanding prudent policy strategies.

Prophylaxis is used to prevent an infection. When an infection is already present, the antimicrobial drugs are administered
for therapy.
Antibiotic policy, antimicrobial stewardship [11]
Activities to optimize antimicrobial use among patients to
- improve patient outcomes
- ensure cost-effective therapy, and
- reduce adverse sequelae of antimicrobial use (including antimicrobial resistance).
Antibiotic committee
Consists of clinicians, ID physicians, medical microbiologists, hospital epidemiologists, hospital pharmacists.
Formulary
List of drugs. Facilitates restriction policies and stock management by the pharmacy.
Clinical practice (antibiotic) guidelines for infectious diseases
A systematic review of the literature and graded conclusions followed by recommendations based on the conclusions.
Antibiotic guide:
Treatment advice based on the recommendations of the guidelines.
132
2.2 Literature search C-reactive protein, or procalcitonin. A

A systematic literature search was per- recent prospective study in 202 patients
formed in Medline for the period 1978– with pyelonephritis showed a prognostic
2009 with the following key words: value of CRP levels concerning length
“Anti-Bacterial Agents” [Mesh] AND of stay, duration of therapy and the
(“Urinary Tract Infections/drug therapy” risk of relapse [17] (LoE 3). However,
[Mesh] OR “Urinary Tract Infections/pre- even when the cause of low grade fever
vention and control” [Mesh] OR “Urinary is infection, one should ask if it wise to
Tract Infections/therapy” [Mesh]) NOT treat it with antimicrobial drugs. A first
(“tuberculosis” [MeSH Terms] OR principle to avoid overuse is not admin-
“Anthelmintics” [Mesh] OR “Case Reports istering antibiotics in situations when
“[Publication Type]) and the follow- they will not work or when there are
ing limitations: Humans, Clinical Trial, alternatives. In terms of efficacy, many
Letter, Meta-Analysis, Practice Guideline, of our indications for antimicrobial use
Randomized Controlled Trial, English, need re-evaluation. Even when a small
Core clinical journals. benefit from antimicrobial use is sug-
Seventy-nine articles were found and gested, this should always be weighed
screened by title and abstract and 32 against the disadvantages of adverse
were finally included into the review sup- effects, resistance and costs.
plemented by key publications known to Pregnant women are one of the few
the author. patient groups for which it is indicated to
The studies were rated according treat asymptomatic bacteriuria [18] (LoE
to the level of evidence (LoE) and the 1); there is no indication to treat asymp-
grade†of recommendation (GoR) using tomatic bacteriuria in children, diabetics
ICUD standards (for details see Preface) or patients with indwelling catheters [19]
[15–16] (LoE 1). Also, four randomised controlled
trials in nursing homes showed no benefit
from treating asymptomatic bacteriuria
in institutionalised elderly people [20–23]
3. EVIDENCE BASED PRINCIPLES OF (LoE 1).
PRUDENT ANTIBIOTIC PRESCRIBING If the chance to cure the infection with
antimicrobial drugs alone is small, such
3.1 Is there an indication? Are as when an infection is complicated by a
antibiotics necessary? perirenal abscess or in the presence of a
foreign body (stents), a surgical or radio-
3.1.1 Antibiotic therapy for UTI logical intervention to drain the focus or
When considering antimicrobial therapy to remove the device should be consid-
in a patient with fever whom we suspect ered without delay. Even when antibiot-
of having a urinary tract infection (UTI), ics are administered, removal of foreign
one should first answer the following bodies will enhance the effect. Patients
questions: with a long-term indwelling catheter may
First, is the fever caused by the UTI? carry also enterococci, yeasts and staphy-
If so, clinical and laboratory data are lococci, in addition to Enterobacteriaceae,
needed to determine the severity of the such as Serratia, Providencia and
infection, the potential site of infection Acinetobacter. If the indwelling catheter
within the urinary tract, and eventu- is changed at the time of treatment of a
ally a suspected causal microorganism. symptomatic UTI, a higher percentage
Apart from clinical parameters, valu- of patients will exhibit disappearance of
able laboratory parameters are quickly the bacteriuria and a more rapid recov-
available such as leukocyte count, ery from the symptoms [24] (LoE 2a).
133
3.1.2 Surgical prophylaxis evidence is based on only two studies

When antibiotics are considered to pre- comparing vaginal oestrogens to placebo
vent an infection, the concept of number [30] (LoE 1).
of patients to treat to avoid a specific
infection as patient outcome is a useful 3.2 Starting empirical therapy and
measure to weigh the potential advan- prophylaxis timely
tages of antimicrobial drugs [25]. The Timely administration (<4 hours) in
number to treat is calculated from base- patients with UTI is associated with a
line risk and odds ratio of the unfavoura- shorter length of stay [31] (LoE 3).
ble outcome, e.g. a surgical site infection. The recommended period to administer
For example, in the Scottish prophylaxis antibiotics with a relatively short half-
guideline SIGN, antibiotic prophylaxis is life, such as cephazolin, is determined
recommended for transrectal biopsies of at within 1h, from the evidence provided
the prostate and is highly recommended by correlation studies and interventions.
for patients undergoing transrectal resec- [32–35] (LoE 2a). Recently, the optimal
tion of the prostate (TURP) [26]. To avoid period for non-urological procedures has
bacteriuria after transrectal biopsies the been defined at 30 min [13, 35] (LoE 2b).
number of patients to treat (NTT) is 27.
Antibiotic prophylaxis also significantly
3.3 Collecting microbiological
reduces bacteriuria in patients undergo-
samples timely
ing transrectal resection of the prostate
(TURP), but in addition reduces urosep- Good communication with the microbiology
sis from 4.4 to 0.7% [27] (LoE 1), and laboratory for the entire diagnostic process
the NTT is only 8 [26]. The difference from request of the test to interpretation
in NTT explains why the recommenda- and application of the results is a major
tion to use prophylaxis before TURP is determinant of quality of prescribing [36]
stronger. (LoE 3). Upon suspicion of a complicated
UTI, before the start of empiric therapy,
3.1.3 Prevention of recurrent UTI urine must be collected for culture; the
identification of the microorganism will
Continuous antibiotic prophylaxis for direct the selection of an appropriate defin-
six to 12 months reduced the rate of UTI itive therapy [19, 37] (LoE 3).
during prophylaxis when compared to However, waiting time for the urine
placebo. However, side effects are vagi- sample should not exceed a few hours
nal and oral candidiasis and gastrointes- as early administration is shown to be
tinal symptoms [28] (LoE 1). However, beneficial for the outcome (see 2 a). In
there are a few alternatives to antibi- case of an UTI with systemic symptoms
otics to prevent recurrent infection in (fever, but also chills and low tempera-
women. This would help to reduce selec- ture) two sets of blood cultures must be
tion pressure and allows for the use of performed. Two sets allow for the differ-
narrower agents in case of unavoidable entiation between true bacteremia and
prophylaxis failures. There is some evi- contamination.
dence that cranberry juice may decrease
the number of symptomatic UTIs over a
12 month period, particularly for women
3.4 SELECTING THE ANTIBIOTICS
with recurrent UTIs [29] (LoE 1). Its
effectiveness for other groups (children,
older women) is less certain. For post- 3.4.1 Empirical therapy
menopausal women, vaginal oestrogens If antimicrobial drugs are necessary, one
have proved to be effective, although the should determine the choice of the drug
134
and the dosage regimen. Three possible resistance data of invasive E. coli isolates
situations arise: are available for 30 European countries.
Figure 3 shows the increasing fluoroqui-
– The clinical picture is uniformly nolone resistance rates for E. coli [40].
caused by one microorganism, and Compared to general wards and the
the susceptibility in the area is pre- community, resistance is uniformly higher
dictable, e.g. scarlet fever caused by in urology departments. The Netherlandsí
penicillin-susceptible Streptococcus NethMap also provides national suscepti-
pyogenes. This situation does not occur bility data for E. coli from urology depart-
in urological infections. ments (mostly outpatients) [39].
– The clinical picture is associated with More than 15% of E. coli isolated from
a typical microorganism, but the patients in urology departments are now
susceptibility is not predictable, e.g. resistant to fluoroquinolones, and in other
urethritis (Ècoulement) caused by hospital departments resistance to these
Neisseria gonorrhoeae, posing on-going agents has reached the 5–10% range.
problems for individual case manage- In view of this high degree of resist-
ment and disease control [38]. ance among patients admitted to urol-
– The clinical picture can be caused by ogy departments, fluoroquinolones are
different microorganisms, and the sus- not considered as appropriate empirical
ceptibility is not predictable: all com- antimicrobial therapy in the Netherlands
plicated UTIs. anymore.
In severely ill or hospitalized patients,
Resistance is variable in time, accord- the Gram stain of urine samples can help
ing to geographical region and patient to fine tune the broadness of empirical
populations. For some infections encoun- therapy (Gram-negative bacteria versus
tered in the community, e.g. uncom- enterococci) in an early stage. Whether
plicated UTI in women, local/regional/ the infection is community-acquired or
national resistance surveillance data of nosocomial and whether the patient has
the most likely causing pathogens (E. been exposed to previous antimicrobial
coli, K. pneumonae) isolated from unse- therapy should also be taken into account
lected urine samples allow recommenda- when selecting an agent for empirical
tion of first line antibiotics in treatment therapy.
guidelines without the need for perform- A profile of the optimal antimicrobial
ing cultures for the individual patient. drug is described in Table 3.
An example is the Dutch practitionerís Blind empirical therapy often consists
UTI guidelines, in which the selection of of high-dose, broad spectrum drugs or a
antibiotics is based on the annual sur- combination of drugs. A rational choice
veillance report (available on www.swab. of antibiotic can only be expected if the
nl) from the national resistance surveil- prescriber is aware of the most likely
lance system conducted by the Working infective agent, and as explained above,
Party on Antibiotic Policy (SWAB) in the of the prevailing susceptibility patterns.
Netherlands [39]. Ongoing surveillance of antibiotic resist-
In complicated UTI, surveillance data ance must be performed in every institu-
of resistance rates from invasive iso- tion [41] (LoE 4). Regularly updated (six
lates or pathogens isolated from relevant months) local hospital surveillance data
patient groups (e.g. urology wards) should should be available to provide rational
be used to guide the formulation of recom- regimens in the local hospital antibi-
mendations for the selection of empirical otic guide. The national guidelines pro-
antibiotics: the so-called Well informed vide a framework for these policies [42]
bacteriological guess. Epidemiological (LoE 4).
135
Figure 3 Trends of fluroquinolone resistance by country, 2001–2007. www.rivm.nl/earss
136
Table 3 The ideal antibiotic for therapy or prophylaxis.
• Is highly active against the (suspected) causative organism

• Reaches effective concentrations at the site of infection
• Has a long half-life
• Has very little toxicity
• Does not induce allergy
• Has no interactions with other drugs
• Does not select for emergence of resistant microorganisms in the patient or the environment
• Can be administered by the desired route
• Is not expensive
Prior antimicrobial use is strongly kept their susceptibility to older, narrow

associated with resistance. Multivariate spectrum drugs e.g. Group B haemolytic
analysis demonstrated that isolation of streptococci to penicillin, these infections
imipenem-resistant P. aeruginosa was can and should still be treated with that
strongly associated with antibiotic (fluo- narrow spectrum drug.
roquinolone) use, and the strength of the In Northern Europe, this ìtailoringî to
association varied with the duration of narrow spectrum therapy has been con-
exposure [43] (LoE 3). One study on the sequently taught for many years in medi-
association between antibiotic resistance cal schools and this strategy has resulted
and prescribing showed that trimetho- in prudent prescribing [45] (LoE 4). In
prim resistance in bacteria isolated from Denmark, which has one of the lowest
urine samples was significantly associ- incidences of antibiotic resistance, nar-
ated with prior trimethoprim use. The row spectrum drugs are most frequently
association was strongest for patients prescribed [46] (LoE 3).
recently exposed to trimethoprim (within Prioritization of tested antimicrobials
eight to 15 days prior to the date of the and selective reporting of susceptibility
urine sampling), but lasted up to six profiles (e.g. not routinely reporting sus-
months before the date of urine culture. ceptibility of a microorganism to broad
There was no association between tri- spectrum antibiotics can prevent inad-
methoprim resistance and exposure more vertent overuse of these drugs and sup-
than six months earlier [44] (LoE 3). port the prudent use of antimicrobials
and direct appropriate therapy based on
3.5 Streamlining empirical therapy local guidelines) [7] (LoE 4).
Replacing an empirically chosen agent
by a more narrow-spectrum agent that 3.6 Determining the right dose and
is active against the isolated pathogen route
is a traditional strategy of infectious dis- In this paragraph, the impact of pharma-
eases consultants, called “streamlining”. cokinetics and pharmacodynamics on the
Rationale for this strategy is avoidance of optimal selection of dosing schedules is
selection pressure by blindly chosen broad explained.
spectrum agents. Until recently, it was
not prospectively studied. Intensive care
physicians discovered the strategy and 3.6.1 Activity of the antibiotic
termed it “de-escalation”. For example, One of the major characteristics of anti-
when pathogens are cultured that have biotics that determine the time course
137
of their activity is whether their kill- have shown that the most elegant strat-
ing of bacteria is dependent on the drug egy is to administer a initial large dose (6
concentration or on the duration of expo- or 7mg/kg) to all patients, and to adjust
sure [47]. subsequent doses (or intervals) with indi-
The concentration-time curve of a vidual pharmacokinetic monitoring as
drug possesses two major characteristics: soon as possible [49] (LoE 3). A once-daily
the peak concentration (Cmax) and the dosing regimen of 7 mg/kg gentamicin
area under the concentration-time curve produced Cmax/MIC ratios > 10 in criti-
(AUC). Both pharmacokinetic parameters cally ill patients [50] (LoE 2b). For fluo-
can be related to the minimum inhibi- roquinolones, some authors suggest that
tory concentration (MIC) of a microor- the best PK/PD index associated with effi-
ganism by determining the ratio between cacy is the Cmax/MIC ratio, which should
the two to obtain pharmacokinetic/phar- be > 10, while others suggest the AUC/
macodynamic (PK/PD) indices. Thus MIC ratio is the best index, which should
the AUC/MIC and Cmax/MIC ratios are be > 30–40 for gram positive and 100–125
obtained [48]. for gram negative bacteria [51] (LoE 4).
It is essential to understand the most The second activity pattern is char-
important PK/PD principles in order to acterised by time-dependent killing and
justify their recommended dosage regi- minimal-moderate persistent effect.
mens. A large number of in vitro and ani- Higher drug concentrations are not asso-
mal studies have been conducted allowing ciated with higher killing rates and opti-
the determination of PK/PD properties of malisation of efficacy is reached through
the major antibiotic classes. extending the duration of exposure.
Three activity patterns have been β-lactams (penicillins, cephalosporins)
described and are important to con- are characterised by time-dependent kill-
sider when defining the optimal ing. For these drugs, the time serum
dosage of antibacterial agents in levels remain above the MIC (T>MIC) is
patients with infections. the PK/PD index correlating with treat-
The first activity pattern is charac- ment efficacy. It has been demonstrated
terised by concentration-dependent kill- that concentrations of approximately
ing in which the [Cmax]/(MIC) and /or four times the MIC exert the maximum
the (AUC)/MIC ratios are the best PK/ effect and that higher concentrations
PD indices correlating with efficacy. The are not associated with increased bacte-
dosing of antibacterial agents exhibiting ricidal activity [52]. In immunocompro-
this activity pattern is optimised via the mised patients and for difficult to reach
administration of large (once daily) doses. infection sites (prostate, abscesses), it is
Several antibiotic classes display this agreed that multiples of MICs are needed.
pattern of activity, e.g. aminoglycosides T>MIC should be long, from 40 to 70% of
and fluoroquinolones. Pharmacokinetic the interval time between doses [47] (LoE
properties of ‘once a day’ aminoglycoside 4). As T>MIC is the most important PK/
regimens are superior to ‘multiple doses PD index correlating with the efficacy of
a day’ regimens in that they achieve β-lactam antibiotics, continuous infusion
higher peak levels while avoiding toxic of these agents is an attractive theoretical
trough levels. However, the definition of concept. Several animal studies showed
concentration-dependent has a maximum improved efficacy of continuous infusion
and there is a level beyond which increas- over intermittent infusion, especially in
ing a drugís concentration relative to the neutropenic animals [52]. A meta-analy-
MIC does not improve bacterial killing. sis of RCTs comparing continuous versus
For aminoglycosides, this level appears to intermittent infusion of different anti-
be at a peak/MIC ratio of 10–12. Studies biotic classes in patients with various
138
infections showed a trend towards lower has also been used to describe fluoroqui-
clinical failure, favouring continuous nolone drug exposures associated with
infusion, but the differences were not either increased or decreased risk of
statistically significant [53] (LoE 1). The resistance emergence. Apart from ensur-
difference was significant in a subset of ing increased efficacy, high peak concen-
RCTs using the same total daily dose in trations, greater than eight to 10 times
both arms. No differences in mortality the MIC are expected to decrease the
were found. Larger, well designed trials emergence of resistant strains. In addi-
are needed to further evaluate the ben- tion, insufficient Cmax/MIC ratios (ie,
efits of continuous infusion of β-lactam <10) have been associated with fluoroqui-
agents [51–53]. Prolonged infusion rates nolone resistance [55–58].
are probably a more feasible alternative
in non ICU wards. 3.6.2 Route
The third activity pattern is character-
ised by time-dependent killing and pro- The parenteral route of administration
longed persistent effects. Although higher should be used for empirical therapy in
concentrations are not associated with severely ill patients, in patients with gas-
more efficient killing, higher concentra- trointestinal dysfunction and for drugs
tions do produce prolonged suppression with poor oral bio-availability. However,
of growth of the micro-organism. The in practice, cultural factors seem to influ-
AUC/MIC ratio is the index most closely ence the choice of route of administra-
related to drug efficacy. Azithromycin, tion. Although the site and the severity of
tetracyclines and clindamycin, and the infection in European acute general hos-
glycylcyclines (such as tigecycline) exhibit pitals were probably comparable, 60% of
this pattern of activity. in-patients were treated with oral antibi-
Reviews of PK/PD have recommended otics in the UK, while in Italy over 80%
the AUC/MIC as the pharmacodynamic were injected with over half being intra-
parameter that best correlates with a muscular injections [59] (LoE 3).
successful outcome associated with the
use of vancomycin based in part on data 3.6.3 Step down to oral
from animal models, in vitro studies, and Attaining sufficiently high serum and
limited human studies [47, 54]. There are tissue concentrations is the main cri-
very few human studies evaluating the terion for using antimicrobial agents
pharmacodynamics of vancomycin, and orally. When limited to oral drugs with
the findings of most of those studies have excellent bio-availability, i.e. good gas-
not been conclusive in determining which tro-intestinal absorption with minimal
parameter is most valuable in predicting absorption-related drug interactions and
patient outcome. The majority of stud- well-documented interactions with food,
ies have involved relatively small patient sequential therapy is optimal.
populations and patients with a variety of
infection types.
However, for most drug/pathogen com- 3.6.4 Toxicity
binations, much less is known on which For drugs with a narrow therapeutic
PK/PD index correlates with develop- index e.g. aminoglycosides, dose adap-
ment of resistance. Traditionally, PK/ tation in the presence of renal failure
PD parameters have been used to pre- is mandatory. Pharmacokinetic param-
dict antibiotic efficacy, but there is now eters are also important in relation to
increasing interest in trying to use PK/ toxicity. The toxicity of antimicrobial
PD parameters to minimize develop- drugs varies considerably. Most anti-
ment of resistance. The AUC/MIC ratio microbial agents are eliminated by the
139
kidney. The therapeutic/toxic index is There are some studies and Cochrane
much larger for β-lactams, which are rel- reviews on the duration of treatment of
atively nontoxic for humans, compared acute pyelonephritis, lower UTI in chil-
to aminoglycosides, which are toxic to dren, uncomplicated UTIs in elderly
kidneys and the inner ear. Monitoring of women, cystitis and bacteriuria in preg-
the serum concentrations of aminoglyco- nant women. A retrospective study of the
sides is extensively used in clinical prac- duration of treatment of pyelonephritis
tice. Moreover, experiments in rats have showed that, independently of the drug
shown that the incidence of aminoglyco- administered, there is a strong risk of
side-induced nephrotoxicity is reduced by treatment failure whenever the treat-
once-daily dosing [60]. Thus, high peaks ment lasts less than 10 days [64] (LoE
of aminoglycosides, e.g. gentamicin, are 3). According to the guidelines of the
associated with optimal efficacy and low Infectious Diseases Society of America
troughs are associated with minimal (IDSA) a total duration of treatment for
toxicity. Therefore, aminoglycosides are an acute pyelonephritis of 10–14 days
administered in a once daily dosing regi- should be adequate. For women with this
men. In patients with severe renal fail- disease seven to 14 days should be suf-
ure, aminoglycosides are probably best ficient [65]. When ciprofloxacin is pre-
avoided in long term definitive therapy. scribed, a course of seven days for women
A randomised, double blind study showed with pyelonephritis was sufficient [66]
that once-daily dosing had a lower prob- (LoE 1), but when β-lactam antibiot-
ability of causing nephrotoxicity in ics are prescribed treatment for seven
patients with a normal baseline renal days would be too short [65]. Antibiotic
function [61] (LoE 1). Fear of toxicity can therapy for three days is similar to pro-
lead to under-dosing of aminoglycosides longed therapy in achieving symptomatic
[62] (LoE 2b). cure for cystitis, while the prolonged
treatment is more effective in obtaining
3.7 Limiting the duration of bacteriological cure [67] (LoE 1). Short-
antibiotic exposure to the course treatment (three to six days) could
essential be sufficient for treating uncomplicated
UTIs in elderly women, although more
3.7.1 Therapy and duration studies on specific commonly prescribed
There is a lack of evidence-based infor- antibiotics are needed according to a
mation on the appropriate duration of recent Cochrane review. Conclusions are
treatment for most infectious diseases. hampered by inconsistent study design
Even the duration of treatment for com- [68] (LoE 1). Another meta-analysis of 10
mon infections is often based on tradition. randomized controlled trials showed that
There are also cultural differences. In a a two to four day course of oral antibiot-
1991 European survey, mean duration of ics is as effective as seven to 14 days in
treatment was shortest in the UK (eight eradicating lower tract UTI in children
days) and longest in France (12 days) [69] (LoE 1). In pregnant women, a dou-
[59]. For some infections, studies have ble-blind, randomized, placebo controlled
addressed the question whether it is safe non-inferiority trial on duration treat-
to stop treatment after specific infection ment of bacteriuria showed that a one
parameters are returned to normal val- day regimen of nitrofurantoin is signifi-
ues. For example, in spontaneous bacte- cantly less effective than a seven day reg-
rial peritonitis antimicrobials can safely imen [70] (LoE 1).
be terminated once ascitic fluid PMN It is clear from these studies that, as
counts are less than or equal to 250 cells/ for many other types of infections, the
mm3 [63]. optimal duration for UTIs is defined by
140
the absence of relapse after an arbitrar- to increase transparency (for the health
ily chosen number of days e.g. seven, 10, care worker and the public). As urology
14, of treatment. Often, the minimum services generally have higher levels of
duration required is not known. To fur- antimicrobial resistance against Gram-
ther reduce volume of consumption, and negative bacteria (E. coli, K. pneumo-
therefore selection pressure, more studies niae, P. aeruginosa) compared to general
on shorter treatments are needed. wards, urology ward-specific surveillance
data and inpatient versus outpatient data
3.7.2 Prophylaxis and duration should be available to the antibiotic com-
In surgical prophylaxis, many stud- mittee to select appropriate antibiotics
ies have shown that a single dose of an for UTI treatment guidelines in urologi-
antimicrobial drug is sufficient for most cal patients.
surgical procedures. Inappropriate use
of prophylaxis is often due to prolonged 4.3 Guideline implementation
administration [71] (LoE 2b), and many
interventions have been successful in Guideline implementation can be facili-
reducing postoperative prophylaxis [72] tated through provider education and
[13] (LoE 2b). feedback on antimicrobial use and patient
outcomes [7]. Specific antimicrobial
stewardship teams, mostly consisting
of an ID physician and a hospital phar-
4. ANTIBIOTIC STEWARDSHIP
macists have been established in many
PROGRAMS
countries to fight high resistance levels
by mounting programs adopting similar
Antibiotic stewardship programs include techniques as the committees [7, 11, 73].
antibiotic policy structures, tools, and A Cochrane review on interventions to
dedicated personnel. improve antibiotic prescribing practices
for hospital inpatients is available [74].
4.1 Antibiotic committees Printed educational materials and edu-
Antibiotic committees should be multi- cational conferences alone have had
disciplinary and include at least an infec- little effect on changing prescribing prac-
tious diseases physician, a (medical) tices for antibiotics or other medications
microbiologist, a hospital pharmacist in the outpatient setting. More inten-
and clinicians from the major disciplines. sive and multifaceted interventions are
The major tasks of an antibiotic commit- generally required. Face-to-face educa-
tee are development of evidence-based tional sessions provided by physicians
practice guidelines that incorporate local or pharmacists, sometimes known as
microbiology and resistance patterns, academic detailing, have been successful
regular monitoring of the local surveil- in improving antibiotic-prescribing prac-
lance of resistance and use, identifying tices. Participative physician feedback
potential problem areas for audit and and multidisciplinary interventions have
feedback or other interventions including also been found to be effective methods to
restriction. increase the judicious use of antibiotics
and reduce costs [74].
4.2 Antibiotic guidelines
Antibiotic guidelines are intended to 4.4 Quality indicators
improve the quality of care, to sup- In a Dutch study, a systemic evidence-
port public health decisions, to dimin- and consensus-based approach was
ish unwanted diversity of practice and used to develop a set of valid quality
141
indicators to evaluate antibiotic use for or novel combinations would be a very

complicated UTIs. A multidisciplinary useful alternative while awaiting novel
panel reviewed and prioritized recom- drugs. PK/PD research should provide the
mendations extracted from a recently knowledge for selecting better regimens
developed evidence-based national guide- of older and new antibiotics. Finally,
line. The content validity, the feasibility, more well-conducted clinical studies are
interobserver reliability, opportunity for needed on the optimal duration of antibi-
improvement, and case-mix stability of otic therapy.
the potential indicators was assessed for
a data set of 341 inpatients and outpa-
tients with complicated UTIs. The panel 6. CONCLUSIONS
selected and prioritized performance of
urine culture, prescription of treatment By applying the strategies for appropri-
in accordance with guidelines, tailoring of ate prescribing described in this chapter,
treatment on the basis of culture results, i.e. optimizing the indication, selection,
and a switch to oral treatment when dosing, route of administration, duration,
possible, selective use of fluoroquinolo- and timing of antibiotic therapy, selec-
nes, administration of treatment for at tion of resistant microorganisms should
least 10 days, prescription of treatment be reduced to the minimum. This goal
for men in accordance with guidelines, should be reached in parallel with maxi-
replacement of catheters in patients with mizing clinical cure or prevention of infec-
UTI, and adaptation of the dosage on the tion and minimal toxicity and costs.
basis of renal function [75] (LoE 3). These
quality indicators can be used to moni-
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Chapter |3|
Urinary tract infections

in special groups of
adult patients
Chair: Kurt G. Naber
CHAPTER OUTLINE
3.1 Introduction 148
3.2 Diagnosis of uncomplicated urinary tract infections 151
3.3 The quantitative urine culture for the diagnosis of
urinary tract infection 160
3.4 Antibiotic treatment of uncomplicated urinary tract
infection in premenopausal women 170
3.5 Urinary tract infections in pregnancy 200
3.6 Urinary tract infections in patients with diabetes mellitus 216
3.7 Urinary tract infections in postmenopausal women 225
|3.1|
Introduction
Kurt G. Naber
Technical University of Munich, Munich, Germany
Address of corresponding author: Prof. Kurt G. Naber, MD, PhD, Karl-Bickleder-Str. 44c, D-94315 Straubing, Germany
Tel +49-9421-33369, kurt@nabers.de
Uncomplicated urinary tract infections specific diagnostic steps, because experts

(UTIs) are extremely common infec- agree in general that the full diagnostic
tions in the community. About 50% of program including urine culture is not
adult women report a UTI some point always necessary in otherwise healthy
during their lifetime [1]. Approximately women with uncomplicated cystitis and
2,500,000 women in the United Kingdom typical symptoms. On the other hand the
experience an attack of dysuria and final diagnosis of UTI requires microbio-
frequency each year and 100,000 suf- logical confirmation according to Lindsay
fer recurrent infections [2]. In the USA Nicolle from Winnipeg, MB, Canada.
5,740,000 office visits to physicians were However, urine specimens should be col-
reported in 1990 for one of the follow- lected minimizing contamination and also
ing primary complaints: painful urina- considering quantitative criteria. A group
tion, frequency and urgency, or UTI [3]. comprising of Kurt G. Naber (Straubing,
Most of the visits (75.8%) were made by Germany), Björn Wullt (Malmö, Sweden),
females to general physicians. and Florian ME Wagenlehner (Giessen,
In this section the diagnostic and ther- Germany) discuss the antibiotic treatment
apeutic considerations of UTI are pre- of uncomplicated cystitis and pyelonephri-
sented in special groups of adult patients, tis in otherwise healthy premenopausal
such as premenopausal, pregnant and women. Most studies have been performed
postmenopausal women, and diabetic in this group of patients in whom short
patients. Each group has some peculiar term therapy of uncomplicated cystitis can
problems to be considered, but they also be considered today as standard. However,
have much in common. the choice of antimicrobials depends very
Richard Colgan, Samantha Hyner from much on the susceptibility pattern of E.
Baltimore, MD, and Stephanie Chu from coli, the most frequent uropathogen, which
Boston, MA, USA, discuss the evidence for may differ considerably between countries.
UTIs in pregnant women play an impor- the risk of complications or treatment

tant role. Even asymptomatic bacteriuria failure. This classification can also be
(ASB) may have a negative impact on the applied to women with recurrent UTI if
pregnancy. Therefore careful screening such risk factors can be excluded. Each
and management of any UTI including acute infection episode can be handled
ASB – and other urogenital infections as similarly, but additional care is necessary
presented in chapter 4.6 – is necessary to prevent recurrences (see chapter 4).
as outlined by Alexander D. Griffin and Most researchers would also agree that
Thomas Hooton from Miami, FL, and UTI in otherwise healthy postmenopau-
Richard Grady from Seattle, WA, USA. sal and diabetic women with stable met-
Because of the physical changes during abolic conditions still can be considered
pregnancy especially any obstruction of as “uncomplicated”, although UTI may
the upper urinary tract has to be looked occur more frequently in these groups of
for by ultrasonography and in case of patients and standard short term ther-
pyelonephritis early hospitalisation may apy is not as well established or even
be considered. not so effective as in otherwise premeno-
Patients with diabetes mellitus pausal women. In contrast, UTI in preg-
(Suzanne Geerlings, Amsterdam, The nant women and in otherwise healthy
Netherlands) and postmenopausal women young men (discussed elsewhere [5–6])
(Raul Raz, Afula, Israel) have in common are often classified as “complicated” per
an increased rate of UTI episodes. The se, even if no additional risk factors can
bacterial spectrum of these two groups be recognized. This classification is usu-
of patients is usually similar to that of ally argued for in terms of the normal
premenopausal women; if no additional physical changes in pregnancy and the
risk factors are present [4]. However, frequent involvement of the prostate in
short term therapy of cystitis is not so men as documented by a transient rise of
well established and is probably less serum PSA. If this is generally accepted,
effective than in premenopausal women. then how should we classify a UTI in
More studies are needed to establish the these groups of patients if additional
best management in these two groups of risk factors are present? “More compli-
patients. cated”? Other differences have also to
If no additional risk factors are present, be considered, for example in pregnant
treatment of cystitis and pyelonephri- women asymptomatic bacteriuria must
tis usually results in high cure rates. be treated, but this is not indicated in the
There is, however, no agreement between other groups of patients.
experts, whether a UTI without any addi- In each group of patients it is very
tional risk factors in all these groups of important to differentiate whether a UTI
patients can uniformly be considered as occurs in a patient without (otherwise
“uncomplicated”. healthy) or with additional risk factors,
The usual definition of uncomplicated such as renal insufficiency, obstruction
UTI comprises UTI in a patient without of the urinary tract, neurogenic bladder
abnormalities in the urinary tract (uropa- disturbances or indwelling urinary cath-
thies); without kidney diseases (neph- eter. These considerations already dem-
ropathies), and without comorbidities onstrate that a classification with only
favouring UTI and leading to a more seri- two categories, complicated and uncom-
ous outcome requiring additional diagnos- plicated, is difficult to use, because every
tic and therapeutic care. Uncomplicated time one category is defined very strictly
UTI (cystitis and pyelonephritis) are the other category becomes more heterog-
mostly seen in premenopausal women enous. This inherent problem can only be
without any risk factor known to increase solved by better differentiation of patients’
149
Chapter |3| Urinary tract infections in special groups of adult patients
characteristics (groups of patients) and 4. Naber KG, Schito G, Botto H, Palou J,

the additional risk factors, e.g. urological/ and Mazzei T, Surveillance study in
nephrological pathologies, and/or relevant Europe and Brazil on clinical aspects and
comorbidities, e.g. immunosuppressive Antimicrobial Resistance Epidemiology in
therapy in transplant patients. Females with Cystitis (ARESC): implica-
tions for empiric therapy. Eur Urol, 2008.
In the last section of the textbook a
54(5): 1164–75.
group of experts has made an attempt
5. Stamm WE, Urinary tract infections in
to introduce a more differentiated clas-
young men, in Urinary tract infections,
sification system. Whether it can replace Bergan T, Editor. 1997, Karger: Basel;
the traditional classification system [7–8] London. p. vii, 142 p.
remains to be seen. 6. Krieger JN, Ross SO, and Simonsen JM,
Urinary tract infections in healthy
university men. J Urol, 1993. 149(5):
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7. Rubin RH, Beam TR, Jr., and Stamm
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150
|3.2|
Diagnosis of uncomplicated
urinary tract infections
Richard Colgan1*, Samantha Hyner1, Stephanie Chu2
1
University of Maryland School of Medicine, Baltimore, Maryland, USA
2
Boston University School of Medicine, Boston, Massachutes
Corresponding author: Richard Colgan, M.D., Associate Professor, Director Undergraduate Education,
Department of Family and Community Medicine, University of Maryland School of Medicine,
29 S. Paca Street, Lower Level, Baltimore, Maryland 21201, USA
Phone: +1 (410) 328-3525, Fax: +1 (410) 328-8726, rcolgan@som.umaryland.edu
ABSTRACT and acute uncomplicated pyelonephri-

tis (AUP), which involve infection of the
The most common bacterial infections in lower and upper urinary tracts, respec-
women are urinary tract infections, the tively. Throughout the chapter we high-
majority of which are uncomplicated, light differences upon evaluation that,
yet there have been few recent studies if present, can be helpful in differentiat-
investigating the diagnosis of uncompli- ing between AUC and AUP. The history
cated urinary tract infection (uUTI). This is the most important tool for diagno-
chapter uses information from the most sis. The presence and absence of certain
recent studies, reviews, and guidelines symptoms and risk factors can have a
found by searching Medline, Pubmed, positive predictive value of infection as
and the Cochrane database to give an high as 90%. The physical exam is often
overview on the diagnosis of uUTIs. An normal in patients with AUC, but can be
important step in diagnosing an uUTI is particularly important for distinguishing
ruling out the presence of a more seri- patients with AUP. Urine dipstick test-
ous complicated urinary tract infection ing, which interestingly does not appear
(cUTI), thus we first discuss some of to depend on preparatory cleansing for
the most agreed upon criteria and risk accuracy, is also an important tool for
factors for cUTI. The remainder of the diagnosis. Authors vary in opinion as to
chapter focuses on the history, physical the necessity of urine culture in AUC,
exam, and laboratory findings of patients but it is indicated when AUP or a resist-
with acute uncomplicated cystitis (AUC) ant uropathogen is suspected. Further
studies beyond urinalysis and urine cul- 3. Additional diagnostic studies: Women
tures are rarely indicated for uUTIs. who present with atypical symptoms
Finally, we discuss how women who have of either acute uncomplicated cystitis
had recurrent uUTIs are usually accu- or acute uncomplicated pyelonephritis,
rate in self-diagnosing when they have as well as those who fail to respond
an infection, and present evidence that to appropriate antimicrobial therapy
cases diagnosed by phone have similar should be considered for additional
outcomes as compared to cases diagnosed diagnostic studies (LoE 4, GoR B)
by the clinician in his/her office.
Key words: Diagnosis, Uncomplicated 1. INTRODUCTION
Urinary Tract Infections, Acute Uncom-
plicated Cystitis Infections of the urinary tract are the
most common bacterial infections in
women. The term urinary tract infec-
SUMMARY OF RECOMMENDATIONS tion (UTI) encompasses several differ-
ent manifestations of bacterial infections
1. Clinical Diagnosis: The diagnosis of of one or more structures in the urinary
acute uncomplicated cystitis can be tract. UTIs can be classified using vari-
made with a high probability based on ous different criteria, such as community
a focused history of urinary irritative acquired versus nosocomial, acute versus
symptomatology (dysuria, frequency recurrent, or asymptomatic versus symp-
and urgency) and the absence of vagi- tomatic, for examples. In this chapter we
nal discharge or irritation, in those discuss the division of UTIs according to
women who have no other risk factors whether they are uncomplicated (uUTI)
for complicated urinary tract infec- or complicated (cUTI). It is important to
tions [1] (LoE 2, GoR B) make this distinction when diagnosing a
2. Laboratory Diagnosis: UTI, because cUTIs are more often asso-
ciated with multiple pathogens, or mul-
2.1 Urine dipstick testing, as
tiple drug resistances, and thus carry a
opposed to urinary microscopy,
higher risk for treatment failures than
is a reasonable alternative to
uUTIs [7–8]. This chapter will focus on
urinalysis in diagnosing acute
the diagnosis of uUTIs, but given that a
uncomplicated cystitis [2–3]
main objective of diagnosing an uUTI is
(LoE 3, GoR B)
ruling out a cUTI, complicated infections
2.2 Urine cultures are recommended will be discussed briefly.
for those with: i) suspected acute
pyelonephritis; ii) symptoms that
do not resolve or recur within 2. METHODS
2–4 weeks after the completion of
treatment and iii) those women Here we provide information from a litera-
who present with atypical symp- ture search done over the past three years,
toms at presentation [4–5] (LoE 4, including published studies, reviews, and
GoR B) guidelines found by searching Medline,
2.3 A colony count of greater than > or PubMed, and the Cochrane database
equal to 103 CFU/ml of a uropatho- using keywords urinary tract infection
gen is microbiologically diagnostic and cystitis. Because of the sparse amount
in women presenting with symp- of new research in this area important
toms of acute uncomplicated cysti- older studies have been included as well
tis [6] (LoE 3, GoR B) if new research in these areas is lacking.
152
Diagnosis of uncomplicated urinary tract infections | 3.2 |
In PubMed the MeSH term “urinary tract be seen following a stroke or spinal cord
infection” with the subheading of diagno- injury). Additional qualifiers include labo-
sis was used. Only publications in English ratory findings of a resistant pathogen in
addressing uUTIs in adult women were the urine or recent antibiotic use [10–11].
ultimately included. We found over 100 The typical patient with AUC is a female
publications in this search and included of reproductive age who notes urinary irri-
38 in our analysis. tative symptomatology. Postmenopausal
The studies were rated according to women and women with diabetes without
the level of evidence (LoE) and the grade underlying functional or structural abnor-
of recommendation (GoR) using ICUD malities of the urinary tract may also be
standards (for details see Preface) [9–10]. considered as included with the acute
uncomplicated UTIs, as the management
for these two groups does not differ. The
3. DIAGNOSIS OF UNCOMPLICATED classic symptoms of AUC include dysu-
URINARY TRACT INFECTIONS ria, frequent voiding of small volumes,
and urgency, though sometimes hematu-
The classification of UTI’s is based on fac- ria and less often suprapubic discomfort
tors in the history, physical exam, and lab- can also occur. According to Bent and col-
oratory testing. We will be discussing two leagues, the pretest probability of UTI in
types of uUTI, acute uncomplicated cystitis women is 5%, but when a woman presents
(AUC) and acute uncomplicated pyelone- to her physician with the acute onset of
phritis (AUP). AUC is the most common even just one of the classic symptoms of
type of UTI and involves sudden-onset AUC, the probability of infection rises
infection of the lower urinary tract (blad- tenfold to 50% [13]. Thus presenting to a
der, urethra), while AUP is a sudden-onset clinician with one or more symptoms of
infection that has spread to the upper uri- an AUC is cited in and of itself as a valu-
nary tract (kidney involvement). able “diagnostic test.” The probability of
infection further increases in the absence
3.1 Historical diagnosis of certain symptoms. Patients who also
report a vaginal discharge or irritation are
3.1.1 Acute uncomplicated cystitis less likely to suffer from AUC and more
The focus of this chapter is on the diag- likely to have vaginitis or cervicitis. These
nosis of uncomplicated urinary tract authors report that the new onset of fre-
infections, and we begin with the single quency and dysuria, together with the
greatest tool in diagnosing woman with absence of vaginal discharge or irritation,
an uUTI : the history. Before diagnosing has a positive predictive value of 90% for
a woman with an uUTI it important to UTI, effectively ruling in the diagnosis
be sure that she does not have a compli- based on history alone. Furthermore, the
cated UTI (cUTI) as the evaluation and authors note that while the pretest prob-
treatment may be different. Qualifiers ability of UTI in the average patient who
which denote a cUTI are male gender, presents with one or more symptoms is
preadolescents, or pregnant women and approximately 50%, the actual probabil-
those with metabolic, functional, or ana- ity varies considerably depending on the
tomic abnormalities of the genitourinary patient‘s risk profile. One cohort study of
tract [1, 11–12]. A UTI can also qualify as 796 sexually active young women found a
complicated based on many items in the strong dose-response relationship between
past medical history, such as a history of risk of infection and both recent sexual
childhood UTIs, polycystic renal disease, intercourse as well as use of diaphragms
immunosupression, indwelling catheteri- with spermicide [14]. There was also an
zation, or neurogenic bladder (as may association between the incidence of AUC
153
and history of recurrent infection. In addi- resistance was common. Factors identified
tion to these three well-established risk as independent risk factors for TMP-SMX
factors, genetics have also been shown to resistance in this population were diabe-
play a role in an individual’s susceptibility tes, recent hospitalization, and the use of
to AUC [4]. antibiotics, particularly TMP-SMX [22].
A study of women with AUC done at
3.1.2 Acute uncomplicated an urban primary care clinic was able
pyelonephritis to show that Asian ethnicity and travel
outside the state or country were predic-
Women with AUP often present with
tive of resistance of E. coli to TMP-SMX.
the same symptoms discussed for AUC
It was demonstrated that if the clinician
(dysuria, frequency, urgency, haematu-
asked the patient if she was of Asian eth-
ria, suprapubic pain), and commonly also
nicity and if she had travelled outside the
present with flank or back pain, which are
state or country in the past three months,
classical symptoms of upper urinary tract
the correct antibiotic could be chosen for
infection. Additionally, these women can
this group of patients more than 95% of
sometimes present with systemic symp-
the time [23]. Further studies specifi-
toms, such as nausea, vomiting, fever,
cally enrolling women with AUC from a
chills, and abdominal pain. Risk fac-
broader demographic area are needed to
tors for AUP include all those mentioned
confirm these findings.
for AUC; however diabetes and inconti-
A recent study looking at risk factors
nence have been shown to independently
for E coli resistance by Trimethoprim-
increase the risk for pyelonephritis in
Sulfamethoxazole among emergency
otherwise healthy women [15–16].
department patients with pyelonephri-
tis showed that only Trimethoprim-
3.1.3 Using history to predict antibiotic Sulfamethoxazole exposure within two
resistance days before presentation and Hispanic eth-
According to one study, the history can nicity were associated with E coli resist-
also guide the choice of an antibiotic for ance to Trimethoprim-sulfamethoxazole,
treatment. Several studies have attempted compared with resistance rates of approx-
to elucidate individual risks that predict imately 20% among women lacking these
trimethoprim-sulfamethoxazole resist- risk factors [24].
ance in those with uUTIs [17–22]. In a
retrospective study of women with acute
uncomplicated cystitis seen at a univer- 3.1.4 Self-diagnosis and diagnosis
sity health center and at primary care by phone
clinics in southeastern Michigan from Given the increased difficulty that many
1992–1999 women who had recently women face in gaining access to a clinician
taken TMP-TMX were more than 16 when suffering from uUTI, researchers
times as likely as women who had not have investigated the effectiveness of self-
taken antibiotics recently to be infected diagnosis and self-treatment of these infec-
with an isolate resistant to this agent. tions. Women who have had uUTIs before
Those who had taken any other antibi- are usually accurate in determining when
otic were more than twice as likely to they are suffering from another uUTI. In
be infected with a resistant isolate [17]. one study of 172 women with a history of
In another study at an emergency depart- recurrent UTI, 88 women self-diagnosed
ment in a tertiary care university hospital UTI on the basis of symptoms, and self-
enrolling 448 patients 14 years or older treated with ofloxacin or levofloxacin [25].
with any urinary tract infection, not just According to laboratory evaluation, 84% of
AUC, investigators found that TMP-SMX cases showed a uropathogen, 11% showed
154
sterile pyuria, and only 5% of cases were 3.3 Laboratory studies

negative for pyuria and bacteriuria. 3.3.1 Urine sample collection
Laboratory-confirmed cases showed clini-
cal and microbiological cure rates of 92% So as to avoid contamination, convention
and 96%, respectively [25]. has called for a mid-stream, clean-caught
Again, because of increased difficulties urine specimen for those presenting with
when suffering from uUTI, women often a potential UTI; however, at least two
seek help and obtain care by consult- studies have shown that there is no sig-
ing with their physician over the phone. nificant difference in numbers of con-
A small randomized controlled trial com- taminated or unreliable results between
pared the outcomes of uUTIs in healthy specimens collected with and without
women managed over the phone with preparatory cleansing [2–3]. In one of
those managed in the office. No difference these studies, patients using the clean-
in symptom scores or satisfaction was ing method were instructed to wash their
noted. The authors conclude that short- hands and then use three provided cotton
term outcomes of managing suspected wool swabs to cleanse the genital area
UTIs by telephone appear to be compara- with soap and water [26]. They were told
ble with usual office care [26]. to part the labia and wipe from front to
back three times using a clean swab each
3.2 Physical examination time. Participants not using the cleaning
method were instructed simply to pass
3.2.1 Acute uncomplicated cystitis some urine in to the toilet, stop, and then
The physical exam of those suffering from catch the next urine in a sterile boric acid
AUC is usually normal, except in the container. An infection was classified as
10–20% of women who have suprapubic one with greater than 108 organisms per
tenderness [26]. The presence of vaginal liter of urine in the presence of signifi-
discharge on exam decreases the like- cant numbers of white cells (greater than
lihood of UTI, although this finding is 104 cells per liter) with or without the
less powerful than when the symptom of presence of red blood cells. Again, there
vaginal discharge reported by the patient was no significant difference in numbers
[13]. The authors further suggest that one of contaminated or unreliable results
may consider not proceeding with a urine between the two groups.
dipstick test if the patient presents to the
clinician with frequency and dysuria and 3.3.2 Urine dipstick testing
without vaginal discharge, as the positive Urine dipstick testing is widely used in
predictive value of UTI is already 90%. clinical practice and has largely replaced
microscopic analysis and urine cultures
3.2.2 Acute uncomplicated in the evaluation of uUTI because of its
pyelonephritis low cost, speed, and convenience. Two
More often than women with AUC, high quality systematic reviews looking
women with AUP will appear uncomfort- at the accuracy of dipstick analysis both
able or ill. They may or may not have show the nitrite positive and leukocyte
objective findings of fever, tachycardia, or esterase positive combination to be the
costovertebral angle (CVA) tenderness. If most accurate in predicting the existence
present, the tenderness is most commonly of a UTI [27–28]. The dipstick alone is a
unilateral over the involved kidney, useful test in aiding clinicians when diag-
though discomfort can occur bilaterally. nosing UTI. According to the review by
The discomfort is usually not subtle and Hurlbut and Littenberg, this combination
may be elicited with mild or moderately has a sensitivity of 75% and a specificity
firm palpation [16]. of 82%. If the dipstick alone is used, the
155
posttest probabilities for women with culture testing is needed to confirm these
symptoms of a UTI are 81% (positive test) cases.
and 23% (negative test) [2]. Pyuria is almost always present in
Several reviews recommend that a women with AUC. While its presence is
diagnosis of uUTI can be made in women supportive of this diagnosis, the absence
with typical urinary irritative symptoma- of pyuria does not exclude a urinary tract
tology who are found to have a positive infection in those with symptoms sugges-
urine dipstick test or urinalysis, with- tive of AUC [5], The presence of blood in
out obtaining a urine culture [7, 29–31]. the urine of those with AUC is common
McIsaac et al [32] found three decision and non-specific. Microscopic hematuria
variables (burning or discomfort with uri- is found in 40–60% of patients with UTI
nation, the presence of leukocytes greater [33]. Almost all patients with AUP have
than a trace amount, and the presence of significant pyuria, however gross hema-
any nitrites) in a cohort of 331 females turia occurs infrequently with pyelone-
with suspected cystitis demonstrat- phritis and is more common with lower
ing significant association with a posi- UTI [16].
tive urine culture result (>102 CFU/ml).
There was, however, a graded relation-
ship between the number of decision aid 3.3.3 Urine cultures
criteria and the outcome of a positive Opinions differ as to the necessity of
urine culture result (p<0.001). The rate doing a urine culture in diagnosing
of positive urine culture result was 23.1% AUC. One school of thought is that a
with 0 criteria, 43.2% with 1 criterion, urine culture is not necessary to diag-
68.8% with 2 criteria, and 89.1% with 3 nose AUC, and adds substantially to the
criteria. Incorporating the 3 significant cost of therapy [35]. A more aggressive
variables (empirical antibiotics without approach would advocate for a microbio-
culture if >2 variables present: otherwise logic diagnosis of all UTIs, and require
obtain a culture and wait for results) had that a quantitative isolation of a uropath-
a sensitivity of 80.3% and a specificity of ogenic organism from an appropriately
53.7%. collected urine specimen be done. Urine
Nitrite tests may be negative if the cultures are indicated in women with a
UTI is caused by a non-nitrate reducing suspected AUP [16], and should be done
pathogen (e.g. enterococci, S. saprophyti- for women with any variety of UTI whose
cus, Acinetobacter) or if the urine is too symptoms do not resolve or recur within
dilute [33]. The sensitivity of the nitrite two to four weeks after the completion
test alone ranges from 35% to 85%, yet of treatment and for those women who
with a higher specificity of 95% [30]. present with atypical symptoms at pres-
According to one large meta-analysis, the entation. In the emergency room set-
urine dipstick test was found to be use- ting, urine cultures are recommend in
ful in all populations to exclude the pres- patients at high risk for pyelonephritis or
ence of infection if the results for nitrites bacteremia/urosepsis, as well as in those
or leukocyte esterase are negative [34]. expected to have uncommon or resistant
Sensitivities of the combination of both organisms [36].
tests vary between 68–88% in different Previously, a quantitative count of
patient groups, but according to Deville greater than or equal to 105 colony forming
et al. positive test results must be con- units (CFU) per milliliter was the accepted
firmed. While the combination of positive standard for diagnosing AUC [36], but
test results is very sensitive in family 30–50% of women presenting with symp-
practice, with high pre-test probabili- toms suggestive of AUC have lower col-
ties, what is not clear is whether urine ony counts in the 103 to 105 range [5, 37].
156
Therefore, a colony count of greater than on epidemiological data obtainable by the

or equal to 103 CFU/ml of a uropathogen is primary care physician.
now the commonly accepted microbiologic
diagnostic criteria for AUC [38]. Of inter-
est is the fact that as many as 10–20% of 5. CONCLUSIONS
symptomatic women have negative urine
cultures, and yet the clinical response to The clinician should identify all suspected
treatment of these women is similar to that cases of UTIs as being either uncom-
of women with positive urine cultures [39]. plicated or complicated based upon a
Up to 95% of episodes of AUP are associ- focused history, physical exam, and basic
ated with greater than or equal to 105 laboratory studies, including a urinalysis
CFU/mL of a uropathogen, though as with and possibly a urine culture. The history
AUC, some patients with AUP have lower is the greatest tool in diagnosing uUTIs,
colony counts. It is proposed that a quanti- and it can be used to asses a patient’s
tative count of greater than or equal to 104 risk of having an antibiotic resistant
CFU/mL defines significant bacteriuria in uropathogen. A history of back or flank
AUP [38]. pain, along with certain physical exam
and laboratory findings can sometimes
help distinguish AUC from AUP. Women
3.4 Additional diagnostic studies
who have previously had an uUTI are
Further studies beyond urinalysis and usually accurate in identifying when they
urine cultures are rarely indicated in are suffering from an uUTI, and phone
diagnosing an uncomplicated urinary triaging has been shown to have similar
tract infection. Patients presenting with beneficial outcomes when compared to
atypical symptoms of either AUC or AUP, care rendered by the clinician in his/her
as well as those who fail to respond to office.
appropriate antimicrobial therapy, may
need imaging studies such at computed Acknowledgements
tomography (CT) scans or ultrasound to
rule out complicated disorders. The pres- The authors thank Drs. John W. Warren
ence of a renal abscess or an obstructing and Kalpana Gupta for their thoughtful
calculus in the genitourinary tract of a review of this chapter.
patient with clinical pyelonephritis would
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159
|3.3|
The quantitative urine culture

for the diagnosis of urinary
tract infection
Lindsay E. Nicolle
Professor, Department of Medical Microbiology and Internal Medicine, University of Manitoba Health Sciences Centre,
Room GG443 – 820 Sherbrook Street, Winnipeg, MB R3A 1R9
Tel: (204) 787-7029, Fax: (204) 787-4826, e-mail: lnicolle@hsc.mb.ca
ABSTRACT and all patients with pyelonephritis. It is

likely also appropriate for specimens col-
A diagnosis of urinary tract infection lected through an indwelling urethral
requires microbiological confirmation. The catheter, as these are subject to contami-
only exception is the clinical presentation nation from organisms growing in bio-
of acute uncomplicated urinary tract infec- film on the catheter. Further studies are
tion in women. A urine specimen for cul- needed to determine what proportion of
ture must be obtained prior to initiation selected symptomatic populations, includ-
of antimicrobial therapy, use a collection ing men and patients with short term ind-
method which minimizes contamination, welling catheters, meet this quantitative
be forwarded promptly to the laboratory, criterion. When lower quantitative counts
and processed in the laboratory using or multiple organisms are isolated from
appropriate standard procedures. The voided specimens in patients in whom the
quantitative diagnostic criterion for uri- clinical diagnosis of urinary tract infection
nary tract infection for a voided urine is considered, careful assessment of the
specimen is ≥ 105 cfu/ml of a single organ- clinical presentation and the number and
ism. Lower quantitative counts, gram pos- types of organisms isolated is necessary to
itive organisms, and multiple organisms avoid overinterpretation of contaminated
usually represent contaminants. This urine specimens. Specimens obtained by
quantitative criterion is generally relevant in and out catheter, including intermittent
for all patients with asymptomatic bacte- catheterization, or by suprapubic aspira-
riuria, complicated urinary tract infection, tion, are less subject to contamination,
The quantitative urine culture for the diagnosis of urinary tract infection | 3.3 |
and lower quantitative counts are consist- Gram-positive organisms to identify

ent with urinary infection with these col- asymptomatic bacteriuria in men.
lection methods. 4.2 For specimens collected using a
Key words: urinary tract infection, freshly applied external condom
bacteriuria, urine culture, complicated catheter, a quantitative count
urinary infection, uncomplicated urinary of ≥ 105 cfu/ml of any number of
infection organisms identifies bacteriuria
(GoR B).
5. For voided specimens from women
SUMMARY OF RECOMMENDATIONS with acute uncomplicated urinary
tract infection:
1. A urine specimen for culture should 5.1 Isolation of a single predomi-
be collected prior to the initiation of nant gram negative organism
antimicrobial therapy using a collec- or Staphylococcus saprophyti-
tion method which minimizes contam- cus at any quantitative count is
ination, be forwarded promptly to the consistent with urinary infection
laboratory, and processed following (GoR B).
standard laboratory procedures 5.2 Isolation of gram positive organ-
(GoR B). isms other than S. saprophyticus
2. The usual diagnostic criterion for in any quantitative count, or
urinary tract infection with a voided multiple organisms without a pre-
specimen is ≥ 105 cfu/ml of a single dominant Gram-negative isolate,
gram negative organism (GoR B). should be interpreted as contami-
2.1 For specimens collected by in and nation (GoR B).
out catheter, a quantitative count 6. For women or men presenting with
≥ 102 cfu/ml of any number or type acute uncomplicated pyelonephritis,
of organisms is considered diag- the quantitative criterion for infection
nostic (GoR B). is ≥ 105 cfu/ml (GoR B).
2.2 For specimens collected by 6.1 In 5% of episodes, urine cultures
suprapubic aspiration, any quanti- may have quantitative counts
tative count of any number or type between 104–105 cfu/ml (GoR B).
of organisms is considered diag- 7. For symptomatic men, isolation of
nostic (GoR B). a single gram negative organism in
3. For asymptomatic women, a single quantitative counts ≥ 103 cfu/ml is
voided urine culture with ≥ 105 cfu/ml consistent with urinary infection.
of a gram negative organism identifies 7.1 Further evaluation is needed to
bacteriuria (GoR B). define the appropriate quantita-
3.1 A second urine specimen with the tive count for symptomatic infec-
same organism isolated identifies tion for specimens collected with
women with persistent asympto- an external catheter.
matic bacteriuria (GoR B). 8. For patients with indwelling
4. For asymptomatic men, a single catheters:
voided urine culture with ≥ 105 cfu/ml 8.1 Further evaluation is necessary to
of a gram negative organism is con- define the appropriate quantita-
sistent with bacteriuria (GoR B). tive count for diagnosis of symp-
4.1 No recommendation can be tomatic infection in patients with
made for quantitative criteria for short term indwelling catheters.
161
8.2 For patients with chronic ind- of asymptomatic bacteriuria in these

welling catheters, a quantitative women is beneficial [7]. However, in the
count of ≥ 105 cfu/ml in bladder early 1980s several reports revisited
urine collected following catheter limitations of the uniform application
replacement is consistent with of a quantitative count of ≥ 105 cfu/ml
symptomatic or asymptomatic for a diagnosis of urinary infection. In
urinary tract infection (GoR B). particular, the relatively high propor-
9. For patients with spinal cord injury tion of women with acute uncomplicated
and a urine specimen collected by urinary tract infection from whom lower
intermittent catheter, a quantitative quantitative counts of uropathogens are
count of ≥ 102 cfu/ml is consistent with isolated was recognized [8]. Subsequent
symptomatic or asymptomatic infec- guidelines for identification of urinary
tion (GoR B). infection proposed variable quantita-
tive criteria for bacterial growth depend-
ing upon the clinical presentation, from
≥ 103 to ≥ 105 cfu/ml [9]. These varying
1. INTRODUCTION diagnostic recommendations led to confu-
sion in clinical practice and, in particu-
It has been 50 years since the descrip- lar, overinterpretation of contaminated
tion of the quantitative criterion of ≥ 105 urine cultures leading to inappropriate
cfu/ml of organisms isolated in a urine antimicrobial treatment. This document
culture for the microbiologic diagnosis of reviews evidence addressing the question
urinary tract infection [1–4]. The defini- of the appropriate quantitative count of
tive studies of Kass et al in the late 1950s organisms isolated from urine specimens
were instrumental in validating this for the microbiologic diagnosis of urinary
criterion and promoting the rapid and infection, and provides recommendations
widespread implementation into practice for the interpretation of this important
[3, 5]. In these investigations, Kass con- diagnostic parameter.
cluded that “bacilluria is the most sig-
nificant finding, and significant bacilluria
occurs when more than 105 bacteria/ml 2. METHODS
are found in the urine” [5]. However,
Kass also recognized that “certain defined This document was developed using
circumstances which inhibit bacterial available reviews and guidelines, includ-
multiplication in urine may lead to lower ing the 2005 Infectious Diseases Society
bacterial counts in urine in the presence of America Guideline for the Management
of infection” [5]. These variables include of Asymptomatic Bacteriuria [7] and the
inoculum size, intrinsic microorganism IDSA/FDA recommendations [9]. These
growth in urine, urine pH, urine constit- were updated using a systematic lit-
uents, urine flow rate, frequency of void- erature search performed in Medline,
ing, residual urine volume, and urinary Cochrane and Embase. Key words
antiseptics [6]. included urine culture, quantitative urine
The introduction of the quantitative culture, symptomatic urinary infection,
urine culture facilitated a rapid advance and asymptomatic urinary tract infection.
in the understanding and management Limitations included adult, clinical stud-
of many clinical aspects of urinary tract ies, English, and peer reviewed. The infor-
infection. An important early success was mation identified through the literature
the reliable ascertainment of asympto- review was supplemented by other papers
matic bacteriuria in pregnant women, identified by the author. The studies were
leading to recognition that treatment rated according to the level of evidence
162
(LoE) and the grade of recommendation of symptomatic women; none of these

(GoR) using ICUD standards (for details organisms were isolated in quantitative
see Preface) [10–11]. counts ≥ 105 cfu/ml. Diphtheroids ≥ 102
cfu/ml were isolated from 42% of asymp-
tomatic women (including 1.8% with ≥ 105
3. DEFINITIONS cfu/ml) and 27% of symptomatic women.
Other Gram-positive organisms isolated
Asymptomatic urinary infection, also at ≥ 102 cfu/ml included Corynebacterium
called asymptomatic bacteriuria, occurs spp (64% of asymptomatic and 46% of
when organisms are isolated from a urine symptomatic), Lactobacillus spp (55%
culture in quantitative counts meeting and 35%), Gardnerella spp (15% and
microbiological criteria for infection, but 1.2%), and Streptococcus spp (37.4% and
without acute symptoms or signs refera- 22%). Quantitative counts ≥ 105 cfu/ml
ble to the urinary tract [7]. Symptomatic were isolated for Corynebacterium spp
infection occurs when there are symptoms (3.9% asymptomatic and 2.4% symp-
referable to the urinary tract, including tomatic), Lactobacillus spp (13% and
the bladder, kidneys or, in men, the pros- 1.2%), Gardnerella spp (5.4% and 1.2%)
tate. Uncomplicated urinary tract infec- and Streptococcus spp (1% and 1.2%)
tion is symptomatic lower tract (bladder) [14]. A more recent study of 120 young
infection occurring in women with a nor- women presenting with acute uncompli-
mal genitourinary tract. Complicated uri- cated cystitis compared paired voided
nary tract infection occurs in individuals and in and out catheter urine speci-
with functional or structural abnormali- mens. Organisms isolated in any quan-
ties of the urinary tract. titative count from the voided specimen
but not present in the catheter speci-
men included 14 of 15 Enterococcus spp,
4. URINE COLLECTION METHOD 16 of 17 group B streptococci, and 123 of
132 mixed Gram-positive organisms [15].
These recommendations assume the Thus Gram-positive bacteria other than
urine specimen for culture is collected S. saprophyticus isolated from otherwise
prior to antimicrobial therapy being ini- healthy symptomatic or asymptomatic
tiated, using a method which minimizes women should be interpreted as contam-
contamination, and forwarded promptly inants (LoE 2a). For men, contamina-
to the laboratory where appropriate lab- tion of voided specimens is less frequent,
oratory methods are followed for isola- reported to be only 1–4% with ≤ 105 cfu/ml
tion, identification, and quantification of organisms isolated [16].
organisms [12]. Urine specimens collected by catheter
A voided urine specimen collected from puncture or from the collecting port of an
a woman will be contaminated with one indwelling urethral catheter are subject
or more organisms from the periurethral to contamination by organisms present
and vaginal flora, usually in quantitative in biofilm which has formed along the
counts of ≥ 102 cfu/ml [13]. These organ- catheter. A urine specimen obtained by
isms are predominantly gram positive bac- in and out bladder catheterization is less
teria which are normal flora of the skin or subject to contamination, although small
mucous membranes. In a comprehensive numbers of organisms, usually present at
study, Kunin reported that 77% of asymp- < 102 cfu/ml, are attributable to contami-
tomatic women had a Staphylococcal spe- nation as the catheter passes through the
cies other than S. saprophyticus grown urethra [13]. Urine obtained by suprapu-
in quantitative counts of ≥ 102 cfu/ml bic aspiration is presumed to be sterile,
from voided urine specimens, and 51.8% and any quantitative count is interpreted
163
as positive [13]. Particularly for women, with ≥ 105 cfu/ml of a gram negative
use of collection methods which are less organism isolated, but only 4.4% had two
susceptible to contamination may be con- consecutive specimens [21]. However,
sidered to confirm urinary infection when in another study a second specimen
a voided specimen is not diagnostic but remained positive with a single gram
the clinical presentation is suggestive. negative organism ≥ 105 cfu/ml in over
90% of pregnant women, and a third
specimen remained positive in 87% [22].
5. ASYMPTOMATIC BACTERIURIA In this study, pyelonephritis in later preg-
nancy occurred with similar frequency for
For women who are asymptomatic, two untreated women with mixed gram posi-
consecutive urine specimens with the tive and gram negative organisms iso-
same gram negative organism isolated lated from urine cultures at ≥ 105 cfu/ml
at ≥ 105 cfu/ml is recommended to iden- and women with specimens with quan-
tify asymptomatic bacteriuria [7] (LoE titative counts of < 103 cfu/ml isolated,
2a). Transient asymptomatic bacteriuria consistent with the mixed cultures repre-
appears to be frequent, particularly in senting contamination [22].
young women. A second specimen con- Asymptomatic bacteriuria may be
firmed an initial isolate of E. coli ≥ 105 more likely to persist in older women. In
cfu/ml in only 42% of women aged 23–29 Swedish women resident in the commu-
years when the repeat urine was obtained nity of mean age 83 years, 85% with an
weekly or monthly [17], but for 90% of initial urine specimen from which a sin-
40–64 year old women in Finland with an gle Gram-negative organism ≥ 105 cfu/ml
initial positive repeated within two weeks was isolated had a second positive urine
[18]. For diabetic women of mean age 56 specimen obtained within two weeks [23].
years, a repeat urine specimen within Residents of a Canadian long term care
two weeks confirmed bacteriuria in 69% facility of mean age 83.4 years had bac-
[19], and 56% of diabetic women aged teriuria confirmed by a repeat specimen
18–75 years with a repeat urine speci- within two weeks in 90% of women [24].
men obtained at two to four months [20]. However, a repeat positive specimen was
A single positive specimen with a Gram- reported from only 55–68% of institution-
negative organism ≥ 105 cfu/ml is likely alized Swedish women of mean age 85
true bacteriuria in most women cases, years [25].
but a second specimen obtained within a An initial voided urine specimen with
few days or weeks will identify persist- ≥ 105 cfu/ml of a Gram-negative organ-
ent bacteriuria, which may be more clini- ism isolated was confirmed on a follow-
cally relevant. Lower quantitative counts up specimen at one week in 58 (98%) of
of any organism, or ≥ 105 cfu/ml of more 59 men [26]. The interpretation of lower
than one organism, including mixed gram quantitative counts of Gram-negative
negative and gram positive cultures, organisms or any Gram-positive organ-
should be interpreted as contamination isms isolated in asymptomatic men has
[13–14, 17]. If it is essential to confirm not been reported. When urine specimens
the presence of asymptomatic bacteriuria are collected from elderly men using
and repeated specimens, including first freshly applied clean condom catheters,
morning voids, continue to grow < 105 of a the positive predictive value is 85–100%
single gram negative organism, obtaining for ≥ 105 cfu/ml in the voided culture
a specimen by in and out catheter to doc- being confirmed with the catheter speci-
ument bacteriuria should be considered. men, and a negative predictive value of
Katz and Hodder reported 7.0% of 86–94% [27–28]. For asymptomatic men
pregnant women had an initial specimen with spinal cord injury using external
164
urine collecting devices, 81% of organ- contaminated (< 105 of any organism or
isms isolated from a suprapubic aspirate ≥ 105 cfu/ml of multiple organisms) voided
were isolated in counts ≥ 105 cfu/ml from specimen had consistently negative cul-
the voided specimen [29]. However, 79% tures from the suprapubic aspirate. Thus,
of these subjects were receiving prophy- older women who present with acute cys-
lactic antimicrobials or antiseptics. Thus, titis are less likely to have < 105 cfu/ml of
for collection by voided external catheter organisms isolated from the urine culture
collected specimens, ≥ 105 cfu/ml is the compared with younger women (LoE 3a).
appropriate quantitative count (LoE 2a).
6.2 Acute uncomplicated
(nonobstructive)
6. ACUTE UNCOMPLICATED URINARY pyelonephritis
TRACT INFECTION Over 95% of individuals presenting with
acute uncomplicated pyelonephritis will
6.1 Cystitis have ≥ 105 cfu/ml of a single gram nega-
tive organism isolated from the urine cul-
25–30% of young women who present
ture [3, 34, 36–37]. The small proportion
with acute uncomplicated urinary tract
of individuals with pyelonephritis from
infection will have < 105 cfu/ml of a gram
whom lower quantitative counts are iso-
negative organism or S. saprophyticus
lated will usually have 104–105 cfu/ml of
isolated [8, 30–32]. Lower quantitative
organisms.
counts of other gram positive organisms
or of yeast should be interpreted as con-
tamination [13–14]. The explanation for 7. COMPLICATED URINARY TRACT
this high proportion of specimens with INFECTION
lower quantitative counts of uropatho-
gens isolated is unclear. Frequent void-
7.1 Symptomatic urinary infection
ing leading to limited bladder dwell time
in men
together with dilution attributable to
increased fluid intake likely explains part A study comparing urine specimens col-
of this observation. Infection initially lected from men by suprapubic aspirate,
localized to the urethra (i.e. urethritis) voided specimen without cleaning of the
has also been suggested [14]. It should meatus, voided specimen with clean-
be recognized, however, that the major- ing of the meatus, or in and out catheter
ity of these women will have ≥ 105 cfu/ml reported the optimal sensitivity for bacte-
isolated. riuria of voided compared to suprapubic
For post-menopausal women with or catheter specimens was ≥ 103 cfu/ml
acute cystitis, lower quantitative counts [38]. This study, however, enrolled men
may be less common, being reported in with irritative genitourinary symptoms
10% of episodes in healthy women aged or scheduled for a urologic procedure (i.e.
55–75 years in the community [33], and both symptomatic and asymptomatic), did
15% of women from a long term care not distinguish between Gram-positive
and community population of mean age and Gram-negative organisms, and
80 years [34]. For women of mean age included subjects receiving antimicro-
81 years with genitourinary or atypical bial therapy. For the uncommon, in men,
symptoms, 88% of voided specimens with syndrome of acute uncomplicated cystitis
≥ 105 cfu/ml of a single organism isolated the quantitative counts of gram negative
had the same organism isolated from a organisms isolated from young men was
paired suprapubic aspirate [35]. In con- of < 105 cfu/ml in 35% [39] and < 104 in
trast, individuals with a negative or 19% [40] of patients. Thus, the frequency
165
of lower quantitative counts isolated the indwelling catheter with a new cath-
from these men may be similar to young eter, with bladder urine for culture sam-
women with acute uncomplicated urinary pled through the new catheter. Of note,
infection (LoE 3a). organisms isolated from the bladder
urine at quantitative counts < 105 fol-
lowing catheter replacement tend not to
7.2 Indwelling urethral catheter
persist [43]. When suprapubic aspirates
When daily urine cultures are monitored are compared with specimens obtained
following insertion of a short term cathe- by needle puncture of the catheter in pre-
ter, a quantitative count of ≥ 102 cfu/ml of sumably asymptomatic men, isolation of
any organism isolated after an initial neg- organisms in quantitative counts ≥ 105
ative culture progresses to ≥ 105 cfu/ml cfu/ml was similar when the catheter had
of the same organism within 48–72 hours been in place for over one month [44]. In
if antimicrobial therapy is not initiated these individuals, growth of ≥ 105 cfu/ml
and the catheter remains in situ [41]. from the catheter urine was confirmed
This was observed, however, for only 20% in the suprapubic urine in 25 of 32 speci-
of all patients with short term catheters mens (81%). When the organism was not
inserted in the study facility, bacteriu- present in the suprapubic aspirate, five
ric patients were all asymptomatic, and out of six patients had had the catheter
over one-half of organisms isolated were in situ less than one month, and four of
coagulase negative staphylococci or yeast. these for less than two weeks. Pending
While this study has been interpreted as further studies in symptomatic subjects,
supporting a recommendation for a quan- ≥ 105 cfu/ml is likely the appropriate diag-
titative count of ≥ 102 cfu/ml for the diagnostic criteria for bladder urine in symp-
nosis of bacteriuria in individuals with a tomatic or asymptomatic subjects with a
short term indwelling catheter, the lower chronic indwelling catheter (LoE 3a).
quantitative counts likely reflect contami-
nation by bacteria present on the biofilm,
7.3 Patients with spinal cord
rather than bladder bacteriuria. A quanti-
injury using intermittent
tative count of ≥ 105 cfu/ml likely remains
catheterization
appropriate to identify asymptomatic
bacteriuria for patients with a short term A specimen obtained by intermittent
indwelling catheter [4]. Further study catheterization is, conceptually, an in
is necessary to identify the appropri- and out catheter specimen. Gribble et al
ate quantitative count for patients with compared intermittent catheter speci-
a short term indwelling catheter and mens with suprapubic aspirates and con-
symptomatic urinary infection, given the cluded ≥ 102 cfu/ml for gram negative or
potential for biofilm contamination of gram positive organisms was the opti-
specimens collected through the catheter. mal quantitative count from an inter-
An established biofilm incorporating mittent catheter specimen [45]. In this
multiple organisms is present on a long study, however, four of five subjects with
term indwelling catheter. Specimens col- definite symptomatic urinary infection
lected from the catheter have substantial had ≥ 105 cfu/ml of organisms isolated.
contamination with organisms present Thus, defining the appropriate quantita-
in the biofilm, and a larger number of tive criteria for symptomatic infection
organisms at higher quantitative counts warrants further study. Currently, how-
are present when compared with bladder ever, the National Institute on Disability
urine [42]. If a urine specimen for culture and Rehabilitation Research Consensus
is indicated in these patients contamina- Statement (NIDRRCS) recommends ≥ 102
tion from biofilm is avoided by replacing cfu/ml as criteria [46].
166
8. GUIDELINES isolated from voided specimens should

usually be interpreted as contamination.
Several guidelines addressing urinary When lower quantitative counts are iso-
tract infection provide statements rel- lated from urine specimens, a careful
evant to the appropriate quantitative evaluation of the urine culture results
count of organisms from urine culture, considering the method of specimen col-
although this topic is not the primary lection, handling in transportation to the
objective of the guidelines. These include laboratory, and the number and types of
the IDSA Guidelines for asymptomatic organisms isolated, together with the
bacteriuria [7] and catheter acquired uri- clinical presentation, is necessary.
nary tract infection [47], the European
Union (EU) Guidelines [48], and
NIDRRCS [46]. In addition, the Clinical REFERENCES
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sulfamethoxazole for 14 days. J Infect Dis, press).
1991. 163(2): 325–30. 48. Naber KG, Bishop MC, Bjerklund-
38. Lipsky BA, Ireton RC, Fihn SD, Johansen TE, Botto H, Cek M, Grabe M,
Hackett R, and Berger RE, Diagnosis of Lobel B, Palou J, and PT, Guidelines on
bacteriuria in men: specimen collection the Management of Urinary and Male
and culture interpretation. J Infect Dis, Genital Tract Infections. EU Guidelines,
1987. 155(5): 847–54. 2006.
169
|3.4|
Antibiotic treatment of
uncomplicated urinary tract
infection in premenopausal
women
Kurt G. Naber1, Björn Wullt2, Florian M.E. Wagenlehner3
1
2
Department of Urology, Skåne University Hospital, Malmö,
3
Department of Urology, University of Giessen-Marburg, Giessen, Germany
Corresponding Author: Kurt G. Naber, MD, PhD, Karl-Bicklederstr. 44c, D-94315 Straubing, Germany
Tel +49-9421-33369, E-mail: kurt@nabers.de
ABSTRACT recommendations for empiric treatment

of acute uncomplicated cystitis and acute
Uncomplicated urinary tract infections uncomplicated pyelonephritis and for fol-
(UTI) in otherwise healthy premenopau- low-up strategies were developed.
sal women are one of the most frequent Key words: uncomplicated urinary
infections in the community. Therefore tract infection, cystitis, pyelonephritis,
any improvement in management will premenopausal women, empiric therapy,
have a high impact not only on the qual- aminoglycosides, ampicillin, amoxicil-
ity of life of the individual patient but lin, cephalosporines, cefpodoxime, cipro-
also on the health system. In placebo- floxacin, cotrimoxazole, fluoroquinolones,
controlled studies antimicrobial treat- fosfomycin, levofloxacin, nitrofurantoin,
ment was significantly more effective ofloxacin, pivmecillinam, trimethoprim
than placebo, but on the other hand
showed more adverse events. The choice
of antibiotic depends on the spectrum and
susceptibility patterns of the uropatho- SUMMARY OF RECOMMENDATIONS
gens, its effectiveness for this indication,
its tolerability, its collateral effects and 1. Principles for choosing an antibiotic
cost. After a systematic literature search, for empiric therapy: the choice of an
Antibiotic treatment of uncomplicated urinary tract infection | 3.4 |
antibiotic for empiric therapy should and susceptibility patterns of

be guided by i) spectrum and suscep- uropathogens causing uncom-
tibility patterns of the uropathogens; plicated cystitis can be used as
ii) efficacy for this indication; iii) toler- guide for empiric therapy (GoR B).
ability; iv) collateral effects; v) cost; However, S. saprophyticus is to be
and vi) availability (GoR A). less considered in acute pyelone-
phritis as compared to acute cysti-
2. Uncomplicated cystitis
tis (GoR B).
2.1 Antibiotic therapy is recom-
mended because clinical success 3.2 In mild and moderate cases of
is significantly more likely in acute uncomplicated pyelonephri-
women treated with antibiotics tis an oral therapy of 10–14 days
versus those treated with placebo is usually sufficient.
(GoR A). 3.2.1 A fluoroquinolone for 7–10
2.2 According to available susceptibil- days can be recommended
ity patterns fosfomycin trometamol as first-line therapy if the
3 g as a single dose, pivmecillinam resistance rate of E. coli
400 mg for 3 days and nitrofuran- is still below 10% (GoR
toin macrocrystal 100 mg bid for A). If the fluoroquinolone
5 days, can be considered the first dosage is increased, the
drugs of choice in many countries, treatment can probably be
where available (GoR A). reduced to 5 days (GoR B).
2.3 Cotrimoxazole 160/800 mg bid for However, increasing rates
3 days or trimethoprim 200 mg for of fluoroquinolone resist-
5 days should only be considered ant E. coli also in the com-
as the first drug of choice in areas munity are already found
with known resistance rates of in some parts of the world
E. coli below 20% (GoR A). restricting the empiric use
of fluoroquinolones.
2.4 Alternative antibiotics are cipro-
floxacin 250 mg bid, ciprofloxacin 3.2.2 A 3rd generation oral cepha-
ER 500 mg qd, levofloxacin losporin, e.g. cefpodoxime
250 mg qd, norfloxacin 400 mg bid proxetil or ceftibuten, may
and ofloxacin 200 mg bid, each as be an alternative (GoR B).
a 3-day course (GoR B). However, However, available studies
collateral effects have to be con- demonstrated only equiva-
sidered (GoR B). lent clinical, but not micro-
biological, efficacy compared
2.5 Symptomatology may be sufficient with ciprofloxacin.
for routine follow-up (GoR C).
3.2.3 Because of increasing E. coli
2.6 In treated patients where resistance rates above 10%,
symptoms do not resolve and cotrimoxazole is not suitable
in patients with early relapse for empiric therapy in most
(<2 weeks) urine culture and anti- areas, but can be used
microbial susceptibility testing as test conform therapy
should be performed for guidance when susceptibility of the
of therapy (GoR B). pathogen is already known
3. Acute uncomplicated pyelonephritis (GoR B).
3.1 Because of lacking suitable sur- 3.2.4 Amoxiclav is not recom-
veillance studies the spectrum mended as a drug of first
171
choice for empiric oral ther- diagnostics and/or the patient has
apy of acute pyelonephritis clinical signs and symptoms of
(GoR B). It is recommended sepsis (GoR B)
when susceptibility testing 3.5 After improvement, the patient
shows a susceptible Gram- can be switched to an oral
positive organism (GoR C). regimen using one of the above-
3.2.5 In communities with high mentioned antibacterials, if active
rates of fluoroquinolone against the infecting organism, to
resistant and ESBL produc- complete the 1–2 week course of
ing E. coli (>10%) an initial therapy (GoR B).
empiric therapy with an 3.6 In women whose pyelonephritis
aminoglycoside or a carbap- symptoms do not improve within
enem has to be considered 3 days, or that resolve and then
until susceptibility test- recur within 2 weeks, a repeat
ing demonstrates that oral urine culture, antimicrobial sus-
drugs can also be used ceptibility testing and an appro-
(GoR B). priate investigation, such as renal
3.3 Patients with severe pyelonephri- ultrasound, computertomography
tis who cannot take oral medica- or scan, should be performed
tion because of systemic symptoms (GoR B). In the patient with no
like nausea and vomiting, have to urological abnormality, it should
be treated initially with one of the be assumed that the infecting
following parenteral antibiotics organism is not susceptible to the
3.3.1 a parenteral fluoroqui- agent originally used and an alter-
nolone, in communities with native tailored therapy should
resistance rates of E. coli be considered based on culture
to fluoroquinolones <10% results (GoR B).
(GoR B) 3.7 For those patients who have a
3.3.2 a 3rd generation cepha- symptomatic relapse with the
losporin, in communities same pathogen as the initial
with resistance rates of infecting strain, diagnosis of
ESBL producing E. coli uncomplicated pyelonephritis
<10% (GoR B) should be reconsidered and fur-
ther diagnostic steps are neces-
3.3.3 an aminopenicillin plus a sary (GoR C).
beta-lactamase-inhibitor in
case of a known susceptible 3.8 Routine post-treatment urinalysis
Gram-positive pathogen and urine cultures in an asymp-
(GoR B) tomatic patient may not be indi-
cated (GoR C).
3.3.4 an aminoglycoside or a
carbapenem in communities 4. Follow up
with resistance rates to fluo- 4.1 Uncomplicated Cystitis
roquinolones and/or ESBL 4.1.1 Routine post-treatment uri-
producing E. coli >10% nalysis or urine cultures in
(GoR B). asymptomatic patients are
3.4 Hospital admission should be not indicated (GoR B).
considered if complicating factors 4.1.2 In women whose symptoms
cannot be ruled out by available do not resolve by the end
172
of treatment and in those 1. INTRODUCTION AND DEFINITION

whose symptoms resolve but
recur within 2 weeks, urine Uncomplicated urinary tract infections
culture and antimicrobial (UTI) in otherwise healthy premenopau-
susceptibility tests should sal women comprise uncomplicated cys-
be performed (GoR B). titis and uncomplicated pyelonephritis.
4.1.3 For therapy in this situa- Uncomplicated UTI is classified as UTI
tion, one should assume that without relevant structural and func-
the infecting organism is tional abnormalities within the urinary
not susceptible to the agent tract (uropathies), without relevant kid-
originally used. Retreatment ney diseases (nephropathies), and with-
with a 7-day regimen using out relevant comorbidities which can
another agent should be lead to more serious outcomes and there-
considered (GoR C). fore require additional care (see chapter
4.2 Uncomplicated Pyelonephritis Introduction).
Since uncomplicated cystitis in females
4.2.1 Routine post-treatment is one of the most frequent infections in
urinalysis and urine cultures the community, each improvement of
in an asymptomatic patient management will have a high impact not
may not be indicated (GoR C). only on the quality of life of the individ-
4.2.2 In women whose pyelone- ual patient but also on the health system
phritis symptoms do not and thus on health economics. The rec-
improve within 3 days, ommended diagnostic steps are discussed
or resolve and then recur elsewhere (see chapter Colgan et al).
within 2 weeks, repeated Before antimicrobial therapy is consid-
urine culture and antimi- ered, the natural history of this infection
crobial susceptibility tests should be known and also the evidence
and an appropriate investi- based indication for antimicrobial ther-
gation, such as renal ultra- apy. The choice of an antibiotic agent
sound or scan, should be depends on the spectrum of uropatho-
performed (GoR B). gens, their antimicrobial susceptibility
4.2.3 In the patient with no uro- and whether a drug is suitable for this
logical abnormality, it should indication. This again depends on the
be assumed that the infect- dosage regimen, which form of admin-
ing organism is not suscep- istration is available, efficacy, tolerance
tible to the agent originally and collateral effects in comparison with
used and tailored treatment other drugs. Some of these aspects have
with a 2-week regimen using already been discussed in more details in
another agent should be section 4, but will briefly be summarized
considered (GoR B). in their context as far as necessary.
4.2.4 For those patients who
relapse with the same 2. METHODS
pathogen, the diagnosis of
uncomplicated pyelonephri- Up until 1997 the meta-analysis of
tis should be reconsidered. Warren et al [1], the basis for the guide-
Appropriate diagnostic steps lines of the Infectious Diseases Society
are necessary to rule out of America (IDSA) for the treatment of
any complicating factors uncomplicated UTI, was used also for this
(GoR C). article. The most relevant studies from
173
this meta-analysis are included in Tables antibiotic versus placebo treatment of

1 and 3. For the following period up until women with uncomplicated cystitis [7]
30 April 2008 two different searches were were also considered. The studies were
performed in MEDLINE: one for the rated according to the level of evidence
therapy of acute uncomplicated cystitis (LoE) and the grade of recommendation
and one for the therapy of uncomplicated (GoR) using ICUD standards (for details
pyelonephritis of adult non pregnant see Preface) [8–9].
women.
The following key words were used:
cystitis, urinary tract infection, pyelone- 3. UNCOMPLICATED CYSTITIS
phritis, kidney infection; with the follow-
ing limitations: included and published
3.1 Natural history and
in PubMed 1 January 1998 until 30 April
placebo-controlled studies
2008, human, female, adults 19 years
and older, clinical studies, randomised There seems to be no long-term adverse
controlled trials (RCT) or studies, meta- effects with respect to renal function
analysis, English, German, only publica- or increased mortality associated with
tions with abstracts. acute uncomplicated cystitis in the non-
From the MEDLINE search 1219 pub- pregnant population, even in women
lications were identified. After elimination who experience frequent recurrences.
of duplicates according to title and abstract Untreated cystitis rarely progresses to
27 prospective, randomised, controlled symptomatic upper tract infection. The
studies for the treatment of acute uncom- significance of lower tract infection in
plicated cystitis were found (Table 1). non-pregnant women seems to be limited
Two of them [2]–[3] were not considered, to the morbidity of symptoms caused by
because in the first study not only women the infection, which can lead to substan-
with uncomplicated UTI were included tial disruption of the lives of affected indi-
and in the second study only Japanese cri- viduals. In fact, most lower UTIs clear
teria were used which are quite different. spontaneously if untreated, although
Seven studies on oral treatment of symptoms may persist for several months.
uncomplicated pyelonephritis were found, In a prospective, placebo-controlled study
in an additional six studies (seven publi- (LoE 1b) [10], 288 of a total of 1143
cations) oral therapy followed after initial women consulting for symptoms sugges-
parenteral therapy, and in four studies tive of UTI were treated with placebo for
parenteral therapy only was performed seven days. Interestingly, the associations
(Table 3). In some of these studies acute between all symptoms and bacteriuria or
uncomplicated pyelonephritis in female bacterial counts were unpredictable.
patients was studied with the same pro- The spontaneous cure rate of symp-
tocol as complicated UTI/pyelonephritis. toms was 28% after the first week, and
Unfortunately substratification of the after five to seven weeks 37% had neither
patients was not always available. For symptoms nor bacteriuria. Considering
parenteral use, two earlier uncontrolled the high dropout rate after the first fol-
studies were added (cefepime, mero- low-up visit, the spontaneous cure rate of
penem). These publications were supple- symptoms and bacteriuria was calculated
mented by studies known by the authors to be 24% at the end of the study.
and considered relevant for this topic. In a recently published meta-analysis
In addition, three meta-analyses on on antibiotic versus placebo treatment
general aspects of antibiotic therapy for of women with uncomplicated cystitis by
acute uncomplicated cystitis [4–6] and Falagas and coworkers [7] among system-
one recently published meta-analysis on atic literature searches in the PubMed
174
Table 1 Relevant clinical trials on antimicrobial therapy of acute uncomplicated cystitis in adult non-pregnant females.
Test Dosage Dosage First author,

Antibiotic (mg) Duration Comparison (mg) Duration LoE year Ref Remarks
Amoxicillin/ 500/125 bid 3 days Ciprofloxacin 250 bid 3 days 2b Hooton 2005 [33] Amoxiclav was significantly inferior to
Clavulanic Acid ciprofloxacin
Cefdinir* 100 bid 5 days Cefaclor 250 tid 5 days 1b Leigh 2000 [37] Cefdinir as effective as cefaclor 250 mg
tid for 5 days, but more adverse events
Cefpodoxime 100 bid 3 days TMP-SMX 800/160 bid 3 days 1b Kavatha 2003 [38] Cefpodoxime as effective and as tolerable
proxetil as TMP-SMX for 3 days
Cefuroxime 125 bid 3 days Ofloxacin 100 bid 3 days 1b Naber 1993° [35] Cefuroxime similar effective and as toler-
axetil able as TMP-SMX. Study underpowered
to show equivalence
Ciprofloxacin 500 SD 1 day Norfloxacin 400 bid 3 days 1b Auquer 2002 [61] Ciprofloxacin as effective and as tolerable
as norfloxacin 400 mg bid for 3 days.
Ciprofloxacin 100 bid 3 days Ofloxacin 200 bid 3 days 1b McCarty 1999 [62] Ciprofloxacin as effective as ofloxacin
and TMP-SMX, but significantly better
TMP-SMX 800/160 bid
tolerable
Ciprofloxacin 100 bid 3 days Nitrofurantoin 100 bid 7 days 1b Iravani 1999 [63] Ciprofloxacin as effective as cotrimoxa-
zole and nitrofurantoin
TMP-SMX 800/160 bid 7 days
Ciprofloxacin 500 SD 1 day Norfloxacin 400 bid 7 days 1b Iravani 1995 [64] Ciprofloxacin 3 days as effective as 5–7
days and 7 days norfloxacin, respectively,
100–500 bid 3–7 days
but more effective as 500 mg SD
Ciprofloxacin 250 bid 3 days Ciprofloxacin 250 bid 7 days 1b Vogel 2004 [65] For treatment of postmenopausal, not in
long-term facilities, and otherwise healthy
women 3 days as effective as 7 days
Ciprofloxacin 250 bid 3 days Norfloxacin 400 bid 7 days 1b Arredondo- [66] Ciprofloxacin similarly effective as nor-
Garcia 2004 floxacin and TMP-SMX. Study underpow-
ered for equivalence. Highest drug-related
adverse events in the TMP-SMX group.
Antibiotic treatment of uncomplicated urinary tract infection
continued
175
| 3.4 |
Table 1 Relevant clinical trials on antimicrobial therapy of acute uncomplicated cystitis in adult non-pregnant females – cont’d
176
Chapter

Ciprofloxacin 500 qd 3 days Ciprofloxacin 250 bid 3 days 1b Henry 2002 [67] Ciprofloxacin XR 500 mg qd as effective
|3|
XR* and as tolerable as ciprofloxacin 250 mg

bid for 3 days
Ciprofloxacin 500 qd 3 days Ciprofloxacin 250 bid 3 days 1b Fourcroy 2005 [68] Ciprofloxacin XR 500 mg qdas effective as
XR* ciprofloxacin 250 mg bid for 3 days, but
better tolerable
Enoxacin 200 bid 3 days Enoxacin 600 SD 1 day 1b Backhouse [69] Enoxacin 3 days better than SD, but
1989° statistically underpowered
Fleroxacin* 400 SD 1 day Fleroxacin 200 qd 7 days 1b Iravani 1993 [70] Fleroxacin comparable clinical success,
but decreased microbiological eradication
Ciprofloxacin 250 bid 7 days
than 7 days
Fleroxacin* 200 SD 3 days Fleroxacin 200 qd 7 days 1b Iravani 1995° [71] Fleroxacin as effective and as tolerable
as 7 days fleroxacin 200 mg qd or
ciprofloxacin 250 mg bid (abstract)
Fosfomycin 3000 SD 1 day Pipemidic acid 400 bid 5 days 1b Jardin 1990 [72] Fosfomycin as effective as pipemidic acid
trometamol and better tolerable
Fosfomycin 3000 SD 1 day Norfloxacin 400 bid 7 days 1b Boerema 1990 [73] Fosfomycin as effective as norfloxacin,
trometamo l but more (not significant) adverse events.
Study underpowered to show equivalence
Fosfomycin 3000 SD 1 day Norfloxacin 400 bid 5 days 1b De Jong 1991 [74] Fosfomycin as effective as norfloxacin but
trometamol significantly less adverse events. Study
underpowered to show equivalence
Fosfomycin 3000 SD 1 day Nitrofurantoin 50 q6h 7 days 1b Van Pienbroek [75] Fosfomycin as effective as nitrofurantoin,
Urinary tract infections in special groups of adult patients
trometamol but more gastrointestinal sideeffects with

fosfomycin
Fosfomycin 3000 SD 1 day Not applicable - - 1a Lecomte 1996 [76] Meta analysis of 15 comparative studies:
trometamol TA in general as effective and as toler-
Lecomte 1997° [22]
able as the comparators if compared to
SD as well as to longer duration therapy;
TA long term results even better than
comparators
Fosfomycin 3000 SD 1 day Trimethoprim 200 bid 5 days 1b Minassian 1998 [23] Fosfomycin as effective and as tolerable
trometamol as trimethoprim
Fosfomycin 3000 SD 1 day Nitrofurantoin 100 bid 7 days 1b Stein 1999 [24] Fosfomycin as effective and as tolerable
trometamol macrocrystal as nitrofurantoin
Fosfomycin 3000 SD 1 day no comparator - - 1b Bonfiglio 2004 [77] Open, not comparative study by GPs, 387
trometamol female patients,18–65y, after 8–10 d
94.5% microbiological eradication and
88.9% clinical success (cure + improve-
ment), GI adverse events 4.3%
Gatifloxacin* 400 SD 1 day Gatifloxacin 200 qd 3 days 1b Richard 2002 [78] Gatifloxacin as effective and as tolerable
as gatifloxacin and ciprofloxacin for 3
days each
Gatifloxacin* 400 SD 1 day Gatifloxacin 200 qd 3 days 1b Naber 2004 [79] Gatifloxacin as effective and as tolerable
as gatifloxacin and ciprofloxacin for 3
days each
Levofloxacin 250 qd 3 days Ofloxacin 200 bid 3 days 1b Richard 1998° [32] Levofloxacin as effective and as tolerable
as ofloxacin, but better tolerable
[80]
Lomefloxacin* 400 qd 3 days Lomefloxacin 400 qd 7 days 1b Neringer 1992 [81] Lomefloxacin as effective and as tolerable
as norfloxacin, but less tolerable
Norfloxacin 400 bid 7days
Lomefloxacin* 400 qd 3 days Lomefloxacin 400 qd 7 days 1b Nicolle 1993 [82] Lomefloxacin as effective and as tolerable
as norfloxacin
Norfloxacin 400 bid 7days
Nitrofurantoin 50–100 q6h 3 days Nitrofurantoin 50–100 q6h 5–7 days 2b Goettsch 2004° [29] Nitrofurantoin 3 days less effective than
than 5–7 days
MC 100 bid 100 bid (MC)
Nitrofurantoin 100 bid 5 days TMP-SMX 800/160 bid 3 days 1b Gupta 2007 [31] Nitrofurantoin 5 days equivalent to 3 days
MC TMP-SMX
Nitrofurantoin 100 bid 7 days Trimethoprim 200 bid 7 days 1b Spencer 1994 [30] Bacterial elimination rate was low
MC (77%–83%) for all three comparators
(nitrofurantoin, trimethoprim, TMP-SMX)
Norfloxacin 400 bid 3 days Norfloxacin 400 bid 7 days 1b Inter-Nordic [83] Norfloxacin 3 days as effective and as
1988 tolerable as 7 days, but recurrence rate
higher with 3 days than with 7 days
177
| 3.4 |
continued
Table 1 Relevant clinical trials on antimicrobial therapy of acute uncomplicated cystitis in adult non-pregnant females – cont’d
178
Chapter

|3|
Norfloxacin 400 bid 3 days Norfloxacin 400 bid 7 days 1b Piipo 1990 [84] Norfloxacin 3 days as effective and as
tolerable as 7 days
Norfloxacin 800 qd 3 days Norfloxacin 400 bid 3 days 1b Pimentel 1998 [85] Norfloxacin 3 days as effective and as
tolerable as 800 mg qd
Ofloxacin 100 bid 3 days TMP-SMX 800/160 bid 3 days 1b Block 1987 [86] Ofloxacin as effective and as tolerable as
3 days TMP-SMX
Ofloxacin 200 bid 3 days TMP-SMX 800/160 bid 7 days 1b Hooton 1989 [87] Ofloxacin as effective and as tolerable as
7 days TMP-SMX
Ofloxacin 200 bid 3 days Ofloxacin 400 SD 1 day 1b Hooton 1991 [88] Ofloxacin as effective and as tolerable
as 7 days TMP-SMX ; ofloxacin SD less
effective
Pefloxacin* 800 SD 1 day Norfloxacin 400 bid 5 days 1a Naber 1994° [89] Pefloxacin as effective and as tolerable
as norfloxacin and TMP-SMX, but less
TMP-SMX 800/160 bid 3–7 days
tolerable. Pefloxacin should be taken with
meals to reduce gastrointestinal adverse
events
Pefloxacin* 400 bid 5 days Ofloxacin 200 bid 5 days 1b Kadiri 1999 [90] Pefloxacin as effective as ofloxacin, but
study underpowered to show equivalence
Pivmecillinam* 200 bid 7days Cephalexin 250 q6h 7 days 1b Menday 2000 [91] Pivmecillinam as effective and as tolerable
as cephalexin
Pivmecillinam* 200 bid 3 days Pivmecillinam 200 bid 7 days 1a Nicolle 2000° [25] 3 days TA less effective than 7 days
Urinary tract infections in special groups of adult patients
(review)
Pivmecillinam* 400 bid 3 days Norfloxacin 400 bid 3 days 1b Nicolle 2002 [26] Pivmecillinam clinically as effective as nor-
floxacin, but bacteriological less effective,
Menday 2002 [27]
however significantly less Candida vagini-
tis with pivmecillinam
Pivmecillinam* 200 bid-tid 7 days Placebo - 7 days 1b Ferry 2007 [11] Pivmecillinam 7 days more effective as
3 days, and both significantly more effec-
400 bid 3 days
tive than placebo
Rufloxacin* 400 SD 1 day Pefloxacin 800 SD 1 day 1b Jardin 1995 [92] Rufloxacin as effective as pefloxacin and
norfloxacin but less tolerable (more CNS
adverse events)
Sparfloxacin* 400, 200, 200 3 days Ofloxacin 200 bid 3 days 1b Henry 1998 [93] Sparfloxacin as effective as ofloxacin
qd 200 mg bid for 3 days, but higher rate
of phototoxicity. ofloxacin higher rate of
sleeplessness
Sparfloxacin* 400, 200, 200 3 days Ciprofloxacin 250 bid 7 days 1b Henry 1999 [94] Sparfloxacin as effective as ciprofloxacin
qd 250 mg bid for 7 days, and better than SD,
but higher rate of phototoxicity
Trimethoprim 200 bid 5–7 days (metaanalysis) - - 1a Warren 1999 [1] Trimethoprim recommended as standard,
if E. coli resistance is below 20%
Trimethoprim 200 bid 3 days Trimethoprim 200 bid 5–7 days 2b Goettsch 2004° [29] 3 days less effective than 5–7 days
Trimethoprim 200 bid 3 days Trimethoprim 200 bid 10 days 1b Gossius 1985° [95] Trimethoprim 3 days less adverse events
than 10 days
Trimethoprim 200 bid 3 days Trimethoprim 200 bid 5 days 1b Van Merode [96] Trimethoprim 3 days not different to 5 days,
2005 but follow up too short. In the abstract
number of patients and dosage are missing.
TMP-SMX 320/1600 SD 1 day TMP-SMX 160/800 bid 3 days 1b Gossius 1984 [97] TMP-SMX single dose as effective as 3–10
days, but less side effects
10 days
TMP-SMX 160/800 bid 3 days (metaanalysis) - - 1a Warren 1999 [1] TMP-SMX recommended as standard if
the E. coli resistance is below 20%; 3-day
course trend to higher recurrence rate,
but better tolerable than longer treatment
TMP-SMX 160/800 bid 3 days TMP-SMX 160/800 bid 3 days 2a Raz 2002 [40] Clinical and microbiological success in
E. coli S E. coli R female patients due to suceptible as com-
pared to resistant E. coli about twice as high
LoE-level of evidence; SD-single dose; qd-once daily; bid-twice daily; tid-three times daily; q6h-four times daily; TMP-SMX-cotrimoxazole; MC-macrocrystal.
*not available in all countries; ° not found in Warren 1999 and MEDLINE search 1998 until 2008.
179
| 3.4 |
database, Cochrane Central Register of guide therapeutic decisions (GoR A),

Controlled Trials (both up to 7 November although the trend away from routinely
2008), and Scopus (up to 12 November culturing patients with uncomplicated cys-
2008) as well as by hand-searching the titis may unfortunately lead to the lack of
bibliographies of relevant articles, five such data. The resistance pattern of E. coli
individual RCTs were considered as eli- strains causing an uncomplicated UTI,
gible for inclusion in their meta-analysis however, may vary considerably between
[11–15]. All five RCTs enrolled adult European regions and countries, so that
women with clinical symptoms suggestive no general recommendations are suitable
of a lower UTI. In all five included stud- throughout Europe. In an international
ies, the enrolled patients had documented survey of the antimicrobial susceptibility
bacteriuria. In the five studies different of uropathogens from uncomplicated UTI,
antibiotics (pivmecillinam, nitrofuran- the overall resistance rate was lowest in
toin, cefixime, amoxicillin, cotrimoxazole, the Nordic countries and Austria, and
and sulphadimidine) with different dos- highest in Portugal and Spain (LoE 2b)
age regimens (single dose, three-day or [16–17].
seven-day courses) were compared with A recently published international sur-
placebo. In all five RCTs, the patients veillance study on women with uncom-
allocated in the placebo treatment arms plicated cystitis was performed in nine
were treated with placebo for the same European countries and in Brazil [18]
durations as the patients allocated in and determined the susceptibility of
the respective antibiotic treatment arms. the uropathogens for nine oral anti-
The duration of follow up varied between biotics according to CLSI breakpoints
three days after treatment initiation and [19]. Escherichia coli was most fre-
three months after the end of treatment. quent causative pathogen (74.6%), fol-
Clinical success (cure and improvement) lowed by Enterococcus faecalis (4.0%),
was significantly more likely in women Staphylococcus saprophyticus (3.6%),
treated with antibiotics than in those Klebsiella pneumoniae (3.5%), and Proteus
treated with placebo. Antibiotics were mirabilis (3.5%). E. coli showed the high-
also superior to placebo regarding cure est rate of susceptibility to fosfomycin
(complete disappearance of all clinical (98.1%), followed by mecillinam (95.8%),
symptoms), microbiological eradication at nitrofurantoin (95.2%), and ciprofloxacin
the end of treatment and microbiological (91.8%). The lowest rates were found for
reinfection and relapse. However, adverse ampicillin (45.1%), cotrimoxazole (70.5%).
events were more likely to occur in anti- Amoxicillin combined with clavulanic acid
biotic-treated patients than in placebo- (amoxiclav) (82.1%), cefuroxime (82.5%),
treated women (four RCTs, 1068 patients, and nalidixic acid (82.5%) showed mod-
REM, OR=1.64, 95%CI=1.10–2.44). No dif- erate susceptibility rates. For the total
ference was found between the compared spectrum the order was for fosfomycin
treatment arms regarding study with- (96.4%), mecillinam (95.9%), ciprofloxacin
drawals from adverse events, the develop- (90.3%), and nitrofurantoin (87.0%). In all
ment of pyelonephritis and emergence of countries a susceptibility rate to E. coli
resistance. above 90% was found only for fosfomy-
cin, mecillinam, and nitrofurantoin; and
to the total spectrum only for fosfomycin
3.2 Bacterial spectrum and
(96.4%), and mecillinam (95.9%), but not
antimicrobial susceptibility
for nitrofurantoin (87.0%). The suscep-
Knowledge of the antimicrobial susceptibil- tibility rates varied significantly from
ity profile of uropathogens causing uncom- country to country, except for fosfomycin,
plicated UTIs in the community should mecillinam, and nitrofurantoin.
180
3.3 Treatment modalities cefadroxil, cefuroxime axetil, cefpodoxime

Short courses (1–3–5 days) of antimicro- proxetil, ceftibuten, pivmecillinam, riti-
bials are highly effective in the treatment penem axetil), fosfomycin trometamol, and
of acute uncomplicated cystitis in pre- nitrofurantoin (Table 1).
menopausal women (LoE 1a) [1, 20]. The following conclusions regarding
Short-course regimens are desirable antimicrobial therapy can be made con-
because of the improved compliance that sidering epidemiology especially in the
they promote, their lower cost, lower fre- light of the recent results of the ARESC
quency of adverse reactions in the indi- study [18], efficacy, tolerance and collat-
vidual patient and less collateral effects eral effects (see also Chapter 2.6).
on the environmental flora (see Chapter
2.6). However, in assessing the potential 3.3.1 Fosfomycin
advantages of short-course regimens, The findings on susceptibility/resistance
it is necessary to consider the potential of E. coli to fosfomycin closely resemble
added expense associated with treat- those from other surveys [16–17, 21].
ment failures or recurrences arising from Fosfomycin’s low level of resistance does
short-course therapy. It is also important not seem to be jeopardized by its high
to consider the potential psychological consumption in some areas [17]. A meta-
aspects of single-dose therapy; as symp- analysis of 15 comparative studies and
toms may not subside for two or three two additional large comparative stud-
days, the patient may have misgivings ies published later showed an equivalent
during this time about the “insufficient” clinical and bacteriologic efficacy and tol-
treatment provided to her. Such a sce- erance between fosfomycin trometanol
nario may result in unnecessary visits or (FT) 3 g as single dose and comparative
calls to the physician. drugs [22–24]. Therefore FT can be rec-
A wide variety of antimicrobial regimens ommended as a drug of choice in coun-
comprising different drugs, doses, sched- tries where it is available for the empiric
ules and durations have been used to treat therapy of uncomplicated cystitis in
these common bacterial infections. Only a women.
few of these regimens have been compared
directly in adequately designed studies. To
develop evidence-based guidelines for the 3.3.2 Mecillinam
antimicrobial therapy of uncomplicated After fosfomycin, mecillinam showed the
acute bacterial cystitis and pyelonephritis lowest resistance rates in all countries.
in women, a committee of the IDSA sys- In two studies pivmecillinam was either
tematically reviewed the English medical used as 200 mg for seven days or as 400
literature up to 1997 and developed guide- mg bid for three days [25–26]. Three
lines for the antimicrobial treatment of day pivmecillinam was compared with
acute uncomplicated bacterial cystitis and norfloxacin 400 mg bid for three days.
pyelonephritis in women [1]. Using this Norfloxacin was superior in terms of bac-
database and more recent publications teriologic outcome, although differences
(up until April 2008) the following anti- in clinical outcome were less marked. On
microbials were considered: trimethoprim the other hand adverse events, especially
(TMP), trimethoprim-sulfamethoxazole candida vaginitis, occurred less frequent
(TMP-SMX), fluoroquinolones (cipro- in patients treated with pivmecillinam
floxacin, enoxacin, fleroxacin, gatifloxacin, than in those treated with norfloxacin
levofloxacin, lomefloxacin, norfloxacin, [27]. Although not available in all coun-
ofloxacin, pefloxacin, rufloxacin), ß-lactams tries, pivmecillinam 400 mg twice daily
(amoxycillin, ampicillin-like compounds, for three days can also be considered as
181
one drug of choice in countries where it that the high proportion of E. coli strains
is available for the treatment of uncom- causing community-acquired UTI has
plicated cystitis in women. Because already acquired at least a first-step qui-
pivmecillinam short term therapy was nolone resistance.
not equivalent with norfloxacin in bac- In several studies ciprofloxacin has
teriological outcome, the recent Swedish been very effective in the treatment of
guidelines recommended a dosage of uncomplicated cystitis. It was used in
200 mg tid for five days as a compromise, various dosage regimens, mainly 100 mg
although no studies have been performed bid, 250 mg bid, or in the slow release
using this dosage regimen [28]. form 500 mg qd, each dosage for three
days. The same applies to other fluoroqui-
3.3.3 Nitrofurantoin nolones. According to a Cochrane analysis
[4] all fluoroquinolones suitable for the
In all countries, susceptibility rates of
treatment of UTI showed the same effec-
E. coli were above 90%, which did not
tiveness for this indication, but the toler-
apply to the total spectrum. However
ability differed. Levofloxacin, for example,
the resistance rates of the total spectrum
is used as 250 mg qd for three days and
stayed, below 10%. Thus, nitrofuran-
is as effective as ofloxacin 200 mg bid for
toin could also be an alternative drug for
three days, but has better tolerance [32].
empiric therapy but is not suitable for
However, due to the already consider-
short term therapy [29–30]. A 5-d therapy
ably increased rate of resistance to E. coli
with nitrofurantoin was equivalent to
in some countries, fluoroquinolones should
a three day therapy with cotrimoxazole
not be recommended as first-line drug
[31]. In this study the resistance rate of
for the empiric therapy of uncomplicated
E. coli for cotrimoxazole was not as high
lower UTI. However, if they are used (for
(12%). In some countries the usage of
any reason) they should not be used in low
nitrofurantoin is limited. In Germany, for
dosages (ciprofloxacin or ofloxacin 100 mg
example, nitrofurantoin can only be pre-
bid), as low doses may promote the emer-
scribed if no other effective or tolerable
gence of resistance according to expert
drugs are available. Under these precau-
opinion. These drugs should be reserved
tions nitrofurantoin macrocrystal 100 mg
for pyelonephritis and more complicated
bid for 5 days can be considered a good
infections in higher suitable dosages and
alternative for the treatment of uncom-
when susceptibility testing is available.
plicated cystitis in women.
3.3.4 Fluoroquinolones 3.3.5 Aminopenicillins

Comparable dosages considered, the sus- In the ARESC study [18] ampicillin
ceptibility/resistance rates of ciprofloxacin showed the highest resistance rates in all
can be extrapolated to other fluorquinolo- countries and can therefore not be recom-
nes recommended for the treatment of mended for empiric therapy. Amoxiclav
UTI. In the ARESC study [18] on average showed a wide range of susceptible E. coli
91.8% of E. coli were susceptible and 8.1% strains between 51.9% and 93.5% (mean
resistant to ciprofloxacin, with significant 82.1%). Similar susceptibility rates were
variations between different countries. In found for the total spectrum. Amoxiclav
Brazil, Hungary, Italy, Russia, and Spain is not suitable for short term therapy,
the rate of resistance was already over because a 3-d therapy was inferior to
10% (up to 12.9% in Russia). The vary- a three day therapy of ciprofloxacin
ing resistance of E. coli to nalidixic acid [33]. Therefore amoxiclav could only be
(on average 18.5%), from 6.3% in the regarded second choice for empiric ther-
Netherlands to 32.6% in Hungary, shows apy of uncomplicated cystitis.
182
3.3.6 Oral cephalosporines One sound study with cefpodoxime

The oral cephalosporines of group 2, proxetil (100 mg bd for three days) showed
e.g. cefuroxime, have improved activ- equivalent results to co-trimoxazole 960
ity against E. coli compared with those mg bid for three days in the treatment of
of group 1, e.g. cephalexin, cefaclor, uncomplicated cystitis [38].
cefadroxil, but lower activity compared
3.3.7 Cotrimoxazole
with those of group 3, e.g. cefpodoxime,
cefixime, ceftibutin [34]. In the ARESC A 3-d therapy with cotrimoxazole was
study [18] the overall susceptibility pat- considered standard in the past [30–31].
tern of E. coli and of the total bacterial According to the ARESC study [18] the
spectrum for cefuroxime was very simi- resistance rates to co-trimoxazole var-
lar to that of amoxiclav. There are, how- ied significantly between countries.
ever, country specific differences. Three The resistance rates of E. coli are above
day therapy with cefuroxime axetil is 20% in most countries tested (range:
not well established because studies 20.0–45.4%), except in France (12.2%)
have been underpowered to demonstrate as well as for the total spectrum (range:
its equivalence to cotrimoxazole [35]. 26.0–39.2%), except for France (13.4%),
It is also debatable whether the same the Netherlands (17.1%), and Poland
breakpoints can be applied for the oral (19.2%). For other studies see also chap-
form as for the parenteral form, because ter 2.2. Therefore, recommendations for
the absolute bioavailability of the cotrimoxazole (trimethoprim) have to
parenteral form is about six to 12 times be country specific. For most European
higher when the usual intravenous dose countries and in Brazil cotrimoxazole
of 750 mg is compared with the usual can no longer be recommended as first
oral dose of 250 mg (or 125 mg), assum- choice drug for empiric therapy of uncom-
ing an enteral reabsorption of about plicated cystitis. A resistance rate above
50%. Therefore much lower breakpoints 20% is recommended as threshold [1, 39],
are suggested in other systems for the because patients infected with resistant
oral form than for the parenteral form, E. coli strains showed significantly infe-
e.g. ≤1 mg/l as susceptible and >4 mg/l rior microbiologic and clinical outcomes
as resistant according to DIN 58940 as compared with those infected with sus-
[36], which means less susceptible/more ceptible strains [40]. This applies also for
resistant strains. In this case the resist- trimethoprim as monotherapy, which has
ance rate would increase from 2.3% to the advantage of a lower rate of adverse
17.5%, because 15.2% were intermediate events than cotrimoxazole due to the sul-
according to CLSI breakpoints, which phonamide part.
then become resistant if the DIN break-
points are used. 3.4 Conclusion for the treatment of
A treatment course with cefdinir 100 uncomplicated cystitis (Table 2)
mg bid for five days was as effective as Despite wide cross-country variability of
cefaclor 250 mg tid for 5 days, but had bacterial susceptibility/resistance rates
more adverse events [37]. The clinical to the other antimicrobials tested, fosfo-
cure rates by patient at test of cure (5–9 mycin, mecillinam, and nitrofurantoin
days post-treatment) were 91.3% and have preserved their in vitro activity in
93.0%, respectively, and the microbiologi- all countries investigated. They represent
cal response rates by patient were 84.7% effective options for the empiric therapy
and 79.7%, respectively, while the resist- of patients with uncomplicated lower
ance rate of admission pathogens was UTI (cystitis) (GoR A). Other antibiotics,
higher for cefaclor than for cefdinir. such as cotrimoxazole, fluoroquinolones,
183
Table 2 Recommended empiric antimicrobial therapy in acute uncomplicated cystitis in otherwise healthy premenopausal
women.
Substance Daily dosage Duration
Fosfomycin trometamol° 3000 mg SD 1 day
Nitrofurantoin 50–100 mg q6h 5–7 days
Nitrofurantoin MC 100 mg bid 5–7 days
Pivmecillinam* 400 mg bid 3 days
Pivmecillinam* 200 mg bid 7 days
Alternatives:
Ciprofloxacin 250 mg bid 3 days
Levofloxacin 250 mg qd 3 days
Norfloxacin 400 mg bid 3 days
Ofloxacin 200 mg bid 3 days
Cefpodoxime proxetil 100 mg bid 3 days
If local resistance pattern is known (E. coli resistance <20%):

TMP-SMZ 160/800 mg bid 3 days
Trimethoprim 200 mg bid 5 days
MC= macrocrystal; °not in all countries available.

*not in all countries available.
cephalosporins and amoxiclav, should For therapy in this situation, one should
be considered as second choice taking assume that the infecting organism is
account of the local susceptibility pat- not susceptible to the agent originally
terns of the uropathogens, tolerability, used. Retreatment with a 7-day regimen
and collateral effects (GoR B). using another agent should be considered
(LoE 4, GoR C).
3.5 Follow up
Symptomatology may be sufficient for 4. ACUTE UNCOMPLICATED
routine follow-up (LoE 4, GoR C). Routine PYELONEPHRITIS
post-treatment urinalysis or urine cul-
tures in asymptomatic patients are not The appearance of uncomplicated
indicated (LoE 4, GoR B) because the pyelonephritis can be mild, moderate, but
benefit of detecting and treating asymp- in some cases severe and septic.
tomatic bacteriuria in healthy women
has been demonstrated only in preg-
4.1 Diagnosis
nancy and prior to urological instrumen-
tation or surgery [41]. In women whose Acute pyelonephritis is suggested by
symptoms do not resolve by the end of flank pain, nausea and vomiting, fever
treatment and in those whose symptoms (>38°C), or costovertebral angle tender-
resolve but recur within two weeks, urine ness, and may occur with or without
culture and antimicrobial susceptibil- cystitis symptoms. The presentation of
ity testing should be performed (GoR B). an acute uncomplicated pyelonephritis
184
usually varies from mild to moderate ill- Assuming the susceptibility pat-
ness. A life-threatening condition with tern found in the ARESC study [18] for
multi-organ system dysfunction, includ- uncomplicated cystitis is similar to that
ing sepsis syndrome with or without of uncomplicated pyelonephritis (for
shock and renal failure, must be consid- which no systematic surveillance studies
ered a complicated case. The diagnostic are available), the following conclusions
procedure is discussed in more details in can be drawn for initial therapy from
chapter 3.2. their analysis.
Unfortunately, no systematic surveil- In Table 3, the antimicrobial treatment
lance studies for uncomplicated pyelone- options of acute uncomplicated pyelone-
phritis have been published. From the phritis in adult pre-menopausal non-
published clinical trials, however, it can pregnant women according to LoE and
be seen that the bacterial spectrum and GoR as defined in chapter Preface are
the susceptibility pattern is similar for summarized. However, in some studies
uncomplicated pyelonephritis and cysti- acute uncomplicated pyelonephritis was
tis. However, S. saprophyticus seems to treated with the same protocol as compli-
be less frequent in acute pyelonephritis cated UTI/pyelonephritis and substratifi-
as compared to acute cystitis. cation was not always available.
4.2 Treatment of uncomplicated 4.2.1 Trimethoprim-sulphamethoxazole

pyelonephritis (TMP-SMX)
4.2.1.1 TMP-SMX can only be consid-
There are no placebo-controlled studies
ered as empiric therapy in communities
available because, according to clinical
in which the resistance rate of E. coli to
experience, early and effective antimi-
TMP is known to be <10%. In this case,
crobial therapy is considered to be the
two weeks of therapy with TMP-SMX
treatment of choice to prevent prolonga-
for acute uncomplicated pyelonephritis
tion of the infection and more serious
appears to be adequate for the majority
outcome.
of women [43](LoE Ib).
Of several hundred articles screened
by the IDSA group [1], only five were pro-
4.2.1.2 In communities in which the
spective, randomized, controlled trials
resistance rate of E. coli to TMP is >10%,
[42–46]. One study [42] used a variety
TMP-SMX should only be considered if
of antimicrobial regimens and therefore
the pathogen is known to be suscepti-
was not suitable for further evaluation.
ble, e.g. for a step down therapy from
Eleven randomized studies [47–58] were
parenteral to oral therapy.
published thereafter. In some of these
studies acute uncomplicated pyelone-
phritis was treated with the same pro- 4.2.2 Fluoroquinolones
tocol as complicated UTI/pyelonephritis. A fluoroquinolone can be recommended
Unfortunately substratification was as drug of choice for empirical therapy
not always available. For parenteral, if the resistance rate of E. coli is below
two earlier uncontrolled studies were 10%. A 7-day regimen of ciprofloxacin,
added (cefepime,meropenem) [48, 50]. 500 mg twice daily, showed a signifi-
Inclusion of such studies seems to be jus- cantly higher rate of bacterial eradica-
tified, because in general the therapeutic tion and a lower rate of adverse effects
outcome in female patients with acute when compared with a 14-day ther-
uncomplicated pyelonephritis is usually apy using TMP-SMX, 960 mg twice
more favourable than in patients with daily (LoE 1b) [58]. The higher efficacy
complicated UTI. with ciprofloxacin was mainly due to
185
Table 3 Relevant clinical trials on therapy of acute uncomplicated pyelonephritis. In some trials patients with acute uncomplicated pyelonephritis were treated with the same protocol as
186
patients with complicated pyelonephritis or urinary tract infections, but substratification was not possible.
IV/
Test antibiotic Dosage Duration Comparison Dosage Duration LoE Author, year Ref oral Remarks
Ampicillin 30 g per day for 7 days Ampicillin moderate 1 month 1b Ode 1980 [44] IV Ampicillin in excessive high
3 days, then 20 dosages dosage was inferior to nor-
g per day for 4 (abstract) mal dosage, conventional
days therapy relatively bad results
(Cure 9/21), low number
Cefepime 1 g bid 8.5 days no comparator - - 4 Giamarellou [48] IV Cefepime 1g bid is safe and
(mean) 1993 effective as other parenteral
cephalosporins for the treat-
ment of acute bacterial UTI
and serious bacterial infec-
tions (historical comparison)
Cefixime 400 mg qd 10 days Ceftriaxone 1 g qd 10 days 1b Sanchez 2002 [55] IV/ After initial ceftriaxone i.v.
Initial Ceftriaxone 1g oral oral cefixime as effective as
IV ceftriaxone 1g qd i.v. for
10 days in women with acute
uncomplicated pyelonephritis
Ciprofloxacin oral 500 mg bd 7 days TMP-SMZ 800/160 mg 14 days 1b Talan 2000 [58] IV/ Ciprofloxacin significantly
+ Ciprofloxacin IV + 400 mg IV bd + Cetriaxone IV bid + 1 g IV qd oral more effective than ceftri-
axone/cotrimoxazole for 10
days, also with trend of bet-
ter tolerance
Ciprofloxacin XR* 1000 mg qd 7–14 days Ciprofloxacin 500 mg bid 7–14 days 1b Talan 2004 [56– oral Cefpodoxime as effective
57] and as tolerable as 7–10 days
ciprofloxacin 500 mg bid
Cefpodoxime 200 mg bid 10 days Ciprofloxacin 500 mg bid 10 days 1b Naber 2001 [52] oral Clinically, but not micro-
proxetil biologically as effective as
ciprofloxacin 500 mg bid
Ceftibuten 200 mg bid 10 days Norfloxacin 400 mg bid 10 days 1b Cronberg 2001 [47] IV/ Clinically, but not micro-
+ initial + 750 mg bid + initial + 750 mg bid oral biologically as effective as
Cefuroxime Cefuroxime norfloxacin 400 mg bid for
10 days. Both treatment
regimens after initial cefuro-
xime i.v.
Doripenem IV 0.5 g tid 10 days Levofloxacin IV 250 mg qd 10 days 1b Naber 2009 [98] IV/ Doripenem 0.5 g tid is as
+ followed by oral + 250 mg qd + followed by oral effective as levofloxacin
(optional) oral 250 mg qd for the treatment
(optional) of uncomplicated pyelone-
Levofloxacin
Levofloxacin phritis and complicated UTI
Ertapenem 1.0 g qd 4 ( 2–14) Ceftriaxone (after 1 g qd 4( 2–14) 1b Wells 2004 [99] IV/ Ertapenem 1 g qd is as ef-
(after >3 days days >3 days possible days oral fective as ceftriaxone 1 g qd
possible oral oral therapy, usu- for the treatment of uncom-
therapy, usually ally ciprofloxacin) plicated pyelonephritis and
ciprofloxacin) complicated UTI followed by
appropriate oral therapy
Gatifloxacin* 400 mg qd vs 10 ( 5–14) Ciprofloxacin 500 mg bid 10 ( 5–14) 1b Naber 2004 [51] oral Levofloxacin as effective and
200 mg qd days days as tolerable as ciprofloxacin
500 mg bid
Levofloxacin 250 mg qd 10 days Ciprofloxacin 500 mg bid 10 days 1b Richard 1998 [54] oral Levofloxacin as effective and
as tolerable as ciprofloxacin
500 mg bid (underpowered)
Levofloxacin 250 mg qd 10 days Lomefloxacin 400 mg qd 10 days 1b Richard 1998 [54] oral Levofloxacin as effective and
as tolerable as lomefloxacin
400 mg qd (underpowered)
Levofloxacin IV/oral 750 mg qd 5 days Ciprofloxacin IV/ 400/500 mg 10 days 1b Klausner 2007 [49] IV/ Levofloxacin as effective and
(IV-optional) oral (IV optional) bid Peterson 2008 oral as tolerable as ciprofloxacin
[53]
IV/ 400/500 mg bid for 10 days.
oral Both treatment regimens
after initial i.v. therapy. Both
studies refer to the same
cohort.
187
continued
Table 3 Relevant clinical trials on therapy of acute uncomplicated pyelonephritis. In some trials patients with acute uncomplicated pyelonephritis were treated with the same protocol as
188
patients with complicated pyelonephritis or urinary tract infections, but substratification was not possible – cont’d
IV/
Test Antibiotic Dosage Duration Comparison Dosage Duration LoE Author, year Ref oral Remarks
Meropenem 1 g tid ? Ceftazidime + 2 g tid ? 4 Mouton 1995 [50] IV Meropenem is as well toler-
Amikacin 15 mg/kg per ated and as effective as the
day combination of ceftazidime
plus amikacin in the treat-
ment of serious infections
(including pyelonephritis)
Piperacillin/ 2/0.5 g tid 5–14 days Imipenem/ 0.5/0.5 g tid 5–14 days 1b Naber 2002 [100] IV Piperacillin/Tazobactam
Tazobactam Cilastatin 2/0.5 g tid is as effective as
imipenem/cilastatin 05/05 g
tid for the treatment of un-
complicated pyelonephritis
and complicated UTI
Pivampicillin(PA)/ 0.5 gPA/0.4 1 week Pivampicillin(PA)/ 0.5 gPA/0.4 3 weeks 1b Jernelius 1988 [45] oral 1-week treatment is too
Pivmecillinam(PM) gPM tid Pivmecillinam(PM) gPM tid short. Side-effects more com-
mon with 3-week treatment
(0.5 gPA/0.4 gPM tid 1 week
+ 0.25 gPA/0.2 gPM tid 2
week) and bacteriological
success still low (69%)
TMP-SMX 160/800 mg bid 14 days TMP-SMX 160/800 mg 6 weeks 1b Stamm 1987 [43] oral As effective as TMP-SMX for
bid 6 weeks, but better tolerable
TMP-SMX + 160/800 mg bid 14 days Ampicillin + IV 1 g q6h for 14 days 1b Johnson 1991 [46] oral Cotrimoxazole more effec-
initially Gentamicin IV for 3 days, initially 3 days, then tive than ampicillin due to
then oral Gentamicin oral 500 mg 1) more resistant strains and
+ GM tid q6h 2) increased recurrence even
+ GM tid with susceptible strains
*not available in all countries; TMP = trimethoprim; SMX = sulphamethoxazole.

TMP-resistant E. coli strains. In clinical In areas with a rate of E. coli resistance

trials, the following fluoroquinolones were to fluoroquinolones >10% and in situations
comparable to conventional ciprofloxacin in which fluoroquinolones are contrain-
500 mg twice daily, ciprofloxacin extended dicated (e.g. pregnancy, lactating women,
release formulation (1000 mg once daily), adolescence), group three oral cepha-
gatifloxacin (400 mg once daily), levo- losporin, such as cefpodoxime proxetil or
floxacin (250 mg twice daily), and lom- ceftibutin, or an aminopenicillin plus a
efloxacin (400 mg once daily) (LoE 1b) BLI, e.g. amoxiclav, sultamicillin (ampicil-
[51, 54, 56]. An interesting concept with lin + sulbactam), for a pyelonephritis due to
fluoroquinolones is the use of higher dos- a Gram-positive pathogen is recommended,
age and shorter treatment duration. In a either for initial use, or if a patient has to
double-blind, randomized study [49, 53] be switched to an oral regimen (LoE 3).
levofloxacin 750 mg once-daily for five
days was as effective and tolerable as cip- 4.3 Conclusion of treatment
rofloxacin 400/500 mg twice-daily for 10
days in the treatment of complicated UTI An algorithm of the clinical manage-
and acute pyelonephritis. In this study ment of acute pyelonephritis is shown
most of the patients were females with in Figure 1. (modified according to EAU
uncomplicated pyelonephritis. guidelines 2008 [59]
4.2.3 Aminopenicillins 4.3.1 Mild and moderate cases of

uncomplicated pyelonephritis
Aminopenicillins (mono without beta-
(Table 4)
lactamase inhibitors), e.g. ampicillin,
amoxicillin, are not longer suitable for In mild and moderate cases of acute uncom-
the empiric therapy of acute uncompli- plicated pyelonephritis an oral fluoroqui-
cated pyelonephritis (GoR A), because nolone for seven days can be recommended
resistance rates are generally too high as first-line therapy (GoR A). In situations
and TMP-SMX is preferred to ampicillin where a fluoroquinolone is not indicated (see
(LoE 1b) [46]. No controlled study used above), a group three oral cephalosporin,
TMP alone. e.g. cefpodoxime proxetil, ceftibuten, may
be an alternative for empirical therapy
4.2.4 Aminopenicillins plus BLI and oral (GoR B). Cotrimoxazole or an aminopeni-
cephalosporins cillin plus a BLI should only be used if the
pathogen is known to be susceptible, e.g. for
For an aminopenicillin plus a BLI, e.g. step down therapy after initial parenteral
amoxiclav, as well as for most group two therapy (GoR B). In communities with a
and group three oral cephalosporins, high rate of ESBL in E. coli (>10%) an ini-
there are no sufficiently powered com- tial therapy with an aminoglykoside or a
parative studies versus a fluoroquinolone carbapenem has to be considered until sus-
or TMP-SMX. In one prospectively rand- ceptibility testing is available demonstrat-
omized study, cefpodoxime proxetil 200 ing that other, preferably oral, drugs (see
mg twice daily compared to ciprofloxacin above) can also be used.
500 mg twice daily (LoE 1b) [52] and in
another prospectively randomized study
with ceftibuten 200 mg once daily com- 4.3.2 More severe cases of acute
pared with norfloxacin 400 mg twice uncomplicated pyelonephritis
daily [47], each treatment for 10 days, the (Table 4)
cephalosporins showed equivalent clinical Patients with severe pyelonephritis who
but not microbiological outcome as the cannot take oral medication because of
fluoroquinolones. the severity of the infection with nausea
189
Symptoms/signs of
pyelonephritis
fever, flank pain
pyuria, leucozytosis
Nausea
vomiting
instability
NO YES
Urinalysis und urine

Urinalysis und urine
culture sonography
culture sonography
(in all patients)
(if anomaly suspected)
Consider hospitalisation
outpatient therapy
and initial parenteral
initial oral therapy
therapy for 1-3 days
Ciprofloxacin or levofloxacin
Aminopenicillin plus BLI Ciprofloxacin or
Cephalosporin Gr. 3 e.g.
levofloxacin
cefpodoxime proxetil Aminopenicillin-or
TMP-SMX, only if piperacillin plus BLI
susceptibility of Cephalosporin (Gr.3)
pathogen is known Aminoglycosid
(not for empiric therapy)
Clinical improvement No clinical improvement Clinical improvement No clinical improvement

within 72 hrs or even detoriation within 72 hrs or even detoriation
Switch to oral therapy
Oral therapy continued Switch to parenteral Parenteral therapy
(test conform)
(test conform) Therapy (test conform) continued (test conform)
Outpatient therapy
Total duration of therapy Total duration of therapy
1-2 Weeks Hospitalisation 1-2 Weeks Hospitalisation continued
Urine culture at day 4 Additional urine and blood Urine culture at day 4 Additional urine and blood
of therapy (optional) cultures urological investigation of therapy (optional) cultures urological
Urine culture at 5-10 days for complicating factors Urine culture at 5-10 days investigation for complicating
after end of therapy drainage, in case of after end of therapy factors drainage, in case
Urological investigation if obstruction or abscess Urological investigation if of obstruction or abscess
atypical course or Total duration of therapy atypical course or complicating Total duration of therapy
complicating factors suspected 2-3 Weeks factors suspected 2-3 Weeks
BLI = beta-Lactamase inhibitor; TMP = Trimethoprim; SMX = Sulfamethoxazole
Figure 1. Clinical management of acute pyelonephritis (modified according [59].
190
Table 4 Recommended initial empiric antimicrobial therapy in acute uncomplicated pyelonephritis (AUP) in otherwise healthy
premenopausal women. Limitations for each antimicrobial substance see text.
I. Oral therapy in mild and moderate cases
Substance Daily dosage Duration Reference
Ciprofloxacin1 500–750 mg bid 7–10 days [58]
Levofloxacin1 250–500 mg qd 7–10 days [54]
Levofloxacin 750 mg qd 5 days [49, 53]
Alternatives (only clinical but not microbiological equivalent efficacy as compared with
fluoroquinolones):
Cefpodoxime proxetil 200 mg bid 10 days [52]
Ceftibuten 400 mg qd 10 days [47]
Only if the pathogen is known to be susceptible (not for initial empiric therapy):
TMP-SMZ 160/800 mg bid 14 days
Amoxiclav 2,3
0.5/0.125 g tid 14 days
II. Initial parenteral therapy in severe cases
After improvement, the patient can be switched to an oral regimen using one of the above-mentioned antibacterials (if
active against the infecting organism) to complete the 1–2 weeks’ course of therapy. Therefore only daily dosage and no
duration is indicated:
Substance Daily dosage Reference
Ciprofloxacin 400 mg bid [58]
Levofloxacin 1
250–500 mg qd [54]
Levofloxacin 750 mg qd [49]
[58]
Alternatives:
Cefotaxime2 2 g tid
Ceftriaxone 1,4
1–2 g qd [99]
Ceftazidime2 1–2 g tid [50]
Cefepime1,4 1–2 g bid [48]
AmoxiClav2,3 1.5 g tid
Piperacillin/ Tazobactam1,4 2. 5–4.5 g tid [100]
Gentamicin 2
5 mg/kg qd
Amikacin2 15 mg/kg qd
Ertapenem4 1 g qd [99]
Imipenem/Cilastatin 4
0.5/0.5 g tid [100]
continued
191
Table 4 Recommended initial empiric antimicrobial therapy in acute uncomplicated pyelonephritis (AUP) in otherwise healthy
premenopausal women. Limitations for each antimicrobial substance see text – cont’d
Substance Daily dosage Reference
Alternatives:
Meropenem4 1 g tid [50]
Doripenem4 0.5 g tid [98]

1
lower dose studied, but higher dose recommended by experts.
2
not studied as monosubstance in AUP.
3
mainly for Gram positive pathogens.
4
same protocol for AUP and complicated UTI (stratification not always possible).
and vomiting, have to be treated initially 4.4. Follow up

with suitable parenteral antibiotics, such Routine post-treatment urinalysis and
as a fluoroquinolone (in communities with urine cultures in an asymptomatic patient
resistance rates of E. coli to fluoroquinolo- may not be indicated (GoR C). In women
nes <10%), an aminopenicillin plus a BLI whose pyelonephritis symptoms do not
(in case of a susceptible Gram-positive improve within three days, or resolve and
pathogen), a group three cephalosporin then recur within two weeks, repeated
(in communities with resistance rates of urine culture, antimicrobial susceptibility
ESBL <10% of E. coli), an aminoglycoside testing and an appropriate investigation,
and a carbapenem in communities with such as renal ultrasound or scan, should
a rate of ESBL >10% of E. coli. (GoR B). be performed (GoR B). In the patient
Hospital admission should be considered, with no urological abnormality, it should
especially when complicating factors can- be assumed that the infecting organism
not be ruled out by available diagnosis not susceptible to the agent originally
tics and/or the patient has clinical signs used and tailored treatment with a two-
and symptoms of sepsis (GoR B). In gen- week regimen using another agent should
eral, also severe cases of uncomplicated be considered (GoR B). For those patients
pyelonephritis can be treated with antibi- who relapse with the same pathogen the
otics alone. diagnosis of uncomplicated pyelonephritis
After improvement, the patient can be should be reconsidered. Appropriate diag-
switched to an oral regimen using one of nostic steps are necessary to rule out any
the above-mentioned antibacterials (if complicating factors (GoR C).
active against the infecting organism) to
complete the 1–2 week course of therapy
(GoR B).
Although approximately 12% of patients 5. FURTHER RESEARCH
hospitalized with acute uncomplicated
pyelonephritis have bacteraemia [60], it is Since the recommendations for empiric
common practice to obtain blood cultures therapy depend very much on the epide-
only if the patient appears ill enough to miology and bacterial susceptibility pat-
warrant hospitalization. There is no evi- terns, valid and timely updated local or
dence that bacteraemia has prognostic regional results need to be available for a
significance or warrants longer therapy rational decision. It is not clear how this
in an otherwise healthy individual with can be managed, if on the other hand no
pyelonephritis. routine urine culture is recommended
192
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199
|3.5|

in pregnancy
Alexander D. Griffin1, Richard Grady2, Thomas M. Hooton1*
1
University of Miami Miller School of Medicine, Miami, FL
2
University of Washington School of Medicine, Seattle, WA
*Corresponding author: Thomas M. Hooton, M.D., Professor of Medicine, University of Miami Miller School of Medicine
1120 NW 14th Street, Suite 1144, Miami, FL 33136, USA,
Tel +1 (305) 243 2576, Fax +1(305) 243 4037, THooton@med.miami.edu
ABSTRACT of screening is governed by the cost of

screening and the prevalence of asymp-
Urinary tract infection (UTI) in pregnant tomatic bacteriuria, which varies among
women is common and has a spectrum different socioeconomic groups [3].
that ranges from lower tract infection Antimicrobial selection is dictated by
(asymptomatic bacteriuria and acute cys- drug safety concerns and urine culture
titis) to upper tract infection (pyelone- susceptibility data in the face of emerging
phritis). The epidemiology of UTI is resistance.
similar to that in non-pregnant women, Acute pyelonephritis during pregnancy
although the anatomic and physiologic is associated with preterm delivery, yet
changes of the urinary tract in pregnancy there are conflicting data on fetal out-
result in an increased susceptibility to comes [4]. Although pregnant women with
progress from asymptomatic bacteriuria acute pyelonephritis have traditionally
to pyelonephritis [1]. Asymptomatic bac- been hospitalized for parenteral therapy,
teriuria is associated with an increased outpatient antimicrobial therapy has been
risk of pyelonephritis and adverse out- shown to be safe and effective for selected
comes of pregnancy [1–2]. Such outcomes women prior to the third trimester [5].
are significantly reduced by appropriate A minority of UTI in pregnancy is com-
antimicrobial treatment of asymptomatic plicated by factors which warrant drain-
bacteriuria early in pregnancy [1–2]. age or longer courses of treatment. Such
Thus, antepartum screening is recom- factors include obstruction of urinary
mended to detect asymptomatic bacteriu- drainage or compromised immunity. Such
ria in pregnancy. The cost effectiveness patients may require drainage and/or
Urinary tract infections in pregnancy | 3.5 |
longer durations of antibiotics than is Follow-up

normally recommended.
In summary, urinary tract infections 6. Urine cultures should be obtained
are common in pregnancy and contrib- soon after completion of therapy for
ute to morbidity in the mother and pos- asymptomatic bacteriuria and sympto-
sibly the fetus. Appropriate diagnosis and matic UTI in pregnancy (GoR A).
treatment modalities are an important
aspect of optimal maternal health care. Prophylaxis
Key words: bacteriuria, asymptom- 7. Post-coital prophylaxis should be
atic bacteriuria, cystitis, pyelonephritis, considered in pregnant women with a
pregnancy history of frequent urinary tract infec-
tions prior to the onset of pregnancy
to reduce their risk of UTI (GoR B).
SUMMARY OF RECOMMENDATIONS
Treatment of pyelonephritis
Definition of significant bacteriuria
8. Outpatient management with
1. In an asymptomatic pregnant appropriate antibiotics should be
woman, bacteriuria is considered considered in women with pyelone-
significant if two consecutive voided phritis in pregnancy provided symp-
urine specimens grow ≥105 cfu/ml of toms are mild and close follow-up is
the same bacterial species on quan- feasible (GoR A).
titative culture; or a single catheter-
ized specimen grows ≥105 cfu/ml of a Complicated UTI
uropathogen (GoR A).
2. In a pregnant woman with symptoms 9. Prolonged courses of antibiotic ther-
compatible with UTI, bacteriuria is apy (7–10 days) should be considered
considered significant if a voided or in this patient population (GoR B).
catheterized urine specimen grows When indicated, ultrasonography or
≥103 cfu/ml of a uropathogen (GoR B). magnetic resonance imaging should
be used preferentially in this patient
Screening population to decrease risk to the
fetus (GoR B).
3. Pregnant women should be screened
for bacteriuria during the first trimes- 1. INTRODUCTION
ter (GoR A).
Treatment of asymptomatic Urinary tract infection in pregnancy

bacteriuria encompasses asymptomatic bacteriuria,
lower tract infection (acute cystitis), and
4. Asymptomatic bacteriuria detected in upper tract infection (acute pyelonephri-
pregnancy should be eradicated with tis). Each of these entities is reviewed
antimicrobial therapy (GoR A). here. In addition, the concept of compli-
cated urinary tract infection in pregnancy
Duration of therapy and resultant special considerations are
discussed. The overall object of this chap-
5. Short courses of antimicrobial therapy ter is to provide a broad review of aspects
(3 days) should be considered for the of urinary tract infection in pregnancy
treatment of asymptomatic bacteriuria with a focus on evidence-based recom-
and cystitis in pregnancy (GoR A). mendations for diagnosis and treatment.
201
2. METHODS and disadvantaged socioeconomic sta-

tus are also significant risk factors [1,
A systematic literature search was per- 3]. Bladder catheterization should be
formed in PubMed over the last 60 years avoided in pregnancy due to an associa-
using the following key words: “asympto- tion with the development of bacteriuria
matic bacteriuria in pregnancy”, “urinary [1]. Enterobacteriaceae comprise approxi-
tract infection in pregnancy”, “pyelone- mately 95% of urine isolates, of which
phritis in pregnancy”, and “complicated E. coli is the most common pathogen [10].
urinary tract infection”. Search results Gram positive organisms including Group
were limited to studies of pregnant B Streptococci and Staphylococcus sapro-
women written in the English language. phyticus are isolated in a small propor-
A total of 1,462 publications were found tion of women with bacteriuria [1].
and subsequently screened by title and, Acute cystitis has been shown to com-
when appropriate, abstract. Eighty-four plicate 1%–2% of pregnancies, with a
publications that the authors felt were microbial spectrum similar to that of
applicable to the subject matter were asymptomatic bacteriuria in pregnancy
included for analysis. These publications and uncomplicated UTI in non-pregnant
were supplemented by an additional 31 women [9, 11]. In contrast to the impact
publications obtained from their bibliog- on pyelonephritis, screening and treat-
raphies. For complicated UTI, an addi- ment programs to eradicate asymptomatic
tional 114 publications were found and bacteriuria in pregnancy do not seem to
screened by title and abstract. Of these, reduce the incidence of cystitis. In 9,734
10 publications were included in this pregnant women in a US Air Force base
review and were supplemented by pub- hospital over six years, 126 (1.3%) devel-
lications mentioned in the selected pub- oped acute cystitis, mostly in the second
lications or known by the authors. The trimester [11]. The majority had negative
studies were rated according to the level initial screening cultures (64%), while
of evidence (LoE) and the grade of recom- 31% had acute cystitis on initial presen-
mendation (GoR) using ICUD standards tation. This was in contrast to those who
(for details see Preface) [6–7]. developed pyelonephritis, in whom only
20% had a negative initial screening cul-
ture [11]. No correlation has been estab-
3. EPIDEMIOLOGY lished between acute cystitis of pregnancy
and increased risk of low birth weight,
The prevalence and microbiology of bac- preterm delivery or pyelonephritis [10].
teriuria are similar in pregnant and The incidence of pyelonephritis in
non-pregnant women. Asymptomatic pregnant women in the era of routine
bacteriuria occurs in 4–7% of pregnant prenatal screening for asymptomatic
women [1, 8], though in certain popu- bacteriuria is approximately 14 per 1000
lations rates as high as 10% have been deliveries [4]. In a study of 440 episodes
reported [1]. Detection and eradication of in 32,282 pregnant women, the majority
asymptomatic bacteriuria in pregnancy of cases occurred in the second trimester
have been shown to reduce the risk of of pregnancy (53%), but 20% occurred in
subsequent pyelonephritis and fetal com- the first trimester. Enterobacteriaceae
plications [2]. Risk factors for asympto- caused approximately 75% of episodes
matic bacteriuria in pregnancy include and Gram-positive organisms comprised
underlying genitourinary anatomic or most of the other episodes [4]. In another
functional defects, diabetes, sickle cell prospective study of 24,000 pregnant
disease, and history of recurrent uri- women, 656 of whom developed pyelone-
nary tract infections [9]. Multiparity phritis, the incidence was similar in both
202
the second and third trimesters [12]. play an important role in adherence to
Previous upper urinary tract infection, urinary epithelium and pathogenesis of
urinary tract malformations, renal calculi infection. Differences in expression of viru-
and sickle cell disease or trait are risk lence factors may explain why some preg-
factors for the development of pyelone- nant hosts with asymptomatic bacteriuria
phritis during pregnancy [10, 13]. progress to pyelonephritis, whereas others
Septic shock syndrome or its variants do not [10]. One study examined virulence
has been reported in up to 20% of pregnant traits in E. coli strains from 24 pregnant
women with severe pyelonephritis [14]. women with pyelonephritis and compared
Acute renal failure with suppuration has them with E. coli strains from 37 preg-
been reported independent of sepsis [15]. nant women with asymptomatic bacteriu-
Anemia, which may be caused by endo- ria detected in pre-natal screening [19].
toxin-induced hemolysis [16], has been E. coli strains from the pyelonephritis
reported in 23% - 66% of cases [4, 17]. group, compared with E. coli strains from
the asymptomatic bacteriuria group, dis-
played significantly increased human
4. PATHOGENESIS serum resistance (83% vs. 51%, p < 0.05)
and uroepithelial binding capacity (mean
Pregnancy-related changes in the urinary adherence 47 bacteria/cell vs. 18 bacte-
tract predispose to progression of asymp- ria/cell). This binding capacity is partly
tomatic bacteriuria to pyelonephritis. The mediated by bacterial surface molecules
renal pelvis and ureters dilate by the sev- called adhesins, also referred to as pili or
enth week of gestation. By term, the ure- fimbriae. It has previously been demon-
ters may contain over 200 ml of urine [1]. strated that P fimbriae are expressed in
This dilation is secondary to mechani- approximately 80% of E. coli strains caus-
cal obstruction by the expanding uterus ing pyelonephritis, compared with 20% of
and is exacerbated by the smooth muscle strains causing asymptomatic bacteriuria
relaxation and decreased ureteral peri- or cystitis [10]. The E. coli strains from
stalsis caused by progesterone. The result pregnant women with pyelonephritis did
of these anatomic and physiologic changes not significantly differ from those from
of pregnancy is the facilitation of ascent of non-pregnant women [19]. Thus, preg-
bacteria from bladder to kidney and the nancy was shown not to abolish the differ-
greater propensity for development of ence in virulence between E. coli causing
pyelonephritis. Gestational glucosuria, acute pyelonephritis and asymptomatic
aminoaciduria and decreased concentra- bacteriuria, as has been demonstrated in
tion capacity of the urine are physiological other types of complicated UTIs.
co-factors that contribute to a reduction in
the natural antibacterial capacity of urine
and increased bacterial proliferation [1]. 5. DEFINITION OF SIGNIFICANT
Immunosuppression of pregnancy may BACTERIURIA
also play a role in the pathogenesis of
pyelonephritis in that the serum antibody Significant bacteriuria is the level of bacte-
response to E. coli and serum and urine riuria that suggests true bladder bacteriu-
interleukin-6 levels appear to be lower in ria as opposed to contamination. It is based
pregnant women with pyelonephritis com- on urine specimens obtained by using
pared with non-pregnant women [18]. careful handling and processing protocols
As with non-pregnant healthy women, in order to minimize contamination and
bacteria from the fecal reservoir colonize false positive results. The level of bacteriu-
the urinary tract via ascension through ria considered significant in asymptomatic
the urethra. Bacterial virulence factors pregnant women is derived from studies in
203
which colony counts in voided urine speci- obtained decades ago prior to the exclu-
mens were compared with paired catheter sion of pregnant women from most clini-
specimens [20]. In these studies, a bacte- cal trials. As a result, the safety of some
rial count of ≥105 cfu/ml in a catheterized newer antibiotics in pregnant women has
specimen was confirmed by a repeat cath- not been well defined. The pharmacoki-
eterized specimen in >95% of cases, and netic properties of antibiotics are affected
two consecutive voided specimens with by physiological changes during preg-
≥105 cfu/ml predicted bladder bacteriuria nancy since there is an increased volume
with the same degree of accuracy as a sin- of distribution [23], and glomerular fil-
gle specimen obtained through a catheter. tration rate increases by up to 50% [24].
Therefore, two consecutive voided urine Despite this, usual doses of antimicrobi-
specimens with growth of the same bacte- als are typically sufficient for treatment
rial strain in counts ≥105 cfu/ml are highly of UTIs during pregnancy.
suggestive of bladder bacteriuria [21] (LoE Aminopenicillins are commonly used in
2a). In clinical practice, however, only one pregnancy and are not considered tera-
voided urine specimen is typically obtained togenic [24]. Amoxicillin is well absorbed
due to cost and patient convenience, and orally and has been a mainstay of treat-
treatment is usually instigated in women ment. Cephalosporins have generally
with ≥105 cfu/ml without obtaining a con- been considered as safe options. The high
firmatory repeat culture. Routine cath- serum protein binding capacity of ceftri-
eterization to screen for bacteriuria is not axone raises concern about potential dis-
recommended due to the slightly increased placement of bilirubin and development
risk of causing infection. of kernicterus. Therefore, it should be
Although studies to define colony count used with caution shortly before child-
thresholds representing significant bac- birth. Possible teratogenicity of cefaclor,
teriuria in pregnant women with urinary cephalexin and cephradine was noted
symptoms have not been performed, lower in a surveillance study of over 4,000
colony counts have been shown to be sig- Michigan Medicaid recipients exposed to
nificant in symptomatic non-pregnant these agents [25]. Amongst those exposed
women. For example, in women with to these agents in the first trimester of
uncomplicated cystitis, coliform colony pregnancy, the incidence of major birth
counts in voided urine as low as 102 cfu/ml defects (including cardiovascular and oral
have been shown to reflect bladder infec- cleft defects) was higher than expected.
tion [22]. However, most clinical labo- However, other factors such as maternal
ratories do not routinely quantify urine health and concurrent use of other phar-
isolates to 102 cfu/ml, so it is reasonable to maceuticals may have obfuscated the
use a quantitative count ≥103 cfu/ml in a results. In addition, these findings were
symptomatic person, whether catheterized not corroborated in a cohort of 308 women
or not, as an indicator of symptomatic UTI also exposed to cephalosporins during
(LoE 4). It should be noted, however, that the first trimester [26]. Cephalosporins
95% of women with pyelonephritis will are widely used in pregnancy; however,
have ≥105 cfu/ml on quantitative culture. the potential teratogenic associations
seen in the Michigan Medicaid cohort
6. PRINCIPLES OF ANTIMICROBIAL may warrant further investigation.
TREATMENT IN PREGNANCY Nitrofurantoin remains a viable first
choice agent or alternative in the setting of
penicillin allergy for asymptomatic bacte-
6.1 Safety
riuria in pregnancy or cystitis [27]. A meta-
Much of the data addressing antibiotic analysis of the use of nitrofurantoin
safety in the pregnant population was during pregnancy failed to demonstrate
204
any link to the development of congenital fluoroquinolones is contraindicated dur-

malformations [28]. However, it has been ing pregnancy.
reported to cause hemolytic anemia in the
mother with G-6PD deficiency and this can
6.2 Resistance
potentially occur in the fetus. Therefore, it
is not recommended for use near term by Sulfonamides, cephalosporins, nitrofuran-
some authors [27]. An acute immune-me- toin and aminopenicillins have demon-
diated pulmonary reaction characterized strated equivalent efficacy in eradicating
by fever, cough, dyspnea and diffuse pul- asymptomatic bacteriuria in pregnancy
monary infiltrates occurs at an incidence [39–40] (LoE 1b). However, the increasing
of 0.00018% [29]. A case was described in incidence of resistance to aminopenicillins
a 16-week pregnant woman that resulted and sulfonamides highlights the impor-
in severe respiratory insufficiency six days tance of susceptibility testing to guide
into a treatment course of nitrofurantoin treatment choice. Caution should be used
for an E. coli UTI. Cessation of nitro- when choosing amoxicillin, ampicillin or
furantoin and use of steroids resulted in sulfonamides as treatment options when
convalescence [30]. A chronic pulmonary antibiotic susceptibility has not yet been
reaction, characterized by diffuse intersti- confirmed. A review of 1,142 outpatient
tial pneumonitis and fibrosis has also been E. coli strains causing UTIs in patients
reported [31]. Although such complications from the USA and Canada between
occur very rarely, clinicians utilizing pro- 2003 and 2004 was carried out by the
longed courses of nitrofurantoin for proph- North American Urinary Tract Infection
ylaxis of UTI should be aware of them. Collaborative Alliance (NAUTICA) [41].
Despite infrequent use in the US, fosfo- The overall resistance to ampicillin was
mycin appears to be safe in pregnancy and 37.7% and to trimethoprim-sulfameth-
may play a role in targeting drug resist- oxazole 23.3%, whereas only 1.1% of the
ant isolates [32]. Trimethoprim should isolates were resistant to nitrofurantoin.
be avoided in the first trimester due to Of note, no distinction was made between
potential teratogenicity associated with symptomatic UTI and asymptomatic bac-
antagonism of folate metabolism [33]. teriuria, and approximately 20% of the
Sulfonamides have been reported to cause isolates were obtained from males. Similar
kernicterus and should be avoided late in results, however, were seen in a study
pregnancy [34]. Clindamycin is an alter- of 4,734 adult women presenting with
native for the treatment of group B strep- acute uncomplicated cystitis in Europe
tococcus in the penicillin-allergic host. and Canada. Of the 2,478 E. coli isolates
Teratogenicity has not been reported [35]. tested from this group, the prevalence of
Aminoglycosides are ototoxic but no other resistance to ampicillin was 30% and to
teratogenic effects have been described [23]. trimethoprim-sulfamethoxazole 14%, but
Tetracyclines are contraindicated during only 1.2% were resistant to nitrofurantoin
pregnancy due to discoloration of deciduous and 0.7% to fosfomycin [42].
teeth and reports of maternal acute fatty Nitrofurantoin and fosfomycin also
liver degeneration [36]. appear to be active in vitro against
Animal studies have demonstrated ESBL-producing E. coli strains from the
an association between fluoroquinolone urinary tract [43]. Moreover, in a recent
use and fetal arthropathy [37]. However, case-control study including 113 patients
no developmental abnormalities have with ESBL E. coli UTIs, no resistance to
been described in children exposed in fosfomycin was detected and clinical cure
utero. Specifically, no significant mus- rates were high (93%) [44].
culoskeletal deficits in infants have been Despite the necessity for caution with
noted [37–38]. Despite this, the use of the use of aminopenicillins or sulfonamides,
205
in most cases of asymptomatic bacteriuria initial culture is negative, routine repeat

in pregnancy there is no urgency to treat screening is not warranted given that the
until susceptibility data are available. majority of cases of asymptomatic bacte-
riuria are detected on the initial screen,
with only 1.0%–2.0% developing bacte-
7. ASYMPTOMATIC BACTERIURIA riuria subsequent to the initial screen
[1, 48]. In a study of 216 pregnant women
7.1 Diagnosis in Sweden, only 1.1% of women developed
asymptomatic bacteriuria between the 12th
Asymptomatic bacteriuria is defined as
week of pregnancy and term. The authors
the presence of significant bacteriuria in
concluded that the 16th week of pregnancy
women without symptoms or signs ref-
is the optimum time to screen for bacte-
erable to the urinary tract, regardless of
riuria [49]. A subset of pregnant women
the presence or absence of pyuria.
is at higher risk for the acquisition of
bacteriuria, including those with urinary
7.2 Screening
tract anomalies and history of recurrent
Up to 40% of pregnant women with urinary tract infections. Consideration
asymptomatic bacteriuria will proceed should be given to perform surveillance
to develop pyelonephritis and potential cultures in such individuals at regular
adverse effects in the fetus if not treated intervals throughout pregnancy.
[45–46]. A fall in the incidence of pyelone- Newer methodologies, including dipstick
phritis in pregnancy from 4.0% to 0.8% enzymatic assays, have been advocated
subsequent to the introduction of routine as potential rapid screening modalities
screening and treatment of asymptomatic to obviate the costs of routine urine cul-
bacteriuria was reported in one study [47]. ture [50–51]. In a study of 528 pregnant
A recent Cochrane meta-analysis of 14 women who underwent urine culture, the
randomized trials compared outcomes in efficacy of nitrite and leukocyte esterase
pregnant women with asymptomatic bac- reagent strips and Gram stain for detect-
teriuria who were treated with antibiotics ing significant bacteriuria was determined
against those who received no treatment [50]. Using ≥105 cfu/ml as the gold stand-
or placebo. The risk of complications was ard for significant bacteriuria, the sensi-
shown to be reduced significantly by the tivity and specificity of the reagent strip
eradication of asymptomatic bacteriu- for detecting significant bacteriuria was
ria [2] (LoE 1a). Thus, antibiotic therapy 47.2% and 80.3%, respectively, and the
results in significantly greater clearance Gram stain was 100% and 7.7%, respec-
of asymptomatic bacteriuria (risk ratio tively. None of these techniques provide
[RR] 0.25, 95% C.I. 0.14 – 0.48), signifi- sufficient sensitivity and specificity to
cantly lower incidence of pyelonephritis replace urine culture as the gold stand-
(RR 0.23, 95% C.I. 0.13 – 0.41), and signif- ard to detect asymptomatic bacteriuria in
icantly lower incidence of low birth weight pregnancy. Furthermore, urine cultures
infants (RR 0.66, 95% C.I. 0.49 – 0.89), provide microbiologic information that
but not preterm delivery [2]. assists with selection of an appropriate
Given these potential benefits from antimicrobial agent.
screening and treating asymptomatic Ultimately, the cost effectiveness of a
bacteriuria in pregnancy, the current rec- screening/treatment approach to asympto-
ommendation from the American College matic bacteriuria in pregnancy is contin-
of Obstetricians and Gynecologists is to gent on the cost of the screening test, the
screen for bacteriuria at the initial pre- prevalence of asymptomatic bacteriuria
natal visit by performing a midstream in the local population, and the propor-
clean-catch urine culture (LoE 2b). If the tion of those that progress to symptomatic
206
urinary tract infection. Despite uniform course therapy [1]. Thus, a urine cul-
national guidelines, the level of adher- ture should be repeated approximately
ence to screening is unknown. one week after completion of therapy as
a test of cure, then monthly until com-
7.3 Treatment choice and duration pletion of the pregnancy (LoE 4). If the
urine culture remains positive a week
Choice of antimicrobial agent is gov- after treatment with an appropriate
erned by safety, as described above, and antibiotic, a further course of therapy of
uropathogen resistance data obtained longer duration [10] or with another anti-
from the urine culture. Short-course biotic is warranted. Failure to respond
regimens (e.g., 3 to 5 days) are usually to two or more courses of antibiotics or
effective in eradicating asymptomatic bac- further recurrences of asymptomatic
teriuria of pregnancy [52–53] (Table 1). In bacteriuria during pregnancy warrants
this regard, a single dose of fosfomycin consideration of suppressive therapy or
has also been successfully used to treat prophylaxis, respectively, for the duration
asymptomatic bacteriuria in pregnancy of pregnancy. Uropathogen susceptibility
with eradication rates comparable to must be taken into account when select-
those with longer courses of other antimi- ing an agent for suppression or prophy-
crobials [54]. A meta-analysis of 10 studies laxis. Daily nitrofurantoin 50–100mg or
comparing single-dose versus longer regi- cephalexin 250mg are each reasonable
mens showed no clear difference in the choices for prophylaxis [56].
cure or recurrence rates for asymptomatic
bacteriuria, or in the risk of preterm
births or pyelonephritis [55] (LoE 1a). 8. ACUTE CYSTITIS
Likewise, duration of antibiotic treat-
ment was not associated with any of the 8.1 Diagnosis
outcome measures in a more recent meta-
analysis of treatment of asymptomatic Urinary symptoms are common in preg-
bacteriuria in pregnancy [2]. Short course nant women, and therefore, symptoms
regimens are desirable as the host is of acute cystitis in pregnancy are less
asymptomatic and can be closely followed specific than in non-pregnant women.
and retreated if bacteriuria persists, and The constellation of typical lower uri-
fetal drug exposure is minimized. nary tract symptoms (dysuria, frequency,
urgency, suprapubic discomfort) along
with pyuria and significant bacteriuria
7.4 Follow-up
(≥103 CFU/ml) establishes the diagno-
Up to 30% of women will fail to clear sis of acute cystitis. Urine culture helps
asymptomatic bacteriuria following short- separate those who have true infection
Table 1 Treatment Regimens for Asymptomatic Bacteriuria in Pregnancy.
Antibiotic Duration of therapy Comments
Nitrofurantoin (Macrobid®) 100mg q12 hours 5–7 days Avoid in G6PD deficiency
Amoxicillin 500mg Q12 hours 3–7 days Increasing resistance
Amoxicillin/Clavulanate 500mg q12 hours 3–7 days
Cephalexin (Keflex®) 500mg Q12 hours 3–7 days Increasing resistance
Fosfomycin 3gm Single dose
207
from the 10%–15% that have pyuria in pregnancy. Recurrent cystitis can be man-
the absence of infection [10]. Symptoms aged with another short-course regimen
and signs of pyelonephritis such as flank based on susceptibility data from previous
pain, costovertebral angle tenderness or cultures, and continuous or post-coital anti-
fever (> 38 centigrade) must be absent. microbial prophylaxis may be indicated.
A subset of women has co-existing medical
8.2 Treatment choice and duration conditions that may exacerbate the risk of
complications from UTI (such as diabetes or
The choice and duration of antibiotic
sickle cell anemia). Prophylaxis should be
treatment are similar to that of asymp-
considered after the first episode of cystitis
tomatic bacteriuria (Table 1). A Cochrane
in this setting. Acute cystitis is frequently
review of acute cystitis in pregnancy
related to sexual activity, and postcoital
failed to identify any particular regimen
prophylaxis is a reasonable prophylac-
as superior in rates of cure, rates of recur-
tic strategy in women who are sexually
rence or rates of preterm delivery [57].
active. The antibiotic of choice is governed
All antibiotics studied were effective and
by susceptibility of the urine culture iso-
complications were rare. Thus, there
late. Either nitrofurantoin 50–100 mg or
appears to be no difference in outcome for
cephalexin 250–500 mg postcoitally or daily
short (one to three days) or long (five or
are reasonable choices, providing they are
more days) courses of therapy. Three-day
active against the uropathogen(s) causing
regimens are effective and should be con-
recent infections.
sidered in pregnant women, as has been
Women with a history of recurrent UTI
recommended for uncomplicated UTI [58].
prior to the onset of pregnancy are also at
Of note, short regimens of nitrofuran-
increased risk of developing symptomatic
toin have not performed as well as other
UTI during pregnancy. Such cases of recur-
antibiotics in non-pregnant women with
rent UTI in women of childbearing age are
uncomplicated UTIs in some studies, and
often related to sexual intercourse. The
such regimens have generally not been
potential role of postcoital antibiotics to
recommended. However, a recent pro-
prevent UTIs during pregnancy in this pop-
spective open-label trial comparing three
ulation has been examined. Thirty-three
days of trimethoprim-sulfamethoxazole
women with a history of recurrent UTI
to five days of nitrofurantoin in 338 cases
who had 39 pregnancies were observed.
of uncomplicated cystitis found that clini-
During a mean observation period of seven
cal and microbiological cure rates were
months, 130 symptomatic UTIs were iden-
equivalent [59]. Although no such studies
tified. Following the institution of postcoi-
have been performed in pregnant women,
tal prophylaxis with 250 mg of cephalexin
a 5-day course of nitrofurantoin is likely
or 50 mg of nitrofurantoin, only one UTI
to be similarly effective in acute cystitis
during pregnancy was observed [56].
in pregnancy. Fosfomycin is approved in
Therefore, post-coital prophylaxis should
a single-dose regimen for treatment of
be considered in pregnant women with a
cystitis in pregnancy [32], and it is a rea-
history of frequent urinary tract infections
sonable first-line choice in pregnancy.
prior to the onset of pregnancy (LoE 2b).
8.3 Follow-up
A surveillance culture should be performed 9. ACUTE PYELONEPHRITIS
approximately one week after completion
of therapy for acute cystitis to ensure erad-
ication of significant bacteriuria. Persistent 9.1 Diagnosis
bacteriuria should be managed as described The clinical spectrum of pyelonephri-
above for asymptomatic bacteriuria in tis in pregnancy is equivalent to that in
208
non-pregnant women, except that preg- to concerns about microbial resistance.

nant women are more likely to have In addition, aminoglycosides have been
involvement of other organ systems, such associated with ototoxicity following pro-
as respiratory insufficiency, renal insuffi- longed fetal exposure [27], and therefore
ciency or anemia [4, 14]. The constellation should be avoided unless intolerance or
of typical upper urinary tract symptoms resistance prohibits the use of less toxic
or signs (fever, chills/rigors, nausea, agents.
vomiting and costovertebral angle pain Improvement in clinical parameters
and tenderness) along with pyuria and should be observed by 24–48 hours. The
significant bacteriuria establishes the absence of improvement within this time
diagnosis of acute pyelonephritis. Lower frame warrants investigation for urinary
urinary tract symptoms may or may not obstruction or complication such as renal
be present. abscess. Once the patient is afebrile for
48 hours it is reasonable to switch to an
9.2 Treatment choice and duration oral agent as appropriate based on sus-
ceptibility data. There are no studies that
Traditionally, hospitalization has been
address the optimal duration of treat-
recommended for pregnant women with
ment for pyelonephritis in pregnancy,
pyelonephritis, and parenteral beta
but most practitioners use a 14-day
lactams or aminoglycosides have been
course [10]. However, it is likely that
used for treatment. See Table 2 for rec-
shorter courses of treatment, such as a
ommended treatment regimens. The ini-
seven-day regimen, are as effective. This
tial choice of empiric antimicrobial agent
has been demonstrated for pyelonephritis
should be tailored to local microbiology
in non-pregnant women [61].
data. In a randomized trial of 179 women
Some studies have addressed the fea-
with acute pyelonephritis prior to the 24th
sibility of outpatient management of
week of pregnancy, the efficacy of intra-
pyelonephritis in pregnancy. In one such
venous ampicillin and gentamicin was
study, 120 women under 24 weeks gesta-
equivalent to that of intravenous cefazo-
tion were randomized to receive either
lin or intramuscular ceftriaxone [60]. Of
outpatient intramuscular ceftriaxone
note, only 5.2% of the pathogens were
for two days followed by oral cephalexin,
resistant to cefazolin, which is lower
or inpatient intravenous cefazolin fol-
than that observed in other reports [5].
lowed by oral cephalexin at discharge
Thus, monotherapy with first generation
[5]. Clinical response and birth outcomes
cephalosporins is not recommended due
were similar in both arms, although six
patients in the ceftriaxone group required
Table 2 Treatment Regimens for Pyelonephritis. eventual admission. One of these devel-
oped septic shock during the emergency
Antibiotic Dosing department observation period and
Ceftriaxone 1–2gm IV or IM q24 hours two developed recurrent pyelonephri-
tis after completion of oral antibiotics.
Aztreonam 1gm IV q8-12 hours
Nevertheless, we recommend empiric
Piperacillin-tazobactam 3.375–4.5gm IV use of ceftriaxone IM or IV once daily for
q6 hours
outpatient treatment of pregnant women
Cefepime 1gm IV q12 hours with mild symptoms provided daily fol-
Imipenem-cilastatin 500mg IV q6 hours low-up or contact with the patient is fea-
sible (LoE 1b). We do not recommend the
Ampicillin + 2gm IV q6 hours
use of first generation cephalosporins for
Gentamicin 3–5mg/kg/day IV in 3 empiric treatment of pyelonephritis for
divided doses
the reasons expressed above.
209
9.3 Prophylaxis exstrophic bladder [68]); and conditions

The risk of recurrent pyelonephritis dur- that decrease the immunological response
ing pregnancy following the first episode to infection including sickle cell disease or
is 6%–8% [60, 62]. In a randomized pro- trait, gestational and nongestational dia-
spective study, 200 subjects were followed betes mellitus, and immunosuppression
after an episode of acute pyelonephritis secondary to solid organ or bone marrow
in pregnancy. One group received antimi- transplantation [69–71]. Patients with
crobial prophylaxis and the other group any of these conditions are at increased
underwent surveillance cultures. Despite risk for the development of complicated
the lower incidence of recurrent or per- cystitis and pyelonephritis during preg-
sistent bacteriuria in the prophylaxis nancy [71–72].
arm, the incidence of recurrent pyelone- Pathogenic bacteria that produce ure-
phritis was similar in both groups- 7% in ase increase the risk of struvite stone for-
the prophylaxis group versus 8% in the mation. These calculi increase the risk
surveillance group [62]. Although this of a UTI complicated by acute or chronic
study did not demonstrate a reduction in urinary tract obstruction and increase the
the incidence of recurrent pyelonephri- risk for xanthogranulomatous pyelone-
tis, antimicrobial prophylaxis and urine phritis. Some pathogens can also cause
surveillance is recommended by some for emphysematous pyelonephritis during
the remainder of the pregnancy following pregnancy. E. coli is the most common
the first episode of pyelonephritis [63], bacteria to cause emphysematous pyelone-
using the same prophylaxis strategies phritis, but other Enterobacteriaceae may
mentioned above for lower urinary tract also be responsible [73].
infection. A complicated UTI during pregnancy
should be suspected clinically when a
patient fails to respond to a standard
course of antibiotic therapy or presents
10. COMPLICATED UTI IN with urosepsis or acute renal failure.
PREGNANCY Imaging studies, such as ultrasonographic
or magnetic resonance imaging, should be
Although UTI during pregnancy is by def- performed in these situations [72, 74–75]
inition considered complicated, compared (LoE 4). Both of these imaging techniques
with UTI in the non-pregnant healthy are believed to present minimal risk to the
woman, a minority of pregnant women developing fetus since no ionizing radia-
will experience a more complicated UTI, tion is used for either imaging modality.
such as a UTI occurring in a person with Ultrasonographic imaging, in particular,
compromised urinary drainage or immu- is advantageous when intervention such
nity. Host factors that increase the risk as percutaneous nephrostomy or retro-
for complicated UTI during pregnancy grade ureteral stent placement is required
include congenital anomalies such as to relieve obstruction since it offers excel-
bladder exstrophy, cloacal anomalies, lent visualization while avoiding fetal
and versicoureteral reflux [64–65]. Other exposure to ionizing radiation.
risk factors include obstructive phe- The body of knowledge surrounding
nomena such as renal or ureteral calculi the management of pregnant women
[66]; neurogenic bladder conditions that with complicated UTI is largely experi-
impair bladder emptying such as diabetic mental, principally because complicated
cystopathy, multiple sclerosis, spina bif- UTIs in pregnancy are uncommon. The
ida, and spinal cord injury [67] (includes optimal duration of antimicrobial treat-
patients who have undergone augmenta- ment is not known. Recommended treat-
tion cystoplasty to treat a neurogenic or ment durations for complicated UTI in
210
non-pregnant persons have ranged from nitrofurantoin is widely considered a safe

7 to 21 days, depending on the severity antibiotic for use in pregnancy. Pregnancy
of the infection, but 7 to 10 days should is a common and complicated condition,
be adequate in the vast majority of indi- and more resources should be allocated to
viduals (LoE 4). In addition, drainage in address these infection-related issues.
either a retrograde or antegrade fash-
ion must be performed in the setting
of obstruction. The second trimester of 12. CONCLUSION
pregnancy is the safest time to intervene;
rates of fetal loss and premature delivery
Urinary tract infection is a common com-
are lower during the second trimester fol-
plication of pregnancy. Physiological
lowing a surgical intervention.
changes of pregnancy predispose to the
progression of asymptomatic bacteriuria
11. FURTHER RESEARCH to pyelonephritis with ensuing maternal
morbidity and suboptimal fetal outcomes.
Urine culture remains the gold standard
Many aspects of urinary tract infection to detect asymptomatic bacteriuria in
in pregnancy warrant further investiga- pregnancy, and screening is an important
tion in adequately constructed clinical element of routine prenatal care during
trials. Such areas include: acquiring a early pregnancy. Antimicrobial treatment
better understanding of the mechanism should be selected on the basis of uropath-
by which bacteriuria results in adverse ogen susceptibility data and fetal safety.
pregnancy outcomes; further characteri- Short courses of therapy are effective in
zation of the virulence factors of bacterial eradicating bacteriuria and significantly
strains causing asymptomatic bacteriuria reducing the incidence of pyelonephritis.
and pyelonephritis in pregnancy; evalu- Close follow-up is warranted following
ation of adherence to prenatal screening therapy for asymptomatic bacteriuria or
guidelines and cost effectiveness of the symptomatic urinary tract infection, as
screening/treatment approach of asympto- some women may benefit from antimi-
matic bacteriuria of pregnancy; the utility crobial suppression or prophylaxis for
of repeat urine culture or other screening the remainder of pregnancy. Complicated
tests to confirm the presence of asymp- UTI in pregnancy may require drainage
tomatic bacteriuria following a positive and/or longer durations of treatment for
initial prenatal screening culture; char- optimal results.
acterization of the optimum duration of
antimicrobial therapy for asymptomatic
bacteriuria of pregnancy; identification
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215
|3.6|
Urinary tract infections in

patients with diabetes mellitus
Suzanne E. Geerlings
Corresponding author: Suzanne E. Geerlings, MD PhD, Academic Medical Center, F4-217, Center for Infection and
Immunity Amsterdam (CINIMA), Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Phone: 31(0)205664380, Fax: 31(0)206972286, e-mail: s.e.geerlings@amc.nl
ABSTRACT UTI is present in older patients with

DM type 2. Imaging should be reserved
Epidemiology: Patients with diabetes for those patients who do not respond
mellitus (DM) have a higher prevalence to therapy after 48–72 hours especially
of asymptomatic bacteriuria (ASB) and with conditions, such as DM, predispos-
incidence of urinary tract and other infec- ing to (complications of an) infection.
tions compared to patients without DM. Computerised tomography (CT) has now
Pathogenesis: It seems that the become accepted as a sensitive modality
increased prevalence of ASB in diabetic for diagnosis and follow-up of a compli-
women is not the result of a difference in cated UTI.
bacteria, but due to an increased adher- Clinical symptoms: Diabetes patients
ence of E. coli expressing type 1 fimbriae with a UTI have the same symptoms of
to uroepithelial cells in women with DM. lower and upper UTIs as patients with-
The bacterial growth in urine after the out diabetes, but they more often develop
addition of glucose is increased in vitro, severe and rare complications.
however glucosuria is not a risk factor for Treatment: ASB in patients with DM
ASB or the development of urinary tract does not lead to complications and there-
infections (UTIs) in vivo. fore screening and treatment is not war-
Diagnosis: The diagnosis of a UTI is ranted. No randomized prospective trials
primarily based on typical patient symp- are present answering the question of
tomatology and urinary evaluation for what the optimal duration of treatment of
the presence of bacteria and white blood UTIs in diabetic patients is. The analysis
cells. Easy obtainable parameters can of a large retrospective database demon-
predict whether a (complicated course of) strated that women with diabetes receive
Urinary tract infections in patients with diabetes mellitus | 3.6 |
longer and more potent antimicrobial 6. The agent of choice can be the same
treatment but have more recurrences of in diabetic and non-diabetic patients
their UTIs. However, the results about and depends on the local resistance
treatment failure in women with DM in patterns of commonly found uropatho-
other studies are not consistent. gens (GoR B).
Key words: diabetes mellitus; uri- 7. Besides the high resistance percent-
nary tract infections; asymptomatic age of most uropathogens to trimetho-
bacteriuria prim/sulfamethoxazole (TMP/SMX),
this agent can lead to hypoglycaemia
and therefore also is not a good first
SUMMARY OF RECOMMENDATIONS choice in diabetes patients (GoR C).
8. Women with diabetes with a lower
Diagnosis urinary tract infection need a longer
treatment duration compared to
1. Predictors for recurrent UTIs in women women without diabetes, but it is
and lower UTIs in men, with DM type not clear what the optimal treatment
2 older than 45 years are: age, number duration is (GoR B).
of GP visits, urinary incontinence, cere-
brovascular disease or dementia in
men and women and also renal disease
in only women (GoR B). 1. INTRODUCTION
2. Predictors for a complicated course
Diabetes Mellitus (DM) is an increasingly
(pyelonephritis, prostatitis, recurrent
important endocrine disease; the preva-
cystitis) of a UTI in patients with DM
lence worldwide in 2000 was 2.8% and is
type 2 older than 45 years are: age
estimated to be 4.4% in 2030 [1] (LoE 3).
above 60 years, chronic use of antibiot-
The incidence of infections is increased in
ics, more than 6 physician contacts in
diabetes (type 1 and type 2) patients com-
the previous year, hospitalization in the
pared to controls [2] (LoE 2a); [3] (LoE 2a)
previous year, the presence of renal dis-
and the urinary tract is the most preva-
ease and incontinence of urine (GoR B).
lent site of these infections [4] (LoE 2a).
3. Because of the frequency and severity It has been suggested that the presence
of UTI and the development of rare of glucosuria can explain this increased
and severe complications in diabetes incidence, but this has never been scien-
patients, prompt diagnosis and early tifically confirmed. Furthermore, some
therapy is warranted (GoR C). experts consider UTIs in diabetic patients
4. Discontinuate metformin from the day generally as complicated UTIs and there-
of contrast injection, if the Glomerular fore recommend treating them longer
Filtration Rate (GFR) is < 60 ml/ than non-diabetic patients. In this chap-
min/1.73 m2, and restart it 2 days fol- ter the epidemiology, pathogenesis, diag-
lowing contrast infusion providing the nosis, clinical symptoms and treatment
GFR has not significantly deteriorated of UTIs in diabetes patients will be dis-
(GoR C). cussed and recommendations for diagno-
sis and treatment will be made.
Treatment
5. Asymptomatic bacteriuria in patients 2. METHODOLOGY

with diabetes does not lead to compli-
cations, therefore screening and treat- A systematic literature search was per-
ment is not warranted (GoR A). formed for the last 10 years in PubMed
217
with the following key words: diabetes in a clean voided midstream urine, iso-
mellitus and urinary tract infections or lated from a patient without symptoms of
diabetes mellitus and bacteriuria and the a UTI.
following limitations: humans, adults, Symptomatic urinary tract infection
English. A total of 216 (DM and UTI) and (UTI) is defined as the presence of bac-
40 (DM and ASB) publications were iden- teriuria in a patient with symptoms of
tified, which were screened by title and a UTI.
abstract (when available). After exclusion
of duplicates a total of 27 were included 3.3 Pathogenesis
into the review (analysis), supplemented 3.3.1 Pathogens
by 10 citations known by the author.
The studies were rated according to the The increased prevalence of ASB and UTI
level of evidence (LoE) and the grade of in diabetic patients can be the result of
recommendation (GoR) using ICUD differences in the host responses between
standards (for details see Preface) [5–6]. diabetic and non-diabetic patients, or a
difference in the infecting bacterium itself.
It seems that the increased prevalence of
3. DEFINITION OF THE DISEASE ASB in diabetic women is not the result of
a difference in bacteria, because the same
3.1 Epidemiology number of virulence factors were found in
the infecting Escherichia coli (most com-
Patients with DM have a higher preva- mon causative microorganism of ASB) in
lence of asymptomatic bacteriuria (ASB) diabetic women with ASB, as listed in the
(26% in women with compared to 6% to literature for non-diabetic patients with
those without DM) [7] (LoE 2a) and inci- ASB [10] (LoE 3). Also no differences were
dence of urinary tract and other infections found in the resistance percentages to
compared to patients without DM [2] (LoE the most commonly used antimicrobials
2a). Compared to patients without DM in these isolates from diabetic patients
the relative risk (RR) of a symptomatic compared to other uropathogens iso-
UTI ranged between 1.39 and 1.43 for all lated from the general population in the
diabetic patients in a large retrospective Netherlands [11] (LoE 2a).
Canadian study [2] (LoE 2a) and Odds It has been suggested that the pres-
Ratios (ORs) were 1.56 for DM type 1 ence of glucosuria and impairment in
and 1.21 for DM type 2 Dutch patients [3] granulocyte functions are the patho-
(LoE 2a), and 2.2 for American postmeno- genetic mechanisms which explain the
pausal diabetic women [8] (LoE 2a). increased prevalence of ASB and UTI.
The bacterial growth in vitro is increased
3.2 Classifications after the addition of glucose in concen-
Diabetes mellitus (DM) is defined follow- trations found in urine of poorly control-
ing the criteria of the American Diabetes led patients [12] (LoE 3), but in a large
Association as a fasting plasma glucose cohort of 636 diabetic women it could not
≥ 7,0 mmol/l. DM type 1 is defined as the be confirmed that glucosuria is a risk fac-
absolute deficiency of insulin secretion tor for ASB [7] (LoE 2a) or the develop-
and the absence of C-peptide, and DM ment of UTIs in vivo [13] (LoE 2a).
type 2 as the combination of resistance to
insulin action and an inadequate compen- 3.3.2 Host response
satory insulin secretory response [9]. Concerning the host response, it seems
Asymptomatic bacteriuria is defined that glucosuria or impaired granulocyte
as the presence of bacteriuria, at least dysfunctions cannot explain the increased
10e5 cfu/ml of one or two microorganisms incidence of bacteriuria, but more that a
218
quantitative decrease of leukocytes plays visits, urinary incontinence, cerebrov-

a role in the pathogenesis of ASB and ascular disease or dementia. In women,
UTI in patients with DM [14] (LoE 2a). the presence of renal disease was an
Furthermore, considering the microor- additional predictor [19] (LoE 2a). The
ganism-host interaction it has been dem- combined outcome measure for a com-
onstrated that E. coli expressing type 1 plicated course was a defined episode of
fimbriae (the virulence factor that plays acute pyelonephritis, prostatitis or recur-
an important role in the pathogenesis rent cystitis. Independent predictors for
of UTIs) adhere better to uroepithelial a complicated course were age above 60
cells isolated from the urine of women years, chronic use of antibiotics, more
with DM compared to those isolated from than six physician contacts in the previ-
women without DM [15] (LoE 2a). ous year, hospitalization in the previous
year, the presence of renal disease and
incontinence of urine [20] (LoE 2a).
4. CLINICAL EVALUATION / RISK Considering additional diagnostic
ASSESSMENT imaging for the assessment of all patients
with a UTI, intravenous urogram and
ultrasound have traditionally been used,
4.1 Diagnosis
allowing detection of calculi, obstruc-
The diagnosis of a UTI is primarily based tion and incomplete bladder emptying.
on typical patient symptomatology and However, these imaging techniques have
urinary evaluation for the presence of limitations and computerised tomogra-
bacteria and white blood cells. Because of phy (CT) has now become accepted as a
the frequency and severity of UTI and the more sensitive modality for diagnosis and
development of rare and severe complica- follow-up of a complicated UTI. Contrast-
tions in diabetics, prompt diagnosis and enhanced CT allows different phases of
early therapy is warranted [16] (LoE 4). excretion to be studied and can define
Imaging should, in general, be reserved extent of disease and identify significant
for all patients who do not respond to complications or obstruction. However,
therapy after 48–72 hours especially ultrasound is harmless, cheaper and eas-
with conditions, such as DM, predispos- ier to perform and for that reason still can
ing to (a complication of) an infection [17] be diagnostic for possible complications in
(LoE 4). For example, emphysematous patients, who are very ill at the moment
cystitis has a highly variable presentation of presentation or remain ill after 48–72
and course, with a considerable potential hours. Furthermore, DM and the pres-
for complications. Knowledge of this rare ence of renal diseases are important risk
entity may lead to early diagnosis and factors for the development of contrast-
appropriate management [18] (LoE 3). induced nephropathy, which is associated
For the diagnosis of emphysematous cys- with an increased mortality. Therefore
titis a plain abdominal X-ray is highly it has been recommended to discontinue
sensitive (97.4%), but CT is the most metformin from the day of contrast injec-
sensitive and specific diagnostic tool [18] tion, if the Glomerular Filtration Rate
(LoE 3). (GFR) is < 60 ml/min/1.73 m2, and to
To recognize a UTI and a possible restart it two days after contrast infusion,
complicated course of it in patients with providing the GFR has not significantly
DM, a prediction rule was developed deteriorated [21] (LoE 4). Nuclear medi-
in DM type 2 patients aged 45 years cine has a limited role in the evaluation
or older. Predictors for recurrent UTIs of UTIs in adults. Its main role is in the
in women and lower UTIs in men were assessment of renal function, often prior
age, number of general practitioner (GP) to surgery. Magnetic resonance imaging
219
(MRI) has a limited but increasing role. be treated with antimicrobial therapy or
It is particularly useful in those with placebo to keep them nonbacteriuric [26]
iodinated contrast allergies [17] (LoE 4). (LoE 1b). The investigators did show that
See also Chapter, Diagnostics of uncom- the incidence of symptomatic UTIs (pri-
plicated UTI. mary endpoint) and the serum creati-
nine increase (secondary endpoint) were
4.2 Clinical presentation not different between the two groups.
In conclusion, ASB in patients with DM
Diabetes patients with a UTI have the
does not lead to complications and there-
same symptoms of lower and upper UTIs
fore screening and treatment is not war-
as patients without diabetes, but they
ranted [27] (LoE 1a).
more often develop severe and rare com-
plications such as emphysematous cys-
titis and papillary necrosis [22] (LoE 4); 5.2 Choice antimicrobial agent
[23] (LoE 3). Patients with DM also are
The causative microorganisms of UTIs in
at higher risk for intrarenal abscess, with
patients with DM are comparable to those
a spectrum of disease ranging from acute
found in other UTIs. Microorganisms
focal bacterial pyelonephritis to renal cor-
other than E. coli are more often cul-
ticomedullary abscess or carbuncle [16]
tured than in women without DM [28]
(LoE 4). Some infections, for example
(LoE 2a), In the ARESC study [29] (LoE 3)
emphysematous cystitis [18] (LoE 3) or
the proportion of E. coli in premenopau-
pyelonephritis [24] (LoE 4) are mainly
sal women with uncomplicated cystitis
present in patients with DM, and clas-
and without any risk factors was 81%
sic symptoms of a UTI can be absent in
and thus significantly (multivariate
these diseases. The results of a prospec-
analysis; p<0.001) higher than in female
tive study with bacteraemic patients
patients with DM with clinical symptoms
showed that patients with DM compared
of an acute episode of uncomplicated cys-
with those without DM more often had
titis since 67% of them had E. coli. This
bacteraemia and that the urinary tract
proportion is, however, still much higher
was the most prevalent focus for these
than in patients with complicating fac-
infections [4] (LoE 2a). Concerning the
tors within the urinary tract with about
mortality due to these infections it was
50% of E. coli [30] (LoE 1b) and above
demonstrated that diabetic patients have
all much higher than in patients with
a higher mortality outside (RR 1,38, 99%
mainly nosocomial UTI [31] (LoE 3).
CI 1,23-1,55) [2] (LoE 2a), but not inside
Despite the lower proportion of E. coli
the hospital [4] (LoE 2a).
found in patients with DM the percent-
ages of resistance to the most commonly
prescribed antimicrobials: amoxicillin,
5. TREATMENT
nitrofurantoin, trimethoprim/sulfameth-
oxazol (TMP/SMX) seem comparable [11]
5.1 Asymptomatic bacteriuria
(LoE 2a). Amoxicillin, nitrofurantoin,
No differences in the renal function dete- trimethoprim/sulfamethoxazol (TMP/
rioration between diabetic women (not SMX) seem comparable [11] (LoE 2a).
very well regulated, mean HbA1c 8.5%) Therefore, the choice of treatment can
with and without ASB were demonstrated be the same in diabetic and non-diabetic
after the follow-up of a cohort with 644 patients and depends on the local resist-
diabetic women for a mean period of six ance patterns of the commonly found
years [25] (LoE 2a). This is in concordance uropathogens. Besides the high resistance
with an earlier study in which women percentage of most uropathogens to TMP/
with DM and ASB were randomized to SMX, this agent can lead to hypoglycemia
220
and therefore is not a good first choice in without diabetes. However, despite this
this patient group [32] (LoE 4). more aggressive treatment, both pre-
and postmenopausal women with diabe-
tes had more recurrences of their UTIs.
5.3 Duration
Besides that, hospitalisation for compli-
It has been suggested that diabetes cations of the UTI was seen significantly
patients more often have upper tract more often in postmenopausal women
involvement when they have a UTI [33] with diabetes [42] (LoE 2a). Therefore,
(LoE 4). However, in a prospective study it seems that women with diabetes need
only 0.5% of the diabetes patients with a longer treatment duration for a lower
a UTI had clinical symptoms of pyelone- UTI compared to women without diabe-
phritis [34] (LoE 2a) compared to 0.2% in tes, but it is not clear what the optimal
controls [35] (LoE 4). Others have dem- treatment duration is.
onstrated that the risk ratio for pyelone-
phritis in diabetic patients compared to
those without diabetes ranges from 1.86 6. FURTHER RESEARCH
to 4.4 [36] (LoE 4); [37] (LoE 2a).
No randomised trials are present Considering the pathogenesis, the micro-
answering the question as to what the organism-host interaction especially
optimal duration of treatment of UTIs in must be further elucidated, because
diabetic patients is. Some experts sug- it has been demonstrated that E. coli
gest considering these patients as having expressing type 1 fimbriae adhere better
a complicated UTI and therefore treating to uroepithelial cells of patients with DM
them during a period of 7–14 days [38] compared to controls. The study ques-
(LoE 4); [33] (LoE 4). However, in a tion is whether this is due to a higher
(national) guideline it has been recom- number of receptors which are present
mended not to consider all UTIs in dia- on the uroepithelial cell or to a difference
betic women as complicated UTIs, but to in the uroepithelial cell receptor itself,
differentiate between a lower and upper for example in the glycosylation of this
UTI and consequently treating the lower glycoprotein in diabetes patients. Clinical
UTI with the same agents and only a lit- research should be done to define better
tle bit longer (seven instead of five days) risk factors for UTI in DM patients as
as in women without DM [35] (LoE 4). predictors of more severe complications.
However, the results relating to treat- Furthermore, randomised trials must
ment failure in women with DM are not be performed, to answer the question
consistent: in two studies more recur- as to what the optimal agent choice and
rences were seen after UTI treatment in treatment duration of UTIs in diabetic
diabetic patients compared to those with- patients is.
out DM [39] (LoE 2a); [3] (LoE 2a). In
contrast, a subanalysis of two large retro-
spective studies in women in a lower [40] 7. CONCLUSIONS
(LoE 2a) and upper UTI [41] (LoE 2b)
could not confirm this finding. Patients with DM have a higher preva-
The analysis of a large retrospective lence of ASB. ASB, however, does not lead
database with pharmacy dispensing data to complications and therefore screening
demonstrated that both pre- and post- and treatment of ASB in diabetic patients
menopausal women with diabetes receive is not warranted. There is also a higher
longer and more potent antimicrobial incidence of symptomatic UTIs, which
treatment for lower UTI’s (cystitis) com- lead more often to complications com-
pared to pre- and postmenopausal women pared to those without DM. Therefore
221
these UTIs have to be diagnosed and Study Group. Diabetes Care, 2000. 23(6):
treated as early as possible and followed 744–9.
more carefully not to overlook a compli- 8. Boyko EJ, Fihn SD, Scholes D, Chen CL,
cated course. No prospective clinical trials Normand EH, and Yarbro P, Diabetes and
are present, which answer the question the risk of acute urinary tract infection
as to what the optimal antimicrobial among postmenopausal women. Diabetes
Care, 2002. 25(10): 1778–83.
treatment strategy (especially duration
of treatment) in diabetic patients with 9. Report of the Expert Committee on the
Diagnosis and Classification of Diabetes
a UTI is, but it seems that despite more
Mellitus. Diabetes Care, 1997. 20(7):
aggressive treatment, women with diabe- 1183–97.
tes have more recurrences of their UTIs. 10. Geerlings SE, Brouwer EC, Gaastra W,
Stolk R, Diepersloot RJ, and Hoepelman
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mellitus. Drugs, 2002. 62(13): 1859–68. Chemother, 2004. 53(3): 512–7.
39. Lawrenson RA and Logie JW, Antibiotic 42. Schneeberger C, Stolk RP, Devries JH,
failure in the treatment of urinary tract Schneeberger PM, Herings RM, and
infections in young women. J Antimicrob Geerlings SE, Differences in the pat-
Chemother, 2001. 48(6): 895–901. tern of antibiotic prescription profile and
40. Goettsch WG, Janknegt R, and Herings recurrence rate for possible urinary tract
RM, Increased treatment failure after infections in women with and without
3-days’ courses of nitrofurantoin and tri- diabetes. Diabetes Care, 2008. 31(7):
methoprim for urinary tract infections in 1380–5.
224
|3.7|

postmenopausal women
Raul Raz
Infectious Diseases Unit, Ha‘Emek Medical Center, Afula, Rappaport Faculty of Medicine, Technion, Haifa, Israel
Corresponding Author: Prof. Raul Raz, Infectious Diseases Unit, Ha’Emek Medical Center, Afula, Rappaport Faculty of
Medicine, Technion, Haifa, ISRAEL
Tel 00972-4-649.4259, Fax 00972-4-649.4470, raz_r@clalit.org.il, hana_e@clalit.org.il
ABSTRACT Another study described the incidence

and risk factors of acute cystitis among
UTI is the most common bacterial infec- nondiabetic and diabetic postmeno-
tion in women in general and in post- pausal women. Independent predictors
menopausal women in particular. There of infection included insulin treated
are two groups of elderly women with patients and a lifetime history of uri-
recurrent UTI that should be differenti- nary infection. Borderline associations
ated regarding age and general status: included a history of vaginal estrogen
healthy young postmenopausal women cream use in the last months, kidney
aged ~50–70 years, who are neither insti- stones and asymptomatic bacteriuria at
tutionalized nor catheterized, and elderly baseline.
institutionalized women with or without Another important factor in postmeno-
catheter. pausal women is the potential role that
Bacteriuria occurs more often in eld- estrogen deficiency plays in the develop-
erly functionally impaired women but ment of bacteriuria. There are at least
in general it is asymptomatic. However, two studies showing a beneficial effect
the risk factors associated with recurrent of estrogen in the management of recur-
UTI in elderly women has not previously rent bacteriuria in elderly women. One
been widely described. In a multivari- of these studies showed that vaginal
ate analysis it was found that urinary estrogen cream reduced vaginal pH from
incontinence, a history of UTI before 5.5 ± 0.7 to 3.6 ± 1.0, restore lactobacil-
menopause and non-secretor status were lus and decreased new episodes of UTI.
strongly associated with recurrent UTI in Another study reported similar results
young postmenopausal women. using an estriol vaginal ring. However,
contradictory results are found in the lit- Diagnosis in postmenopausal

erature. For example, additional studies women
found that the use of an estriol containing 7. History, physical examination and
vaginal pessaries was less effective than urinalysis, including culture (GoR B).
macrocristals oral nitrofurantoin in pre-
venting UTI in postmenopausal women 8. Treatment according to physician
and two other also did not find any ben- clinical judgment (GoR C).
efit in the reduction of UTI by oral estro- 9. Genitourinary symptoms are not nec-
gen therapy. Unfortunately the use of essarily related to UTI and are not
estrogen in preventing UTI in postmeno- necessarily an indication for antimi-
pausal women remains questionable. crobial treatment (GoR B).
New strategies were searched for
reducing the use of antibiotics in the pre- Treatment
vention and treatment of UTI. Two of
them are probiotics and cranberry juice 10. Treatment of acute cystitis in post-
or capsules. Although there are several menopausal women is similar as in
studies regarding probiotics and cran- premenopausal women however short
berry reporting reduction of episodes of term therapy is not so well estab-
UTI, there is not any conclusive evidence lished as in premenopausal women
that they are useful in the prevention of (see chapter 3.4).
UTI in postmenopausal women. As for 11. Treatment of pyelonephritis in
the optimal drug, dosage and length of postmenopausal women is similar
treatment for UTI in the elderly, there as in premenopausal women (see
are no studies comparing these data with chapter 3.4).
the treatment for young women. 12. Asymptomatic bacteriuria in elderly
Key words: Bacteriuria in elderly women should not be treated with
women, urinary tract infection, post- antibiotics. (GoR A) (see chapter 5.2).
menopausal women. 13. The optimal antimicrobials, dosages
and duration of treatment in elderly
women appeared to be similar to
SUMMARY OF RECOMMENDATIONS those recommended for younger post-
menopausal women (GoR C).
Risk factors in postmenopausal
women Prevention
1. In older institutionalized women, 14. Estrogen (especially vaginal) could be
urine catheterization and functional administered for prevention of UTI
status deterioration appeared to be yet results are contradictive (GoR C).
the most important risk factors associ- 15. Alternative methods, like cranberry
ated with UTI (GoR A). and probiotic lactobacilli, can con-
2. Atrophic vaginitis is a risk factor to be tribute but they are not sufficient to
considered (GoR B). prevent recurrent UTI (GoRC).
3. Incontinence, cystocelle and post- 16. Once complicating factors, like uri-
voiding residual volume (GoR A). nary obstruction, neurogenic bladder
4. UTI before menopause (GoR A). disturbances etc, could be ruled out,
an antimicrobial prophylaxis should
5. Non-secretor status (GoR A). be carried out as recommended for
6. Bacteriuria per-se did not appear to be premenopausal women (see chapter
a risk factor for mortality (GoR A). 4.2) (GoR C).
226
Urinary tract infections in postmenopausal women | 3.7 |
1. INTRODUCTION A total of 190 papers were screened by

title and abstract: 111 for the first key-
UTI is the most common bacterial infec- word and 79 for the second. Only English
tion in young and elderly women. Despite publications addressing the keywords
the higher incidence of bacteriuria in eld- were screened.
erly women, most UTI research has been The 25 references used in the text were
conducted in young women. This chap- assessed according to the level of scien-
ter will discuss epidemiological studies tific evidence involved. The studies were
regarding risk factors associated with rated according to the level of evidence
bacteriuria in elderly women. Bacteriuria (LoE) and the grade of recommendation
in the elderly is associated with high mor- (GoR) using ICUD standards (for details
tality rates, however in most of the cases see Preface) [1–2].
bacteriuria is asymptomatic and not a
causal factor of death.
3. DEMOGRAPHY
Estrogen deficiency plays an impor-
tant role in the development of bacteriu-
ria. Several studies have been conducted Urinary Tract Infection (UTI) is the most
showing the efficacy of estrogen (orally common bacterial infection in women.
and vaginally) in the prevention of UTI. There are three groups of women with
Yet, the literature is divided on this sub- recurrent UTI that should be distinguished
ject and other studies have not shown on the basis of age: pre-menopausal
any advantage in using estrogen. women, healthy post-menopausal women
This chapter will focus on the updated between the ages ~50–70 years who are
known data regarding the use of estro- neither institutionalized nor catheterized,
gen in the prevention of bacteriuria in and elderly institutionalized women, who
elderly women. The alarming increase of are in many cases catheterized.
multidrug resistant uropathogens makes Bacteriuria occurs more often in func-
it imperative that alternative strategies tionally impaired women than in those
are found. One strategy is the restora- not impaired, persistent bacteriuria is
tion of flora with lactobacilli using probi- seen more often in nursing home resi-
otics and another is the use of cranberry, dents, and transient bacteriuria more
a competitive compound that inhibits the often in young healthy postmenopausal
attachment of bacteria to the uroepithe- women. The majority of elderly women
lial mucosa and thereby reduces the fre- with bacteriuria are asymptomatic [3–4]
quency of UTI. and should not be treated with antibi-
otics (LoE 1b). In young to middle-age
women, the prevalence of UTI is <5%,
2. METHODOLOGY rising considerably with advancing age.
Epidemiologic studies have shown that
A systematic literature search was ~15%–20% of 65–70 year old women have
performed covering the last 15 years. bacteriuria, compared with ~20%–50% of
Recently, few recent studies have inves- women >80 years old.
tigated the management of UTI in post- Despite the high incidence of bacteriu-
menopausal women. The data was ria in postmenopausal women (young and
collected from the most up-to-date pub- institutionalized), most UTI researches
lished studies and guidelines found by were conducted in younger women.
searching Medline, PubMed and the Hence, the most common UTI risk factors
Cochrane database using the following among healthy younger women such as
keywords: bacteriuria in elderly women frequent vaginal intercourse, spermicide,
and postmenopausal women and UTI. diaphragm, condom use, a previous UTI
227
history, a recent antibiotic use and non- cystitis among non-diabetic and diabetic
secretor status were not widely investi- postmenopausal women and the possi-
gated in middle-aged and elderly women ble effect of estrogens on those women.
(LoE 2a) [5]. During 1773 person-years of follow-up,
138 symptomatic UTIs occurred (inci-
dence 0.07 person-year). Independent
4. BACTERIURIA IN YOUNG VERSUS prediction of infection included insulin
ELDERLY WOMEN dependent diabetes (Hazard Ratio 95%
C.I, 1.7-7.0) and a lifetime history of UTI
Foxman et al. conducted a case-control (Hazard Ratio for six or more infections =
study investigating the role of health 6.9, 95% C.I, 3.5 – 13.6). However, a bor-
behavior and sexual and medical history derline association included a history
in UTI risk among otherwise healthy of vaginal estrogen cream use in recent
women aged 40–65 years. They showed months (Hazard Ratio = 1.8; 95% C.I,
that sexual activity was not associated 1.0 – 3.4) and a history of kidney stones
with acquiring UTI in this age group, (Hazard Ratio = 1.95, 95% C.I, 0.9-3.5).
but a history of UTI during the past year, However, sexual activity, urinary incon-
urine loss, antibiotic use during the pre- tinence, parity, post-coital urination,
vious 2 weeks and exposure to cold dur- vaginal dryness, use of cranberry juice,
ing the previous 2 weeks were positively vaginal bacterial flora and post void
associated with UTI. In addition, drink- residual bladder volume were not associ-
ing cranberry juice and taking vitamin C ated with the incidence of acute cystitis
were moderately protective (LoE 2b) [4]. after multivariable adjustment.
A study by Moore et al. found that
recent sexual intercourse, as described
5. RISK FACTORS for younger women, was also strongly
associated with the incidence of UTI in
A case control study compared 149 post- other healthy post-menopausal women
menopausal women with a history of (LoE 2b) [7]. In the older, institutional-
recurrent UTI with 53 age-matched ized women, urine catheterization and
women with no history of UTI. They functional status deterioration appeared
looked for risk factors in healthy non- to be the most important risk factors
institutionalized and non-catheterized
women. Three urological factors, namely
incontinence (41% of case patients vs. 9%
Table 1 Major factors predisposing adult women to
control patients; p<0.001), presence of a urinary tract infection (UTI) as related to age. [9]
cystocele (19% vs. 0%; p<0.001) and post
voiding residual volume (28% vs. 2%; Age group Predisposing factor
p<0.000008), were strongly associated
with recurrent UTI. Multivariate analy- 15 – 50 y Sexual intercourse; Diaphragm/
spermicide; Spermicide;
sis showed that urinary incontinence Antimicrobials; Prior UTI; Maternal
(OR 5.79; 95% CI’ 2.05 – 16.42; p=0.0009) history of UTI; Childhood history
a history of UTI before menopause (OR, of UTI; Nonsecretor status
4.85; 95% C.I; 1.7 – 13.84; p<0.003) and 50 – 70 y Lack of estrogen; Urogenital
non secretor status (OR, 2.9; 95% C.I.; surgery; Incontinence; Cystocele;
Postvoid residual urine;
1.28 – 6.25; p=0.005) were most strongly
Nonsecretor status; Prior UTI
associated with recurrent UTI in post
menopausal women (LoE 2a) [5]. > 70 y Catheterization; Incontinence;
Urogenital surgery; Diminished
Jackson et al. (LoE 2a) [6] described mental status; Antimicrobials
the incidence and risk factors for acute
228
associated with UTI (LoE 2a) [8]. The Estrogen stimulates the prolifera-
risk of UTI increases dramatically with tion of lactobacillus in the vaginal epi-
catheterization. Table 1 describes the thelium, reduces pH and avoids vaginal
major factors predisposing adult women colonization of Enterobacteriaceae, which
to urinary tract infection (UTI) as related are the main pathogens of the urinary
to age [9]. tract. Figure 1 describes the relation-
ship between estrogen and the vaginal
flora and the pathophysiology of urinary
6. BACTERIURIA AND MORTALITY tract infections in elderly women (LoE
1a) [17]. In addition, the absence of estro-
Bacteriuria has been discovered as a gen decreases the volume of the vaginal
cause of increased mortality in elderly muscles, resulting in slackness of the
individuals. Studies of Greek, Finnish ligaments holding the uteric pelvic floor
and American patients showed decreased and the bladder, resulting in the develop-
longevity associated with UTI (LoE 1b) ment of prolapse of the internal genitalia.
[10–12]. The elderly patients with UTI Kicovic et al. (LoE1b) [18] showed that
were suffering from a variety of diseases vaginal cream decreased urogenital com-
other than UTI that might have increased plaints associated with atrophic vaginitis.
their susceptibility to infections as well A previous randomized, double-
as their mortality. blind, placebo-controlled study, demon-
Nordestam et al. studied a popula- strated that vaginal estriol treatment
tion of elderly patients and compared had a dramatic effect on recurrent UTI
their longevity in relation to bacteriuria in postmenopausal women. The results
(LoE 1b) [13]. There was no increase in showed that the incidence of UTI in
mortality related to bacteriuria for oth- women who received vaginal estriol was
erwise healthy individuals. Bacteriuria reduced to 0.5 episodes/year compared to
per-se did not appear to be a risk factor 5.9 episodes/year in women who received
for mortality. In patients with concomi- placebo. In addition, after one month of
tant disease, bacteriuria was associated treatment, lactobacillus appeared in 60%
with increased mortality, but was not the of the estrogen-treated group but in none
cause. of the placebo group and the vaginal pH
decreased from 5.5 ± 0.7 before treatment
to 3.6 + 1.0 after treatment (LoE 1b) [19].
7. THE ROLE OF ESTROGEN Several years later, similar results were
obtained by Eriksen, using an estradiol-
Another important factor in post- vaginal ring (LoE1b) [20]. In that study,
menopausal women is the potential role the women in the estradiol group had a
that estrogen deficiency plays in the devel-
opment of bacteriuria. Postmenopausal
↓ Estrogen
women frequently present with genitouri-
nary symptoms, half have genitourinary
disorders and 29% urinary incontinence ↓ Vaginal lactobacilli
(LoE 1b) [14]. Postmenopause is charac-
terized by a significant reduction of ovary ↑ Vaginal pH
estrogen secretion, which is often associ-
ated with vaginal atrophy. Clinically, it
↑ Colonization of the vaginal with Enterobacteraceae from
manifests as a syndrome characterized by the rectum
vaginal dryness, itching, dyspareunia and
Figure 1 Relationship between estrogen and the vaginal
urinary incontinence. This may some- flora and pathophysiology of urinary tract infections in elderly
times imitate UTI (LoE 2a) [15–16]. women. [17]
229
significant reduction in the frequency of Brown et al. (LoE 3) [22] assessed the
urogenital symptoms, such as vaginal effects of hormonal therapy on UTI fre-
dryness, dyspareunia and urge and stress quency and examined potential risk fac-
incontinence, and after 36 weeks of study tors. They used data from the Health
45% of the women receiving estradiol were and Estrogen/Progesterone Replacement
still free from UTI, in contrast to only 20% Study, a randomized, blinded trial of the
of the women treated with placebo. effect of hormone therapy on coronary
However, contradicting results are heart disease events among 2763 post-
found in the literature. For example, menopausal women aged 44–79 with
another study showed that the use of coronary diseases. UTI frequency was
estriol-containing vaginal pessaries was higher in the group receiving hormone
less effective than the use of oral nitro- treatment (0.625 mg conjugated estrogen
furantoin macrocrystals in the prevention plus 2.5 mg medroxy progesterone ace-
of bacteriuria in postmenopausal women. tate or placebo followed for a mean of 4.1
This study also showed the failure of the years), although the difference was not
estriol-containing vaginal pessaries to statistically significant. Statistical signif-
restore vaginal lactobacilli and to reduce icant risk factors for UTI in multivariate
vaginal pH in those women (LoE 1a) [21]. analysis included: women with diabetes
Indications
Oral Therapy Advantages
– Young postmenopausal women – Avoid menopausal symptoms
– Prevent osteoporosis
– Prevent ischemic heart disease
– Prevent UTI
Vaginal Therapy Advantages
– Women > 60 years old – Improve symptoms related to atrophic vaginitis
– Improve urge incontinence

– Prevent UTI
Contraindications
Absolute Relative
– Endometrial carcinoma – High blood pressure?
– Breast carcinoma – Diabetes mellitus?
– Thromboembolic disorders – Gall stones?
– Liver disease
Difficulties in vaginal therapy
Physical limitations
Tremor; Obesity; Status after cerebrovascular accident; Dementia;
Psychological problems; Education/cultural behavior
Figure 2 Indications and contraindications for estrogen therapy in UTI. [3]
230
on treatment (insulin OR 1.81, 95% C.I, younger women. Raz et al. [23] (LoE 1b)
1.4 – 2.34); oral medication (OR 1.44, 95% published a study in post-menopausal
C.I, 1.09 – 1.9); poor health (OR 1.34; women (mean age 65 years) with an
95% C.I, 1.14 – 1.57); vaginal itching (OR uncomplicated UTI in which ofloxacin,
1.63, 95% C.I, 1.07 – 2.5); and urge incon- 200 mg once daily for 3 days, was signifi-
tinence (OR 1.51, 95% C.I, 1.30 – 1.75). cantly more effective in both short- and
UTIs in previous years were strongly long-term follow-up than a 7-day course of
associated with a simple UTI (OR 7.00, cephalexin, 500 mg four times daily, even
95% C.I, 5.91 – 8.92) as well as multiple though all the uropathogens were suscep-
UTIs (OR 18.51, 95% C.I, 14.27 – 24.02). tible to the two agents. In another double-
In addition, data from the Hearth blind study [24] (LoE 1b), including a total
and Estrogen/Progesterone Replacement of 183 post-menopausal women of at least
Study compared women aged 44–79 65 years of age with acute uncomplicated
years, randomized in two groups, receiv- UTI, similar results were obtained with
ing 0.625 mg conjugated estrogens plus either a 3-day or a 7-day oral course of
2.5mg of medroxyprogesterone acetate ciprofloxacin 250 mg two times daily (bac-
or placebo, and followed up for a mean of terial eradication 2 days after treatment
4.1 years. In this study no effect was seen 98% vs 93%, p=0.16), but the shorter
in reducing UTI episodes in the women course was better tolerated. The rate of
treated with oral hormone therapy in bacterial eradication in this study was
comparison to the placebo group. Jackson generally high and the rate of bacterial
et al. did not see that the use of oral or resistance to ciprofloxacin low. (GoR A).
vaginal estrogen was a protective factor in Asymptomatic bacteriuria in elderly
order to avoid recurrent UTI (LoE 2a) [6]. women should not be treated with antibi-
In conclusion, the efficacy of estrogen otics (GoR A).
in the prevention of UTI in postmeno- The optimal antimicrobials, dosages
pausal women with recurrence remains and duration of treatment in elderly
questionable. From a clinical perspec- women appeared to be similar to those
tive, the current recommended use of recommended for young postmenopausal
estrogen (probably vaginal and not oral) women (GoR C). however, these results
is in postmenopausal women, especially should not be extended to the frail of an
those infected with multi-drug resistant elderly geriatric population with sig-
uropathogens which limit the options nificant comorbidities, who frequently
and effectiveness of antimicrobial proph- present with UTI caused by more resist-
ylaxis, and in women where the symp- ant Gram-negative organisms and in
toms were related to atrophic vaginitis. whom treatment duration should better
Figure 2 summarises the indications be prolonged as in complicated UTI.
and contraindications for estrogen ther- Estrogen (especially vaginal) could be
apy in UTI [3]. administered for prevention of UTI yet
results are contradictive. (GoR C). There
are at least two clinical studies showing
8. TREATMENT that vaginal estriol and estradiol-releas-
ing vaginal ring restore vaginal flora,
Treatment of acute cystitis and pyelone- reduce pH and the number of sympto-
phritis in otherwise healthy post- matic and asymptomatic bacteriuria (19,
menopausal women is similar as in 20). However, it appears that oral estro-
premenopausal women (see chapter gen does not reduce the incidence of UTI
Naber et al.), however, short-term therapy in PMN. (See chapter Hooton et al.)
in post-menopausal women is not as well Alternative methods, like cranberry
documented by controlled studies as in and probiotic lactobacilli, can contribute
231
to prevent recurrent UTI in PMN but groups. In addition, trimethoprim had a

more well conducted studies are required very limited advantage over cranberry in
to define their exact role and efficiency. the prevention of recurrent UTI in older
(GoRC). women but had more adverse effects and
Once complicating factors, like urinary withdrawals.
obstruction, neurogenic bladder distur- However, few clinical studies have
bances etc, could be ruled out, an anti- been conducted and in small and hetero-
microbial prophylaxis should be carried genic populations an advantage in the
out as recommended for premenopausal use of cranberry juice or other oral prep-
women (see chapter Hooton et al.) (GoRC). arations in the prevention of bacteriuria
has been shown. In the elderly popula-
tion there is only one clinical quasi-ran-
9. NEW STRATEGIES domized study (GoR C) [28] in elderly
women with asymptomatic bacteriuria,
The alarming increase of multidrug which showed that bacteriuria and pyu-
resistant uropathogens makes it imper- ria were significantly reduced in women
ative that alternative strategies are taking cranberry juice in comparison with
found. One strategy is the restoration of women who received placebo. However,
the normal flora with lactobacilli using since asymptomatic bacteriuria in the
probiotics. Another option is the use of elderly is not treated, the clinical signifi-
a competitive compound that inhibits cance of this study remains inconclusive.
attachment of bacteria to the uroepi-
thelium. Unfortunately both methods
have been evaluated without conclusive 10. FURTHER RESEARCH
results, although there is some evidence
that probiotics and cranberry are useful Further wide randomized studies are
in preventing UTI. essential to define and establish the
Reid et al. [25] demonstrated the pos- exact role of estrogen therapy, probiot-
sibility of preventing uropathogen infec- ics, lactobacilli and other possible and
tion by using lactobacillus in vitro. available methods to reduce the use of
Several clinical studies have shown that antibiotics.
L. rhamnosus Gr-1 and L. fermentum-RC
are able to colonize the vagina, a first
step in the management to prevent bac- 11. CONCLUSIONS
teriuria (LoE 2a). However, more studies,
especially clinical studies, should be car- Bacteriuria, particularly asymptomatic
ried out in order to determine the role of bacteriuria, is a very frequent finding in
probiotics in the prevention of UTI. both healthy postmenopausal and insti-
Another possibility is the use of cran- tutionalized women. Urological factors,
berry. Cranberries contain a proanthocy- such as urinary incontinence, presence
anidin that can prevent the colonization of any grade of cystocele and a post-void-
of the E.coli uropathogen in the vaginal ing residual volume, together with pre-
mucosa and reduce the frequency of bac- vious UTI and non-secretor status, are
teriuria (GoR C) [26]. McMurdo et al. associated with recurrent UTI in this
(GoR C) [27] carried out a randomized population. Some studies showed a rela-
controlled trial in elderly women to com- tionship between bacteriuria and dia-
pare the efficacy in preventing UTI of betes or sexual intercourse. The role of
cranberry capsules with trimethoprim. vaginal/oral estrogen, together with the
The time to first recurrence of UTI was use of probiotics and lactobacilli remains
not significantly different between both questionable.
232
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2004. 170(4): p. 469–73.
233
25. Reid, G. and J. Burton, Use of recurrent urinary tract infections? A ran-
Lactobacillus to prevent infection by path- domized controlled trial in older women.
ogenic bacteria. Microbes Infect, 2002. J Antimicrob Chemother, 2009. 63(2):
4(3): p. 319–24. p. 389–95.
26. Raz, P., Urinary tract infection in elderly 28. Avorn, J., et al., Reduction of bacteriuria
women. Int J Antimicrob Agents, 1998. and pyuria after ingestion of cranberry
10(3): p. 177–9. juice. JAMA, 1994. 271(10): p. 751–4.
27. McMurdo, M.E., et al., Cranberry or
trimethoprim for the prevention of
234
Chapter |4|
Prevention of recurrent
urogenital tract infections
in adult women
Chair: Thomas M Hooton
CHAPTER OUTLINE
4.2 Antibiotic prophylaxis in women with recurrent
urinary tract infections 240
4.3 Immunoactive prophylaxis of uncomplicated recurrent
4.4 Use of cranberry for prophylaxis of uncomplicated
recurrent urinary tract infections 269
4.5 Probiotics for the prophylaxis of uncomplicated recurrent
urinary tract infections in females 278
4.6 Prevention of prematurity by early diagnosis and
treatment of bacterial urogenital infections – the role
of bacterial vaginosis 288
|4.1|
Introduction
Thomas M. Hooton
University of Miami Miller School of Medicine, Miami, FL, USA
Corresponding author: Thomas M. Hooton, M.D., Professor of Clinical Medicine, University of Miami Miller School of
Medicine, 1120 NW 14th Street, Suite 1144, Miami, FL 33136, USA
Tel: +1 (305) 243 2576, THooton@med.miami.edu
Recurrent UTIs are common in women, having a mother with a history of UTI,
including healthy young women, and are and having a UTI during childhood. There
associated with considerable morbidity are several behaviors that are thought to
and expense. Moreover, their manage- increase the risk of recurrent UTI, but
ment can be problematic for clinicians in their association with UTI has not been
this era of increasing antimicrobial resist- clearly demonstrated in trials. These
ance. In contrast, recurrent UTIs are include reduced fluid intake, habitually
rare in healthy men. Non-antimicrobial delaying urination, delaying post-coital
prevention strategies are desirable given urination, wiping from back to front after
the adverse effects associated with anti- defecation, douching, and wearing occlu-
microbials and the increasing problem sive underwear. In older women, risk fac-
with antimicrobial resistance. This sec- tors include urinary incontinence, history
tion reviews different approaches to the of UTI before menopause, blood group
prevention of recurrent UTIs. Of note, antigen nonsecretor status, and having a
most recurrent UTIs in young women cystocele and an increased post-void resid-
are reinfections, rather than relapses, in ual. Not surprisingly, intercourse has also
which retreatment can be accomplished been shown to be a risk factor for recur-
with short-course antimicrobial regimens rent UTI in post-menopausal women [2].
and urologic evaluation is not indicated In addition, there is a growing body of
generally. evidence that UTIs in children and adults
In young healthy women, sexual inter- are associated with genetic mutations that
course is the risk factor most highly asso- affect the innate immune system [3–4].
ciated with recurrent UTI [1]. Other risk Given the frequency of recurrent UTI
factors in young women include spermi- and associated morbidity even in healthy
cide use, having a new sexual partner, young women, different prevention
strategies have been investigated. Although drugs. Non-antimicrobial approaches to

there are no well-designed studies address- prevent recurrent UTIs include behav-
ing the impact of behavioral changes in ioral modification as mentioned above,
reducing recurrent UTIs, there are some and the use of topical estrogen (in post-
strategies that are highly likely to be effec- menopausal women) (not reviewed in this
tive. Reducing sexual activity is one such section), cranberry products, probiotics
strategy, even if it is not always feasible. and immunoprophylaxis.
Reducing use of spermicides that include Estrogen alleviates atrophy of vaginal
nonoxynol-9 is also likely to be highly and urethral epithelium in older women.
effective, although the number of women Although oral estrogens appear not to
who use these products is relatively small. reduce the incidence of UTI in postmeno-
Women with recurrent UTI should be pausal women, topical vaginal estrogens
counseled about the pathogenesis of UTI do appear to have a beneficial effect [5].
and how behavior modification might be One randomized placebo-controlled study
useful in reducing one’s risk. For example, showed a dramatic benefit of vaginal
women should understand the rationale for estriol in reducing UTI risk and reconsti-
proper wiping habits and how early post- tution of vaginal flora [6]. In this 8-month
coital micturition might reduce one’s risk study, the rate of recurrent UTI went
of infection. from 5.9 to 0.5 UTI per year, and reconsti-
Antimicrobial prophylaxis, as reviewed tution of the vaginal flora with lactobacilli
in this section by Drs. Lichtenberger and was demonstrated in the estriol group.
Hooton, is highly effective in reducing the Similar beneficial results were shown in
risk of recurrent UTI, and is occasion- a study with an estradiol-releasing vagi-
ally warranted to prevent bothersome nal ring [7].
recurrent UTIs. These authors review Cranberry products, reviewed by
the antimicrobial prevention strategies Dr. Botto, are widely used by women
that have been shown to be effective in for UTI prevention. Cranberry products
preventing UTIs: continuous prophylaxis, block attachment of E. coli to uroepithe-
post-coital prophylaxis and intermittent lial cells via a non-dialyzable condensed
self-treatment. The decision as to which tannin, the proanthocyanidin type A. The
approach to use depends upon the fre- evidence for their clinical effectiveness
quency and pattern of recurrences and remains inconclusive, although recent
willingness of the patient to commit to a small studies suggest a beneficial effect.
specific regimen. Adverse events, patient’s A recent Cochrane review of clinical stud-
lifestyle and compliance and plans for ies concluded that there is some evidence
a pregnancy should be considered. The for use of cranberry in young women, but
choice of antibiotic should be based upon it is not clear what is the optimum dosage
the identification and susceptibility pat- or method of administration (e.g., juice
tern of the organism causing the patient’s or tablets), and that further properly
UTIs and history of drug allergies. designed trials with relevant outcomes
Before considering antimicrobial are needed. Such studies are ongoing.
prophylaxis to prevent UTI, however, one Until such data are available, it is rea-
should try non-antimicrobial approaches sonable to support the use of cranberry
to avoid antimicrobial side effects. as a preventive strategy in women with
Common side effects include rash, nau- recurrent UTI.
sea, diarrhoea, vaginal candidiasis, and Probiotics, reviewed by Drs. Cadieux
antibiotic-associated diarrhea. A major and Reid, offer a natural approach to
concern with any antimicrobial use is health maintenance with the potential
the selection of microbial flora resistant for reduced cost. Probiotics are living
to the drug being used as well as other microorganisms administered to promote
237
Chapter |4| Prevention of recurrent urogenital tract infections in adult women
the health of the host by treating or pre- are warranted to determine their effective-
venting disease. The correlation between ness, optimal regimens, and appropriate
depletion of vaginal lactobacilli and risk target populations.
of UTI has led to efforts to replenish the Hoyme discusses a novel strategy
lactobacilli organisms as a means to pre- to prevent premature birth, a common
vent recurrent UTI. Clinical studies pro- syndrome with very costly complica-
vide limited evidence that Lactobacillus tions. Bacterial vaginosis, a syndrome in
rhamnosus GR-1 with L. reuteri RC-14 which vaginal microflora is altered due
and L. crispatus CTV05 can populate the to unknown causes, is commonly found
vagina and displace urogenital patho- in pregnancy. Bacterial vaginosis is asso-
gens leading to reduced risk of infection. ciated with an increased risk for prema-
However, studies with larger sample sizes turity, and treatment has been shown
and well characterized and reliably pro- to reduce this risk. Hoyme describes the
duced products are needed to strengthen results of a trial to determine whether
the level of evidence. Although many self-screening of vaginal pH with gynae-
products are touted as probiotics, the con- cologic consultation for elevated vaginal
tent and viability of most are unreliable. pH results in reduced rates of prema-
Further study of probiotics and their role turity. Women participating in the trial
in reconstituting vaginal lactobacilli and were observed to have a reduced rate of
reducing the risk of recurrent UTI are prematurity compared with those who
clearly indicated. had routine care during pregnancy. This
Naber et al. performed a meta-analysis simple approach needs to be confirmed in
to assess the therapeutic efficacy and randomized trials, but it could possibly
safety of bacterial lysates in the prevention reduce the incidence of the common and
of recurrent UTIs. Such trials are based on extremely costly complications associated
the presence in the urinary tract of immu- with prematurity at minimal cost.
nological and cellular machinery necessary In summary, effective and safe strate-
for an efficient antibacterial defence and gies to prevent recurrent UTIs that avoid
the development of approaches to activate the use of antimicrobials are highly desir-
it. Several placebo-controlled trials have able. Education and counselling with the
been performed with an oral immunos- aim of behavioural modification should
timulant (OM-89 capsules, heat killed be offered to all persons with recurrent
uropathogenic Escherichia coli), and these UTI. Topical estrogen should be consid-
trials have shown a mean reduction of ered in post-menopausal women with
36% in the number of UTIs (some trials recurrent UTI. Although cranberry prod-
define UTI as the presence of significant ucts have not definitively been proven
bacteriuria) in OM-89 treated patients as effective, there is no reason to discour-
well as a reduction in the use of antibac- age their use as we await more defini-
terials. Smaller placebo-controlled stud- tive trials. Although vaginal colonization
ies using a vaginal vaccine (heat killed and clinical effectiveness data on pro-
uropathogenic E. coli, Proteus vulgaris, biotics are sparse, preliminary data
Klebsiella pneumoniae, Morganella mor- with some lactobacilli preparations are
ganii and Enterococcus faecalis) suggest promising; however, there are no widely
that this vaccine is also effective in reduc- available products with these lactoba-
ing UTI when administered with a booster cilli species commercially available for
cycle. Other promising vaccine approaches persons who would like to try them.
are mentioned in the review. Vaccine Immunoprophylaxis with OM-89 appears
approaches offer an exciting alternative to be significantly superior to placebo
to antimicrobial prophylaxis for prevent- in reducing UTI recurrences, but is not
ing UTI, but larger more definitive trials available in many countries, including
238
the United States. Cranberry, probiotics, female anatomy. Lancet Infect Dis, 2004.
and immunoprophylaxis are promising 4(10): 631–5.
antimicrobial-sparing approaches that 4. Lundstedt AC, Leijonhufvud I,
warrant further study. For those women Ragnarsdottir B, Karpman D, Andersson
with frequent recurrent UTIs not respond- B, and Svanborg C, Inherited susceptibil-
ing to the measures discussed above, one ity to acute pyelonephritis: a family study
of urinary tract infection. J Infect Dis,
should consider antimicrobial approaches,
2007. 195(8): 1227–34.
especially the intermittent self-treatment
5. Perrotta C, Aznar M, Mejia R, Albert X,
strategy to reduce antimicrobial exposure.
and Ng CW, Oestrogens for preventing
recurrent urinary tract infection in post-
menopausal women. Cochrane Database
REFERENCES Syst Rev, 2008(2): CD005131.
6. Raz R and Stamm WE, A controlled trial
1. Hooton TM, Recurrent urinary tract infec- of intravaginal estriol in postmenopau-
tion in women. Int J Antimicrob Agents, sal women with recurrent urinary tract
2001. 17(4): 259–68. infections. N Engl J Med, 1993. 329(11):
2. Moore EE, Hawes SE, Scholes D, Boyko 753–6.
EJ, Hughes JP, and Fihn SD, Sexual inter- 7. Eriksen B, A randomized, open, parallel-
course and risk of symptomatic urinary group study on the preventive effect of an
tract infection in post-menopausal women. estradiol-releasing vaginal ring (Estring)
J Gen Intern Med, 2008. 23(5): 595–9. on recurrent urinary tract infections in
3. Finer G and Landau D, Pathogenesis postmenopausal women. Am J Obstet
of urinary tract infections with normal Gynecol, 1999. 180(5): 1072–9.
239
|4.2|
Antimicrobial prophylaxis in
women with recurrent urinary tract
infections
Paola Lichtenberger, Thomas M. Hooton
Division of Infectious Disease, Department of Medicine, University of Miami Miller School of Medicine,
Miami, FL, United States
*Corresponding author: Thomas M. Hooton, M.D., Professor of Clinical Medicine,
University of Miami Miller School of Medicine
1120 NW 14th Street, Suite 1144, Miami, FL 33136, USA, Tel +1 (305) 243 2576, THooton@med.miami.edu
ABSTRACT compliance and plans for a pregnancy also

need to be considered. The choice of anti-
Recurrent urinary tract infections (UTIs) in microbial should be based upon the suscep-
women are common, result in considerable tibility pattern of the organisms causing
morbidity and expense, and can be a man- the patient’s previous UTIs and history of
agement problem for clinicians. Behavioral drug allergies.
changes can be useful antimicrobial-sparing
measures in the prevention of recurrent Key words: Recurrent UTI, antimicrobial
UTIs, but antimicrobial prophylaxis may prophylaxis, prophylactic antimicrobials,
be necessary in those who continue to and suppressive treatment
have recurrences. Continuous prophylaxis,
post-coital prophylaxis and intermittent SUMMARY OF RECOMMENDATIONS
self-treatment with antimicrobials have
all been demonstrated to be effective in
the prevention of recurrent uncomplicated 1. Antimicrobial prophylaxis for
UTIs. The decision as to which approach to prevention of recurrent UTI should
use depends upon the frequency and pat- be considered only after counseling
tern of recurrences and willingness of the and behavioral modification have been
patient to commit to a specific regimen. attempted (GoR A).
The risk of adverse events, including anti- 2. Continuous or post-coital antimicro-
microbial resistance, patient’s lifestyle and bial prophylaxis should be considered
Antimicrobial prophylaxis in women with recurrent urinary tract infections | 4.2 |
to prevent recurrent uncomplicated 3. In appropriate women with recurrent

cystitis in women in whom non- uncomplicated cystitis, self-diagnosis
antimicrobial measures have been and self-treatment with a short-course
unsuccessful (GoR A). For drug regi- regimen of an antimicrobial should be
mens see Tables 1 and 2. considered for management (GoR A).
1. INTRODUCTION
Table 1 Continuous antimicrobial prophylaxis regimens
for women with recurrent urinary tract infection.
Adapted from [60]. Recurrent urinary tract infections (UTIs)
are common in women, result in consid-
Expected erable morbidity and expense, and can
Regimens UTIs per year be a vexing management problem for
TMP-SMX* 40mg/200mg once daily 0 to 0.2 clinicians. In a study of college women
with their first UTI, 27% experienced at
TMP-SMX 40mg/200mg thrice weekly 0.1
least one culture-confirmed recurrence
Trimethoprim 100mg once daily 0 to 1.5** within the six months following the ini-
Nitrofurantoin 50mg once daily 0 to 0.6 tial infection and 2.7% had a second
recurrence during this same time period
Nitrofurantoin 100mg once daily 0 to 0.7
[1]. When the first infection is caused
Cefaclor 250mg once daily 0.0 by Escherichia coli, women appear to
Cephalexin 125mg once daily 0.1
be more likely to develop a second UTI
within six months than those with a
Cephalexin 250mg once daily 0.2
first UTI due to another organism [2]. In
Norfloxacin 200mg once daily 0.0 a Finnish study of women ages 17 to 82
Ciprofloxacin 125mg once daily 0.0
who had E. coli cystitis, 44 percent had a
recurrence within one year [3].
Fosfomycin 3gm every 10 days 0.14 Most recurrences in young healthy
*Trimethoprim-sulfamethoxazole. women are thought to represent episodes
**High recurrence rates observed with trimethoprim use associ- of exogenous reinfection, typically months
ated with trimethoprim-resistance.
apart [4]. In the normal host, most
uropathogens originate in the rectal flora,
colonize the periurethra, and ascend to
the bladder. Increasing evidence suggests
Table 2 Post-coital antimicrobial prophylaxis regimens
for women with recurrent urinary tract infection.
that alteration of the normal vaginal
Adapted from [60]. flora, especially loss of hydrogen peroxide-
producing lactobacilli, may predispose
Expected to introital colonization with E. coli and
Regimens UTIs per year to UTI [5]. Only rarely do young women
TMP-SMX* 40mg/200mg 0.30 with recurrent UTI have anatomical or
functional abnormalities of the urinary
TMP-SMX 80mg/400mg 0.00
tract, and excretory urography, cystogra-
Nitrofurantoin 50mg or 100mg 0.10 phy and cystoscopy are therefore of little
Cephalexin 250mg 0.03
use in the evaluation of such women [6].
Of note, recent studies in mice have
Ciprofloxacin 125mg 0.00
shown that E. coli may invade and repli-
Norfloxacin 200mg 0.00 cate within bladder epithelial cells and
Ofloxacin 100mg 0.06
reemerge later to cause infection [7].
There is new evidence that this pathway
*Trimethoprim-sulfamethoxazole.
may occur in women with cystitis in whom
241
evidence of intracellular bacterial commu- In addition, the lack of estrogen causes

nities has been found in exfoliated cells in marked changes in the vaginal microflora
urine [8]. Further studies are needed to including loss of lactobacilli and increased
determine whether this pathway occurs in colonization by E. coli. Topically applied
women and causes same-strain recurrent intravaginal estriol cream is an effective
UTI and, if it does, how it might influence preventive measure in such women [12].
prophylactic strategies. The risk of recurrent UTI in women
In a large case-control study of women has been demonstrated to be reduced by
with and without a history of recurrent the use of prophylactic antimicrobials
UTIs, the frequency of sexual intercourse [13–14]. Prophylactic antimicrobials have
was the strongest risk factor for recurrent been advocated for women who have expe-
UTI in a multivariate analysis [9]. Other rienced two or more symptomatic UTIs
risk factors identified were spermicide over a six-month period (13) or three or
use during the past year, having a new more over a 12-month period [15] after
sex partner during the past year, having a an existing infection has been eradicated
first UTI at or before 15 years of age and as demonstrated by a negative urine cul-
having a mother with a history of UTIs. ture one to two weeks after treatment.
In a recent population-based case-control However, the discomfort or inconvenience
study of 1,278 women ages 18–49, the risk experienced by the woman as a result of
of both recurrent cystitis and pyelonephri- her recurrent infections should be consid-
tis was significantly increased for women ered when deciding whether antimicro-
reporting female relatives with a history bial prophylaxis should be tried.
of UTI, with associations similar in magni-
tude to those for behavioral exposures such 2. METHODS
as new or multiple sex partners, inter-
course frequency, and spermicide exposure
A systematic search in the English litera-
[10]. These data strongly suggest a possi-
ture was performed in PubMed for the last
ble genetic role for increased susceptibility
20 years using the following key words:
to these infections in community-dwelling
recurrent UTI, antimicrobial prophylaxis,
women.
recurrent UTI in women, prophylactic
Postmenopausal women may also have
antimicrobials, and suppressive treatment
frequent recurrences of UTI. Risk factors
for recurrent UTI. We reviewed published
for UTI in postmenopausal women are
randomized controlled trials as well as
similar to those in younger women, but
case-control studies, cochrane reviews
other factors also appear to play a role.
and meta-analyses. Publications were
In a case-control study of 149 healthy
screened by title and, when appropri-
postmenopausal women with a history of
ate, abstracted. These publications were
recurrent UTI and 53 controls without a
supplemented by additional publications
history of UTI, mechanical and/or physi-
obtained from their bibliographies. The
ologic factors that affect bladder empty-
studies were rated according to the level
ing were found to be strongly associated
of evidence (LoE) and the grade of recom-
with recurrent UTIs [11]. Multivariate
mendation (GoR) using ICUD standards
analysis showed that urinary inconti-
(for details see Preface) [16–17].
nence (odds ratio (OR) 5.79), a history
of UTI before menopause (OR 4.85) and
non-secretor status (OR 2.9) were the 3. PREVENTION STRATEGIES
factors most strongly associated with
recurrent UTI (presence of a cystocele or Several strategies have been used in an
a postvoid residual urine were excluded attempt to prevent recurrent UTIs. These
because of low frequency in the controls). preventive approaches are reviewed in
242
this section of the book. Although many 4.1 Continuous prophylaxis

such strategies have not been adequately
Continuous prophylaxis has been dem-
tested in well-designed studies, patients
onstrated to decrease the number of
and providers often hold very strong
recurrent episodes of UTI by up to 95%
biases about their effectiveness. Non-
in several studies in different popula-
antimicrobial approaches to prevent UTI
tions (LoE 1b) [13, 18–20]. A Cochrane
should first be tried as a way of minimiz-
meta-analysis evaluated 19 trials involv-
ing antimicrobial exposure. Thus, women
ing 1120 healthy non-pregnant women
with recurrent UTI who are sexually
with two or more UTIs during the previ-
active or who use spermicides should be
ous 12-month period. Ten of those nine-
counseled about the possible associa-
teen trials compared antimicrobials with
tion between their infections and sexual
other antimicrobialss or placebo [20].
intercourse and use of spermicides and
Antimicrobial agents reviewed in the
advised, when appropriate, to decrease
meta-analysis included norfloxacin, cip-
or eliminate the usage of spermicide-
containing products. It is reasonable to rofloxacin, nitrofurantoin, trimethoprim-
counsel women about the use of cranberry sulfamethoxazole, cephalexin, cefaclor
to prevent UTI (see Botto), although and perfloxacin. During active prophy-
there is no definitive study showing that laxis, the range of microbiological recur-
cranberry products are effective in pre- rences was 0 to 0.9 per person-year in the
venting UTI. Probiotics (see Cadieux et antimicrobial group compared with 0.8 to
al.) and vaccines (see Naber et al.) for the 3.6 in the placebo group. The relative risk
prevention of recurrent UTI hold promise (RR) of having one microbiological recur-
but are not widely available and warrant rence was 0.21 (95% CI: 0.13 to 0.33) in
further trials to determine efficacy. favor of antimicrobial prophylaxis. For
clinical recurrences, the RR was 0.15 (95%
CI: 0.08 to 0.28) in favor of antimicrobial
4. ANTIMICROBIAL PROPHYLAXIS prophylaxis. Side effects included vaginal
and oral candidiasis and gastrointestinal
There are several approaches to choose symptoms. No conclusions could be made
from when using antimicrobial prophy- regarding the best antimicrobial or the
laxis. Continuous prophylaxis, post- optimal duration of prophylaxis (the max-
coital prophylaxis and intermittent imal duration tested was one year).
self-treatment (which is not really a There are few data available evaluating
prophylactic method) have all been fosfomycin for prophylaxis. In a double-
demonstrated to be effective in the man- blind randomized placebo-controlled
agement of recurrent uncomplicated study, the efficacy and safety of fosfo-
UTIs. The decision as to which approach mycin for prophylaxis was assessed in
to use depends upon the frequency and 317 non-pregnant women with a his-
pattern of recurrences and willingness of tory of recurrent UTIs for a period of 12
the patient to commit to a specific regi- months [21]. Fosfomycin was adminis-
men. The choice of antimicrobial should tered in 3-gram sachets every 10 days
be based upon the identification and sus- for six months. The number of UTIs per
ceptibility pattern of the organism caus- patient-year in the fosfomycin group was
ing the patient’s UTIs and the patient’s 0.14 compared with 2.97 in the placebo
history of drug allergies. Before any group (P<0.001). The time to first infec-
prophylaxis regimen is initiated, eradication recurrence was significantly longer
tion of a previous UTI should be assured in the fosfomycin group (38 days) than
by a negative urine culture one to two in the placebo group (6 days) (P<0.01).
weeks after treatment. Fosfomycin was well tolerated.
243
Some authorities recommend that anti- compared with placebo (3.6 per patient-
microbial prophylaxis be administered for year), and the regimen was effective for
a six-month period followed by an obser- patients with both low and high inter-
vation period based upon observations course frequencies [31]. In another rand-
that UTIs seem to cluster in some women omized trial, postcoital ciprofloxacin was
[22–23]. However, some trials suggest that as effective in reducing recurrent cystitis
prophylaxis does not appear to modify the as daily ciprofloxacin in sexually active
natural history of recurrent UTI and that young women [32].
most women revert back to their previous The regimens used for postcoital proph-
patterns of recurrent UTI once prophy- ylaxis are shown in Table 2.
laxis is stopped [20]. In those patients
who continue to have symptomatic infec- 4.3 Self-diagnosis and
tions after antimicrobial prophylaxis is self-treatment
stopped, prophylaxis may be restarted and
Many women do not want to take antimi-
extended to two or more years [13, 24–25].
crobials over an extended period of time
The use of trimethoprim-sulfamethoxazole
and prefer to minimize their intake of anti-
for as long as five years has been reported
microbials. If such women are reliable, they
to be effective and well-tolerated [25].
may be candidates for self-diagnosis and
Nitrofurantoin has also been shown to be
self-treatment with a short-course regimen
safe and well-tolerated in long-term (12
of an antimicrobial such as trimethoprim-
months) prophylaxis regimens, although
sulfamethoxazole or a fluoroquinolone
16% of women did not benefit in one study
(LoE 1b). In a randomized, crossover trial,
[26]. In addition, there are concerns about
38 women with recurrent cystitis were
toxicity with long term nitrofurantoin use
assigned to use either continuous prophy-
as discussed below.
laxis with trimethoprim-sulfamethoxazole
The regimens used for continuous
or intermittent self-administered ther-
prophylaxis are shown in Table 1.
apy with trimethoprim-sulfamethoxazole
(single-dose of 320/1600mg) at the onset
4.2 Post-coital prophylaxis
of urinary symptoms [33]. The infection
A single postcoital dose of antimicrobials rate for those on prophylaxis was 0.2 epi-
may be a more efficient and acceptable sodes per patient-year compared with 2.2
method of prevention than continuous episodes per patient-year for patients on
prophylaxis in women whose symptoms intermittent self-therapy (P<0.001). In the
appear related to sexual intercourse (LoE self-treatment group, UTI was correctly
1b). Depending upon the frequency of sex- diagnosed in 35 (92%) of 38 symptomatic
ual activity, postcoital prophylaxis usu- episodes and self-treatment was effective
ally results in receipt of smaller amounts in 30 (86%) of the 35 infections. In another
of antimicrobials than continuous proph- study, 34 women with recurrent cystitis
ylaxis. Uncontrolled studies suggest a were similarly evaluated for the self-treat-
comparable reduction in infection rates ment of UTIs with norfloxacin [34]. The
with postcoital trimethoprim-sulfameth- incidence of microbiologically confirmed
oxazole, nitrofurantoin, cephalexin and UTIs was 2.3 per patient-year (range 0 to
the fluoroquinolones [19, 27–30]. The 9). There was a total of 84 symptomatic
only published placebo-controlled trial episodes, in which 78 (92%) responded
of postcoital prophylaxis for recurrent clinically to self-treatment. Similar results
uncomplicated UTI showed a decrease were found in a third study of 172 women
in cystitis recurrence rates with postcoi- with recurrent UTI, 88 of whom self-
tal trimethoprim-sulfamethoxazole at a diagnosed 172 UTI and then started self-
dose of 40/200mg (0.3 per patient-year) treatment with ofloxacin or levofloxacin.
244
Clinical and microbiological cure occurred 5.2 Nitrofurantoin

in 92% and 96%, respectively, of culture- Nitrofurantoin, a synthetic nitrofurane
confirmed episodes, and there were no derivative, has maintained excellent
serious adverse events [35]. in vitro activity against E. coli and
Use of this strategy should be restricted Enterococcus faecalis even though it has
to those women who have clearly docu- been on the market for over 50 years. It
mented recurrent infections and who is one of the most commonly used antimi-
are motivated, compliant with medical crobials for prophylaxis. Nitrofurantoin,
instructions and have a good relation- unlike trimethoprim or the fluoroquinolo-
ship with a medical provider. The trials nes, appears not to select for drug-resistant
have been performed with trimethoprim- bowel flora or to eradicate coliforms from
sulfamethoxazole or a fluoroquinolone, the bowel flora [26]. Thus, during long-
but any of the first-line agents discussed term prophylaxis with nitrofurantoin in 92
below should be adequate to use with this women, nitrofurantoin-sensitive coliforms
strategy. Women should be reminded to were present in the fecal flora of almost
call their provider if they have symptoms all patients during antimicrobial prophy-
suggestive of pyelonephritis or if their laxis; no resistant organisms were found
symptoms are not completely resolved by in 80 women [26]. In the 12 women who
48 hours on treatment. had nitrofurantoin-resistant organisms in
their fecal flora, none had breakthrough
infections with these organisms.
5. ANTIMICROBIALS USED FOR UTI A review of 1,142 outpatient E. coli
PROPHYLAXIS strains causing UTIs in patients from the
USA and Canada between 2003 and 2004
5.1 Trimethoprim-sulfamethoxazole was carried out by the North American
Trimethoprim-sulfamethozaxole has been Urinary Tract Infection Collaborative
employed for more than 30 years as a Alliance (NAUTICA) [40]. The overall
first-line therapy for UTI [36]. It is also a resistance to ampicillin was 37.7% and
first-line choice for prophylaxis for recur- to trimethoprim-sulfamethoxazole 23.3%,
rent cystitis. However, antimicrobial resist- whereas only 1.1% of the isolates were
ance to this agent has been increasing over resistant to nitrofurantoin. Similar results
the years, approaching 18–22% in some were seen in a study of 4,734 adult women
areas of the United States and Europe, presenting with acute uncomplicated cysti-
raising questions about its role in the treat- tis in Europe and Canada [41]. Of the 2,478
ment of cystitis [37–38]. A more recent E. coli isolates tested from this group, the
surveillance study of antimicrobial resist- prevalence of resistance to ampicillin was
ance in women with cystitis from nine 30% and to trimethoprim-sulfamethoxazole
countries of Europe and Brazil (ARESC 14%, but only 1.2% were resistant to nitro-
study) reported high rates of resistance furantoin and 0.7% to fosfomycin. However,
among E. coli to several commonly used in a recent survey performed in Italy, more
antimicrobials used for UTI, including than 20% of E. coli strains were resistant
trimethoprim-sulfamethoxazole (29%) and to nitrofurantoin [42].
fluoroquinolones (8%) [39]. In the US, but Nitrofurantoin is well tolerated, but
perhaps not in Europe and some other with long-term exposure, as with proph-
parts of the world, the use of trimethoprim- ylaxis, acute, subacute and chronic pul-
sulfamethoxazole for prophylaxis to prevent monary reactions, chronic hepatitis and
recurrent UTI is reasonable if previous neuropathy have been reported. These
causative isolates are susceptible to this toxicities are exceedingly rare, but the
agent. It is well-tolerated and inexpensive. patient should be warned about them.
245
5.3 Fluoroquinolones long-term prophylaxis with fluoroquinolo-

Ciprofloxacin and levofloxacin are the nes, especially those undergoing strenuous
most commonly used fluoroquinolones for physical activity and those with chronic
the treatment of UTI. The other agents in use of steroids, should be counseled about
this class do not offer any advantages over the risk of tendon rupture.
these two. Of concern, fluoroquinolones Fluoroquinolones are classified by the
are increasingly used for treatment and manufacturer as pregnancy category
prophylaxis of UTI and, as noted above, C. They cross the placenta and produce
resistance among UTI strains is increas- measurable concentrations in the amni-
ing. They are generally well tolerated, otic fluid and cord serum [47]. Although
although they can cause gastrointesti- an increased risk of teratogenic effects has
nal, neurological and cardiovascular side not been observed in animals or humans,
fluoroquinolones should not be used dur-
effects, including a prolonged QTc interval
ing pregnancy because of concerns of car-
and, infrequently, Torsade de pointe [43].
tilage damage in immature animals [48].
Fluoroquinolones are not recommended
Contraception and pregnancy plans should
in patients with a history of prolonged
be discussed before prescribing fluoroqui-
QTc interval, in patients with uncorrected
nolones to females of child-bearing age.
hypokalemia or hypomagnesemia, or with
Fluoroquinolones should not be consid-
concomitant use of medications that can
ered as first- line agents for prophylaxis
increase the QTc interval.
for recurrent uncomplicated cystitis given
The use of fluoroquinolones has also
concerns about selection for resistance.
been associated with tendon, mainly the
However, if other measures have failed
Achilles, rupture. A recent Danish study
in women with frequent bothersome
suggested that the risk of Achilles tendon
recurrences, it is reasonable to consider
rupture within 90 days of fluoroquinolone
their use.
use was 17.7 per 100,000 person-years
(95% CI: 5.7–41.3) which was three times 5.4 Cephalosporins
higher than that calculated for the back-
ground population [44]. This corresponds Cephalosporins have been studied as an
to only one excess Achilles tendon rupture alternative to nitrofurantoin or placebo
per 8300 treatments. Another study of for the prophylaxis of recurrent UTIs in
46,776 patients treated with fluoroquinolo- women with good clinical and microbio-
nes found 704 cases of Achilles tendinitis logic outcomes [49–50]. In the ECO.SENS
and 38 cases of Achilles tendon rupture project that determined antimicrobial
accounting for an overall excess risk of 3.2 susceptibility of bacterial pathogens caus-
cases of tendon problems for every 1000 ing community acquired UTIs in 16 coun-
person-years of exposure [45]. However, tries of Europe and Canada, resistance to
the risk of having Achilles tendon disease cefadroxil was seen in only 53/2478 E. coli
after 30 days of exposure to fluoroquinolo- strains tested [41]. In one study of 49
nes was the same compared with the non- patients taking long-term cephalosporins
exposed population [45]. Achilles tendon as prophylaxis for recurrent UTI, only 13
rupture is mainly related to physical activ- bacteriuric episodes were detected and
ity, although rheumatoid arthritis, the use among those, only 50% were resistant to
of corticosteroids, age and male sex are cephalosporins – findings were similar in
additional risk factors [43, 45–46]. The the comparator nitrofurantoin group [49].
mechanism behind the fluoroquinolones
effect is unknown, but it is probably due to 5.5 Fosfomycin tromethamine
direct toxicity and degenerative changes on Fosfomycin tromethamine is a phosphonic
collagen fibers [44]. Patients undergoing acid derivative, bactericidal cell-wall
246
active antimicrobial agent effective with susceptibility to the drug of potential

a broad spectrum of antibacterial activity uropathogens colonizing the patient’s
[51]. This antimicrobial has good in vitro perineal flora [18, 23]. In one study of
activity against most of the bacterial spe- long-term prophylaxis with cefaclor or
cies responsible for uncomplicated cysti- nitrofurantoin, patients reported lack
tis and is approved for the treatment of of compliance shortly before the onset
uncomplicated cystitis caused by E. coli of an episode of bacteriuria with cul-
and E. faecalis [52]. The rate of resist- tures reporting susceptible strains [49].
ance to fosfomycin among uropathogens Monitoring rectal or vaginal flora for the
is quite low, even in countries such as presence of resistant organisms has not
Japan, Spain, Germany, France, Brazil been proven to be helpful in anticipating
and South Africa, where it has been used breakthrough infections in patients on
extensively for more than 20 years [39, antimicrobial prophylaxis [18]. Moreover,
53]. Clinical studies have shown that, the emergence of uropathogens resist-
in countries where fosfomycin has been ant to the agents being used for UTI
used for many years, about 3% of bacte- prophylaxis is not frequently seen [18,
rial pathogens are resistant to fosfomy- 23, 26], but has been reported in some
cin and this percentage has been stable studies. For example, in one study com-
for several years [54–55]. The emergence paring post-intercourse versus daily cip-
of fosfomycin-resistance is mainly due to rofloxacin prophylaxis for UTIs, 5 of 62
mutation of genes controlling the alpha patients receiving daily prophylaxis for
glycerolphosphate transport [55]. three months had breakthrough UTIs,
There appears to be little cross- two with organisms resistant to cipro-
resistance between fosfomycin and other floxacin [32]. Likewise, in a long-term
antibacterial agents [56], possibly because trimethoprim-sulfamethoxazole proph-
it differs from other agents in its general ylaxis study, breakthrough infecting
chemical structure and site of action. Loss organisms were generally resistant to tri-
of fitness due to resistance mutations methoprim-sulfamethoxazole, and organ-
may explain the stably low incidence of isms colonizing the periurethral and rectal
fosfomycin resistance. regions also tended to be resistant to the
trimethoprim-sulfamethoxazole [25].
Cross resistance was evaluated in 2478
6. PRECAUTIONS WHEN USING E. coli isolates from the Pan-European
ANTIMICROBIAL PROPHYLAXIS ECO.SENS Project [56]. Ampicillin/ sul-
FOR RECURRENT UTI famethoxazole resistance, seen in 8.7%
of strains, was the most common pattern
6.1 Antimicrobial resistance of multiple resistance. This was followed
Antimicrobial resistance is a concern in by ampicillin/sulfamethoxazole/trimetho-
persons on antimicrobial prophylaxis, prim/trimethoprim- sulfamethoxazole
especially with those antimicrobials that resistance, observed in 6.4% of all strains.
have other important uses in medicine, With the exception of fosfomycin, resist-
such as fluoroquinolones. However, the ance to any agent was associated with
contribution that antimicrobial prophy- increased resistance to the other agents
laxis has on overall resistance has not tested. This study showed that a multiple-
been determined. This concern warrants resistant phenotype involving fluoro-
further study. quinolone resistance is present in most
The prophylactic efficacy of any anti- countries in Europe, and that this phe-
microbial agent depends upon compliance notype is selected for not only by the
with taking the drug and the continued use of quinolones, but also by the use
247
of ampicillin, sulfamethoxazole and UTI. More research is warranted to deter-

trimethoprim-sulfamethoxazole. mine the impact of long-term antimicro-
bial use as a contributing factor for the
6.2 Contraceptives emergence of multi-drug resistant bac-
teria in gut and vaginal flora. More data
Some antimicrobials interfere with the are needed on side effects associated with
effectiveness of oral contraceptives by long-term use of low-dose antimicrobials
interrupting the enterohepatic recycling used for prophylaxis.
of estrogen by altering the gut flora that
participate in the process or by inducing
hepatic estrogen metabolism. As a result,
8. CONCLUSIONS
estrogen concentrations may be reduced.
Examples of such drugs include rifampin,
some macrolides, tetracyclines, metroni- Antimicrobial prophylaxis should be con-
dazole and penicillins [57]. Women who sidered in women with frequent recurrent
use an oral contraceptive and who are UTIs when non-antimicrobial measures
placed on such an antimicrobial should are not working. Antimicrobial prophy-
be warned to use a second contraceptive laxis is highly effective, but is usually used
alternative such as a barrier contracep- for long periods of time and, thus, likely
tive while on the antimicrobial. contributes to the widespread problem of
antimicrobial resistance. Post-coital proph-
ylaxis and self-diagnosis/self-treatment
6.3 Antimicrobial-associated
result in less antimicrobial use and should
diarrhea
be used in appropriate settings.
Almost all antimicrobials used for UTIs
have been associated with an increased risk
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251
|4.3|
Immunoactive prophylaxis of
tract infections
Kurt G. Naber1, Yong-Hyun Cho2, Tetsuro Matsumoto3, Anthony J. Schaeffer4
1
Technical University Munich, Munich, Germany
2
St. Marys Hospital, The Catholic University of Korea, Seoul, South Korea
3
Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
4
Department of Urology, Northwestern University Medical School, Chicago, Illinois, USA
Corresponding Author: Prof. Dr. Dr. h.c. Kurt G. Naber, Karl-Bickleder-Str. 44c, D-94315 Straubing, Germany
Tel +49-9421-33369, E-mail: kurt@nabers.de
ABSTRACT immunostimulant (OM-89 capsules, heat

killed uropathogenic Escherichia coli) of
Background: Recurrent urinary tract which 5 (1000 adult patients) could be
infections (UTIs) are the most common retained for analysis with an observation
medical complaint, particularly among period of 6–12 months. The mean number
women in their reproductive years. There of UTIs was significantly lower, by an
is an increasing need for alternatives to average of 36%, in the OM-89 treated
antibacterial prophylaxis, particularly patients in all the trials analysed; also
measures to increase defences. Various the use of antibacterials was lower.
bacterial lysates have been proposed with Four of these studies dealt with a
this indication. vaginal vaccine (heat killed uropatho-
Methods: The objective of this review and genic E. coli, P. vulgaris, K. pneumonia,
meta-analysis is to assess the therapeutic M. morganii & E. faecalis), of which three
efficacy and safety of bacterial lysates in small studies could be retained for anal-
the management of recurrent UTIs. ysis with a total of 220 adult patients.
Results: Electronic databases identified 11 The results suggest that this vaginal vac-
studies with the descriptors UTI, immu- cine is effective when administered with
notherapy or vaccines and double blind. a booster cycle (no recurrence of UTI
Seven of these studies dealt with an oral in 50% vs. 14% with placebo). No blind
Immunoactive prophylaxis of uncomplicated recurrent urinary tract infections | 4.3 |
controlled studies could be identified with sexually active women have at least one
other bacterial lysates claiming the same such infection, and up to 60% of all women
indication. will develop a UTI at some time in their
Conclusions: Among the various immu- lives. At least one in four of these women
notherapeutic products offered on the will have a recurrence within a year [1].
market only one (OM-89) has published Urinary tract infections (UTIs) fre-
studies which are in accordance with cur- quently present with acute onset of dysu-
rent standards. This product was shown ria, frequency or urgency and suprapubic
to be effective under conditions of daily pain. The UTIs are confirmed by urine
practice. The second product, also seems analysis > 10 WBC/mm3 and urine cul-
effective but adequate phase III studies ture with > 103 colony forming units/mL
are necessary. of uropathogen in mid-stream sample of
urine. UTIs were defined as recurrent
Key words: Urinary tract infections,
if there were at least three episodes of
bacterial lysates, clinical review, meta-
uncomplicated infection documented by
analysis, OM-89, Uro-Vaxom, Solco-Urovac
culture within a 12 month period. On
average, each episode of acute UTI in
SUMMARY OF RECOMMENDATIONS pre-menopausal women was shown to be
associated with 6.1 days of symptoms,
1. OM-89 (Uro-Vaxom®) is sufficiently 2.4 days of restricted activity, 1.2 days
well documented and has shown to be in which they were not able to attend
more effective than placebo in several classes or work and 0.4 days in bed [2].
randomised trials. Therefore, it can In women there are several well defined
be recommended for immunoprophy- risk-factors for recurrent UTIs such as a
laxis in female patients with recur- maternal history of cystitis or history of
rent uncomplicated UTI (GoR B). Its previous episodes of cystitis and the use
efficacy in other patients’ groups and of spermicidal agents [3]. In postmeno-
its relative efficacy to antimicrobial pausal women the incidence of recurrent
prophylaxis should be established. UTIs is increased in diabetic patients [4];
2. For other immunotherapeutic prod- in nonsecretor patients, patients with
ucts offered on the market larger urinary incontinence or with a history of
phase III studies are still missing. In UTI before menopause [5–6].
smaller phase II studies StroVac® and The idea of employing bacterial
Solco-Urovac® have been shown to be immune stimulants in order to reduce
effective when administered with a recurrent UTIs was born some 40 years
booster cycle (GoR C). ago and they have been used, rather
empirically, to prevent recurrent infec-
3. For other immunotherapeutic prod- tions in the non-immunocompromised
ucts, e.g. Urostim®, Urvakol®, no host. These early attempts were ham-
controlled studies are available. pered at the time by a lack of knowledge
Therefore no recommendations are regarding the potential mechanisms
possible (GoR D). involved. Only in recent years has bet-
ter understanding of the innate immune
1. INTRODUCTION system provided a solid rationale for such
immune stimulants. The requirements
Urinary tract infections (UTIs) are the for a bacterial extract to be effective are
most common medical complaint among that it stimulates infection-combating,
women in their reproductive years. circulating elements within the lymphoid
Women are 30 times more likely to have tissue and that the target organ envi-
UTIs than men are. Every year, 15% of sioned is immunocompetent in order to
253
adequately translate such a stimulus in and meta-analysis presented herein is to

an efficient response. Bacterial extracts assess the therapeutic efficacy and safety
can act as immune stimulants through of the bacterial lysates currently availa-
the activation of monocyte-derived den- ble in the management of recurrent UTIs.
dritic cells, as was shown for OM-89
[7]. Human monocyte-derived dendritic
cells (moDCs) and circulating conven- 2. METHODS
tional DCs coexpress activating (CD32a)
and inhibitory (CD32b) isoforms of IgG The primary objective of this review is to
Fcγ receptor. The balance between these assess the efficacy and safety of immu-
divergent receptors establishes a thresh- nostimulants based on bacterial lysates
old of dendritic cell activation and enables from a clinical point of view and taking
immune complexes to mediate oppos- into account clinically relevant endpoints.
ing effects on dendritic cell maturation Meta-analysis may produce a stronger
and function. The activating and inhibi- conclusion than can be provided by any
tory FcγRs on DCs offer rational targets individual study. The purpose of meta-
for immunotherapy based on the unique analysis is to increase the statistical
capacity of DCs to play critical roles in power for primary end points, increase the
both immunity and tolerance [8]. general applicability (external validity)
Some bacterial extracts are admin- of findings, resolve uncertainty when
istered orally with the goal of increas- reports disagree, provide quantita-
ing the immune defences of organs with tive estimates of effects, call attention
a mucous lining, although parenteral, to strengths and weaknesses of a body
intravaginal and intranasal applications of research in a particular area and to
have also been described. In animal mod- identify needs for new primary data
els and in normal humans, gut-associated collection.
lymphoid tissue stimulation is able to
induce a generalised response by the
whole mucosal-associated lymphoid tis- 2.1 Search strategy and material
sue. Mucosa-associated lymphoid tissue scrutinized
(MALT) is found in the digestive tract, the Among the data sources consulted in the
respiratory tract and the genitourinary identification of trials were bibliographic
tract. Migration and adherence of lamina databases (TOXLINE, PaperChase brows-
propria lymphocytes are in part dictated ing the databases of the National Library
by integrins and selectins. Lymphocyte of Medicine and the National Cancer
circulation leads to the distribution of Institute i.e. MEDLINE, HealthSTAR,
effector cells to particular parts of the AIDSLINE and CANCERLIT, Embase,
body where homing of the lymphocytes AMED, Cochrane Col., PubMed (/www
is controlled by the expression of various .ncbi.nlm.nih.gov), TOXLINE Special,
receptors on the cell surface and counter DART Special, HSDB, IRIS, ITER,
receptors on the vascular endothelium [9]. GENETOX, CHEMIDplus, Haz-Map), ref-
In addition to the bladder, the urethra erence lists from pertinent review articles
is a highly dynamic immunocompetent and books, and personal contacts with and
tissue possessing all the necessary ele- experts active in the area, up to January
ments for antigen presentation and both 2009. All papers were screened and any
humoral and cellular mucosal immune dealing with prospective clinical trials
responses. It is likely that this region were retained for classification according
plays a dominant role in protecting the to the selection criteria described below.
urogenital tract against ascending infec- In the case of double publications, the
tions [10]. The objective of the review authors retained those which were most
254
recent and/or had appeared in a peer- 10 heat killed uropathogenic bacteria,

reviewed journal. including six different serotypes of
Selection criteria and description of uropathogenic Escherichia coli, Proteus
studies: The search criteria were urinary vulgaris, Klebsiella pneumoniae, Mor-
tract infection double or single blind, and ganella morganii and Enterococcus
bacterial vaccines or immunization or faecalis), Urostim® (‘Other products’;
immunotherapy or vaccination or vac- killed bacterial cells and their lysates
cines. To be retained, a study had to be of four microbial species: uropathogenic
a randomized placebo-controlled clinical Escherichia coli expressing type 1 pili,
trial with the primary aim of reducing Rc mutant of E. coli, Klebsiella pneumo-
the number of UTIs over a period of 6–12 niae, Proteus mirabilis and Enterococcus
months. faecalis) and Urvakol® (‘Other prod-
All trials rendered eligible were clas- ucts’; uropathogenic Escherichia coli,
sified by indication and summarized in Klebsiella pneumoniae, Proteus mirabilis,
a tabulated format by one reviewer. The Pseudomonas aeruginosa and Enterococcus
standard table included a full reference, faecalis; adjuvant activity is provided by
a quality rating, the type of pathology, Propionibacterium acnes). However, this
demographic data and treatments, end- search did not identify additional trials
points and adverse events. The trials complying with the predefined criteria.
were grouped by indication and by treat- The resulting selection of trials was:
ment. These tables were verified and dis- • Product ‘A’: Identified 7 trials;
cussed by the authors until consensus excluded 2 trials, retained for analysis
was reached. No formal validation proc- 5 trials.
ess was employed.
• Product ‘B’: Identified 4 trials;
The electronic databases identified 1°)
urinary tract infection in 25757 references excluded 1 trial, retained for analysis
and 2°) double or single blind in 88121 + 3 trials
10220 references and 3°) bacterial vac- • ‘Other products’: Identified 1 trial;
cines or immunization or immunotherapy excluded 1 trial.
or vaccination or vaccines in 155209 ref-
erences, but only 10 complied with the
2.2 Analysis of data
three descriptors. One additional clinical
study was identified through other chan- The guidelines provided by the Cochrane
nels and duly scrutinized. The search also Collaboration Handbook for Reviews
yielded one meta-analysis [11] concerning [12] and the corresponding software
OM-89 (Product ‘A’; Uro-Vaxom®). As will have been used in the analysis of the
be described under results, three studies clinical data (Review Manager 4.2.7).
were eliminated because of duplication of Ordinal data were compared using the
data, particular patient selection or inad- Mantel-Haenszel-Peto Method [13].
equate reporting (one study each). Significances were calculated using two
Furthermore, the electronic databases sided tests, the threshold of significance
were searched for trials conducted with being p ≤ 0.05 and for non-significance
specific products identified1; that is, p > 0.1; values between p > 0.05 and
OM-89 capsules (Product ‘A’; five differ- p ≤ 0.1 were reported as trends. Means
ent serotypes of heat killed uropathogenic and standard deviations (SDs) cor-
Escherichia coli), Product ‘B’ for intramus- respond to those reported for the ITT
cular or vaginal administration (StroVac® analysis, where available, N patients
and Solco-Urovac® respectively; contain correspond therefore to the number
of patients admitted to the trial and
1 http://focosi.altervista.org/preventionprimaryimmunovaccine.html exposed to the treatment.
255
3. RESULTS in the total population. In all these

studies, recruited patients were suf-
3.1 Product ‘A’: OM-89 fering from UTI, had a history of
(Uro-Vaxom®) recurrent UTIs, were treated with an
antibacterial agent until cure, while
Of the original seven studies identified,
at the same time starting treatment
only five could be retained for further
with OM-89, one capsule daily for
analysis. One study [14] was excluded
three months. Thereafter, there was
because, although double blind, it dealt
a follow-up period of an additional
with a special group of patients: in a six-
three months. In the largest study
month, double-blind, placebo-controlled
(Bauer) [16] the patients received
clinical trial with cross-over, the authors
thereafter a booster treatment at
administered the bacterial extract OM-89
months seven to nine (one capsule
in 70 spinal cord injured patients with
daily during 10 days per month),
chronic lower urinary tract infections. In
again with an additional follow up
the treated patients, compared to those
of three months, thus completing a
given placebo, there was a statistically
study period of 12 months. However,
significant decrease in the degree of bac-
the study design does not allow for a
teriuria, a considerably decreased inci-
distinction between effects due to the
dence of infectious episodes and a lesser
booster treatment and the possible
requirement for antibiotics. One further
‘carry-over’ effects of the initial treat-
trial [15] with 64 out-patients suffer-
ment cycle. In all the studies exam-
ing from an acute recurrent UTI was
ined the patients were comparable
excluded because there was insufficient
at baseline concerning demographic
reporting of demographics and the pub-
and clinical data. In addition to the
lication did not account for drop-outs or
planned visits, the patients could
missing data. In this trial, dysuria, bac-
return for consultation if they were
teriuria, leukocyturia and consumption
symptomatic; these UTIs were assim-
of antibacterials were reported to show
ilated to the following planned visit.
a significant reduction under OM-89 in
Only two trials (Bauer and Pisani)
comparison with the placebo after six
[16–17] reported the type of bacte-
months.
ria identified at baseline, which was
• The five studies [16–20] retained Escherichia coli in about 70% of the
for further analysis present a large cases in both trials.
amount of commonalities, although
they differ in some aspects. A sum-
mary of treatment schedules, various 3.1.1 Mean Number of Urinary Tract
definitions of urinary tract infections, Infections
admission and exclusion criteria, and In all the studies examined, the authors
the patients’ flow is given in Table 1. reported the mean number of UTIs dur-
In four studies [17–20] men were ing the trial or described the actual
also included, but always comprised number of UTIs, which could be trans-
less than 20% of the total patients. formed in the corresponding means. The
Unfortunately, the results could not data were calculated in two ways: ‘as
be stratified by gender. In the larg- reported’ in the studies (that is data after
est study [16], however, only female 6 and 12 months) or employing a cut-off
patients with recurrent uncompli- at six months.
cated urinary tract infection (UTI) For the mean number of UTIs, the
were included, thus the proportion weighted mean difference (inverse of
of men decreased to less than 7% the variance) has been used, because
256
Table 1 Summary of demographic data, definitions of urinary tract infections, admission and exclusion criteria, quality
standards, reporting and patients flow.
1st Author, Bauer, Pisani, Magasi, Schulman, Tammen,

year 2005 [16] 2000 [17] 1994 [18] 1993 [19] 1990 [20]
Quality GCP (ITT / per GCP (ITT / per Not stated (per GCP (per Not stated (per
(Reported as ) Protocol) Protocol) Protocol) Protocol) Protocol)
UTI, variables
rated
Bacteriuria ≥ 103 * > 105 * > 105 > 105 § > 105 §
(bacteria/mL)
Dysuria +++ [++] ** +++ +++ +++
Miction pain +++ [++] ** --- --- ---
Pollakisuria +++ [++] ** --- --- ---
Excluded pyelonephritis, Antibiotic resist- pyelonephritis, anatomical post-coital UTI,

catheter, neuro- ant UTI, pyelone- catheter, obstruc- abnormalities, pyelonephritis,
genic bladder, phritis, catheter, tion, etc. etc. catheter, obstruc-
etc. obstruction, etc. tion, etc.
Definition of Bacteriuria + 2 Bacteriuria Bacteriuria Bacteriuria not defined

UTI symptoms
Age mean(sd)
OM-89 41.7 (15.3) 46.9 (15.9) Range 16–82 45.3 (18.4) 51.2 (20.9)
Placebo 39.8 (15.1) 45 (16.1) 50.4 (19.8)
Gender
Males/ Females 0 / 453 9 / 128 26 / 140 17 / 95 17 / 133
N patients
(OM-89/Placebo)
Admitted 231 / 222 81 / 79 63 / 59 85 / 81 76 / 74
Completed 195 / 191 66 / 71 58 / 54 72 / 68 61 / 59

(184 / 186) §§
*midstream urine sample. Glossary:

**Rated Sum Score fever, dysuria, pollakisuria, stranguria, burning, GCP: Good Clinical Practice.
flank suprapubic and perineal pain, fullness, haematuria, odorous ITT: Intent to treat analysis.
and cloudy urine, other.
Per protocol: analysis excluding protocol violators.
§
105 cfu/ml midstream urine or 104 cfu/ml catheter urine
(cfu – colony forming units).
§§
Between (): Completed 12 months.
outcomes are measured in a standard the data after six or 12 months (test for
way across studies. In view of the het- heterogeneity: P = 0.002; test for overall
erogeneity between trials, both the fixed effect: P < 0.00001). The weighted mean
and the random effect models have been difference for the data after six months
calculated. Treatment yields significantly was -0.26 [95% CI: -0.36, -0.16] (test for
fewer UTIs than placebo in the fixed heterogeneity: P = 0.0004; test for overall
effect model with a weighted mean dif- effect: P < 0.00001). In the random effect
ference of -0.36 [95% CI: -0.48, -0.24] for model, the weighted mean differences
257
were -0.516 [95% CI: -0.80, -0.22] for the 3.1.2 Proportion of Patients without
data after six or 12 months and -0.42 recurrent Urinary Tract Infection
[95% CI: -0.69, -0.16] for the data after There were significantly more patients
six months with significances similar without any UTI among the OM-89
to those reported with the fixed model. treated patients at the end of the studies,
Even after allowing for differences in the regardless of study duration. Regarding
rating method employed for diagnosing the percentages of patients with UTIs,
UTIs, the standardised mean difference shown as difference between OM-89
continues to show a highly significant dif- (41.7% of the patients) and placebo
ference in favour of the active treatment. (62.4% of the patients) in Table 3, the dif-
Examining the mean number of UTIs ference was: -20.7% patients with UTIs
with OM-89, as a function of N UTIs with OM-89 (P<0,001, Odds ratio = 0.43
with placebo, the studies with the largest [95% CI 0.34 - 0.55]). Taking the cut-off as
number of UTIs with placebo were those the end of the sixth month, available for
showing the largest reduction with the all studies, the difference in patients with
active medication (Figure 1). recurrence of UTI between OM-89 (35.1%
Table 2 Mean number of recurrent UTIs, by trial and pooled mean.
OM-89 UV Placebo Difference

Study
N Mean (95% CI) N Mean (95% CI) Mean (95% CI)
Bauer 6 mo. 195 0.47 (0.36, 0.58) 215 0.6 (0.47, 0.73) 0.13 (0.25, 0.01)
Pisani 66 0.23 (0.14, 0.32) 71 0.41 (0.26, 0.56) 0.18 (0.3, 0.06)
Schulman 72 1.22 (0.81, 1.63) 68 1.96 (1.6, 2.32) 0.74 (1.12, 0.36)
Magasi 58 0.47 (0.26, 0.68) 54 1.35 (1.07, 1.63) 0.88 (1.12, 0.64)
Tammen 61 0.82 (0.63, 1.01) 59 1.26 (0.8, 1.72) 0.44 (0.76, 0.12)
Mean 452 0.60 (0.51, 0.69) 467 0.94 (0.82, 1.06) -0.34 (-0.23, -0.45)
Reduction of mean N UTIs as a function of N-UTIs with placebo

1.20
Reduction of mean N UTIs & 2 SEM
1.00
R2 � 0.7142
0.80
OM-89 UV
0.60 Linear (OM-89 UV)
0.40
0.20
0.00
0.00 0.50 1.00 1.50 2.00 2.50
Mean N UTIs placebo
Figure 1 Reduction of the mean number of episodes of UTIs (± 2 SEM) with OM-89, as a function of the mean N UTIs with
placebo (± SEM) in the studies examined.
258
Table 3 Percent patients with recurrence(s) of UTIs, difference between OM-89 and placebo at the end of the studies.
OM-89 Placebo Significance Relative Risk
Bauer et al., 2005 6 mo. 29.90% 39.20% P<0,05 76.20%
Pisani, 2000; 18.50% 36.70% P<0,01 50.40%
Magasi, 1994 35.00% 80.00% P<0,001 43.80%
Schulman 1993 (Re-Anal.). 52.40% 83.30% P<0,001 62.90%
Tammen, 1990; 50.00% 66.20% P<0,05 75.50%
TOTAL 35.10% 54.20% P<0,001 64.80%
Difference -19.10%
Bauer et al., 2005 12 mo. 45.00% 58.10% P<0,01 77.50%
TOTAL 41.70% 62.40% P<0,001 66.80%
Difference -20.70%
of the patients) and placebo (54.2% of the but employed different ways of present-
patients) was -19.1% patients [95% CI ing the data. As shown in Table 4, the
-0.25, -0.13] (P<0,001, Odds ratio = 0.46 Standardised mean difference shows a
[95% CI 0.36 - 0.59]). Both outcomes were significant difference in favour of the
thus significantly in favour of the active active treatment.
treatment in all the trials, although there In conclusion: Although it is difficult to
is a significant heterogeneity between tri- assign a specific value to this assertion
als (P= 0.001). due to differences in the presentation of
In conclusion, Three out of five patients data, it may be concluded that there was
will have no further UTI in the six a significant reduction of the use of anti-
months following OM-89 treatment. Of bacterials with OM-89, in line with the
the remaining OM-89 treated patients reduction of UTIs described above.
still having acute episodes, 35% will have
fewer UTIs than with placebo, on average. 3.1.4 Findings at the end of the trials
3.1.4.1 Dysuria
3.1.3 Consumption of antibacterials for
Urinary Tract Infections Four of the five trials examined reported
on this variable (representing 84.8% of
This variable was examined using the the study population, Table 5). Examining
Standardised mean difference2 method, the outcome at 6 months, only a minority
indicated when an outcome is measured of the patients reported dysuria, signifi-
in a variety of ways across studies (using cantly less so among the OM-89 treated
different scales), as is the case here. One patients: -9.4% of the patients (P<0,001,
study (Magasi) [18] did not provide data Odds ratio = 0.43 [95% CI 0.28–0.66].
concerning the use of antibacterials dur- Examining the outcome as reported at
ing the trial; the remaining four did so the end of the studies (that is, the Bauer
(representing 88.4% of the population), trial at 12 months) the results are simi-
lar; that is with OM-89 -6.6% of the
patients has dysuria (P<0,01, Odds ratio
2 Difference between two means divided by an estimate of the
within-group standard deviation. = 0.49 [95% CI 0.3 - 0.77]).
259
Table 4 Consumption of antibacterials and Standardised mean difference.
Study Bauer Pisani Schulman Tammen Total

(95% CI)
Variable: Prescriptions Patients with days with/3 mo. Prescriptions
OM-89 N 195 66 85 76 422

UV Mean (SD) 2.44(1.75) 0.16(0.36) 2.90(18.00) 0.85(1.65)
N 215 71 81 74 441
Placebo
Mean (SD) 2.79(2.03) 0.35(0.48) 6.90(19.00) 2.78(5.40)
Weight 43.28 17.26 20.81 18.65 100
SMD (random) & -0.18 -0.44 -0.22 -0.48 -0.29

95% CI [-0.38, 0.01] [-0.78, -0.10] [-0.52, 0.09] [-0.81, -0.16] [-0.44, -0.14]
Test for heterogeneity: P = 0.32.

Test for overall effect: P = 0.0001.
Table 5 Incidence of dysuria at final visit.
Bauer, 2005 (6 mo.) 10.8% 18.8% P<0,05 57.1%
Magasi, 1994 3.3% 16.7% P<0,05 20.0%
Schulman 1993 9.8% 16.7% N.S. 58.5%
Tammen, 1990; 6.6% 18.9% P<0,05 34.8%
TOTAL 8.7% 18.1%

P<0,001 48.1%
Difference -9.4%
No data: Pisani, 2000.
In conclusion: the incidence of dysuria representing less than half the popula-
at final visit was significantly lower with tion studied.
OM-89 at final visit.
3.1.4.3 Bacteriuria
3.1.4.2 Leukocyturia Four of the five trials examined reported
Only three of the five trials examined on this variable (representing 85.7% of the
reported on this variable (representing population studied, Table 7). Examining
42.6% of the population studied, Table 6). the outcome at six months, only a minor-
Examining the outcome at six months, ity of the patients reported bacteriuria,
only a minority of the patients reported significantly less so among the OM-89
leukocyturia >5/field, significantly less treated patients: -6.2% of the patients
so among the OM-89 treated patients: (P<0,05, Odds ratio = 0.62 [95% CI 0.42 –
-13.3% of the patients (P<0,001, Odds 0.91]. However, this outcome was driven
ratio = 0.45 [95% CI 0.28 – 0.72]. mainly by one study (Magasi) as shown in
In conclusion: the incidence of leuko- sensitivity analysis. There was significant
cyturia at final visit was significantly heterogeneity between studies. In one trial
lower with OM-89 but the findings were (Schulman) the data were provided for
derived from only three out of five trials, both 105 bacteria/mL and 104 bacteria/mL
260
Table 6 Incidence of leukocyturia at final visit.
Pisani, 2000; 14.8% 19.0% N.S. 78.0%
Magasi, 1994 15.0% 33.3% P<0,05 45.0%
Schulman 1993 15.9% 34.6% P<0,01 45.8%
TOTAL 15.2% 28.6%

P<0,001 53.4%
Differences -13.3%
No data: Bauer, 2005 & Tammen, 1990.
Table 7 Incidence of bacteriuria at final visit.
OM-89 Placebo Chi-square Relative Risk
Bauer, 2005 (6 mo.) 19.5% 20.9% N.S. 93.1%
Pisani, 2000; 3.7% 11.4% (P<0,1) 32.5%
Magasi, 1994 3.3% 21.7% P<0,01 15.4%
Schulman 1993; 11.0% 17.9% N.S. 61.1%
TOTAL 12.4% 18.6%

P<0,05 66.8%
Differences -6.2%
No data: Tammen, 1990.
as cut-off; taking this lower level the dif- 3.1.5 Safety of OM-89 in Placebo
ferences become significant in this trial controlled clinical trials
too (OM-89: 19.5% of the patients; pla- The differences of incidences of adverse
cebo 35.9% of the patients). Examining events in comparative trials showed that
the outcome as reported at the end of the they were slightly more frequent during
studies (that is, the Bauer trial [14] at 12 OM-89 therapy than with placebo (+0.8%)
months) the results are similar; that is and somewhat more patients withdrew
with OM-89: -5.4% patients with bacte- from the trials due to side-effects (+0.6%).
riuria (P<0,05, Odds ratio = 0.65 [95% CI No serious adverse events were attrib-
0.44 – 0.96]). uted to OM-89 in these clinical studies;
In conclusion: the incidence of bacteriu- no disease- or age-related mortality was
ria at final visit was lower with OM-89 recorded in the studied population. The
but the findings are inconsistent between most frequent adverse events reported
trials. However, the incidence of bacteriu- are detailed in Figure 2.
ria among the OM-89 treated patients is
not much higher than the one reported in
the general female population, which has 4. PRODUCT ‘B’
been reported to lie between 2.8% (women
aged 50–59 years) and 17% (women aged There were no blind trials identified
> 75 years) [21]. for the parenteral formulation of this
261
„Flu“; Bronchitis
4.5%
4.0%
Back-pain Cephalea
3.5%
3.0%
2.5%
2.0%
Pollakisuria Sleep disorders
1.5%
1.0%
0.5%
OM-89
0.0%
Placebo
Renal pain Gastric intolerance
Allergic rash Diarrhoea
Vaginitis, Leucorrhoea Nausea / Vomiting
Figure 2 Adverse events reported in controlled clinical trials by 0.7% of the patients or more.
product. This formulation causes signifi- (prevention discontinued in about half

cant undesirable side-effects at the injec- the patients) had a significant delay in
tion site [22] and systemic reactions [23]. interval to reinfection during the first
The published studies in recent years eight weeks and the mean interval until
deal only with the intravaginal formula- reinfection was delayed from 8.7 weeks
tion, which is discussed herein. for placebo treated to 13 weeks for vac-
Because of the similarity of the data, cine treated women (no significances pro-
design and outcomes, it was concluded vided). However, the overall incidence of
that the study by Uehling et al. [24] urinary infections was similar, regardless
published in 2001 was a preliminary of the treatment received (on average, 1.4
presentation of the data published two UTIs per patient).
years later and therefore excluded from In the second and the third study by
analysis. the same group [26–27], a total of 54 and
In a first study with this product [25], 75 women respectively were entered into
a total of 91 women with recurrent uri- the double-blind, placebo controlled trials
nary infections were entered into the using the vaginal suppositories. Patients
double-blind randomized study. Subjects were withdrawn from prophylactic anti-
received three vaginal suppositories at biotics and randomly assigned to one of
weekly intervals. Depending on the treat- three treatment groups, namely placebo
ment group each suppository contained only, primary immunization (given on
one or two vaccine doses or suppository weeks 0, 1, and 2) or primary plus booster
material only. Each patient was followed immunizations (booster given on weeks 6,
for five months to record infection epi- 10 and 14). All women were followed for
sodes and obtain urine, vaginal irrigates six months to determine the time until
and serum to measure immunological first recurrence, number of infections.
responses. The Verum treated women In the second study, the women receiv-
who were off antibiotic prophylaxis ing “primary + booster” remained free
262
of infections for a significantly longer to women in the 20 to 50-year-old age

period than those receiving placebo group. The interest of this study is again
or “primary” immunization only. The limited by the small number of patients
patients receiving “primary + booster” treated and the fact that placebo treated
immunizations had significantly fewer patients were on average nine years older
infections (average = 1.1 UTIs/patient) than the Verum treated patients. Twelve
than the placebo treated women (aver- percent of the women reported episodes
age = 1.5 UTIs/patient) or those receiv- of a burning sensation shortly after treat-
ing “primary” only (average = 1.7 UTIs/ ment both with the active product and
patients). The interest of this study is with placebo. There were single occur-
limited by the small number of patients rences of mild-moderate adverse events
treated and the fact that placebo treated (four with the active product and four
patients were on average 13 years older with placebo).
than the Verum treated patients. Five A quantitative analysis of anti E. coli
of the 36 Verum treated patients expe- IgA and IgG antibodies in the urine and
rienced vaginal irritation within one vaginal fluid samples collected during the
day of immunization or had transient course of these two studies did not reveal
diarrhoea. any significant differences between the
In the third study, the results were three groups. The findings concerning the
similar; that is placebo was equivalent difference between Verum and placebo,
to “primary” immunization, both inferior as percent patients with UTIs, are illus-
to “primary + booster” vaccine (Kaplan- trated below (Table 8).
Meier; p < 0.1). Thirty per cent of the In conclusion, with ‘Product B’, whilst
patients in the placebo group, 57% of the shorter “primary” immunization
the “Primary” only group and 72.5% of was not effective, the longer “primary +
the patients in the “primary + booster” booster” treatment was probably effec-
group remained free of E. coli infection. tive. Confirmation by larger phase III
Furthermore, the results suggested that studies by independent investigators is
the vaccine may provide the most benefit absolutely necessary.
Table 8 Percent patients with UTIs, difference between Verum and placebo. Product ‘B’ vaginal suppositories “primary“ on
weeks 0, 1, 2, and “primary + booster“ additionally on weeks 6, 10, and 14.
Product ‚B’ Placebo Significance Relative Risk
Hopkins, 2007 (27): 53.8% 84.0% P<0,05 64.1%

Primary + Booster
Hopkins, 2007 (27): 75.0% 84.0% N.S. 89.3%

Primary
Uehling, 2003 (26): 44.4% 88.9% P<0,01 50.0%

Primary + Booster
Uehling, 2003 (26): 88.9% 88.9% N.S. 100.0%

Primary
Uehling, 1997 (25): 98.4% 100.0% N.S. 98.4%

Primary
TOTAL 78.9% 89.7%

P<0,05 88.0%
Difference -10.7%
263
5. DISCUSSION is the potential reduction of vulvo-vaginal

infections with OM-89 (Odds Ratio = 0.42
The management of recurrent urinary (95% CI 0.18 – 0.98) vs. placebo in women
tract infections is complex due to the var- with recurrent UTIs.
ious factors predisposing to such bacterial The studies with OM-89 appear to
invasions. It is further complicated by the have good internal and external validity;
increasing prevalence of antibiotic-resist- that is, the investigations were conducted
ant strains of E. coli. These facts stress on out-patients with a relatively broad
the need for therapies directed to dimin- admission / exclusion criteria and thus
ish susceptibility and enhance the host’s can be generalized to the circumstances
defences against urinary tract infection of daily practice. It seems quite probable
rather than administering antibacterials that a particular sub-population might
on a broad base. The urinary tract pos- benefit more than others.
sesses the immunological and cellular From the reported results in the lit-
machinery for an efficient antibacterial erature, it seems that the efficacy of anti-
defence and it seems a sensible approach microbial prophylaxis is superior to the
to activate it. immunization regimens presently avail-
Among the various immunotherapeu- able [2]. However, since 1990, there has
tic products offered on the market only been a steadily increasing rate of resist-
two have published studies which are in ance to trimethoprim/sulphametoxazol,
accordance with current standards. Of reaching >30% in some areas; in the USA
these, ‘Product A’ (OM-89) is fairly well the average resistance rate for E. coli is
documented and has shown to be more 18%. Also resistance rates to fluoroqui-
effective than placebo in several ran- nolones have been increasing worldwide
domised trials. In three small phase II at alarming rates, reaching >20% in
trials ‘Product B’ has been shown to be Spain [28–31]. Another potential down-
effective only when administered with side of antibacterial prophylaxis is the
a booster cycle; larger studies by inde- side effects, such as rash, nausea, diar-
pendent investigators are awaited with rhoea, vaginitis and oral candidiasis
interest. [32–33]. Treatments with antibacterials
Concentrating on OM-89, the data have to be monitored closely since they
show that the product reduces the also can cause major adverse reactions;
number of recurrences of uncomplicated for example, phototoxicity and rare but
UTIs by about 36% and one out of five serious hepatotoxicity has been reported
patients will be entirely free of UTIs for with fluoroquinolones [34], while nitro-
at least six months, with corresponding furantoin is known to infrequently
reduction of antibacterial treatments. It cause both acute and chronic pulmo-
has to be noted, however, that only in one nary reactions (interstitial lung disease
study [16] was a UTI defined as sympto- and pulmonary fibrosis may develop
matic uncomplicated UTI (symptomatic with long-term use) [35], as well as
bacteriuria), whereas in three studies rare cases of blood dyscrasia, Erythema
[17–19] the definition of UTI was based exsudativum multiforme (Stevens-
on bacteriuria alone, and in one study Johnson-Syndrom) and Epidermolysis
[20] there was no precise definition of acuta toxica (Lyell-Syndrom) with
UTI. At the end of the six month observa- trimethoprim+sulfamethoxazol or with
tion period, fewer OM-89 treated patients nitrofurantoin, to mention a few [36].
had dysuria (RR= 48%) and possibly leu- Additionally, oral administration of
kocyturia (RR= 53%) or bacteriuria (RR= antibiotics for treatment of urinary
67%). A further aspect worth examining tract infections can cause ecological
264
disturbances in the normal urethral [37] in female patients with recurrent

and intestinal microflora [38]. Increasing uncomplicated UTI. Its efficacy in other
the mucosal defences through immunoac- patients’ groups and its relative efficacy
tive prophylaxis looks like a compelling to antimicrobial prophylaxis should be
alternative which merits further studies established.
and improvements.
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33. Gradwohl SE (Team Leader) and ACKNOWLEDGEMENT
University of Michigan Health System
(Agency for Healthcare Research and The study was supported in part by a
Quality (AHRQ)), Urinary tract infection. research grant from OM-Pharma, Geneva,
May 2005, Ann Arbor (MI): University of
Switzerland.
Michigan Health System.
The authors are thankful to Dr. Reto
34. Ball P, Mandell L, Niki Y, and Tillotson
G. Brignoli in assistance to prepare the
G, Comparative tolerability of the newer
fluoroquinolone antibacterials. Drug Saf,
statistical analysis and the manuscript
1999. 21(5): 407–21.
35. Sheehan RE, Wells AU, Milne DG, and
FINANCIAL DISCLOSURE
Hansell DM, Nitrofurantoin-induced lung
disease: two cases demonstrating resolu-
tion of apparently irreversible CT abnor- Kurt G. Naber: Bayer: Investigator,
malities. J Comput Assist Tomogr, 2000. speaker at scientific meetings. Combi-
24(2): 259–61. nature/MerLion: Investigator, consultant.
36. Howe RA and Spencer RC, Cotrimoxazole. Daiichi: Speaker at scientific meetings.
Rationale for re-examining its indications Mucos Pharma: Consultant, speaker
for use. Drug Saf, 1996. 14(4): 213–8. at scientific meetings. OM Pharma:
37. Norinder BS, Norrby R, Palmgren AC, Investigator, scientific publication.
Hollenberg S, Eriksson U, and Nord CE, Ocean Spray cranberries: Investigator.
Microflora changes with norfloxacin and Peninsula/Johnson & Johnson/Janssen-
pivmecillinam in women with recurrent Cilag: Investigator, speaker at scien-
urinary tract infection. Antimicrob Agents tific meetings, scientific publication.
Chemother, 2006. 50(4): 1528–30.
Zambon: Investigator, speaker at scien-
38. Edlund C and Nord CE, Effect on the
tific meetings.
human normal microflora of oral antibi-
otics for treatment of urinary tract infec-
tions. J Antimicrob Chemother, 2000. 46 Yong-Hyun Cho: Asia Pharm: Con-
Suppl A: 41–48. sultant, speaker at scientific meetings.
267
Handok Pharmaceuticals: Consultant, scientific meetings. Combinature/

speaker at scientific meetings. Pacific MerLion; Consultant.
Pharma: Consultant, speaker at scientific
meetings. Anthony J Schaeffer: American
Urological Association – editorial fees
Tetsuro Matsumoto: Daiichi Sankyo; and faculty honorarium; IMS Health –
Consultant, Investigator, Speaker at sci- consultant; Alita Pharmaceuticals, Inc. –
entific meetings. Asteras; Consultant, consultant; NovaBay Pharmaceuticals,
Investigator. Kyorin; Investigator, Inc. – consultant; cme2 – speaker at scien-
Speaker at scientific meetings. Meiji; tific meeting; Blackwell Publishing – book
Consultant, Investigator. Nisshin sci- royalty; Advanstar Communications Inc. –
ence; Consultant, Investigator. Takeda; consultant; Elsevier Science USA – book
Speaker at scientific meetings. Taisho- royalty; Regeneron Pharmaceuticals, Inc. –
Toyama; Investigator, Speaker at consultant.
268
|4.4|
Use of cranberry for prophylaxis
of uncomplicated recurrent urinary
tract infections
Henry Botto
Address of Corresponding Author: Prof. Henry Botto, Prof. Assoc. des Universites, France, Service d’Urologie,
Hôpital Foch 40, rue Worth - B.P.36, F-92150 Suresnes Cedex, France
Tel 0033-1-4625.2465, Fax 0033-1-4625.2026, h.botto@hopital-foch.org
ABSTRACT and 750 ml) found a significant reduc-

tion of E. coli adherence (p > 0,001) dose
Over the last few years, an increase in dependent.
the use of cranberry (C) has been noted In 2008 a double-blind randomised
for the following two reasons: i) the high placebo-controlled cross-over trial tested
number of UTIs has lead to increased a commercially available capsule of vac-
antibiotic use and thus increased antibi- cinium macrocarpon containing 36 mg of
otic resistance; and ii) the main mecha- PAC. A statistically significant reduction
nisms of action in reducing UTIs have of bacterial adherence of E. coli was found
been identified. C inhibits the adherence (p < 0,001), dose-dependent. For the first
of E.coli to uro-epithelial cells, the first time this study established clearly the
and necessary step for UTI. This competi- bio-activity of a C. capsule.
tive inhibition is due to a non-dialyzable Two methods of PAC dosage are avail-
compound, a condensed tannin, the able : the reference DMAC and NP-HPLC
proanthocyanidin (PAC) type A. Among with a conversion factor of one to two
the three species of C vaccinium macro- (36 mg PAC by DMAC = 72 mg PAC by
carpon is only one to have PAC-A. NP-HPLC).
The first dosage used was 36 mg served Quantification of bio-activity in urine:
as 300 ml of juice presentation (Avorn). In Given that 36 mg of PAC per day is nec-
2006, a double-blind randomised placebo- essary to obtain a preventive clinical
controlled cross-over trial comparing effect on UTIs (Avorn Study); and given
two dosages of C. juice presentation (250 that we lack a method to evaluate active
metabolites in urine, surrogates are However, steadily over the last few years,
needed to quantify bio-activity in urine. increased C use outside North America
There are two surrogates: i) the red has been noted. It can be seen that this is
blood cell hemagglutination test (Howell) for the following reasons:
and ii) the direct cellular adhesion test The high number of UTIs has lead
(Lavigne). to increased antibiotic use and thus
Jepson and Craig have recently increased antibiotic resistance. From the
reviewed the clinical studies for the ARESC [1] study we have learnt that
Cochrane database. Juice presentation is only three of the antibiotic families are
too unwieldy to be recommended for long possible for empiric prescription. Thus
periods of time as a prophylactic treat- it is mandatory to reduce antibiotic use
ment for recurrent UTI, thus the neces- and therefore to find some other products
sity to develop capsules/tablets. However, to replace antibiotics in certain circum-
there is no standardisation for these; not stances, for example in prophylaxis.
in C species, in method of PAC measure- The main mechanisms of action in
ment, nor in dosage of PAC per day. Apart reducing UTIs have been identified by
from one capsule, there is no data about Foo [2] and Howell [3]. In the past it
the bio-activity of the commercially avail- was thought that C acted through acidi-
able products, no dose-ranging and no fication of urine like other fruits. In fact,
direct correlation between in vitro and the acidification linked to fructose con-
clinical effects. tained in C (as well as in other fruits)
only excretes low and transient acidifica-
tion [4] and only inhibits pili type 1 [5].
SUMMARY OF RECOMMENDATIONS The inhibition of pili type P is not con-
cerned with fructose. Cranberry inhibits
1. Despite the lack of pharmacological the adherence of E.coli to uro-epithelial
data and the few, and weak clinical cells, the first and necessary step for UTI.
studies, there is evidence to consider This competitive inhibition is due to a
C vaccinium macrocarpon to be useful none-dialyzable compound; a condensed
in reducing the rate of lower urinary tannin, the proanthocyanidin (PAC) type
tract infections in women. A. Cranberry contains a high proportion
2. For everyday practice one could of PAC A, unlike other fruit. Only the
recommend (GoR C; LoE 2) the PAC-(A) is able to inhibit E. coli adhesion
daily consumption of C products, through inactivation of pili type P. The
giving a minimum of 36 mg of PAC other PAC (B) found in most fruits does
(proanthocyanindin A, the active not have this capacity. There are three
compound) per day, providing this species of C: vaccinium macrocarpon is
amount is proven. The best approach the only one to have PAC (A). The two
would be to use those compounds that others (vaccinium vitis idaea and oxy-
have demonstrated clear bio-activity coccus) may contain some quantities of
in urine. A-type PAC to inhibit E.coli adhesion but
their efficacy has not been validated.
Despite the low number of clinical
1. INTRODUCTION studies published, it is a trend to support
the role of C products in preventing UTIs.
The traditonal use of cranberry (C) to But some limitations remain and have to
prevent UTIs has been found mainly be clarified.
in North America with limited spread The Cochrane Library [6] review pub-
to other countries, notably European lished in 2008 is clear: “There is some evi-
Countries. dence that cranberry juice may decrease
270
Use of cranberry for prophylaxis of uncomplicated recurrent urinary tract infections | 4.4 |
the number of symptomatic UTIs over a 3. PHARMACOKINETICS

12 month period, particulary for women
with recurrent UTIs. Its effectiveness We know that PAC is one of the active
for other groups is less certain over long compounds of C but the other active
periods of time. It is not clear what is the compounds (metabolites) are not
optimum dosage or method of administra- yet clearly identified. It is generally
tion (e.g. juice, tablets or capsules)”. accepted that active dimers and trimers
Taking into account all these data the are absorbed in the gut. These small
French food and drug agency (AFFSSA) oligomers are unstable and they have
delivered a clear allegation in 2004 [7]: a tendency to polymerize naturally
“The daily consumption of cranberry under the influence of temperature and
vaccinium macrocarpon juice/powder oxygen [11].
containing 36 mg of proanthocyanidins/
day contributes to decrease the fixation
of certain bacteria E. coli on the walls of 3.1 Dosage of PAC
the urinary tract”. The 36 mg PAC were The first dosage used was 36 mg served
measured by DMAC method. as 300 ml of juice presentation [12]. In
“It is the first-ever health claim for the vast majority of the other studies the
cranberries and it is believed to be the first amount of PAC was not clearly stated and
time that any fruit anywhere has been per- only a certain amount of C was declared.
mitted to make a specific health claim” [8]. In 2006 a double-blind randomised pla-
Despite the traditional American use cebo-controlled cross-over trial in twenty
of juice presentation and the conclusions healthy volunteers compared two dosages
of the Cochrane review, more data are of C juice presentation: 750 and 250 ml
needed to confirm the role of C in the pre- using six E.coli strains and a direct
vention of UTIs. Specifically, the pharma- anti-adhesion test [13]. There was a sig-
co-kinetics and the correlations between nificant reduction of E. coli adherence
the in vitro studies and clinical effects (p > 0,001), dose dependent. Thus 300 ml
have to be developed. of juice presentation may not be the right
dosage per day. In this study it was also
2. METHODS shown that the anti-adhesion effect was
independent from antibiotic susceptibility
The studies were rated according to the and type P pili present.
level of evidence (LoE) and the grade of Gupta [14] recently confirmed the dose
recommendation (GoR) using ICUD dependent anti-adhesion effect of E.coli to
standards (for details see Preface) [9–10]. uro-epithelial cells.
Table 1 Index of Adhesion of E. coli (IA) after 2 regimens of Urell® and placebo control.
Strains Placebo Urell Capsule 1 Urell Capsule 3
FimH+ IA = 22,43 IA = 14,35 IA = 5,18 p. < 0,001

Pap GII+ ± 3,73 ± 3,45 ± 4,32
FimH- IA = 4,80 IA = 3,37 IA = 1,74 p. < 0,001

papGII- ± 0,70 ± 0,97 ± 0,75
FimH+ IA = 7,50 IA = 4,73 IA = 2,78 p. < 0,001

papGII- ± 1,60 ± 0,87 ± 1,12
One or three capsules of Urell® caused a highly significant reduction in bacterial adherence to T24 cells as compared with placebo (p< 0,001).
The adherence index obtained with bacteria grown in urine samples collected after intake of three cranberry capsules was lower than that
observed with one Cranberry capsule (p<0,001), even though a reduction in adherence was also noted with one Urell® capsule.
271
In 2008, a double-blind randomised and is reliable with great precision

placebo-controlled cross-over trial tested (95 %) [15].
a commercially available capsule of vac- Meanwhile, the DMAC method has
cinium macrocarpon containing 36 mg of been simplified and shortened and is now
PAC (Urell®/Ellura) using T24 human epi- validated by the USDA and four inde-
thelial cell line and three regimens intake pendent laboratories. The publication of
in the morning : (placebo ; one capsule the revised method yielding 36 mg for 300
of Urell® = 36 mg of PAC ; 3 capsules = g of Cranberry juice drink is currently
108 mg of PAC) (13). A statistically signif- under revision.
icant reduction of bacterial adherence of There are other methods but the
E. coli was found (p< 0,001), dose-depend- results they produce are quite different
ent and independent from antibiotic sus- from the DMAC method :
ceptibiliity and the type of P pili present.
DMAC : 36 mg
For the first time this study established
NP-HPLC : 72 mg
clearly the bio-activity of a C capsule.
(USA)
In our last study, currently under
Pharmacopeia Europe : 89 mg
revision, we correlated the bio-activity
Vannilin : 174 mg
in urine after six and 24 hours with the
Bate Smith : 187 mg
same capsule of Urell® and using three
regimens with intake in the morning : Therefore it is important to refer to the
(half capsule = 18 mg PAC ; one capsule = DMAC method which corresponds to the
36 mg of PAC and two capsules = 72 mg 36 mg PAC in 300 ml C juice drink.
of PAC). As shown in Table 2 anti-adhe-
sion activity is significantly higher with
36 and 72 mg of PAC than with 18 at 4. QUANTIFICATION OF BIO-ACTIVITY
six hours. At 24 hours the anti-adhesion IN URINE
activity is significantly higher with 72 mg
of PAC compared to 36 and there is no Given that 36 mg of PAC per day is nec-
real activity with urine samples collected essary to obtain a preventive clinical
after intake of 18 mg of PAC. effect on UTIs (Avorn study [12]) and
given that we lack a method to evaluate
active metabolites in urine we therefore
3.2 Methods of PAC dosage
need surrogates to quantify bio-activity
The DMAC/PAC003, a proprietary in urine. There are two surrogates :
colorimetric method (4-diméthylamino- The first is the red blood cell hemag-
cinnimaldéhyde), was the first described glutination test, described by Howell [3].
Each E. coli strain is incubated for 20
Table 2 Anti-adhesion activity in urine measured by Lavigne minutes in the volunteer’s urine at a con-
Test with three regimens of Urell® and placebo control.
centration of 105 CFU/ml, to correspond
1
Placebo
to the bacterial concentration indicative
0,9 18 mg of a clinical UTI. Hemagglutination is
Anti-adhesion activity
0,8 36 mg
72 mg carried out on microplates (96 wells) in
0,7
0,6
the presence of group A+ or O+ human
0,5 red blood cells (HRBCs) newly drawn
0,4 in citrated tubes. A 3% suspension of
0,3 HRBCs is added to each well containing
0,2 the bacteria/urine suspensions and the
0,1 microplate agitated for 15 minutes. Each
0 well is evaluated microscopically for the
0H 6H 24H
PAC (proanthocyanidin) presence or absence of hemagglutination.
272
If the HRBCs in a well are not aggluti- but there is no strict standarization for
nated, the urine in that particular well these products. Moreover their labels are
is considered to have C metabolites with very often unscientific, even dishonest,
antiadhesion activity. The results of this because there is little regulation (if any)
rapid and indirect test are given using 3 in the field of food-supplements.
thresholds (0 ; 50% ; 100%). It is indeed In addition a lot of capsules or tablets
a very good test for screening and to contain a mixture of C species: the vali-
compare different available commercial dated form (vaccinium macrocarpon) and
products. the non-validated forms (vaccinium vitis
The second surrogate is a direct cel- idaea (lingonberry) and vaccinium oxy-
lular adhesion test described by Lavigne coccus (European Cranberry)). Thus, it is
[16], adapted from Di Martino [13]. This impossible to compare by using the dos-
study consists of testing the capacity of age of PAC written on the label. The only
the E. coli strains to adhere in vitro to way to compare is by one or two of the
urothelial T24 cell lines. Each strain is surrogate bioactivity methods described,
cultured in the volunteer’s urine for 12 however if any surrogate is used for a pre-
hours. These bacteria are then placed cise product, it is still impossible to take
in contact with the urothelial cells for into consideration the results present in
three hours. After fixing, the bacteria are the leaflet.
stained with 20% Giemsa and examined The final concern regarding the compo-
under a microscope. An adherence index sition of capsules or tablets is their activ-
(AI) corresponding to the mean number of ity in connection with products other than
adherent bacteria per cell for 100 cells is PAC. Up to now, no compound of C other
then calculated. The morphologies of the than PAC has been shown to be active in
different E. coli strains (morphology of the prevention of UTIs.
rod, lengthening, thickening…) are evalu-
ated using an electronic microscope after
fixing the slides containing the bacteria 6. CLINICAL STUDIES
in contact with the cells. Three independ-
ent experiments are carried out for each The existing clinical studies have been
test. An anti-adhesion control test is car- recently reviewed by Jepson and Craig for
ried out. the Cochrane database [6, 18]. For this
reason we did not perform a systematic
literature search, but used the results of
5. FORMULATION OF CRANBERRY the Cochrane database. Only ten stud-
ies met their criteria and two were rap-
Besides the problem of measurement of idly excluded [17, 19] because they were
bio-activity, there is another great con- published only in letter form and no addi-
cern about the chemical composition of tional data were available.
commercialy available C products. Their
composition is not standardized and thus
6.1 Neurologic patients
bio-equivalence between all of them is not
clear. For neurologic patients needing cath-
The first dosage proposed was 36 mg of eterisation (intermittent or indwelling)
PAC extracted from the Avorn study [12]. there was no statistical difference in the
This 36 mg was given by 300 ml of juice number of symptomatic UTIs between C
presentation. But juice presentation is not (juice) and placebo [20–21]. Nevertheless
convenient for long-duration leading to a in a recent study (randomised, double-
withdrawal rate of up to 55% [17] . Thus blind, placebo-controlled with a cross-over
capsules and tablets have been developed design in a 12 month period) involving
273
47 patients with spinal cord injury, Hess study in this field needs to be longer than
[22] found a reduction of UTI to 0.3 per six months.
year during the C period. compared to
1.0 UTI per year while receiving pla-
6.3 Sexually active women
cebo. Interestingly he also reported that
patients with a high glomerular filtration In sexually active women with recur-
rate may receive the most benefit. rent cystitis there were only two studies.
Kontiokari [25] and Stothers [26] each
6.2 Elderly patients recruited 150 women for one year of treat-
ment. In the Kontiokari study patients
In elderly patients three studies were
had one previous UTI, compred to two
available. The first one was conducted by
in the Stothers trial. The absolute risk
Avorn [12] in asymptomatic bacteriuric
reduction of UTI was respectively 20%
patients. However, the group receiving
and 14%. Nevertheless the Kontiokari
placebo were significantly more bacte-
study was stopped prematurely (at six
riuric before their inclusion in the trial.
months) because the C juice supplier
Nevertheless, he concluded that the
stopped producing the juice.
subjects receiving C juice were 58% less
likely than the control group to have bac-
teriuria. Here 300 ml of C juice was used 6.4 Side-effects
containing 36 mg of PAC.
Side effects were very uncommon, mainly
In the second study conducted by
related to juice presentation and limited
McMurdo [23] 376 hospitalised sympto-
to the gastro-intestinal area.
matic patients were recruited. There was
no statistical difference between either
group (C juice and placebo). Because the 6.5 Withdrawals
infection rate observed was lower than
Withdrawals are common with juice pres-
anticipated it made this study under-
entation (up to 55%); the compliance is
powered.
much better with capsule.
The final study was also conducted
by McMurdo [24] in 137 women (mean
age : 63 years) with two or more antibi- 6.6 Conclusions and
otic-treated UTI’s in the previous twelve recommendations
months. They were randomised to either
receive 500 mg of C extract (the amount Juice presentation is too unwieldy to be
of PAC is not stated) or 100 mg of tri- recommended for a long period of time
methoprim for six months. The amount of as a prophylactic treatment for recurrent
UTIs treated by the G.P. were 36% in the UTI. Thus the necessity to develop cap-
C group versus 20% in the trimethoprim sules or tablets.
group, and the microbiologically con- For these there is no standardisation :
firmed UTIs were respectively 16% and - In C species
12%. The authors concluded “trimetho- - In method of PAC measurment
prim had a very limited advantage over C - In dosage of PAC per day
extract in the prevention of UTIs”. In fact
- Apart from one capsule, there is no
the actual infection rate with trimetho-
data about the bio-activity of the
prim was much higher than expected (1%)
commercially available products
and this made the study inconclusive.
Furthermore UTIs often occur in clus- - No dose-ranging
ters, with patients often being symptom - No direct correlation between in-
free for several months. A preventive vitro and clinical effects.
274
At the least, as for active drugs, we need In 2008 a double-blind randomised

a minimum standardisation: placebo-controlled cross-over trial tested
- the precise amont of PAC a commercially available capsule of vac-
cinium macrocarpon containing 36 mg of
- measured by DMAC method
PAC. A statistically significant reduction
- allowing clinical studies with of bacterial adherence of E. coli was found
stronger methodology (p < 0,001), dose-dependent. For the first
if we want to confirm the hopes regarding time this study established clearly the
the efficacy of C in reducing UTIs. bio-activity of a C capsule.
Despite the lack of pharmacological The method of measure of PAC is the
data and the few and weak clinical stud- DMAC method which yields a result of
ies, there is evidence to consider C vaccin- 36 mg PAC for 300 ml C juice drink.
ium macrocarpon to be useful in reducing
the rate of lower urinary tract infections 7.1 Quantification of bio-activity
in women. in urine
Despite the GoR C (LoE 2) referring to
the scientific data, it is logical in every- Given that 36 mg of PAC per day is nec-
day practice to recommend the consump- essary to obtain a preventive clinical
tion of C products giving a minimum of effect on UTIs (Avorn Study [12]) and
36 mg of PAC (vaccinium macrocarpon) given that we lack a method to evaluate
per day providing this amount is proven. active metabolites in urine we therefore
The best approach would be to use those need surrogates to quantify bio-activity
compounds that have demonstrated their in urine. There are two surrogates :
clear bio-activity in urine. The first is the red blood cell hemagglu-
tination test (Howell [3]) ; the second is the
direct cellular adhesion test (Lavigne [16]).
7. SUMMARY
7.2 Clinical studies
Over the last few years, we have noted a
spread of cranberry (C) use for the follow- These have been recently reviewed by
ing two reasons: the high number of UTIs Jepson and Craig [6, 18] for the Cochrane
has lead to an increased use of antibiotics database. Juice presentation is too
and thus increased antibiotic resistance; unwieldy to be recommended for a long
the main mechanisms of action in reduc- period of time as a prophylactic treatment
ing UTIs have been indentified. C inhibits for recurrent UTI. Thus the necessity to
the adherence of E.coli to uro-epithelial develop capsules or tablets. However, there
cells, the first and necessary step for UTI. is no standardisation for these: in C spe-
This competitive inhibition is due to a cies, in method of PAC measurement, in
non-dialyzable compound; a condensed dosage of PAC per day, apart from one cap-
tannin, the proanthocyanidin (PAC) type sule there is no data about the bio-activity
A. Among the three species of C vaccinium of the commercially available products,
macrocarpon is only one to have PAC-A. no dose-ranging and no direct correlation
The first dosage used was 36 mg served between in-vitro and clinical effets.
as 300 ml of juice presentation[12]. In
2006, a double-blind randomised placebo-
controlled cross-over trial comparing 8. CONCLUSIONS
two dosages of C juice presentation (250
and 750 ml) found a significant reduc- Despite the lack of pharmacological data
tion of E. coli adherence (p > 0,001) dose and the few and weak clinical studies
dependent. there is evidence to consider C vaccinium
275
macrocarpon to be useful in reducing the 9. Abrams P, Khoury S, and Grant A,

rate of lower urinary tract infections in Evidence–based medicine overview of the
women (GoR C ; LoE 2). main steps for developing and grading
Despite the GoR C (LoE 2) referring to guideline recommendations. Prog Urol,
the scientific data, it is logical in every- 2007. 17(3): 681–4.
day practice to recommend the consump- 10. U.S. Department of Health and Human
Services Public Health Service Agency for
tion of C products giving a minimum of
Health Care Policy and Research, 1992:
36 mg of PAC (vaccinium macrocarpon)
115–127.
per day providing this amount is proven.
11. Howell A, Bioactive compounds in cran-
The best approach would be to use those berries and their role in prevention of uri-
compounds that have demonstrated their nary tract infections. Mol. Nutr. Food Res,
clear bio-activity in urine. 2007. 51(6): 732–7.
12. Avorn J, Monane M, Gurwitz J, Glynn R,
Choodnovskiy I, and Lipsitz L, Reduction
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277
|4.5|
Probiotics for the prophylaxis of

tract infections in females
Peter Cadieux, Gregor Reid
Canadian Research and Development Centre for Probiotics, Lawson Health Research Institute, (1) and Departments of
Microbiology and Immunology,) and Surgery (2), The University of Western Ontario, London, Ontario, Canada
*Corresponding author: Prof. Gregor Reid, Canadian Research and Development Centre for Probiotics, F2-116 Lawson
Health Research Institute, 268 Grosvenor Street, London, Ontario, N6A 4V2 Canada.
Tel: 519-646-6100 x65256; Fax: 519-646-6031; gregor@uwo.ca.
Running title: Probiotics to prevent UTI
ABSTRACT that has not yet been given a desig-

nated number), L. rhamnosus GR-1 with
Recurrent urinary tract infections (UTI) L. reuteri RC-14, and possibly L. crispatus
in women remain a common occurrence CTV05 can populate the vagina and dis-
despite management with antibiot- place urogenital pathogens leading to
ics and health foods such as cranberry reduced risk of infection. In addition, a
juice. With growing drug resistance, side recent 2009 study provides Level 1 evi-
effects of such therapy, and few new anti- dence supporting the use of orally admin-
biotic classes in the pipeline, alternative istered L. rhamnosus GR-1 and L. reuteri
approaches are needed. The correlation RC-14 for the prevention of rUTI in post-
between depletion of vaginal lactoba- menopausal women. Importantly, while
cilli and risk of UTI has led to efforts to the long-term use of prophylactic antibi-
replenish the lactobacilli organisms as otics in that study strongly promoted bac-
a means to prevent infection. This con- terial drug resistance, the application of
cept, termed probiotics, has some sound GR-1 and RC-14 capsules did not. Thus,
scientific basis, but to date very few certain probiotics have strong support
Lactobacillus strains have been clini- for prophylaxis against recurrent UTI.
cally tested for vaginal benefits. Clinical In order to increase the level of evidence,
studies provide Level 1 and 2 evidence further randomized controlled stud-
that Lactobacillus acidophilus (a strain ies are needed with larger sample sizes,
Probiotics for the prophylaxis of uncomplicated recurrent urinary tract infections | 4.5 |
and manufacturers have to make oral entering the bladder and thereby prevent
and vaginal products more accessible to infection. However, with increasing drug
patients for this approach to truly make a resistance, side effects of treatment, and
dent in the large number of patients suf- failure to prevent recurrences in many
fering each year from UTI. instances, there is a need for alternative
approaches.
Key words: probiotics, urinary tract
The scope of this review will include
infection, lactobacilli, vagina, microbiota,
the scientific basis for why and how pro-
prophylaxis
biotic bacteria might prevent UTI, and
recommendations will be made for clini-
cal practice.
Availability of Probiotics: Accessibility 2. METHODS

of clinically proven probiotics for UTI
prophylaxis is currently not universal. The literature search was performed
The L. acidophilus strain used in the using PubMed, with various search
Lee et al. [1] study is not available, nor words including urinary tract infection,
is L. crispatus CTV05. The L. rhamnosus lactobacillus, probiotics, clinical trials,
GR-1 and L. reuteri RC-14 product is prevention, prophylaxis, antibiotics, and
available as an orally administered cap- vaginal microbiota. Only clinical stud-
sule which has been used vaginally to ies using properly documented probiotic
treat bacterial vaginosis (BV) [2] but not products and strains were included in
for UTI prophylaxis. These capsules have this review, as only they fit the criteria of
also been used orally to prevent UTI [3]. a probiotic (“live microorganisms which
1. Where commercially available, twice when administered in adequate amounts
daily application of the oral probiotic confer a health benefit on the host”). Due
containing strains GR-1 and RC-14 to the limited number of human studies
for the prevention of recurrent UTI is performed in this area, it was not pos-
suggested (GoR C). sible to restrict the citation to the past
three years. However, special mention is
2. It is also reasonable to consider the given to three studies within that recent
intravaginal use of this probiotic for timeframe, and overall almost half of the
recurrent UTI prevention, as it has citations are from 2006 onwards. Of the
been shown to prevent and treat BV, earlier references, many are included to
a condition that increases UTI risk. put the topic and mechanisms of action
Based upon clinical studies, once or into context and to understand why and
twice weekly application could be how probiotics might be useful to pre-
recommended for prophylaxis (GoR C). vent UTI. The studies were rated accord-
ing to the level of evidence (LoE) and the
grade of recommendation (GoR) using
1. INTRODUCTION ICUD standards (for details see Preface)
[4–5].
The purpose of this guideline is to discuss
the rationale and level of evidence for pro-
biotics to prevent urinary tract infections 3. THE RATIONALE FOR PROBIOTICS
(UTI). There are few if any true prophy-
lactic measures to prevent UTI. In most Microorganisms have dominated this
cases, patients are prescribed low dose planet for billions of years and humans
antibiotics designed to kill pathogens have evolved from these simple species.
279
Humans would not be alive but for these direct vaginal application, could enhance
microbes, which outnumber our own cell the host’s ability to defend against infec-
count by over ten to one. In our intesti- tion [22]. This application of beneficial
nal tract, there are organisms capable of bacteria to the host is termed probiotics,
killing us. The fact that they don’t do so defined by the World Health Organization
under normal circumstances is in large and United Nations Food and Agriculture
part due to the epithelial barrier and Organization above. This is an extremely
the development of a highly sensitive, important definition as it means that
integrated and potent immune system, unless a product is suitably prepared
as well as our own non-pathogenic (and with properly speciated strains, appropri-
largely commensal) microbiota. There are ate viable count at end of shelf-life, and
over 1500 species of microbes inside our clinical evidence that the host benefits
gut, and many of these have access to the from the use in a tangible, proven way,
female urinary bladder through ascension then the product is not a probiotic, even
from the rectal skin to the perineum and if it says so on the label or in the manu-
vagina. Yet, relatively few of these sur- script. In many cases, so-called probiotics
vive this ascension and infect the urinary do not meet these guidelines.
tract. The concept of using probiotic lactoba-
One of the main reasons that organ- cilli to prevent UTI was long ignored by
isms residing on the skin or shed from the urological community, in part because
the gastrointestinal tract fail to illicit a it was too simple and the antibiotic option
UTI is the host’s own indigenous micro- was better known and clinically quite
biota which contains a number of mecha- effective, but also because it was viewed
nisms for interfering with pathogenesis. as impossible for lactobacilli to compete
Lactobacillus species are the principal against pathogens that had a wide array
non-pathogens in the healthy vagina of of virulence factors for host cell attach-
most females, and studies have shown ment and invasion, biofilm formation,
that they possess several anti-microbial host-cell cytotoxicity, iron-acquisition,
components capable of killing or inhib- evasion or disruption of host defences and
iting the growth of uropathogens [6–9], increased antibiotic resistance [23–28].
others that can interfere with uropatho- These virulence properties are invariably
gen adhesion and spread [10–11], and fac- encoded as single genes or entire oper-
tors which modulate host anti-infective ons, and their expression is important
immunity [12–13]. The severe depletion for the development and maintenance of
of these lactobacilli has been shown to both primary and recurrent UTI [29]. In
correlate with onset of localized infection, addition, pathogen reservoirs have been
namely bacterial vaginosis (BV), and shown to be key in the establishment of
with UTI [14–16]. The factors responsi- recurrent UTI, with studies identifying
ble for this depletion are not fully known, the gastrointestinal tract, bladder epithe-
but appear to include the use of spermi- lium and vagina all as major sites of their
cides [17], douching [18], menstrual hor- development [30–31].
mones levels [19], and antibiotics [20], as
well as potentially low levels of lactoba-
cilli replenishment from the rectal sur- 4. CLINICAL EVIDENCE OF
face [21]. PROBIOTIC USE TO PREVENT
Given the association between low RECURRENCE OF UTI
lactobacilli counts and increased risk of
UTI, it was proposed by our group that The following evidence will be for studies
replenishment of lactobacilli into the that examine the ability of probiotics to
vagina, either through oral ingestion or reduce recurrences of UTI.
280
4.1 Populating the vagina recovered up to 19 days after instil-

In order for any probiotic to prevent lation [35].
UTI, the organisms must be shown to v. An independent study in ten sub-
populate the vaginal area after oral or jects further confirmed that >109
vaginal administration. Several stud- L. rhamnosus GR-1 and L. reuteri
ies have provided this level of evidence RC-14 administered orally in dried
(LoE 2b). capsule form could lead to vaginal
colonization [36].
i. Following vaginal instillation of 1011
Lactobacillus rhamnosus GR-1 in vi. Using an in vitro bacterial adherence
saline twice weekly until a repeat assay, candidate probiotic L. crispatus
episode of infection occurred, lacto- CTV-05 was shown to adhere well to
bacilli levels in the vagina increased vaginal epithelial cells collected from
in four of five subjects, including a 51 women with a history of recurrent
13 year old girl [32]. Three of the UTI and 51 controls [37].
patients remained infection free for
more than three months, compared 4.2 Clinical evidence that probiotics
to their pre-treatment situation of can prevent UTI
an episode every month.
The ultimate proof-of-concept is for probi-
ii. In a study of 10 women with a otics to actually impact the recurrent rate
history of recurrent symptomatic of UTI. The following studies provide dif-
UTI, a gelatin suppository con- fering degrees of evidence.
taining 109 L. rhamnosus GR-1 vii. Forty-one premenopausal women
and L. fermentum (now known as were treated with three days
reuteri) B-54 was administered norfloxacin or trimethoprim-
vaginally once per week for 12–16 sulfamethoxazole plus randomized
months [33]. Two subjects were to receive intravaginal probiotic
non-compliant, but of the others L. rhamnosus GR-1 and L. reuteri
there was a 66% reduction in UTI B-54 (>109 viable count) or placebo
episodes compared to the previ- twice weekly for two weeks and then
ous year’s history. The lactobacilli at the end of each of the next two
were recovered from the vagina months [38]. UTI recurrence rate
and noted adherent to epithelial was lower in the probiotic treated
cells. group (21% versus 47%). This is a
iii. The development of molecular meth- good study but with small numbers
ods to indentify lactobacilli provided of patients in each group. Still, it
a new tool to examine their ability indicates that probiotics can restore
to survive in the vagina. The first the vaginal lactobacilli in patients
report of this was published in 1994 treated for UTI with trimethoprim-
[34]. A 33 year old woman with a sulfamethoxazole. (LoE 2a)
history of recurrent UTI inserted a viii. Intravaginal probio tic L.
single pessary of >109 L. rhamnosus rhamnosus GR-1 and L. reuteri B-54
GR-1. Subsequent swabs showed (>109 viable count) capsules admin-
that the organism persisted for at istered weekly for one year resulted
least six weeks. in a UTI recurrent rate of 1.6 per
iv. Ten healthy women inserted vagi- 25 patients, compared to six per
nally a capsule containing >109 patient the previous year [39]. This
L. rhamnosus GR-1 and L. reuteri supports the concept but has been
RC-14 and the organisms were criticized because it uses historical
281
comparison of UTI rates from the seven patients had uncomplicated

previous year. (LoE 2b) UTI. The participants’ mean age
ix. A study of 150 women with a was 57.2 ± 17.2 years, and they had
history of UTI caused by E. coli suffered from recurrent UTI for
were randomly allocated into 7.1 ± 5.2 years. A significant reduc-
three groups: 50 ml of cranberry- tion was observed in the number of
lingonberry juice daily for six recurrences during treatment (from
months or 100 ml of L. rhamnosus an average of 5.0 ± 1.6 episodes per
GG drink five days a week for year to 1.3 ± 1.2, P = 0.0007). This
one year, or no intervention. At study supports the concept but is
six months, eight (16%) women in a pilot study in complicated UTI
the cranberry group, 19 (39%) in patients. (LoE 2b)
the L. rhamnosus GG group, and xii. Czaja et al. [43] performed a phase
18 (36%) in the control group had I randomized, placebo-controlled
at least one recurrence [40]. This trial with L. crispatus CTV05
showed that probiotic L. rhamno- (5 × 108 CFU) vaginal supposi-
sus GG given orally did not prevent tory in 30 women for five days. No
UTI recurrence. (LoE 2a) severe adverse events occurred.
x. Another negative outcome with Mild to moderate vaginal dis-
L. rhamnosus GG was reported in charge and genital irritation were
a double-blind study of newborns reported by women in both study
[41]. Five hundred and eighty- arms. Seven women randomized
five infants with a gestational age to L. crispatus CTV-05 developed
<33 weeks or birth weight <1,500 pyuria without associated symp-
g were randomized to receive toms. Most women had high concen-
standard milk feed supplemented trations of vaginal H202-producing
with Lactobacillus GG (Dicoflor, lactobacilli before randomization,
Dicofarm, Rome, Italy) in a dose of therefore it is difficult to verify that
6 × 109 CFU once a day until dis- replenishment of lactobacilli per se
charge (47 days on average), start- occurred. (LoE 2b).
ing with the first feed or placebo.
Although UTIs (3.4 vs. 5.8%) were xiii. Lee et al. [1] showed in a study
found less frequently in the probi- of 120 children who had persist-
otic group compared to the control ent primary vesico-ureteral reflux
group, these differences were not that Lactobacillus acidophilus
significant. (LoE 2a) (108 CFU/g 1 g b.i.d., n = 60) was
as effective at preventing recurrent
In the past three years, three studies UTI as trimethoprim/sulfamethoxa-
have provided further evidence to suggest zole (2/10 mg/kg h.s., n = 60) over
that probiotics can help to reduce recur- a year. The incidence of recurrent
rence of UTI. UTI was 18.3% (11/60) in the probi-
xi. Vaginal suppositories containing otics group, which was not different
L. crispatus GAI 98332, 1.0 × 108 from 21.6% (13/60) in the antibiotic
CFU (colony-forming units) per one group (P = 0.926). The causative
suppository were administered to organisms of recurrent UTI were
nine subjects every two days for not significantly different between
one year [42]. Two of nine patients the two groups (P = 0.938). Even
performed clean intermittent cath- after stratification by VUR grade,
eterization when necessary and age, gender, phimosis, voiding
282
dysfunction and renal scar, the 5. CONCLUSIONS AND FUTURE

incidence of recurrent UTI did not RESEARCH
differ significantly between the two
groups (P > 0.05). This is an excel- There is good evidence to support the
lent study that provides supporting concept that females colonized with lacto-
evidence that probiotic use is as bacilli are at lower risk of UTI. Further
effective as antibiotic prophylaxis studies, now possible with molecular
in patients who commonly receive bacterial identification methods being
long term, low-dose antimicrobial available, are needed to determine if par-
prophylaxis. The one criticism is ticular species of Lactobacillus are bet-
that the strain of L. acidophilus ter able to compete with uropathogens.
needs to be designated. (LoE 1b) Studies on BV have suggested that H202-
producing lactobacilli are more protec-
xiv. In arguably the most important
study to date regarding the use tive and thus the same could be true for
of probiotics for the prevention UTI. At the same time, one might argue
of rUTI, Beerepoot et al. [3] ran- the fact that these strains are displaced
domized 252 postmenopausal during the infection process, imply-
women with rUTI to receive 12 ing that those with better colonization
months prophylaxis with either and persistence may be more important.
trimethoprim/sulfamethoxazole For example, while the low level H2O2-
(TMP/SMX) (480mg 4 times daily) producing L. rhamnosus GR-1 has been
or twice daily oral capsules con- shown to induce membrane stress and
taining 109 CFU L. rhamnosus downregulate virulence in uropathogenic
GR-1 and L. reuteri RC-14. Both E. coli (UPEC) [44], L. iners strains are
groups demonstrated a greater potent colonizers and not as easily dis-
than 50% reduction in the mean placed by pathogens [45]. In addition,
number of reported symptomatic future research should investigate the
UTIs (TMP/SMX – 2.8 vs. 7.0 effects of lactobacilli strains on viru-
pretrial, GR-1/RC-14 – 3.1 vs. lence factor expression in uropathogens.
6.8 pretrial) and median times It has already been shown that lactoba-
to first UTI were 6 and 3 months cilli can down-regulate toxin release in
for the antibiotic and probiotic S. aureus and E. coli [46–47] as well as
arms, respectively. Importantly, expression of both type 1 and P fimbriae
while resistance following the in UPEC [43], thus providing potential
first month of prophylaxis in the mechanisms whereby they counter the
TMP/SMX group increased from uropathogenesis process. Additional stud-
~20–40% up to ~80–95% for TMP/ ies could further this knowledge and help
SMX, TMP and amoxicillin in us determine why and how some persist-
faecal and bacteriuria isolates of ent pathogens only cause symptomatic
E. coli, no such increase in resist- infections when commensals like lactoba-
ance occurred in the probiotic cilli are at low levels.
group. This double dummy double- Lactic acid produced by lactobacilli as
blind randomized non-inferiority a by-product of metabolism is also protec-
trial clearly showed that the pro- tive for the host. This weak acid has been
phylactic use of certain urogenital shown to exhibit potent antibacterial
probiotics can greatly reduce rUTI effects on numerous pathogens includ-
development without increasing ing uropathogenic strains [48], especially
the risk of antibiotic resistance. under nutrient limiting conditions such
(LoE 1b) as those observed in the vagina. A recent
283
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|4.6|
Prevention of prematurity by
early diagnosis and treatment of
bacterial urogenital infections – The
role of bacterial vaginosis
Udo B. Hoyme
Professor and Head of the Department of Gyecology and Obstetrics, HELIOS Hospital Erfurt Ltd.
Nordhäuser Strasse 74, D-99084 Erfurt, Germany
Tel +49-361-781.4001, Fax +49-61-781.4002, E-mail: udo.hoyme@helios-kliniken.de; hoymej@aol.com
ABSTRACT on federal state or national levels in the

decades preceding the study. However,
Bacterial vaginosis has a significant rela- following discontinuation of the cam-
tive risk for miscarriage or prematurity paign the prematurity rates in Thuringia
of 1.4–6.9%. In the initial Erfurt trial (monitored until 2005) returned to rates
0.3% of the neonates with gestational age as high as prior to our state-wide pro-
< 32 + 0 weeks were seen in an interven- gramme in general, as well as for our hos-
tion group vs. 3.3% (p < .01) in the con- pital in particular.
trol group; in the Thuringia campaign Now, following correction, detailed
the figures were 0.94% vs. 1.36% (p < .01) analysis and extensive discussion of the
for the entire state. The rate of newborns data, a model trial of four health insur-
< 1000 g was reduced to 0.38%, the lowest ance providers in five German states
incidence ever seen in any of the German was initiated, aimed at scientific evalu-
states in the past. ation as well as cost-benefit analysis.
The Erfurt and Thuringia programmes The preliminary new data and calcula-
represent a preventional prospective, tions also signal substantial savings as
controlled study. This should count even well as implementation of new simpli-
more, as there was no success in reducing fied pH-measurement techniques and
the rate of underweight children either tools.
Prevention of prematurity by early diagnosis | 4.6 |
Prevention of prematurity by screen- than 25 years; Mycoplasma genitalium,

ing, diagnosis and therapy of genital leptotrichia, and other still uncultivable
infections is without any doubt a step for organisms may prove to be important in
optimising and rationalising the health the future.
care system. Also the extraordinary non- The anatomy and physiology of the
commensurable strain on all parties urogenital tract change dramatically
involved could be reduced in a most ben- during pregnancy: the glycogen content
eficial way. Similar developments take of the urethral and vaginal epithelium
place abroad: the described innovative pH increases, the intravaginal pH decreases,
measurement regime has been introduced the columnar epithelium of the cervix
in more than 20 countries so far. hypertrophies and is exposed to changed
local microbial flora and/or infection. This
Key words: bacterial vaginosis, pre-
leads to an increasing risk of urinary
vention of prematurity, intravaginal
tract infections as well as chorioamnio-
pH-screening
nitis and amniotic fluid infection during
the course of pregnancy and the following
delivery [2–4].
Since C. trachomatis, N. gonorrhoeae,
and bacterial vaginosis (BV) have been
1. Routine screening for N. gonorrhoeae,
associated with an increased risk of
C. trachomatis and bacterial vagino-
febrile morbidity after surgical abor-
sis is indicated in defined populations
tion, routine screening is indicated prior
because of infection associated mis-
to the procedure in most populations
carriage and preterm birth as well as
[5–6], but also considered in general for
postpartum complications (GoR B).
pregnancy [1, 7–8]. Pregnancy loss and
2. The intravaginal pH self-measure- preterm birth comprise the spectrum of
ment as a screening procedure fol- adverse pregnancy outcomes following
lowed by antimicrobial therapy in the urogenital infections. BV in particular has
case of bacterial vaginosis is a signifi- increasingly been recognized as a cause
cant step in reduction of prematurity of prematurity all over the world, e. g. in
(GoR B). Germany, Austria, Brazil, Greece, Sweden,
Denmark, the US, Iran, Korea [8–16].
1. INTRODUCTION
2. METHODS
Ectopic pregnancy, spontaneous abortion
and stillbirth, prematurity, congenital and A systematic literature search was per-
perinatal infections as well as puerperal formed in PubMed beginning in 2004
maternal infections represent outcomes with the following key words: prevention
of pregnancy in which bacterial (sexu- of prematurity, intravaginal pH-measure-
ally transmitted) infectious agents play ment, genital infections, and the following
an important etiologic role, especially in limitations: English abstract available,
pregnant adolescents and young adults non-systemic infection.
compared to older pregnant women, who A total of 110 publications were iden-
are more likely to be involved in a stable tified, which were screened by title and
monogamous relationship [1]. The preva- abstract. After exclusion of duplicates a
lence of bacterial sexually transmitted total of eight were included in the analy-
infections (STI), such as with Chlamydia sis, supplemented by 27 citations known
trachomatis and Neisseria gonorrhoeae is to the author. It has to be considered,
in general highest among women younger however, that prevention of prematurity
289
caused by infection is a fairly new emerg- 4. DEFINITION OF THE DISEASE

ing task. Therefore the literature is still
very limited. Textbooks for obstetrics name a number
The studies were rated according to the of factors as causes for prematurity. The
level of evidence (LoE) and the grade of type in question here is (the more and
recommendation (GoR) using ICUD stand- more preventable) infection-based pre-
ards (for details see Preface) [17–18]. maturity. Currently the quantitatively
relevant, adjustable and scientifically
proven causes of prematurity are gen-
3. THE CURRENT CHALLENGE eral infections of the urogenital tract, as
well as infections of the vagina and cer-
Children born prematurely in general, vix uteri, in particular in the latter those
and especially children with low birth caused by Chlamydia trachomatis (LoE
weight, run a high risk of health and 2a). As a logical consequence e.g. since
development problems. Despite this fact April 1, 1995 screening for Chlamydia in
and despite all interventional efforts pre- pregnancy is obligatory in Germany [7]
maturity rates have remained unchanged (GoR B).
for years, e.g. at about 6–8% throughout Intriguing data implicating bacterial
Germany. In contrast, both perinatal mor- infectious agents in prematurity were
bidity and mortality have been reduced first derived from a study performed
significantly over the last years. With more than 40 years ago [20] investigat-
the current high standard of neonatal ing the role of urinary tract infection
medicine a further improvement of those in prematurity in 279 nonbacteriuric
results can only be expected if we suc- women allocated to treatment with six
ceed in reducing prematurity as the main weeks of oral tetracycline at 1g per day
contributor to perinatal morbidity and (today considered contraindicated in
mortality [19]. Because of the preventive pregnancy) or with placebo prior to 32
character of all measures this is not only weeks of gestation (Table 1). The results
a medical, but also a social-political task. showed that the tetracycline–treated
Table 1 Effect of 6 Weeks of Oral Tetracycline Given Prior to 32 Weeks on Outcome of Pregnancy in 279 Nonbacteriuric
Women (12).
Measurement Tetracycline (N = 148) Placebo (N = 131) p
Mean gestation (weeks) 39.1 38.1 < 0.025
Mean birth weight (g) 3277 3141 NSa
% %
Premature liveborn 5.4 15.2 < 0.025
Stillborn 1.4 0.8
PROM 10 13 NS
Postpartum fever 6 12 < 0.001
Neonatal resuscitation 8 19 < 0.005
Respiratory distress 7 < 0.05

a
Nonsignificant.
290
group had significantly longer gestations, evident reduction of prematurity (GoR B)

fewer preterm infants, fewer episodes [8, 22–24]. The unquestionable efficacy
of postpartum fever, and fewer neona- of the concept which pregnant women
tal complications in comparison with the actively take part in has recently been
placebo-treated group (LoE 1b). Despite investigated in the prospective Erfurt
the limitations of the study this benefit and Thuringia trials [8]: The objective of
suggested the presence of unidentified these trials was to prove the efficacy of
microorganisms in the urogenital tract vaginal pH screening during pregnancy,
(C. trachomatis or BV-associated) that carried out twice per week by the woman
could have contributed to prematurity in herself, because gynecologists’ examina-
the placebo group. This also raises the tions in the alleged intervals (e.g. every
possibility that other as-yet unidentified four weeks during early pregnancy) are
organisms may be associated with infec- not considered to be sufficient. It was not
tion and prematurity, since many bac- intended to investigate the well-studied
teria produce phospholipases that may impact of bacterial vaginosis on prematu-
directly damage the membranes or lead rity, to collect new epidemiological data,
to prostaglandin production [1, 21]. This to reassess diagnostic measures or to
process cannot be reversed at a late stage compare different treatment regimes.
by antibiotics, so the best strategy is pre- Briefly, the patients were recruited
vention of these conditions by early detec- into the program with the help of a sim-
tion and treatment of lower urogenital or ple explanatory leaflet at the end of
genital infection (GoR B). their 12th week of pregnancy. Patients
Pregnant women should be screened for received examination gloves (CarePlan®
urinary tract infection during pregnancy VpH, Selfcare, then Inverness GmbH,
as well as for C. trachomatis, possibly Munich, now Unipath Diagnostics GmbH,
N. gonorrhoeae, syphilis and also facul- Cologne) and a simple documentation
tatively T. vaginalis on their first prena- sheet. Each patient was asked to consult
tal visit and treated if positive (GoR B). her gynaecologist immediately when risk
Screening should be repeated in high risk indicators or symptoms relevant for pre-
groups [1, 7], however, most recommen- maturity occurred, especially when she
dations for management and therapy in found an elevated pH value ≥ 4.7. The
pregnancy lack the support of scientifi- sensitivity of a pH ≥ 4.7 with respect to
cally performed prospectively randomized bacterial vaginosis is 97%; a pH value
studies due to methodical and ethical ≥ 4.7 is only 67 % specific and not sensi-
reasons. tive for other infections [25].
During any unscheduled consulta-
tion due to above mentioned indications
5. CLINICAL EVALUATION: STARTING and after pH control, odour test and wet
POINT OF A BROAD SCALE mount microscopy, the gynaecologist had
PREMATURITY PREVENTIONAL to decide if the elevated pH was attribut-
REGIME able to:
- a physiological condition
Bacterial vaginosis, an anaerobic dys-
- pH elevation without evident affection
biosis, has a significant prevalence in
or pathogen present
pregnancy of up to 20% and a rela-
tive risk for miscarriage or prematu- - bacterial vaginosis or
rity of 1.4–6.9% (LoE 2a). An adequate - a result indicating hospital assign-
treatment regime, especially in the ment, such as rupture of the
early stages of pregnancy, can lead to membranes.
291
Accordingly, following the gynaecologic Another six month trial was conducted
assessment, the patient was assigned to: in the federal state of Thuringia start-
- no therapy ing March 1, 2000. The objective of the
trial was to involve all pregnant women
- a therapy recommendation for a throughout the federal state (about
preparation containing lactoba- 16,000 per year) for a defined period of
cilli (in the Erfurt and Thuringia time with the help of office based gynae-
trial Gynoflor®, Nourypharma, cologists and to achieve a measureable
Oberschleißheim) i. vag. decrease in prematurity rates in the
- a treatment recommendation for annual perinatal state inquiry which had
clindamycin cream (Sobelin-Creme®, previously been reported stable between
Pharmacia & Upjohn, Erlangen) 1992 and 1999 [8].
i. vag., or The method was to send office based
- hospital assignment. gynaecologists test glove kits (total 3833)
free of charge. Women who were at least
12 + 0 weeks pregnant were recruited
6. RISK ASSESSMENT AND for the campaign. Due to the presumed
REDUCTION efficacy of the action it was hypotheti-
cally expected that there would be a
381 women participated in this pilot significant decrease in the prematu-
screening and treatment programme rity rate. Treatment with lactobacillae
[8]; 2341 women did not participate, and or antibiotics was suggested, but was at
served as a control group. An early prema- the discretion of the treating physician.
turity rate of 0.3% amongst participants Acidification of the vagina with acid-
was observed, compared to a 2.2% rate containing pharmaceutical preparations
amongst women who did not participate, was excluded however, because of the
but whose physicians were informed of and lack of scientific evidence supporting this
taking part in the programme and a 4.1% treatment.
rate in a group of pregnant women who The evaluation of the perinatal inquiry
received only conventional prenatal care for the year 2000 in Thuringia (16.276
(Table 2). Compliance with the test glove births) gave a clear result: the total
and with the testing regime was rated as number of early premature births was
outstanding by all parties involved. Many less in the 2nd half of the year accord-
women emphasized the value of the indi- ing to the initially formulated hypothesis
viduality of the self-precaution and as (Figure 1a). Similar results were obtained
result the change from being the object of when comparing the birth weights
care during pregnancy to the subject. (Figure 1b).
Table 2 Prematurity Prevention Campaign 1998: Delivery (controlled for gestational age) at the OB-Department Erfurt
(n = 2722).
Participants Controls A
(pH self (pH measured by Controls B
Delivery measurement) physician) (no measurement)
(gestational age) (n = 381) (n = 1001) (n = 1340)
> 37 + 0 91.9 % 90.7 % 85.4 %
32 + 0/36 + 6 7.9 % 7.1 % 10.4 %
< 32 + 0 0.3 % 2.2 % 4.1 %
292
% % 6,92
9 8,5 7
8,19 1st 6 months 6,01
8 2nd 6 months
6
7
1st 6 months 5
6
2nd 6 months
5 4 Thuringia
4 Perintal Inquiry
3 2,67
3 Thuringia 2,04
1,58
2 0,99*** Perinatal Inquiry 2 1,29
1 0,97
1 0,61
0,38
0
� 32 � 0 week � 37 � 0 week ***p � .001 0
Weight in g < 1000 < 1500 < 2000 < 2500
p-value < .05 < .05 < .005 < .01
Figure 1a Thuringia Prematurity Prevention Campaign 2000
Distribution of Prematurity (n = 16,276; January-June: 7870; Figure 1b Thuringia Prematurity Prevention Campaign 2000
July-December: 8406). Distribution of Birth Weights 2000 (n = 16,582; January-June:
8148; July-December: 8434).
%
A detailed analysis of participants 79,7
80
reporting back (n = 607) vs. controls
70 65,6
(1. half year 2000, n = 7870)* revealed a
reduction in: 60
with
50 without
• prematurity < 32 + 0 wks. (0.3 % vs. PROM
40 34,4
1.58 %; p < .05)
30
• prematurity < 37 + 0 wks. (5.3 % vs. 20,2* Thuringia Perinatal Inquiry
20
8.5 %; p < .01)
10
• the incidence of newborns < 2500 g 0
(3.45 % vs. 6.92 %; p < .001). 1st 6 months 2nd 6 months p* , 0.05
(n 5 125) (n 5 84)
These data allow the conclusion that
with this strategy, even if only < 50% of Figure 2 Prematurity Prevention Campaign 2000: Share
of Premature Rupture Thuringia of Membranes for Early
pregnant women participated in a wider Prematurity (< 32 + 0 weeks).
territory, the number of early premature
births would be significantly reduced. have been scientifically studied to a great
One possible explanation for the suc- extent with regard to their quantitative
cess of this programme was that whereas and qualitative consequences, amongst
more than one third of early premature which the release of bacterial proteases,
births were connected with early rupture the release of phospholiphase A2 from
of membranes during the first half of the membranes, lysosomes and bacteria
year, this was only the case in one in five (Bacteroides and Prevotella spp.), and
during the second half (Figure 2). the resulting synthesis of prostagland-
ines can be relevant (LoE 2a). Another
7. DISCUSSION OF TREATMENT factor is the direct effect of bacterial
endotoxin as well as macrophage activa-
tion with the release of cytokines [24, 26].
The list of risk factors for prematurity
Furthermore, there are indications that
is lengthy. The majority of these fac-
fetal cytokines alone can trigger birth; in
tors are difficult to influence. Cervical
this situation without maternal reaction
and vaginal conditions are factors which
to infection, labour can be induced, which
* Hübner, J., VII. Meeting European Society for Infectious Diseases in
is lifesaving for both mother and child
OB/GYN (ESIDOG), 13.06.2003, Erfurt (LoE 2b) [21].
293
Bacterial vaginosis as dysbiosis rsp. way. As the investigation was carried

dysbalance with an increase in vagi- out in a whole federal state, the posi-
nal anaerobic bacteria concentrations tive results can be regarded as a definite
by 1000-fold is without doubt a risk for breakthrough with respect to the avail-
prematurity. The large American VIP ability of a practicable and widespread
trial (in which enrolment was later in prevention of prematurity. The compari-
the course of pregnancy) found a relative son with other federal states, i.e. Bavaria
rate of 1.6 and therefore as high as for or Saxonia, shows that when evaluat-
Chlamydia infections or similar to tri- ing the quality indicator of birth weight,
chomoniasis at 1.7 (LoE 2a) [22]. Aerobic that the higher rates of prematurity for
types of colpitis with an increase of the Thuringia in 1999 can be changed to
pH value [27] as well as intra- and extra- an unmistakable reduction during the
amnial infections with enteropharyngeal 2nd half of 2000 (Figure 3). The results
pathogens are also thought to contribute achieved in Thuringia in 2000 are the
towards prematurity (LoE 2b) [28–29]. best ever seen in any of the German
In the majority of trials concerning preg- states in the past. However, following
nancy, bacterial vaginosis has been suc- discontinuation of the campaign the pre-
cessfully treated with Clindamycin rsp. or maturity rates in Thuringia (monitored
alternatively with Metronidazole [30–32]. until 2005) returned to rates are as high
Even when labour was already established as prior to our state-wide programme in
a significant prolongation of pregnancy general, as well as for our hospital in par-
could be demonstrated in controlled trials ticular (Table 3).
(LoE 1b) [26]. Dennemark et al. [33] were Prevention of prematurity by screen-
able to show that by early intervention ing, diagnosis and therapy of genital
either with lactobacillus preparations or infections is without any doubt an impor-
preferably with intravaginal Clindamycin tant step for optimising and rational-
treatment a distinct reduction of prematu- ising the health care system (GoR B).
rity could be obtained (LoE 2a). In princi- The concepts and results presented are
ple lactobacillus preparations cannot yet encouraging that an improvement of the
be considered a scientifically proven rsp. situation with simultaneous cost reduc-
causal therapy, but the main objective of tion is indeed possible.
treatment in both the Dennemark and the
Erfurt/Thuringia investigations was the
prolongation of pregnancy. 9. FURTHER RESEARCH
The efficacy of the regime is supported

8. PRINCIPLES OF MANAGEMENT and established in several scientifically
performed prospective studies.
The Erfurt and Thuringia programmes The data of 7731 participating preg-
represent for the first time a prospective, nant women as well as 135,394 controls
controlled study. The main benefit is that are under evaluation at present [27].
because of the active involvement of the In this study, initiated by four German
pregnant women pH changes could be insurance companies, reduction of pre-
recognised as early as possible and as a maturity will be investigated as well as
consequence a huge part of the disorders possible financial savings: preliminary
relevant for late miscarriage or prema- data indicate about 300 Euros per any
ture birth could be addressed with an pregnancy regardless of outcome, so the
immediate adequate therapy. The results possible implementation of the procedure
confirm the positive consequences of the in a guideline is under discussion by the
applied measures in a statistically sound German health authorities.
294
%
Bremen 0,92
Northrhine 0,69
Lower Saxonia 0,62
Bavaria 0,6
Westfalia 0,59
1999
Saxonia-Anhalt 0,58
Hessen (1st 6 months) 0,57
Thuringia 0,53
Saxonia 0,46
Brandenburg 0,39
0 1
Thuringia 1st 6 months 0,61

Perinatal Inquiry
Bavaria 0,6
of the Federal
Saxonia 0,44 States 2000
Thuringia 2nd 6 months 0,38
0 1
Figure 3 Thuringia Prematurity Preventation Campaign 2000 Birth Weights < 1000g Compared to other Federal States.
Table 3 Distribution of Birthweights (%) State of Thuringia 2000–2002.
Year 1999 I/2000 II/2000 2001 2002 2003 2004 2005
N 16233 8162 8458 16408 15995 15436 16058 15633
< 1000 g 0.54 0.61* 0.38 0.46 0.63*** 0.62** 0.60** 0.56**
< 1500 g 1.22** 1.29* 0.97 1.09 1.32** 1.17* 1.15* 1.30**
< 2000 g 2.67*** 2.67* 2.03 2.36** 2.62*** 2.74*** 2.34** 2.60***
< 2500 g 6.76*** 6.91** 5.99 6.64*** 6.72*** 6.80*** 6.35** 6.88***
< 1000 g Perinatal- 1.5 1.0 1.5 1.6 1.5 1.4 1.7
center Erfurt
* p < 0.05; ** p < 0.01; *** p < 0.001.
As further scientific proof for the regime time a simple means for optimising and
of pH-measurement by pregnant women rationalising diagnosis as well as ther-
themselves, as well as worldwide applica- apy. The chance to reduce the extremely
bility, a prospectively randomized study costly complications associated with
will be initiated at the University of Cairo. prematurity with minimal expense
comes with the fact that the immeasur-
10. CONCLUSIONS able extraordinary strain on all parties
involved can be reduced in a beneficial
The investigated concept of pH self- way. Can we as physicians, health care
measurement leads to an efficient reduc- providers and politicians take the liberty
tion of prematurity and is at the same to ignore these encouraging prospects?
295
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166(1 Pt 1): 100–3. BH, A high Nugent score but not a posi-
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Neonatol, 1997. 201(4): 113–4. J Matern Fetal Neonatal Med, 2009.
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Alves VM, and Faro S, Impact of treat- tion. 2006, Washington, DC: National
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297
Chapter |5|
Asymptomatic bacteriuria
Chair: Lindsay E. Nicolle
CHAPTER OUTLINE
5.1 Introduction – The evolution of asymptomatic bacteriuria 300
5.2 Asymptomatic bacteriuria – to treat or not to treat 303
5.3 Asymptomatic bacteriuria with the model strain
Escherichia coli 83972 protects against symptomatic
|5.1|
Introduction – The evolution of

asymptomatic bacteriuria
Lindsay E. Nicolle
Professor, Department of Internal Medicine and Department of Medical Microbiology, University of Manitoba Health
Sciences Centre, Room GG443 – 820 Sherbrook Street,Winnipeg, MB R3A 1R9
INTRODUCTION substantial negative outcomes. In fact,

Kass, the father of the quantitative urine
Studies published in the 1950’s which culture, wrote in 1962, “… there is now
initially defined quantitative bacteriu- clear evidence that bacteriuria is one of
ria as ≥ 105 cfu/ml described a substan- the commonest human infections, that
tial number of men and women with it may be chronic and persistent, that it
urine cultures which met this criteria may influence structure and function out-
but had no symptoms attributable to the side of the urinary tract, and that it plays
genitourinary tract [1]. When these cri- an important role in disease from the cra-
teria for quantitative urine culture were dle to the grave – from prematurity to
applied in studies of pregnant women, hypertension and renal failure” [3].
it was rapidly and repeatedly confirmed This paradigm was soon questioned
that this “asymptomatic bacteriuria”, if [4]. Case control studies and long term
untreated, was associated with a substan- prospective cohort studies initiated in the
tially increased risk of pyelonephritis and 1960’s and continued for decades in both
premature delivery later in pregnancy [2]. school children and non-pregnant adult
In addition, histopathologic evidence of women reported no negative outcomes
“chronic pyelonephritis” in a high propor- associated with initial or subsequent
tion of individuals with end stage renal asymptomatic bacteriuria. More recently,
failure who had no history of symptomatic prospective, randomized clinical trials
urinary tract infection was attributed to enrolling adult women, schoolgirls, long
“occult bacteriuria” [1]. The confluence of term care facility residents, spinal cord
these observations generated a paradigm injured patients, and diabetic women con-
which saw asymptomatic bacteriuria as sistently document no benefits with treat-
a stealthy and dangerous condition with ment of asymptomatic bacteriuria [2].
Introduction – The evolution of asymptomatic bacteriuria | 5.1 |
The observations in these populations are with potential uropathogens, which pre-
distinctly different from those in preg- ceeds symptomatic urinary infection [6].
nant women, in whom the benefits of However, this explanation does not seem
treatment of asymptomatic bacteriuria likely to explain observations in children
have been repeatedly and consistently or subjects with complicated urinary
documented. The histopathological diag- tract infection. An alternate hypothesis
nosis of “chronic pyelonephritis”, on the is that persistent asymptomatic bacte-
other hand, is now recognized as an end riuria with organisms of low virulence
stage of many inflammatory renal dis- prevents other, more virulent, organisms
eases, attributable to urinary infection from gaining access to the urinary tract
rarely, and only in individuals with a his- and establishing symptomatic infection.
tory of symptomatic infection [4]. Potential mechanisms for this would
The paradigm has now fully shifted. include limiting access to uroepithelial
Asymptomatic bacteriuria is recognized receptors or nutrients in the urine, or
as benign, and antimicrobial treatment production of inhibiting molecules. This
of asymptomatic bacteriuria is discour- is “bacterial interference” [5].
aged [2]. These recommendations are The next conceptual shift to con-
irrespective of the presence of pyuria, sider is whether inducing asymptomatic
which is a common accompaniment of bacteriuria is therapeutic for persons
asymptomatic bacteriuria. The exception, with recurrent urinary tract infections.
of course, remains pregnant women who This approach is described in the paper
must be screened for bacteriuria early in by Wullt and Sunden, together with
pregnancy and treated if positive. In addi- the status of clinical trials evaluating
tion, individuals who will undergo inva- this intervention. In selected patients
sive genitourinary procedures likely to be with complicated urinary infection and
associated with mucosal bleeding should impaired bladder emptying preliminary
receive perioperative antimicrobial proph- clinical studies report that establishing
ylaxis to prevent bacteremia and sep- persistent asymptomatic bacteriuria with
sis complicating the procedure. Further the avirulent E. coli 83972 strain protects
clinical trials are needed for some unique the patient from symptomatic episodes
populations such as immunocompromised [7–8]. Thus, this approach seems attrac-
patients with solid organ or bone marrow tive for some patients with recurrent
transplants and neutropenic patients, as infection. Wullt et al have now completed
there is insufficient evidence addressing a randomized, cross-over trial which
outcomes in these groups. should clarify potential efficacy and refine
It is now accepted that asymptomatic some aspects of this approach; the results
bacteriuria is not harmful for most from this trial will be of great interest.
patients, but we are moving beyond this The hurdles in development of this strat-
concept. Several studies suggest that egy, however, are the relatively small
asymptomatic bacteriuria may be bene- number of patients in whom prolonged
ficial. In school girls, healthy women, bacteriuria can be established, and con-
diabetic women and spinal cord injured vincing patients and regulators that an
patients, antimicrobial treatment given “avirulent” strain is safe.
for asymptomatic bacteriuria or other Our perspective of asymptomatic bac-
infections is followed in the short term teriuria, then, has shifted from one pole,
by an increased risk for symptomatic uri- where bacteriuria was considered to be
nary infection [5–6]. One hypothesis to uniformly harmful, to a neutral posi-
explain this observation for adult women tion. If “bacterial interference” proves
is that antimicrobial use disrupts normal to be safe and effective in comparative
vaginal flora, facilitating colonization clinical trials, opinion may shift further
301
Chapter |5| Asymptomatic bacteriuria
towards the completely opposite pole – 5. Sunden F, Hakansson L, Ljunggren E,

that asymptomatic bacteriuria is benefi- and Wullt B, Bacterial interference – is
cial. “Bacterial interference” is a further deliberate colonization with Escherichia
step towards unveiling the many faces of coli 83972 an alternative treatment for
asymptomatic bacteriuria, a journey that patients with recurrent urinary tract
infection? Int J Antimicrob Agents, 2006.
started 50 years ago.
28 Suppl 1: S26–9.
6. Smith HS, Hughes JP, Hooton TM,
REFERENCES Roberts P, Scholes D, Stergachis A,
Stapleton A, and Stamm WE,
1. Kass EH, Asymptomatic infections of the Antecedent antimicrobial use increases
urinary tract. Trans Assoc Am Physicians, the risk of uncomplicated cystitis in
1956. 69: 56–64. young women. Clin Infect Dis, 1997.
2. Nicolle LE, Bradley S, Colgan R, Rice JC, 25(1): 63–8.
Schaeffer A, and Hooton TM, Infectious 7. Wullt B, Connell H, Rollano P, Mansson W,
Diseases Society of America guidelines for Colleen S, and Svanborg C, Urodynamic
the diagnosis and treatment of asympto- factors influence the duration of
matic bacteriuria in adults. Clin Infect Escherichia coli bacteriuria in deliber-
Dis, 2005. 40(5): 643–54. ately colonized cases. J Urol, 1998. 159(6):
3. Kass EH, Pyelonephritis and bacteriuria. 2057–62.
A major problem in preventive medicine. 8. Prasad A, Cevallos ME, Riosa S,
Ann Intern Med, 1962. 56: 46–53. Darouiche RO, and Trautner BW, A bacte-
4. Gleckman R, The controversy of treat- rial interference strategy for prevention
ment of asymptomatic bacteriuria in of UTI in persons practicing intermittent
non-pregnant women – resolved. J Urol, catheterization. Spinal Cord, 2009. 47(7):
1976. 116(6): 776–7. 565–9.
302
|5.2|
Asymptomatic bacteriuria – to
treat or not to treat
Lindsay E. Nicolle
Professor, Department of Internal Medicine and Medical Microbiology, University of Manitoba,
Health Sciences Centre, Room GG443 – 820 Sherbrook Street, Winnipeg, MB R3A 1R9
ABSTRACT evaluation to describe the natural history

and impact of bacteriuria is required.
Asymptomatic bacteriuria is common. Key words: asymptomatic, bacteriuria,
Among healthy adults, bacteriuria urinary infection
increases with increasing age, and occurs
more frequently in women than men.
Individuals with underlying genitourinary
abnormalities such as patients with spinal
cord injuries or with indwelling catheters
also have a very high prevalence of bacte- Diagnosis:
riuria. Bacteriuria in most populations is 1. For women, the quantitative count of
benign. It has been shown to have adverse ≥ 105 cfu/ml of an organism in a voided
outcomes in pregnant women, where it is urine specimen identifies bacteriuria
associated with pyelonephritis and pre- [1] (GoR B).
mature birth, and in patients undergoing
traumatic genitourinary procedures asso- 2. For men, a culture from a voided urine
ciated with mucosal bleeding, where there specimen with a quantitative count
is a high risk of bacteremia and sepsis. ≥ 105 cfu/ml identifies bacteriuria [2]
In other populations, clinical trials have (GoR B).
consistently shown no benefits of screen- 2.1 For men with specimens collected
ing for or treatment of asymptomatic bac- using an external condom cath-
teriuria. For some immunocompromised eter ≥ 105 cfu/ml is the appropri-
persons, such as those with neutrope- ate quantitative criteria [3–4]
nia or renal transplant patients, further (GoR B).
3. For patients with indwelling urethral 1. INTRODUCTION

catheters a quantitative count of ≥ 105
cfu/ml identifies bacteriuria (GoR B). This chapter addresses the diagno-
3.1 For a urine specimen collected by in sis and management of asymptomatic
and out catheter, a quantitative bacteriuria in adult women and men.
count of ≥ 102 cfu/ml is consistent Asymptomatic bacteriuria in pregnant
with bacteriuria [1] (GoR B). women and children is addressed in
4. Pyuria in the absence of signs or other chapters, and will not be discussed
symptoms in a person with bacteriuria in detail here.
should not be interpreted as sympto-
matic infection or as an indication for
antimicrobial therapy [1] (GoR B) 2. METHODS
5. Screening for and treatment of
asymptomatic bacteriuria is recom- This document incorporates and
mended for: updates the 2005 Infectious Diseases
5.1 Pregnant women [1] (GoR A) Society of America Guideline for the
management of asymptomatic bacte-
5.2 Prior to an invasive genitourinary
procedure where there is a risk of riuria [1]. The update used a system-
mucosal bleeding [5–9] (GoR A). atic literature search performed in
Medline, Cochrane, and Embase. Key
6. Screening for or treatment of asymp-
words included bacteriuria and asymp-
tomatic bacteriuria is not recom-
tomatic urinary infection. The limita-
mended for:
tions used included adult with age over
6.1 Premenopausal, non-pregnant 18 years, clinical studies, English and
women [10] (GoR A) peer reviewed. A total of 100 publica-
6.2 Post-menopausal women [10] tions were identified, and screened by
(GoR A) title and abstract. Eleven papers were
6.3 Diabetic women [11] (GoR A) included in the review. The information
6.4 Healthy men [12] (GoR B) identified through the literature review
was supplemented by citations in pub-
6.5 Residents of long term care facili-
ties [13] (GoR A) lished reports as well as other papers
identified by the author.
6.6 Patients with an indwelling ure- The studies were rated according
thral catheter [1, 14–15] (GoR A)
to the level of evidence (LoE) and the
6.7 Patients with nephrostomy tubes grade of recommendation (GoR) using
or ureteric stents (GoR C) ICUD standards (for details see Preface)
6.8 Spinal cord injured patients [22–23].
[16–19] (GoR B)
6.9 Patients with candiduria [20–21]
(GoR A) 3. DEFINITION OF THE DISEASE
7. Screening for or treatment of asymp-
tomatic bacteriuria in renal trans- Asymptomatic bacteriuria is the micro-
plant patients beyond the first 6 biologic diagnosis of urinary tract infec-
months is not recommended (GoR B). tion with isolation of bacteria from urine
8. No recommendation can be made with specimens in appropriate quantitative
respect to screening for or treatment counts together with the absence of clini-
of bacteriuria in patients with neutro- cal signs or symptoms referable to the
penia (GoR D). genitourinary tract.
304
Asymptomatic bacteriuria – to treat or not to treat | 5.2 |
4. EPIDEMIOLOGY infection also may have a high preva-

lence of bacteriuria. Spinal cord injured
Asymptomatic bacteriuria is common in patients have a prevalence of bacteriuria
women of all age groups, and increases of 50%, irrespective of voiding method
with increasing age (Table 1) [1]. used [1]. Persons with long term (over 30
Asymptomatic bacteriuria is uncom- days) indwelling urethral catheters have
mon in younger men, but increases in a prevalence of bacteriuria of 100%, while
otherwise healthy older men over 65 short term indwelling catheters are asso-
years, likely attributable to prostatic ciated with acquisition of bacteriuria at
hypertrophy. A recent population-based the rate of 3–7% per day [24]. Other uro-
study of women and men over 80 years logic devices such as nephrostomy tubes
in the community in a Swedish health or ureteric stents are also associated with
region reported a prevalence of 20% in a high prevalence of bacteriuria while
women and 5–10% in men in three sur- they remain in situ.
veys repeated over 18 months [28].
Bacteriuria is very common in residents 5. RISK FACTORS
of nursing homes, with 25–50% of women
and 15–40% of men having positive urine For pre-menopausal women, risk factors
cultures at any time [13]. Populations for asymptomatic bacteriuria are the same
with functional or structural abnormali- genetic and behavioral determinants asso-
ties of the genitourinary tract who are ciated with recurrent acute uncomplicated
at risk for complicated urinary tract urinary infection [29]. The most important
Table 1 Prevalence of asymptomatic bacteriuria in selected populations.
Prevalence of bacteriuria
Women [1]:
premenopausal 5–10%
55–75 years 10–20%
≥ 70 years [2] 15–20%
long-term care facility [13] 25–50%
diabetic women 5–10%
Men [13]:
≥ 70 years 5–10%
long term care facility 15–40%
Indwelling urinary devices
chronic indwelling catheter [24] 100%
short-term indwelling catheter [24] 3–7%/day
ileal neobladder [25] 57%
Spinal cord injured [26–27]
sphincterotomy 50%
intermittent catheterization 50%
external condom catheter 50%
305
behavioral determinants are sexual inter- or dementia [13]. It is assumed the high
course and use of spermicides for birth prevalence of bacteriuria is attributable
control. For postmenopausal women, the to voiding impairment associated with
strongest associations are genetic, includ- chronic neurologic diseases. The very
ing prior history of urinary tract infection high prevalence of bacteriuria observed
and being a nonsecretor of the blood group in some populations with functional or
substance [30–31]. structural genitourinary abnormalities is
Consistent alterations observed in the also attributed to impaired voiding or to
vaginal flora following menopause are persistence of bacteria in biofilm on ind-
loss of the predominant lactobacillus flora welling devices in the genitourinary tract
which maintains the vaginal acid pH (e.g. catheters, stents, and nephrostomy
with replacement by organisms such as tubes).
Escherichia coli or group B streptococci
[32]. This change is attributed to loss of
an estrogen effect; systemic or topical 6. MORBIDITY AND MORTALITY
estrogen therapy re-establishes the lacto-
bacilli and an acid vaginal pH. Thus, it Asymptomatic bacteriuria may be harm-
has been suggested that estrogen defi- ful for pregnant women, as discussed
ciency contributes to the aging-associated more fully in an alternate chapter [1].
increase in bacteriuria. However, results Persons with bacteriuria are also at risk
of clinical trials are conflicting. One pro- for bacteremia and sepsis when traumatic
spective, randomized trial reported topical genitourinary procedures are performed
estrogen therapy decreased asymptomatic [1]. In other populations, no harms have
as well as symptomatic infection in older been associated with asymptomatic
women in both the community and long bacteriuria.
term care facilitates [33]. However, An individual identified with asymp-
another prospective, placebo controlled tomatic bacteriuria is at increased risk
study reported no decrease in asympto- of subsequent symptomatic urinary tract
matic bacteriuria with systemic estrogen infection [1]. However, the asymptomatic
replacement in women in a nursing home, bacteriuria is likely not causative. This
despite a decrease in vaginal pH [34]. suggests that the biologic determinants of
An increased post-void residual vol- asymptomatic and symptomatic urinary
ume has also been suggested to con- infection are similar. In healthy young
tribute to the observed increase in women a 8% risk of developing sympto-
bacteriuria with age. However, clinical matic urinary infection within one week
studies in both noninstitutionalized [31] of new acquisition of bacteriuria was
and institutionalized [35] older popu- reported [29]. Thus a brief period of bac-
lations report no independent associa- teriuria may immediately precede some
tion of post-void residual volume with symptomatic episodes in these women.
bacteriuria in older men or women. However, persistent asymptomatic bac-
Incontinence is a consistent association teriuria does not precede symptomatic
of asymptomatic bacteriuria in women, infection with the same organism in the
but is unlikely causative [1, 13]. This absence of contributing factors such as
association reflects voiding impairment obstruction or genitourinary trauma. In
which facilitates both incontinence and fact, asymptomatic bacteriuria in some
bacteriuria. patients has been associated with a
In the long term care facility popu- decreased risk for symptomatic infection,
lation, bacteriuria is more common in perhaps due to bacterial interference pre-
the most functionally impaired – those venting other organisms from establish-
with incontinence of bladder or bowel, ing infection within the bladder [36].
306
Table 2 Studies of asymptomatic bacteriuria and mortality.
Population (ref) Subjects Follow-up Mortality
Greece, older women and 342 10 years Significantly shorter survival for bacteriuric men or
men institutionalized [37] women.
Wales and Jamaica women 1530 13 years RR 1.5 (0.96, 2.32) adjusted for age only
15 – 84 yr. [38]
Sweden, men and women >70 2010 9 years Similar mortality with and without asymptomatic
years [39] bacteriuria, with stratification for risk factors.
Finland, men and women >85 561 5 years Bacteriuria had no prognostic significance for
years [40] mortality
US, women, >80 yr. [41] 1491 10 years Multivariate: observational RR 1.1 clinical trial RR
0.92 (0.57, 1.47)
Canada, men mean age 91 6 years No association of bacteriuria with mortality; OR at

78 years, institutionalized [42] 5 years 1.2 (0.38, 3.9)
Swedish, random population 1462 24 years No difference in mortality ASB vs not: 95% CI RR:
based, women [43] (0.74 – 2.52)
Asymptomatic bacteriuria is not asso- virulence characteristics between E. coli

ciated with increased mortality (Table 2) strains isolated from asymptomatic or
[37–43]. Some early studies reported symptomatic infection [29]. However,
decreased survival associated with other studies have reported strains of
asymptomatic bacteriuria, but did not E. coli isolated from women with asymp-
adjust for comorbidity or functional sta- tomatic bacteriuria are characterized by
tus, both of which are independently a lower prevalence of potential virulence
associated with both bacteriuria and factors than strains from symptomatic
increased mortality [37–38]. In elderly infection [47]. Gram-positive organisms,
populations asymptomatic bacteriuria is including group B streptococcus, entero-
correlated with impaired functional sta- coccus species, and coagulase negative
tus, which is itself an independent risk staphylococci other than Staphylococcus
factor for mortality [44]. Subsequent saprophyticus, are isolated more fre-
studies in community and institutional- quently from women with bacteriuria
ized populations which have adjusted for than symptomatic infection.
this potential bias have not reported an For men with asymptomatic bacte-
association of asymptomatic bacteriuria riuria the most common infecting organ-
with mortality (Table 2) [38–43]. isms are E. coli, Enterococcus spp and
coagulase negative staphylococci [48].
Bacteriuric men or women with urologic
7. MICROBIOLOGY abnormalities generally have a broader
spectrum of bacterial species or yeast
The most common organism isolated from isolated. While E. coli may remain the
asymptomatic bacteriuria in women is single most common organism, particu-
Escherichia coli [1]. This is also the spe- larly in women, the repeated courses
cies most often isolated when prolonged of antimicrobial therapy and urologic
bacteriuria with the same organism interventions in health care settings
occurs [45–46]. A prospective study in lead to isolation of more resistant organ-
young women reported no differences in isms such as Pseudomonas aeruginosa,
307
Citrobacter species, and urease produc- 9. TREATMENT

ing organisms such as Proteus mirabilis
and Providencia stuartii. 9.1 Premenopausal women
Antimicrobial treatment of bacteriuria in
premenopausal women may decrease the
8. CLINICAL EVALUATION/DIAGNOSIS
short term prevalence of asymptomatic
bacteriuria, but does not decrease the inci-
8.1 Microbiologic criteria
dence of subsequent symptomatic episodes
The criteria for diagnosing asympto- [1, 10]. Long term prospective cohort stud-
matic bacteriuria in women is two con- ies continuing for several decades have not
secutive specimens with ≥ 105 cfu/ml of reported different outcomes for women ini-
an organism isolated (LoE 2a). This was tially stratified as bacteriuric or not bac-
determined in initial studies evaluating teriuric [16, 49–51]. In fact, antimicrobial
the quantitative urine culture, but the treatment of asymptomatic bacteriuria
specific timing of the second urine speci- may be associated with an increased risk
men was not specified [1]. About 10–15% for symptomatic infection immediately
of initially bacteriuric women will have post therapy [52]. This may be explained
a negative urine culture on repeat test- by vaginal flora changes attributed to
ing. The failure to isolate bacteriuria antimicrobial therapy, but an alternate
on the second specimen may reflect con- explanation may be loss of bacterial inter-
tamination of the first specimen, but in ference when bacteriuria is disrupted by
younger women in particular, transient antimicrobial therapy. Thus, asympto-
bacteriuria is common [11, 28–29]. Thus, matic premenopausal women with bacte-
the longer the period of time between the riuria should not be treated (LoE 1a).
first and second urine specimen being
obtained, the more likely the second spec- 9.2 Post menopausal women
imen will be negative because of sponta-
neous resolution of bacteriuria. For men, Prospective, randomized comparative tri-
a single voided specimen with ≥ 105 cfu/ als [10] and prospective cohort studies
ml is sufficient to identify bacteriuria [2] [37, 49–51] of asymptomatic bacteriuria
(LoE 2a). If a specimen is collected using in healthy post-menopausal women have
an external condom catheter, the appro- not identified benefits with treatment
priate criteria is ≥ 105 cfu/ml [3–4] (LoE or harms with non-treatment (LoE 1b).
2a). For specimens collected by aspira- In particular, there is no decrease in the
tion of an indwelling catheter, ≥ 105 cfu/ occurrence of symptomatic urinary tract
ml is required to identify bacteriuria infection following treatment of asympto-
(LoE 2b). matic bacteriuria [10].
8.2 Pyuria 9.3 Diabetic women

In younger populations, approximately A prospective, randomized placebo con-
50% of women with asymptomatic bacte- trolled trial of antibiotics or no antibiotics
riuria have accompanying pyuria (1). In for treatment of asymptomatic bacteriuria
older women and men, and in patients in diabetic women of all ages reported no
with underlying genitourinary abnormal- benefits with treatment of asymptomatic
ities, pyuria is present in over 90% of per- bacteriuria [11]. Subsequent episodes of
sons with asymptomatic bacteriuria [13, symptomatic cystitis or pyelonephritis
24]. Thus pyuria does not discriminate and hospitalization attributed to urinary
between symptomatic or asymptomatic tract infection or to any other cause were
infection. not decreased in women who received
308
antimicrobial therapy for bacteriuria. decrease the incidence of symptomatic

There was, however, substantially greater infection [14–15]. While there is short
antimicrobial exposure in the treat- term interruption of bacteriuria, sub-
ment group. A prospective cohort study sequent reinfection is with organisms
of women with type II diabetes reported of increased antimicrobial resistance.
that asymptomatic bacteriuria was not Antimicrobial therapy given during the
associated with an accelerated decline in first 3 to 4 days of catheterization or at
renal function [53]. Other cohort studies removal of a short-term catheter is asso-
have also reported no difference in mor- ciated with a decreased prevalence of
tality or progression of complications of asymptomatic bacteriuria [1]. However,
diabetes in women stratified by bacteriu- concerns with increasing antimicrobial
ria or no bacteriuria [54]. Thus asymp- resistance associated with antimicrobial
tomatic bacteriuria in diabetic women use support recommendations that anti-
should not be screened for or treated. microbials for treatment of asymptomatic
bacteriuria be avoided in catheterized
9.4 Men with asymptomatic patients (LoE 1b).
bacteriuria
There are no prospective, randomized tri- 9.7 Spinal cord injured patients
als of treatment of otherwise healthy men Treatment of asymptomatic bacteriuria
with asymptomatic bacteriuria. However, a does not decrease the prevalence of bac-
prospective cohort study of bacteriuric men teriuria or subsequent symptomatic
at a Veteran’s hospital ambulatory clinic infection in spinal cord injured patients
reported a low risk for subsequent symp- [16–19]. Reinfection occurs rapidly, so any
tomatic infection and spontaneous clearing impact of antimicrobial therapy is lim-
of bacteriuria without antimicrobial treat- ited. Attempts to treat asymptomatic bac-
ment for most episodes [12] (LoE 2b). teriuria are, however, associated with an
increased risk of reinfection with resist-
9.5 Elderly residents of long term ant organisms (LoE 2a).
care facilities
Prospective, randomized trials of treat- 9.8 Urological procedures
ment of asymptomatic bacteriuria in
residents of long term care facilities docu- Trauma to the genitourinary tract when
ment no decrease in symptomatic urinary bacteriuria is present is associated with
tract infection, no decrease in prevalence a high risk of bacteremia and sepsis
or severity of chronic genitourinary symp- [5]. Treatment of asymptomatic bacte-
toms, and no impact on survival with riuria, with the antimicrobial initiated
antimicrobial therapy [1] (LoE 1a). There immediately prior to the procedure, will
are, however, negative outcomes with prevent these complications. Thus, it
attempts to treat asymptomatic bacte- is recommended that prior to an inva-
riuria including increased adverse effects sive genitourinary procedure likely to be
attributed to the antimicrobials, reinfec- associated with trauma (e.g. cystoscopy
tion with organisms of increased antimi- in men, mucosal biopsy, stent insertion,
crobial resistance, and increased cost. transurethral resection of the prostate)
antimicrobial therapy should be given
[5–9] (LoE 1b). Ideally the antimicrobial
9.6 Individuals with indwelling
therapy is targeted towards the infecting
urinary catheters
organism. Clinical trials have repeatedly
Treatment of bacteriuria in subjects with documented that prophylaxis is effective
chronic indwelling catheters does not in preventing post-operative sepsis for
309
men undergoing transurethral resection 10. FURTHER RESEARCH

of the prostate, but studies evaluating
other urologic procedures are limited [1]. Unresolved questions include the man-
It is assumed, however, that the risk of agement of asymptomatic bacteriuria in
sepsis is similar for any procedure likely renal transplant and other immunocom-
to be associated with mucosal bleeding, promised patients. In addition, further
and that antimicrobial therapy will have studies to refine the presentations of
a similar benefit for all these procedures. symptomatic infection in older individu-
als, especially residents in long term care
facilities, are necessary.
9.9 Other patient groups
Renal transplant patients: Prospective
clinical trials have not addressed the 11. CONCLUSIONS
question of whether the treatment
of asymptomatic bacteriuria in renal Asymptomatic bacteriuria is common in
transplant patients is associated with women, and increases with age. In men
improved outcomes in patient morbid- it is common at older ages. For healthy
ity or mortality, or graft survival. In the women, the same risk factors reported
initial 6 months following transplant, for recurrent acute uncomplicated uri-
all patients receive prophylactic antimi- nary infection are also associated with
crobial therapy, usually trimethoprim/ asymptomatic bacteriuria. Screening and
sulfamethoxazole [1]. This is effective in treatment of asymptomatic bacteriuria is
preventing symptomatic and asympto- indicated for pregnant women, and prior
matic urinary infection, as well as other to an invasive genitourinary procedure.
infections. Beyond 6 months, cohort stud- No benefits with screening or treatment
ies do not report an association of asymp- have been identified in other popula-
tomatic bacteriuria with graft survival. tions. Thus, for healthy men and women,
Asymptomatic bacteriuria is common, but asymptomatic bacteriuria should not be
tends to be identified in patients who are screened for and, if present, should not
also experiencing repeated symptomatic be treated. There is also no evidence that
urinary tract infection [55–56]. Thus, treatment of asymptomatic bacteriuria is
these individuals are treated for sympto- beneficial for persons with complicated
matic urinary infection, and screening for urinary infection.
or treatment of asymptomatic bacteriuria
have not yet been shown to have addi-
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|5.3|
Asymptomatic bacteriuria with the

model strain Escherichia coli 83972
protects against symptomatic
Björn Wullt1,2, Fredrik Sundén1
1
Department of Urology, Skåne University Hospital, Malmö
2
Department of MIG, Institute of Laboratory Medicine, Lund University, Lund, Sweden, Word count: 1735
Address for correspondence: Björn Wullt, MD PhD FEBU, Department of Urology, Skåne University Hospital,
205 02 Malmö, Sweden, Tel: +46 46 171994, Fax: +46 46 2112595, bjorn.wullt@med.lu.se
ABSTRACT recurrent UTI. The model strain used

for urinary tract colonization, the ABU
The increasing microbial antibiotic isolate E. coli 83972, causes symptom-
resistance is a cause of major con- free colonizations for long periods of
cern and motivates the development of time in UTI prone patients and with
alternatives to conventional antibiotic dysfunctional voiding. Patients in open
treatment. In recurrent urinary tract long-term colonization studies benefit
infections (UTI), “bacterial interfer- subjectively, and UTI treatments are
ence” has gained interest as a possible rare. Furthermore, placebo-controlled
alternative treatment option. Clinical studies demonstrate a significant delay
trials observing patients with asympto- of UTI episodes in colonized patients
matic bacteriuria has shown that a non- as compared to controls. This report
treatment approach reduces the risk summarizes the clinical data on E. coli
for a subsequent symptomatic infec- 839072 colonization trials.
tion. This observation has prompted
clinical trials with deliberate coloniza- Key words: Recurrent Urinary tract Infec-
tion of the human urinary tract as an tions, Bacterial Interference, Escherichia
alternative approach in patients with coli 83972, Asymptomatic Bacteriuria
Asymptomatic bacteriuria with the model strain | 5.3 |
1. INTRODUCTION The strain used for colonization, the

apathogenic E. coli 83972, was originally
Urinary tract infections are one of the isolated from a girl with long term ABU
most common infections in mankind [9–10] and possesses a documented abil-
and counts for about one tenth of all ity to colonize the human urinary tract
antibiotics prescribed in primary care symptom-free for long periods of time
[1]. Antibiotic treatment is effective in [9, 11–12].
sporadic infections, but when repeated Studies on deliberate E. coli 83972 colo-
courses or long-term prophylactics are nizations in UTI prone patients and with
given in recurrent or complicated cases, bladder dysfunctions were initiated in the
the impact of side effects increases; early 1990’ies at the author’s institution
selection of microbial resistance, gastro- [11, 13]. The accumulated clinical experi-
intestinal disturbances and allergic ence in our centre now covers more than
reactions. In addition, recent data on 70 patient-years in 44 patients. This report
increased frequency of multiple antibiotic describes the clinical outcome and protec-
resistance and its relation to antibiotic tive effect of the colonization approach.
consumption in the society, stresses the
need for alternative approaches in infec-
tious diseases [2–3]. In UTI, alternatives 2. DELIBERATE E. COLI 83972
to antibiotic treatments include antibac- COLONIZATION; PATIENTS AND
terial molecules or peptides, vaccination PROTOCOL
strategies, or “ecological therapy”. Recent
reports have demonstrated antibacte- All patients included in colonization tri-
rial peptides within the urinary tract [4], als have had bladder dysfunctions (lower
and their possible role in the treatment motor neuron lesions or neuropathic blad-
of UTI may be promising in the future. ders due to spinal lesions) in combina-
Vaccine strategies, using different E. coli tion with a history of recurrent UTI (3–4
antigens, have shown interesting results UTI/year, the last two years), resistant to
but have in general not been considered optimal conventional measures including
effective enough [5]. repeated, or long-term low dose, antibi-
“Ecological therapy” refers to bacte- otic treatment. Urodynamics, cystoscopy
rial interference; the microbial interac- and upper urinary tract imaging has been
tion by the competition of nutrients and performed to detect treatable diseases
by the production of toxic molecules. This or dysfunctions. In patients with signifi-
causes a microbial balancing on colonized cant residual urine Clean Intermittent
surfaces as the skin and mucosal orifices, Caterization (CIC) has been initiated.
which is considered a potent defense Patients with recurrent pyelonephritis,
against superinfecting pathogenic bacte- upper urinary tract dysfunctions, renal
ria [6]. Asymptomatic bacteriuria (ABU) calculi, corticosteroid treatment, reduced
may be described as an example of bacte- kidney function, severe co-morbidity, or
rial interference. ABU patients are colo- indwelling urethral catheter have not
nized during long periods of time in the been included.
lower urinary tract with the same strain The isolate used for colonization, E. coli
[7], and if left untreated, superinfection 83972, was isolated from a girl for who
with other strains seems to be hindered had carried this strain for three years
[8]. Based on these data a protocol for without subjective symptoms from the
deliberate colonization of the lower uri- lower urinary tract, and without causing
nary tract in patients with recurrent UTI any kidney damage [9–10]. E. coli 83972
[9] has been developed, with the aim of is extensively characterized genotypically
preventing symptomatic superinfections. and phenotypically [14] and it belongs to
315
non-pathogenic OKH serogroups [9]. Like on host responses in the urinary tract by
many ABU strains it carries the adhesin Wullt and Svanborg [17–19]. All patients
gene clusters, including the pap and fim were followed long-term by monthly urine
gene sequences, but does not express cultures, and by regular interviews. The
fimbriae or functional adhesions on its patients were informed of urinary culture
cell surface, and it has been shown that findings, and if spontaneous clearance
the pap and fim gene clusters carry sig- was observed, given the choice to leave
nificant deletions [15–16]. E. coli 83972 is the study or to be subjected to a repeated
sensitive to all common antibiotics used colonization.
for UTI and it carries a small plasmid, In total, E. coli 83972 bacteriuria was
enabling identification through plasmid registered for 602 months (or 50.2 years)
tests. The ability of the non adherent in the 24 patients. Bacteriuria was estab-
ABU isolate E. coli 83972 to cause long lished in one or more periods exceeding
term bacteriuria in patients with dys- three months in 16 of the 24 patients
functional voiding, but not in patients (67%). Four patients were colonized for
with complete bladder emptying, is well periods between three months and one
documented [11]. year, on one or several occasions, and 12
The colonization follows a standard- patients were colonized for more than
ized protocol [9, 11]; appropriate antibiot- one year, on one or several occasions. The
ics is given to sterilize the urine and after longest observed colonization period was
an antibiotic free interval the patient four years, which was recorded in three
is catheterized, and the bladder is emp- patients.
tied. 30 ml of E. coli 83972 (105 cfu/ml) is Several important conclusions were
instilled in the bladder, and the catheter made on the data achieved. Incomplete
is removed. The procedure is repeated bladder emptying was defined as a
once daily for three days. The success prerequisite for the success of bacte-
of the colonization attempt is proven by rial long-term establishment; transient
repeated urine cultures, and the long- superinfections with uropathogens were
term follow up is performed urine cul- outcompeted by E. coli 83972; there were
tures obtained by first weekly and later no serious side effects such as febrile
monthly intervals. UTI or pyelonephritis reported from any
of the patients [11, 13]. During coloniza-
tion with E. coli 83972, UTI requiring
3. OBSERVATIONAL STUDIES ON antibiotic treatment was recorded in nine
E. COLI 83972 COLONIZATION; cases (0.14 treatments per patient year),
SUMMARY AND RESULTS none of these causing a febrile reaction or
raised CRP [13]. All patients with long-
During a 10-year (1995–2005) period term colonization reported subjective
24 (14 females and 10 males, mean age improvement in terms of fewer symptoms
62, range 44–85 years) patients were from the lower urinary tract, and reduc-
included in open trials to study the effect tion of UTI episodes. In case of sponta-
of deliberate colonization with E. coli neous clearance of the bacteriuria, all
83972. The aims were to determine uro- patients asked for a re-inoculation on one
dynamic factors crucial for stable coloni- or more occasions [13].
zation, and to investigate the influence These observational studies demon-
of bacterial adherence factors (using strated the E. coli 83972 colonization
genetically transformed variants of E. approach to be safe and without sig-
coli 83972) on the host response and bac- nificant side-effects, and the suggested
terial establishment. The result of these protective effect against UTI motivated
studies are further discussed in chapter further randomized controlled trials.
316
Asymptomatic bacteriuria with the model strain | 5.3 |
4. PLACEBO-CONTROLLED STUDIES importance of not treating spontaneously

ON E. COLI 83972 COLONIZATION; developed ABU in patients with dysfunc-
SUMMARY AND RESULTS tional lower urinary tracts. However, in
patients who do not develop ABU and, in
To test the protective effect suggested in spite of a strict treatment regimen, are
the observational studies we conducted subjected to repeated courses of antibiot-
a randomized, blinded placebo-controlled ics due to recurrent UTI, the colonization
study, including a cross-over to enable approach should be considered a possible
group-wise and intra-individual analysis treatment alternative.
[20]. After randomization, patients were Further development of the coloniza-
inoculated either with E. coli 83972 or tion approach is warranted, mainly due
saline, and followed until the first report to two issues. A few patients fail to estab-
of a UTI, or until 12 months follow-up lish E. coli 83972 bacteriuria in spite of
before cross-over. Group-wise and intra- repeated attempts, and spontaneous
individual analysis from the 20 patients clearance of the bacteriuria may occur
who fulfilled the protocol demonstrates a in any patient at any time during colo-
significant delay of reported UTI events nization [11, 13]. The underlying mecha-
in the colonization-arm as compared to nisms explaining colonization resistance
the control-arm. In addition, a second or spontaneous clearance are unknown.
randomized study [21], but without cross- In addition, in rare cases, patients have
over, independently performed, have in reported UTI symptoms while being col-
a group-wise analysis demonstrated that onized with E. coli 83972. To study this,
patients initially colonized had a signifi- the colonization approach in itself offers
cant delay in reporting UTI as compared an excellent research-model of host/
to patients in a placebo-arm. parasite interaction in the human uri-
We conclude that randomized studies nary tract (see also the chapter on host
independently have verified the protec- response in the urinary tract by Wullt
tive effect against UTI of E. coli 83972 and Svanborg). This research should aim
colonization in patients with dysfunc- at identifying molecular mechanisms in
tional voiding and recurrent infections. bacterial adaptation and mucosal toler-
ance in vivo in the human urinary tract.
In the future, possibly discrete altera-
5. DISCUSSION tions of bacterial geno- or phenotypic
characteristics could be performed to
Increasing microbial resistance [2] enhance long-term colonization success in
enforces the medical community to use the individually selected patient.
antibiotic treatment only on strict indica-
tions and to find alternative treatments.
In this review we have demonstrated that 6. CONCLUSIONS
deliberate colonization of the lower uri-
nary tract with E. coli 83972 in patients ABU in patients with incomplete blad-
with dysfunctional voiding and recur- der emptying and UTI susceptibility
rent UTI is safe and without serious should not be treated due the protective
side-effects, and that it protects against effect against symptomatic superinfec-
symptomatic infection episodes. This tions. If ABU does not develop sponta-
has been shown by repeated observa- neously protective ABU may be induced
tional studies [12–13] and by two inde- by deliberate inoculation with the
pendent controlled studies [20–21]. The apathogenic isolate E. coli 83972. The
positive effect by the E. coli 83972 coloni- increasing microbial multi-resistance in
zation approach indirectly underlines the gram-negative uropathogens will make
317
the development of alternative therapies, 11. Wullt, B., et al., Urodynamic factors
including the E. coli 83972 bacteriuria influence the duration of Escherichia coli
approach, more important in the future. bacteriuria in deliberately colonized cases.
J Urol, 1998. 159(6): p. 2057–62.
12. Darouiche, R.O., et al., Pilot trial of bacte-
rial interference for preventing urinary
REFERENCES tract infection. Urology, 2001. 58(3):
p. 339–44.
1. Andre, M., et al., Diagnosis-prescribing 13. Sunden, F., et al., Bacterial interference –
surveys in 2000, 2002 and 2005 in is deliberate colonization with Escherichia
Swedish general practice: Consultations, coli 83972 an alternative treatment for
diagnosis, diagnostics and treatment patients with recurrent urinary tract
choices. Scand J Infect Dis, 2008: p. 1–7. infection? Int J Antimicrob Agents, 2006.
2. Goossens, H., et al., Outpatient antibiotic 28 Suppl 1: p. S26–9.
use in Europe and association with resist- 14. Hull, R.A., et al., Virulence properties of
ance: a cross-national database study. Escherichia coli 83972, a prototype strain
Lancet, 2005. 365(9459): p. 579–87. associated with asymptomatic bacteriuria.
3. Pitout, J.D. and K.B. Laupland, Infect Immun, 1999. 67(1): p. 429–32.
Extended-spectrum beta-lactamase- 15. Klemm, P., et al., Molecular
producing Enterobacteriaceae: an emerg- Characterization of the Escherichia coli
ing public-health concern. Lancet Infect 83972 Asymptomatic Bacteriuria Strain:
Dis, 2008. 8(3): p. 159–66. the Taming of a Pathogen. Infection and
4. Chromek, M., et al., The antimicrobial Immunity, 2006. Jan: p. 781–785.
peptide cathelicidin protects the urinary 16. Zdziarski, J., et al., Molecular basis of
tract against invasive bacterial infection. commensalism in the urinary tract: low
Nat Med, 2006. 12(6): p. 636–41. virulence or virulence attenuation? Infect
5. Naber, K.G., et al., Immunoactive prophy- Immun, 2008. 76(2): p. 695–703.
laxis of recurrent urinary tract infections: 17. Wullt, B., et al., P fimbriae enhance the
a meta-analysis. Int J Antimicrob Agents, early establishment of escherichia coli in
2009. 33(2): p. 111–9. the human urinary tract. Mol Microbiol,
6. Falagas, M.E., P.I. Rafailidis, and G.C. 2000. 38(3): p. 456–64.
Makris, Bacterial interference for the 18. Wullt, B., et al., P-fimbriae trigger
prevention and treatment of infections. mucosal responses to Escherichia coli in
Int J Antimicrob Agents, 2008. 31(6): the human urinary tract. Cell Microbiol,
p. 518–22. 2001. 3(4): p. 255–64.
7. Hansson, S., et al., Untreated asympto- 19. Bergsten, G., et al., PapG-dependent
matic bacteriuria in girls: I – Stability of adherence breaks mucosal inertia and
urinary isolates. Bmj, 1989. 298(6677): triggers the innate host response. J Infect
p. 853–5. Dis, 2004. 189(9): p. 1734–42.
8. Hansson, S., et al., Untreated asympto- 20. Sundén, F., et al., Deliberately induced
matic bacteriuria in girls: II – Effect of E. coli 83972 bacteriuria protects against
phenoxymethylpenicillin and erythromy- recurrent lower urinary tract infections
cin given for intercurrent infections. Bmj, in patients with incomplete bladder emp-
1989. 298(6677): p. 856–9. tying. A blinded randomized placebo-
9. Andersson, P., et al., Persistence of controlled cross-over study. In press,
Escherichia coli bacteriuria is not deter- J Urol, July, 2010.
mined by bacterial adherence. Infect 21. Darouiche, R.O., et al., Bacterial inter-
Immun, 1991. 59(9): p. 2915–21. ference for prevention of urinary tract
10. Lindberg, U., Asymptomatic bacteriuria infection: a prospective, randomized,
in schoolgirls. V. The clinical course and placebo-controlled, double-blind pilot
response to treatment. Acta Paediatr. trial. Clin Infect Dis, 2005. 41(10):
Scand., 1975. 64: p. 718–724. p. 1531–4.
318
Chapter |6|

in children
Chair: Rien J.M. Nijman
CHAPTER OUTLINE
6.2 Classification of urinary tract infections in children 323
6.3 Diagnostic work-up of urinary tract infections in children 328
6.4 Antimicrobial therapy of urinary tract infections in children 344
6.5 Non-operative urological management of
urinary tract infections in children 363
6.6 Medical therapy versus surgery in vesicoureteral
reflux from the view of the paediatrician 374
6.7 Vesico-ureteral reflux: An American pediatric
urologic perspective 392
|6.1|
Introduction
Rien J.M. Nijman
Professor and chair department of Urology, University Medical Centre Groningen, Hanzeplein 1
9713 GZ Groningen, The Netherlands
Tel: +31 50 3613248, Fax: +31 50 3619607, Email: j.m.nijman@uro.umcg.nl
Urinary tract infection in children affects incomplete emptying, and even inconti-
3% of children every year. Throughout nence. In neonates and young children
childhood the risk of a UTI is 8% for girls often non-specific symptoms are the first
and 2% for boys. Sexually active girls indication that a UTI may be present.
experience more UTIs than sexually inac- These can include poor feeding, irrita-
tive girls. However, during the first year bility, lethargy, vomiting, diarrhoea, ill
of life, more boys than girls get UTIs, appearance, and abdominal distension.
with a tenfold increased risk for uncir- Fever and flank pain are unusual symp-
cumcised compared to circumcised boys. toms for lower UTI.
Especially in children younger than Pyelonephritis in the older child typi-
two years, UTIs have been associated cally begins as a lower UTI that proceeds
with significant morbidity and long-term to an upper UTI as the infections ascends.
medical problems, such as hyperten- In neonates and the young child pyelone-
sion, impaired renal function and chronic phritis can also result from hematoge-
kidney disease. Prompt diagnosis and nous spread of infection (e.g. bacteremia).
treatment are critical in preventing the Symptoms that occur with upper UTIs
possible pathologic sequelae of UTIs. overlap those for cystitis, in part because
Paediatric UTIs should be considered cystitis is common in both. In upper
as complicated until proved otherwise. UTIs, flank pain and fevers (>39° C) are
Genitourinary abnormalities should be more pronounced and important.
considered subsequent to a diagnosis of In this chapter specific infections like
UTI, and early diagnosis and accurate fungal infections, tuberculosis, schisto-
management should provide an improved somiasis, viral UTI and xantogranuloma-
long-term prognosis. tous pyelonephritis are not described but
Classic symptoms of cystitis include referred to in different textbooks.
urinary frequency, urgency, dysuria, hae- The main focus will be on classification,
maturia, suprapubic pain, sensation of diagnostic work-up and the relationship
of UTI and vexicoureteral reflux and sub- disease. It often is the first sign of under-
sequent treatment of these problems. lying pathology requiring prompt diag-
Also specific congenital and acquired nosis and treatment, but the long term
diseases that may cause UTI are not results are usually good. While the same
included, partly because they do not need pathology, not presenting with a UTI and
further discussion and partly because therefore undiscovered for a longer time,
these anomalies are not addressed in may in the end have a much worse long-
the literature with particular reference term outcome.
to UTI. Because children with UTI are usually
An interesting topic that will be dis- first seen by a GP or paediatrician before
cussed extensively is the use of pro- being referred to a paediatric urologist,
phylactic antibiotics in children with both specialist’s views and recommenda-
recurrent UTI and/or low grade reflux. tions are included in this chapter. At first
There is growing evidence that the use of sight this may cause some confusion,
antibiotic prophylaxis may not be recom- because of the apparent contradictions
mended in these children. and overlap. But it also provides a bal-
Bladder dysfunction and dysfunctional anced overview, with emphasis on differ-
voiding is an issue that needs special ent issues.
attention. In most studies urinary incon- • UTI is one of the most common bacte-
tinence is the main outcome parameter, rial infections in children.
while UTI is a frequent problem in many • If there is clinical suspicion or a
of these children. Why does an overac- positive urinalysis, a urine cul-
tive bladder cause UTI? Is it the high
ture should always be obtained for
intermittent pressure in the bladder or
diagnosis.
the relatively high voiding pressure with
• After a maximum of two UTI epi-
subsequent damage to the urethral epi-
sodes in a girl and one episode in a
thelium causing infection or does it have
boy, further investigations should be
to do with the fact that during increased
undertaken.
bladder pressure the bladder neck opens
• A DMSA scan is the gold standard to
and closes again with the so-called milk-
determine renal scarring.
ing back phenomenon as a consequence
• The main objective of the treatment
that is responsible for recurrent UTI? In
is the elimination of symptoms in the
children with dysfunctional voiding and
acute episode and the prevention of
post void residual urine, it is believed
renal impairment in the long term.
that the incomplete emptying is responsi-
• Prophylactic antibiotics may be used
ble for the UTI, but not all children with
to reduce the risk of recurrent UTI,
residual urine develop UTIs. The changed
but there is growing evidence that
bladder dynamics may play a role, but at
efficacy is poor, except in children
the same time bladder urothelium may be
with dilating VUR and other forms of
different as well, allowing an increased
bacterial colonisation. Although we have obstructive uropathy.
acquired much knowledge about these
problems, there are still many unre- REFERENCES
solved issues and the actual answers are
lacking. 1. Qigley R. Diagnosis of urinary tract infec-
Although the occurrence of a UTI, espe- tions in children. Current Opinion in
cially in the very young, may have a seri- Pediatrics 2009; 21: 194–198.
ous impact on the child and its parents, it 2. Riccabona M. Urinary tract infections
is important to realise that it serves as a in children. Current Opinion in Urology
‘revealing’ symptom rather than a serious 2003; 13: 59–62.
321
Chapter |6| Urinary tract infections in children
3. Mori R, Lakhanpaul M, Verrier-Jones K. 5. Luk WH, Woo YH, Au-Yeung AWS, and
Diagnosis and management of urinary Chan JCS. Imaging in pediatric urinary
tract infection in children: summary of tract infection: A 9-year local experience.
NICE guidance. BMJ 2007; 335: 395–7. AJR 2009; 192: 1253–60.
4. Kass EJ, Kernen KM, Carey JM. 6. Zorc JJ, Kiddoo DA, and Shaw KN.
Paediatric urinary tract infection and the Diagnosis and management of pediatric
necessity of complete urological imaging. urinary tract infections. Clin Microbiol
BJU Int 2000; 86(1):94–6. Rev 2005; 18: 417–22.
322
|6.2|
Classification of urinary tract

infections in children
Chang-Hee Han, Sang Don Lee
Chang Hee Han, MD, Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea
Tel: +82-31-820-3546, Fax: +82-31-847-6133, E-mail: urohan@catholic.ac.kr
Sang Don Lee, MD, Department of Urology, School of Medicine, Pusan National University, Yangsan, Korea
Tel: +82-55-360-2671, Fax: +82-55-360-2164, E-mail: lsd@pusan.ac.kr
ABSTRACT or the existence of complicating factors

(uncomplicated versus complicated) is
In infants and children, urinary tract useful to differentiate children with UTI
infection (UTI) is one of the most com- whether they are at risk of renal damage
mon bacterial infections. The ultimate or not (GoR B).
goal of treatment is the preservation of
kidney function. Many classification sys-
tems have been introduced to differenti- 1. INTRODUCTION
ate children with UTI whose kidneys are
at risk or not. The classification system The classification of urinary tract infec-
presented here is synthesized from other tion (UTI) is complex for historical rea-
systems and may be used in practice to sons, and many classification systems
reach this aim. exist. UTIs can be classified by the site
Key words: UTI, child, classification of infection (lower tract versus upper
tract), by the number of episodes (first
versus recurrent), by severity (simple ver-
SUMMARY OF RECOMMENDATIONS sus severe), by the presence of symptoms
(asymptomatic versus symptomatic), or
Classification according to the site of by the existence of complicating factors
infection (lower tract versus upper tract), (uncomplicated versus complicated)
the number of episodes (first versus recur- (Table 1). Such classifications imply sever-
rent), the severity (simple versus severe), ity of infection when, in fact, this cannot
Table 1 Classifications of urinary tract infections (UTIs) in

3. CLASSIFICATIONS
children.
For practical purposes five classification
1. Classification according to site systems, based on the natural history and
Lower urinary tract (cystitis) subsequent evaluation and management
Upper urinary tract (pyelonephritis) which imply the complication possibility,
2. Classification according to episode (risk of are widely used.
complication)
First infection 3.1 Classification according to
Recurrent infection site of UTIs
Unresolved Understanding and appropriately differ-
Persistence infection entiating cystitis from pyelonephritis is
Reinfection
crucial and imperative for two reasons:
a) to permit identification, treatment, and
3. Classification according to severity (risk of evaluation of children who are at risk for
complication)
kidney damage; and b) to avoid unneces-
Simple UTIs sarily evaluating and treating children
Severe UTIs who are not at risk.
4. Classification according to symptoms
Asymptomatic bacteriuria 3.1.1 Cystitis
Symptomatic bacteriuria Cystitis is an inflammatory condition of
the urinary bladder. General signs and
5. Classification according to complicating factor (risk of
complication) symptoms of cystitis include dysuria, fre-
quency, urgency, malodorous urine, enu-
Uncomplicated UTIs
resis, haematuria, and suprapubic pain.
Complicated UTIs
3.1.2 Pyelonephritis
be documented clinically and “milder” Pyelonephritis is a diffuse pyogenic infec-
infections may require less rigorous tion of the renal pelvis and parenchyma.
evaluation. The onset of pyelonephritis is generally
abrupt. Clinical signs and symptoms
2. METHODS include fever (38.5°C or greater), chills,
along with costovertebral angle or flank
We performed a systemic literature pain and tenderness. Older children may
search in Medline from 1989 to 2008 report cystitis symptoms, such as strong
using the key word UTI with the follow- smelling urine, dysuria, urgency, and
ing limitations: English publications, frequency along with the fever and flank
human studies, review, 0–18 years old. pain. Infants and children may have
A total of 86 publications were found and nonspecific signs such as poor appetite,
screened by title and abstract. Finally failure to thrive, lethargy, irritability,
30 publications were included into this vomiting or diarrhoea.
review. We also reviewed textbooks to
provide relevant background and context
3.2 Classification according to the
for this analysis.
number of UTI episodes
All studies were rated according to
the level of evidence and the recommen- These infections are categorized as first
dations graded to strength according to infection and recurrent infection. The
ICUD standards [1–2]. recurrent UTIs can be subcategorized
324
Classification of urinary tract infections in children | 6.2 |
further as unresolved bacteriuria, bacte- Table 2 Surgically correctable causes of bacterial

rial persistence, or reinfection [3–6]. persistence in children.
3.2.1 First infection Infection stones

Infected nonfunctioning or poorly functioning kidneys or
This is simply the first UTI that is diag- renal segments
nosed. In infants and children, first infec-
Infected ureteral stumps after nephrectomy
tions are considered complicated because
of the potential association with anatomic Vesicointestinal or rectourethral fistula
anomalies. A high prevalence of anatomic Vesicovaginal fistula
anomalies occurs in children and may pre- Infected necrotic papillae in papillary necrosis
dispose them to complications of UTI and
Unilateral medullary sponge kidney
potential renal damage. Therefore, infants
Infected urachal cyst
and children with first infections should
undergo anatomical evaluation [4]. Infected urethral diverticulum or periurethral gland
Dilating vesicoureteral reflux
3.2.2 Recurrent infection Obstructive uropathy (urethral valves, UPJ obstruction etc)
3.2.2.1 Unresolved infection
Unresolved infection indicates that initial usually found early in children because
therapy has been inadequate in eliminat- imaging is performed after the first UTI.
ing bacterial growth in the urinary tract. The treatment options are more compli-
It may be caused by inadequate therapy cated and often require surgical correc-
related to bacterial resistance to the tion of underlying abnormalities with
selected therapeutic agent, inadequate extirpation of the nidus.
antimicrobial urinary concentration
owing to poor renal concentration or gas- 3.2.2.3 Reinfection
trointestinal malabsorption, or an infec- Re-infection is different from bacterial
tion involving multiple organisms with persistence. In re-infection, each episode
differing antimicrobial susceptibilities. It can be caused by a variety of new infect-
can usually be treated successfully once ing organisms, whereas in bacterial per-
proper culture and antimicrobial sensitiv- sistence, the same infecting organism
ity patterns are available. is always isolated. Re-infection most
frequently occurs by the faecal-perineal-
3.2.2.2 Bacterial persistence
urethral route in girls and periurethral
Bacterial persistence is different from colonization in boys. Confusion in this
unresolved infection. It is caused by re- form of pathogenesis sometimes occurs
emergence of bacteria from a site within because Escherichia coli, the most com-
the urinary tract and may be due to a mon general pathogenic species, occur in
nidus for persistent infection that cannot many different serotypes; thus, recurrent
be eradicated. As a result, the same path- Escherichia coli UTI does not equate to
ogen is identified in recurrent infections, infection with the same organism. With
but episodes of sterile urine may occur serotyping, re-infection can be estab-
during and shortly following antimicro- lished, but this is rarely done in the rou-
bial treatment. Bacterial micro-organisms tine clinical setting.
reside in an isolated portion (or anomaly)
of the urinary tract where the pathogens
3.3 Classification according to
are shielded from the current treatment,
severity of UTIs
resulting in a persistent nidus of infection
(e.g. infected stones, Table 2) [3]. Sources From the clinical point of view, sim-
of urinary tract bacterial persistence are ple and severe forms of UTIs should be
325
differentiated because to some extent the (pyelonephritis). Cystitis may represent

severity of symptoms dictates the degree early recognition of an infection destined
of urgency with which investigation and to become pyelonephritis, or bacterial
treatment are to be undertaken (Table 3). growth controlled by a balance of viru-
lence and host response.
3.3.1 Simple UTI
3.5 Classification according to
A child with a simple UTI may have only
complicating factor
mild pyrexia, but is able to take fluids and
oral medication. The child is only slightly Useful criteria for distinguishing compli-
or not dehydrated and has a good expected cated from uncomplicated UTI is summa-
level of compliance. When a low level of rized in Table 4 [7].
compliance is expected, such a child should
be managed as one with a severe UTI. 3.5.1 Uncomplicated UTI
Uncomplicated UTI describes infection
3.3.2 Severe UTI in a patient with a morphologically and
Severe UTI is related to the presence of functionally normal urinary tract. This
fever of > 39ºC, the feeling of being ill, category includes mostly isolated or
persistent vomiting, and moderate or recurrent bacterial cystitis and is usu-
severe dehydration. ally associated with a narrow spectrum
of infecting pathogens which are eas-
3.4 Classification according to ily eradicated by a short course of oral
symptoms antimicrobial agents. Patients can be
managed on an outpatient basis, with
This classification system is based on the emphasis on documenting resolution
existence of local or systemic symptoms.
3.4.1 Asymptomatic bacteriuria Table 4 Clinical classification of pediatric urinary tract

infections (UTIs) according to complicating factor.
Asymptomatic bacteriuria indicates
attenuation of uropathogenic bacteria by History Complicated Uncomplicated
the host, or colonization of the bladder by UTI UTI
nonvirulent bacteria incapable of activat- Age <3 mo >3 mo
ing a symptomatic response.
Systemic symptoms + –
Known urologic + –
3.4.2 Symptomatic bacteriuria (UTI) anomaly
Symptoms associated with UTI include Physical
+ –
irritative voiding symptoms, suprapu- examination
bic pain (cystitis), fever and malaise Fever
+ –
+ –
Flank pain
Table 3 Clinical classification of pediatric urinary tract Abdominal or flank
infections (UTIs) according to severity. mass + –
Laboratory findings + –
Severe UTI Simple UTI
Unusual pathogen + –
Fever >38.5°C Mild pyrexia
Azotemia +
Persistent vomiting Good fluid intake Leukocytosis
Serious dehydration Slight dehydration Radiologic
indication
Poor treatment compliance Good treatment
compliance of obstruction
326
Classification of urinary tract infections in children | 6.2 |
of their bacteriuria followed by elective first versus recurrent, simple versus

evaluation for potential anatomic or func- severe and uncomplicated or complicated
tional abnormalities of the urinary tract. UTI) are widely used. Such classifications
are based on the natural history and sub-
3.5.2 Complicated UTI sequent evaluation and management
All neonates, most patients with clini- which imply the complication possibility.
cal evidence of pyelonephritis, and all
children with known mechanical or func-
tional obstructions of the urinary tract REFERENCES
are considered to have complicated UTI.
Mechanical obstruction is commonly due to 1. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of
the presence of posterior urethral valves,
the main steps for developing and grading
strictures or stones. Functional obstruction
guideline recommendations. Prog Urol,
often results from neurogenic bladder dys- 2007. 17(3): 681–4.
function or dilating vesicoureteral reflux. 2. U.S. Department of Health and Human
Patients with complicated UTI require Services Public Health Service Agency for
hospitalization and parenteral antibiotics. Health Care Policy and Research, 1992:
Prompt anatomic evaluation of the urinary 115–127.
tract is critical to exclude the presence of 3. Shortliffe LMD, Infection and inflamma-
significant abnormalities. If mechanical tion of the pediatric genitourinary tract in
or functional abnormalities are present Campbell-Walsh urology, Campbell MF,
adequate drainage of the infected urinary Wein AJ, and Kavoussi LR, Editors. 2007,
tract is necessary. Saunders Elsevier: Philadelphia, Pa. ;
[Edinburgh]. p. 3232–3268.
4. Shortliffe LMD, Shinghal R, and Seto
4. FURTHER RESEARCH EH, Pediatric urinary tract infections,
in Pediatric urology, Gearhart JP, Rink
Large epidemiological studies have fur- RC, and Mouriquand PDE, Editors.
thered our understandings of paediatric 2001, W.B. Saunders Co: Philadelphia.
UTI. The goal of current practice is the p. 237–258.
early detection of urinary tract pathology 5. Schaeffer AJ, Urinary tract infections, in
and prevention of renal damage. For this Adult and pediatric urology, Gillenwater
JY, Grayhack JT, Howards SS, and
purpose several classification systems
Mitchell ME, Editors. 2002, Lippincott
have been introduced. However, most Williams & Wilkins: Philadelphia, Pa. ;
of the various aspects used for the clas- London. p. 211–272.
sification of UTI in children are not yet 6. Ma JF and Shortliffe LM, Urinary tract
validated in prospective clinical studies, infection in children: etiology and epide-
which should be done in the future miology. Urol Clin North Am, 2004. 31(3):
517–26, ix–x.
7. Burns MW, Burns JL, and Krieger
5. CONCLUSIONS JN, Pediatric urinary tract infection.
Diagnosis, classification, and significance.
For practical purposes four classification Pediatr Clin North Am, 1987. 34(5):
systems (lower tract versus upper tract, 1111–20.
327
|6.3|
Diagnostic work-up of urinary

tract infections in children
Martin Westenfelder, Rolf Beetz
Prof. Dr. med. Martin Westenfelder, Zentrum für Kinderurologie und plastisch rekonstruktive Urologie, HELIOS Klinikum
Krefeld, Lutherplatz 40, 47805 Krefeld
Tel. +49 2151 32 2281, Fax +49 2151 32 2018, E-Mail: martin.westenfelder@helios-kliniken.de
PD Dr. med. Rolf Beetz, Paediatric Nephrology, Center for Paediatric and Adolescent Medicine, University Medical Clinic,
Langenbeckstr.1, 55131 Mainz
Phone +41-6131-17 3937, Fax +41-6131-17 6426, e-mail: beetz@kinder.klinik.uni-mainz.de
ABSTRACT At this point, in most cases, it should

be clear whether there is a significant
Diagnosis of UTI in children should be infection and a clinical risk associated. If
straightforward, clarifying the existence infection is verified, calculated antibacte-
of infection and the risk of a given infec- rial treatment can be started.
tion. It is initially important to consider The main problems arise when clinical
clinical signs and symptoms, to get the signs and symptoms are misinterpreted,
medical history (primary-, secondary-, genitalia are not inspected and urine is
febrile-, a febrile- infection, constipation) not collected properly. Whereas unnec-
and, following inspection of the genitalia, essary antimicrobial treatment is a nui-
to carefully collect a specimen of urine. sance, disturbing medical history and
This is followed by a thorough inves- correct diagnosis, the delay of necessary
tigation with analysis of the freshly antimicrobial treatment can be delete-
obtained native urine using dipstick rious. There is no need to restrict treat-
and (preferably) a phase contrast micro- ment until results of bacteriological and
scope which reveals the whole spectrum serological tests confirm infection.
of corpuscular elements occurring dur- At least in infants and young children,
ing infection: bacteria, leucocytes, eryth- ultrasonography of kidneys and uri-
rocytes, epithelial cells from bladder or nary tract as part of primary diagnostics
kidney, leukocyte cylinders (indicative for should be performed to rule out urinary
pyelonephritis), elements which indicate obstruction, calculi and/or pyonephrosis,
contamination and bacteriological culture especially if pre- or postnatal ultrasound
of urine (and blood). screening has not been done before. This
Diagnostic work-up of urinary tract infections in childrens | 6.3 |
is also true in cases where antibiotic after two UTI episodes in girls and
treatment does not lead to efficient reso- one in boys (GoR B).
lution of symptoms. 3. In children wearing diapers it is first
Secondary diagnosis of the etiol- recommended to inspect and clean the
ogy of a given UTI in children should genitalia, apply a urinary collecting
be planned carefully to prevent over- or bag and proceed with further investi-
underdiagnosis. gations (GoR C).
Vesicoureteral reflux is regarded a risk
4. Urine analysis reveals infecting bac-
factor for renal damage with urinary
tract infections. Therefore, its detection teria (through culture) and an inflam-
has an impact on further treatment and matory response (microscope and
prophylactic strategies. dipstick test). However, urine has to
Whether a DMSA-scan should be done be collected under defined conditions
primarily to verify parenchymal involve- and investigated without delay. Plastic
ment justifying X- ray investigations such bag- and midstream urine require
as VCUG or whether VCUG should be the cautious interpretation, whereas urine
primary investigation to identify reflux obtained by suprapubic aspiration or
is still controversial. Pyelectasy, rarified catheterization give reliable results
parenchyma, dilated ureters, thick walled (GoR B).
bladders, residual urine and renal dupli- 5. C-reactive protein (CRP), urinary
cation require detailed morphological and N-acetyl-ß-glucosaminidase (NAG)
functional investigations of the urinary and Serum-Procalcitonin are widely
tract in order to obtain a clear diagno- used as markers for pyelonephritis
sis. Only after this does it become clear (GoR B) but have a lower sensitivity
whether it is a complicated or uncompli- and specifity than the DMSA-scan.
cated infection requiring prophylaxis or 6. Presence or absence of severe anoma-
surgery. lies of the kidneys and urinary tract
We are still a long way from under- can be predicted with high accuracy
standing all mechanisms leading to UTI; by ultrasonography (GoR A).
however we are well able to prevent paren-
7. When indicated, VCUG is used to
chymal loss if infection is detected early.
detect VUR and to visualize the blad-
Key words: diagnosis of UTI in chil- der and urethra. VUR can also be
dren, urine analysis, leukocyte esterase, detected by sonographic techniques
quantification of bacteriuria, imaging of using contrast medium or direct and
the urinary tract, radionuclide studies, isotopic cystography with comparable
urodynamic evaluation, endoscopy, inves- sensitivity.
tigative strategies in UTI 8. Radionuclide studies are used to
investigate: i) renal function and
obstruction (mercaptoacetyltriglycine
SUMMARY OF RECOMMENDATIONS (MAG-3) or ii) parenchymal loss and
scar formation DMSA-Scan: Tc-99m or
1. Considering that clinical signs and iii) reflux, indirect radionuclide cystog-
symptoms vary with age, differentiat- raphy (GoR B).
ing between a first (primary) episode 9. Excretory urography is needed only
and recurrent infection is important in those cases where morphology can-
(GoR C). not be clarified by other techniques,
2. Further investigation such as ultra- e.g. renal duplication, and where MRI
sonography, VCUG and possibly of the urinary tract is not available
Isotope-studies should be undertaken (GoR C).
329
10. Urodynamic evaluation is used UTI [3–4] (LoE 3 and 2a). The incidence
when voiding disorders or bladder changes after the first year, being 3% in
hypo/hyperactivity is suspected. girls and 1.1% in boys [5] (LoE 3). Young
In most cases, it can be restricted age and the length of the urethra therefore
to uroflowmetry, flow- EMG and are not main risk factors for UTI.
sonographic measurement of resid- The outcome of a UTI is usually
ual urine, whereas a neurogenic benign, but it can progress to renal
bladder requires complete evaluation scarring especially when pyelonephri-
(GoR B). tis remains untreated over several days
11. Endoscopy has no place in the evalu- [6–7]. Although older children may have
ation of acute infections (GoR C). less risk of scarring from infection than
Only in a limited number of chil- those younger than five years of age, vul-
dren may it be helpful to clarify the nerability for scarring persists at least
underlying pathology. until puberty (10 to 15 years) [8–9] (LoE
3 and 2a). In most children with UTI in
whom renal scars are found, the scars are
found on the first set of imaging studies
1. INTRODUCTION and remain unchanged regardless of the
child’s future clinical course [10] (LoE
Bacterial UTIs only occur when special- 2b). Therefore dependent on age, sex and
ized (mostly virulent) uropathogenic whether the infection is febrile or non-
bacteria invade the urinary tract (UT), febrile, primary (first presenting clinical
multiply faster than they are eliminated infection) or secondary (second or recur-
and induce an inflammatory response. rent infection), the urgency of diagnosis
This is usually prevented by a multitude varies.
of mechanisms which interfere with inva-
sion, multiplication and damaging inflam-
matory reactions such as scar formation 2. METHODS
in the kidney.
In principle, UTI in children and adults A systematic literature search was
are comparable; however there are sig- performed up to 1997 in MEDLINE,
nificant differences requiring a different Cochrane and in specific literature using
approach concerning the imminence and the following key words: UTI in children,
urgency of detecting the risk involved in incidence, aetiology, pathogenesis, course
a given UTI. of, diagnosis, with the following limita-
UTI in children is less common than in tions: children up to 14 years; an English
adults and more common in boys (3.7%) abstract had to be available. The authors
than in girls (2%) in the first year of life also had continuously observed the rele-
[1] (LoE 3). By one year of age, 2.7% of vant literature concerning the topic dur-
boys and 0.7% of girls have had bacteriu- ing the last 30 years. Only peer reviewed
ria [2] (LoE 3). articles were included. A total of more
This is partially due to primary infec- than 200 publications were identified,
tions especially during the first three which were screened by title and abstract.
months, which occur in the presence of After exclusion of duplicates and insignif-
severe congenital anomalies as megau- icant articles, a total of 64 were included
reters, vesicoureteral reflux (VUR) and into the review.
urethral valves, intensified when combined The studies were rated according to the
with phimosis. During that period uncir- level of evidence (LoE) and the grade of
cumcised boys have a 10 times greater recommendation (GoR) using ICUD
risk than circumcised boys of having a standards (for details see Preface) [11–12]
330
3. MEDICAL HISTORY AND CLINICAL suprapubic, abdominal or lumbar pain

FINDINGS may be present.
Bacterial epididymitis is rare and
The process leading to the diagnosis of UTI only occurs in combination with signifi-
should be straightforward. Clinical appear- cant UTI or renal duplication and ectopic
ance in combination with medical history, ureters, or due to urethral strictures.
physical examination and ultrasound, com- However, scrotal pain and inflammation
pleted by urine analysis, leads to the sus- in a boy is primarily indicative for testic-
picion of UTI. If the child is in diapers it is ular torsion, or torsion of a hydatide.
helpful to inspect and clean the genitalia
and apply a urinary collection bag before 3.3 Physical examination
further investigations. Often the bladder
is emptied during investigation and urine Physical examination includes a gen-
can be analyzed immediately. eral examination of throat, lymph nodes,
abdomen (constipation) and temperature.
The absence of fever does not exclude
3.1 Medical history UTI. Examination may reveal a palpable
The most important questions are and painful kidney, palpable bladder, phi-
whether this is a primary (first) or sec- mosis, labial adhesion, vulvitis, epididy-
ondary (recurring) infection and if there mo-orchitis, and stigmata of spina bifida
are indications for possible malforma- or sacral agenesis.
tions of the UT e.g. pre- or postnatal
ultrasound screening, family history and
whether there is constipation or signs of 4. URINE ANALYSIS
voiding dysfunction.
Diagnosis of urinary tract infection
depends on detection of bacteria and an
3.2 Clinical signs and symptoms inflammatory response in the urinary
These may vary with age and severity of tract, preferably by a significant positive
the disease. Neonates with pyelonephritis urine culture [16–17] (LoE 4 and 1a).
or even urosepsis may present with non-
specific symptoms, i.e. failure to thrive, 4.1 Urine sampling
jaundice, hyperexcitability and without
Urine has to be collected under defined
any fever. In small children, UTI may
conditions and investigated without
present as gastroenteritis with jaundice,
delay.
vomiting, not drinking, diarrhea, exsicca-
tion. 13.6% of patients with fever have a
UTI [13] (LoE 3). Among febrile infants 4.1.1 Midstream urine (MSU)
(younger than eight weeks of age), the In toilet-trained children and adoles-
prevalence of UTI has been found to be cents, mid stream urine can be obtained.
13.6%, with the majority of infections The child is instructed to spread the labia
occurring in male infants. Fever accounts (for girls) or retract the foreskin (for non-
for about 20% of paediatric office vis- circumcised boys), to clean the urethral
its [14] (LoE 4) and UTI causes 4.1% to meatus and perineum with gauze and liq-
7.5% of these febrile episodes [15] (LoE uid soap twice, to urinate into the toilet,
4). Septic shock is unusual, even with and, midway through urination, to col-
very high fever. Signs of a UTI may be lect the urine in a sterile container [18].
vague and unspecific in small children, Urine contamination rates are higher in
but later on, when they are older than midstream urine that is collected from
two years, frequent voiding, dysuria and toilet-trained children when obtained
331
without perineal/genital cleaning [18]. from a bag urine collection is useful

Collection after cleaning the genitalia is for dipstick urinalysis and microscopic
reliable when dipstick test and (phase evaluation [22]. Nevertheless, bag urine
contrast) microscopy is taken into consid- specimens should not be used for culture,
eration [19] (LoE 1a). where possible [23].
4.1.2.2 Clean-catch urine collection
4.1.2 Urine sampling in infants and
Instead of bag urine, the clean catch
non-toilet trained children
technique is equally non-invasive and
Obtaining urine samples from non-toilet has been reported to have a false-pos-
trained children (i.e., younger than three itive rate of 5% and a false-negative
years of age) involves four main methods rate of 12% in infants [24]. The infant
with varying contamination rates and is placed in the lap of a parent or nurs-
invasiveness. ing staff member, who holds a sterile
foil bowl underneath the infant’s genita-
4.1.2.1 Plastic bag attached to the cleaned lia. The infant is offered oral fluids, and
genitalia urine collection is awaited [24]. Some
This technique is most often used in daily authors have found a good association
practice for infants and young children in results of culture of urine obtained by
who are not toilet-trained. If an ultraclean-catch urine collection and suprapu-
sonography is planned as a part of the bic aspiration (24). However, this method
initial diagnostic, the urine collection bag is time consuming and it needs proper
should be applied before performing it, instruction of parents. Therefore, it can-
since the bladder may be emptied during not be recommended as a routine method
the investigation. for daily practice.
Dipstick negative for both leucocytes
and nitrite or microscopic analysis nega- 4.1.2.3 Bladder catheterization
tive for both pyuria and bacteriuria of a Transurethral catheterization is reliable
bag urine specimen may reasonably be but traumatic, especially in boys, and
used to rule out urinary tract infection bears the risk of nosocomial infection
[20]. However, prospective studies show [15, 25] (LoE 4). However, in experienced
a high incidence of false-positive results, hands this technique may be an alterna-
ranging from 85–99% [16, 19] (LoE 1a tive for suprapubic bladder aspiration,
and 4) if the genitalia are not cleaned even in newborns and non-toilet trained
and if the culture is delayed. In respect infants and children [26].
to bacteriuria it is only helpful when the
culture is negative [16, 19] (LoE 1a and 4.1.2.4 Suprapubic bladder aspiration
4) and has a positive predictive value of Before attained bladder control the most
15% [21] (LoE 4). However, in combina- sensitive method for obtaining an uncon-
tion with (phase contrast) microscopy taminated urine sample is suprapubic
and dipstick test, accuracy and predictive bladder aspiration. The success rate
value is approximately 80% higher [21] regarding sufficient urine sample volumes
(LoE 4). Due to the high contamination is best if ultrasound is used for the assess-
rate and the less than favorable risk pro- ment of bladder filling. In neonates, use of
file, the American Academy of Pediatrics ultrasound guidance simplifies suprapu-
concluded that bag urine specimens are bic aspiration and improves the diagnostic
not useful for diagnosing UTI and should yield of obtaining a urine specimen from
always be followed up with another 60% to almost 97% [27–28]. Complications
method in young children to confirm the of suprapubic bladder aspiration are
diagnosis [15]. However, urine obtained extremely rare and have been reported to
332
be 0.22%, ranging from transient haema- all uropathogens reduce nitrate to nitrite,
turia to bowel perforation [29] e.g. Enterococci, Pseudomonas aeruginosa.
When an infection is caused by Gram-
4.2 Microscopic urine investigation positive bacteria, the test may be negative
[16]) (LoE 4). In cases of high diuresis and/
This is a fast method to get information on or frequent voiding even nitrite-producing
the intensity of a given infection. Freshly pathogens may show a negative test result,
obtained native urine (uncentrifuged) is due to the short transit time in the blad-
investigated (preferably) with a phase der. Whereas contaminated urine, stored
contrast microscope. The whole spectrum too long at a higher temperature before
of corpuscular elements occurring dur- cultivation, may be falsely positive.
ing infection can be identified: bacteria, The nitrite test has a sensitivity of
leucocytes, erythrocytes, epithelial cells only 45–60%, but a very good specificity
from bladder or kidney. Presence of leu- of 85–98% [16, 31] (LoE 4 and 3).
kocyte cylinders is indicative for pyelone-
phritis. The microscopic identification of
bacteria in the urine is more sensitive and 4.3.2 Leukocyte esterase
specific for diagnosing UTI than identi- Leukocytes produce leukocyte esterase.
fication of pyuria [30–31] (LoE 4 and 3). The test for leukocyte esterase has sen-
Identification of bacteria under high dry sitivity of 48–86% and a specificity of
magnification (450× to 570×) represents 17–93% [16, 31, 33–34] (LoE 4, 3, and
about 30,000 bacteria per millilitre. In 1a). Nitrite and leukocyte esterase test-
girls leucocyturia of up to 20 leucocytes/µl ing improve sensitivity and specificity,
are considered to be normal, up to 50/µl but carry the risk of false-positive results
are suggestive, and over 50/µl are indica- [33] (LoE 1a). Bacteriuria without pyuria
tive for infection. In boys older than three is found in 0.5% of mid stream specimens
years leucocyte counts of more than 10/µl and may be due to contaminated urine or
are considered to be pathological [30–31] asymptomatic bacteriuria [33] (LoE 1a).
(LoE 2b and 3). The analysis of urine sam- In febrile children with positive urine
ples obtained by catheter for the presence culture and absence of pyuria urinalysis
of significant pyuria (>=10 white blood should be repeated after 24 hours to clar-
cells/ mm3) can be used to guide decisions ify the situation. Pyuria without bacteriu-
regarding the need for urine culture in ria may be due to antimicrobial treatment,
young febrile children [32]. urolithiasis, foreign bodies, past sur-
gery, infections caused by Mycobacterium
4.3 Dipstick test tuberculosis and other fastidious bacteria,
e.g. Chlamydia trachomatis.
Dipstick tests are readily available and
Thus, neither bacteriuria nor pyuria are
easy to perform. They provide informa-
reliable parameters for UTI [35] (LoE 2a).
tion about the presence of biochemical
However, according to Landau et al. [36]
markers in urine indicative for UTI [16]
(LoE 2a), pyuria in febrile children is indic-
(LoE 4). If both, nitrite and leukocyte
ative of acute pyelonephritis. In neonates
esterase tests are positive, in combination
and children under six months of age, pyu-
with the clinical symptoms, UTI is most
ria, bacteriuria and the nitrite test, sepa-
likely [31, 33] (LoE 3 and 1a).
rately, have minimal predictive value for
UTI [37–38] (LoE 2b and 4). With a posi-
4.3.1 Nitrite tive predictive value of 98%, pyuria with a
Nitrates from the metabolism of most positive nitrite test is more reliable in older
Gram-negative bacteria are degraded to children for the diagnosis of UTI than in
nitrite which can be detected. However, not infants and younger children, [34] (LoE 3).
333
4.4 Microbiology mm3 and > 50,000 cfu/mL in a specimen

What constitutes a “significant” UTI is collected by catheterization are signifi-
unclear. It is controversial whether “colo- cant for a UTI and discriminates between
nization” represents specimen contami- infection and contamination [32, 34, 37]
nation or asymptomatic benign infection. (LoE 3 and 2b).
In severe UTI however more than 105
cfu/mL can be expected. Nevertheless 4.5 Strategy of urine sampling and
the count can vary and be related to the investigation in infants
method of specimen collection, diuresis, Urine cultures by catheterization or
time and temperature of storage until suprapubic aspiration are necessary to
cultivation occurs [17] (LoE 1a). detect urinary tract infections in infants
and non-toilet trained children. However,
4.4.1 Significant bacteriuria these methods are inconvenient and are
The classical definition of more than 105 not accepted in every situation by par-
cfu/mL of voided urine is still used [31, ents and first care physicians. Strategies
38] (LoE 1a and 3) and is the traditional to rule out a UTI from bag or clean catch
definition for a clinically significant UTI urine samples would be useful in daily
[39] (LoE 4). practice. The AAP practice parameter
Other studies have shown that 10,000 for the diagnosis, treatment, and evalu-
or fewer organisms on a voided specimen ation of the initial UTI in febrile infants
may indicate a significant UTI [35, 40] and young children therefore suggests
(LoE 2a and 2b). In MSU or in urine from two options for managing the infant or
a collection- bag more than105 cfu/mL is young child (aged two months to two
considered to be positive [21]. years) with unexplained fever that is
assessed as not being so ill as to require
4.4.2 Urine obtained by catheterization immediate antimicrobial therapy. One
option is immediate suprapubic bladder
For urine obtained by catheterization, a puncture or catheterization; the other is
culture of 104 cfu/mL and more culture is to “obtain a urine specimen by the most
considered to be positive. convenient means and perform a uri-
nalysis. If the urinalysis suggests a UTI,
4.4.3 Urine obtained by suprapubic obtain and culture a urine specimen, col-
aspiration lected by suprapubic bladder aspiration
In urine obtained by suprapubic aspi- or transurethral catheterization” [15]. If
ration any counts are considered to be the urinalysis is negative, then the AAP
significant. However, counts lower than suggests that it is “reasonable to fol-
10³ cfu/ml are unusual. The presence of low the clinical course without initiating
pyuria (more than 10 leucocytes per µl) microbiological therapy” [15]. There are
and bacteriuria in a fresh urine sample currently no new data to motivate any
will reinforce the clinical diagnosis of changes to this recommendation.
UTI [31–32] (LoE 3). Mixed cultures are
indicative for contamination. In these
cases, it is better to repeat the culture or 5. LEVEL OF URINARY TRACT
to evaluate the presence of other signs, INFECTION
such as pyuria, nitrites or other bio-
chemical markers than to draw immedi- The differential diagnosis between upper
ate therapeutic consequences [17] (LoE (pyelonephritis) and lower urinary tract
1a). Combining bacteriuria and pyuria in infection (cystitis, urethritis) has clini-
febrile children, the findings of > 10 WBC/ cal implications, especially in infants and
334
young children. In this age group, the acute pyelonephritis when compared
clinical presentation tends to be nonspe- with those with acute cystitis. However,
cific, and the risk of renal damage with although the sensitivity of these tests
pyelonephritis is considered to be higher are 80–100%, their specificity in chil-
than in older children. Additionally, con- dren under the age of two years was
cepts of further imaging and treatment lower than 28% in a study comparing
are frequently based on the level of UTI clinical and laboratory findings with the
[15]. There are some parameters which finding of acute lesions DMSA-scan as
are used for level diagnosis: gold standard [44]. A relevant problem is
Fever: It is estimated that 60–65% of the cut off level for WBC, ESR, or WBC
patients with a febrile UTI will have an that can afford discrimination between
acute pyelonephritis [37]. acute pyelonephritis and cystitis. For
C-reactive protein: Although non- these reasons, some recommend DMSA
specific in febrile children with bacte- renal scintigram, when available, as the
riuria, C-reactive protein is often used test of choice to make the diagnosis of
in daily practice to distinguish between acute pyelonephritis in young children
acute pyelonephritis and other causes of under the age of two with febrile UTI
bacteriuria. It is considered significant at [44]. In most clinics a DMSA-Scan is not
a concentration above 20 µg/mL. used as a diagnostic tool for determin-
Procalcitonin is also used for early ing the level of infection. Therefore, in
detection of renal parenchymal involve- case of doubt one should treat a symp-
ment and detection of reflux [41–42] (LoE tomatic UTI in early childhood like a
2b and 2b). pyelonephritis.
Urinary N-acetyl-β-glucosaminidase
(NAG): This is a marker of tubular dam-
6. IMAGING OF THE URINARY TRACT
age. It is increased in a febrile UTI and
may become a reliable diagnostic test for
UTIs, although it is also elevated in VUR It is a common practice to investigate
[19] (LoE 1a). with imaging studies in children after
DMSA-Scan (Dimercaptoproprionyl- urinary tract infection. Today, many
acid renal scintigram): Currently, this imaging techniques exist for the detection
investigation is considered as the gold of morphological anomalies of the kidneys
standard for the diagnosis of pyelonephri- and urinary tract, of reflux and of acute
tis. Parenchymal hypoperfusion in zones pyelonephritic lesions as well as for per-
of inflammation are visualized by areas sistent pyelonephritic scarring and renal
of diminished activity of the tracer. dysplasia.
Colour-coded power doppler
6.1 Ultrasonography
sonography is also used for the detec-
tion of hypoperfused parenchymal areas Ultrasonography is an important pri-
but has a lower sensitivity and specifity mary imaging tool and bears no risk but
than DMSA. [43]. requires experience. It delivers immedi-
The presence of fever, as well as the ate information on the anatomy of the
increase of laboratory parameters like urogenital tract: size and configuration
CRP, erythrozyte sedimentation rate of the renal parenchyma, kidney vol-
(ESR) and white blood cell count are ume, the collecting system, dilated ure-
frequently used as signs for kidney ters, pathology of the bladder urethra
involvement in daily clinical practice. and gonads [45–46] (LoE 2a). It gives
Many studies have shown a statistically rough information on renal function,
increased level of acute phase reactants severe infection, scars, and malforma-
(WBC, CRP, and ESR) in patients with tions of kidneys, ureters and the bladder.
335
Sometimes there are even signs of reflux 6.2 Radiological investigations

and ureteroceles. Presence or exclusion 6.2.1 Voiding cystourethrography
of anomalies can be predicted with high
accuracy. Power-Doppler-Sonography VCUG is the most widely used radiologi-
even allows evaluation of renal per- cal exploration for the study of the lower
fusion. To identify or verify parenchymal urinary tract and especially of VUR. It
hypoperfusion as a sign for pyelonephri- is considered mandatory in the evalua-
tis or to detect permanent renal scars, tion of symptomatic UTI in children less
however, DMSA-scanning (technetium- than one year of age. Its main drawbacks
99m dimercaptosuccinic acid-scanning, are the risk of infection [58], if not car-
Tc-99m) is more sensitive [45, 47] (LoE ried out by suprapubic puncture, the
2a and 2b). need for retrograde filling of the blad-
Some authors have stated that ultra- der and the possible deleterious effect
sonography would not be necessary after of radiation on children [59] (LoE 3). In
UTI if antenatal ultrasound screen- recent years, tailored low-dose fluoro-
ing resulted in normal findings [48]. scopic VCUG with digital technique has
However, due to frequent lack of rel- been used for the evaluation of VUR in
evant findings in prenatal ultrasound, order to minimize radiological exposure
it should not be used as a substitute [60] (LoE 3). Voiding cystourethrography
for ultrasound after UTI [49]. In recent is mandatory in the assessment of recur-
years questions have been raised about rent febrile childhood UTI, even in the
the relatively low yield of abnormalities presence of normal ultrasonography. Up
found on renal ultrasound and the clini- to 23% and more, depending on the age
cal significance of those abnormalities of these patients may reveal VUR [61]
[34, 50–52]. The prevalence of abnormal- (LoE 3). The timing of the VCUG after a
ities ranged from 12% to 16%, with most pyelonephritic episode does not influence
findings including dilated renal pelvis, the results [62–66] (LoE 1).
caliectasis, megaureter, and double col-
lecting systems. 6.2.2 Excretory urography
Intravenous pyelography remains a val-
uable tool in the evaluation of urinary
6.1.1 Cystosonography
tract anomalies in children; however it
Contrast material-enhanced voiding should be reserved when images need to
ultrasonography has been introduced be morphologically clarified, e.g. renal
for the diagnoses of VUR without radio- duplication [67] (LoE 3). Its use in UTI is
logical exposure [53–55] (LoE 1a and 2a). debatable unless preliminary imaging has
By transurethral instillation of contrast demonstrated abnormalities requiring
material (e.g. Levovist®), CO2 higher further investigation. The major disad-
than grade I reflux can be visualised [55]. vantages are exposure to contrast media
Compared with VCUG as a gold standard and radiation [46] (LoE 2a). Digital imag-
for reflux detection, contrast-enhanced ing techniques should be used to reduce
cysto-sonography reaches a sensitivity of radiation. The role is declining with the
more than 86% and a specificity of more increasing technical superiority of ultra-
than 92% [56]. Using sophisticated tech- sonography, MRI and CT [68] (LoE 3).
niques like “low-dose contrast-enhanced
harmonic ultrasound imaging” [56] 6.3 Radionuclide studies
or “echo-enhanced colour doppler cys-
tosonography with stimulated acoustic 6.3.1 DMSA-Scan
emission” [57] the sensitivity can further Tc-99m DMSA is a radiopharmaceutical
be increased. that is bound to the basement membrane
336
of proximal renal tubular cells; half of the puncture) reflux is visualized by a gamma
dose remains in the renal cortex after six camera in a sitting or supine position.
hours. This technique is helpful in deter- This method is highly sensitive compa-
mining functional renal mass and ensures rable to radiologic VCUG but gives little
an accurate diagnosis of cortical scarring information about morphology.
by showing areas of hypoactivity indi-
cating lack of function. A UTI interferes 6.3.3 Indirect radionuclide cystography
with the uptake of this radiotracer by the
This investigation is performed by pro-
proximal renal tubular cells, and may
longing the period of scanning after the
show areas of focal defect in the renal
injection of Tc-99m diethylene triamine
parenchyma. A star-shaped defect in the
pentaacetate (DTPA) or as part of a
renal parenchyma may indicate an acute
dynamic renography. It represents a mer-
episode of pyelonephritis. A focal defect
captoacetyltriglycine (MAG-3) attractive
in the renal cortex usually indicates a
alternative to conventional cystography,
chronic lesion or a “renal scar” [69–71]
especially when following patients with
(LoE 4, 3 and 1a). A focal scarring or a
reflux, because of its lower dose of radia-
smooth uniform loss of renal substance as
tion. Disadvantages are a poor image res-
demonstrated by Tc-99m DMSA has gen-
olution and difficulty in detecting lower
erally been regarded as being associated
urinary tract abnormalities [77–78].
with VUR (reflux nephropathy) [72–73]
(LoE 1a and 2a). However, Rushton et
al. [74] (LoE 2a) stated that significant 6.3.4 Diuretic renography
renal scarring may develop, regardless of Diuretic scintigraphy is the most com-
the existence or absence of VUR. Risdon monly used diagnostic tool to detect
[75] (LoE 4) reported that Tc-99m DMSA the severity and functional significance
showed a specificity of 100% and sensitiv- of urine transport problems. 99m Tc –
ity of 80% for renal scarring. The use of MAG3 is the radionuclide of choice. It
Tc-99m DMSA scans can be helpful in the is important to perform the study under
early diagnosis of acute pyelonephritis. standardized circumstances (hydration,
About 50–85% of children will show posi- transurethral catheter) between the
tive findings in the first week. Minimal fourth and sixth week of life [82] (LoE 4).
parenchymal defects, when character- Oral fluid intake is encouraged prior
ized by a slight area of hypoactivity, can to the examination. Fifteen minutes
resolve with antimicrobial therapy [75–76] before the injection of the radionuclide,
(LoE 4 and 2b). However, defects lasting normal saline intravenous infusion at a
longer than five months are considered to rate of 15 mL/kg over 30 min is manda-
be renal scarring [77] (LoE 2a). Tc-99m tory with a subsequent maintenance rate
DMSA scans are considered more sensi- of 4 mL/kgh during the duration of the
tive than excretory urography and ultra- investigation [84] (LoE 3). The recom-
sonography in the detection of renal scars mended dose of furosemide is 1mg/kg for
[78–81] (LoE 2b, 2b, 2a and 3). It remains infants during the first year of life, while
questionable whether radionuclide scans 0.5 mg/kg should be given in children
could substitute for ultrasonography as a aged one to 16 years up to a maximum
first-line diagnostic approach in children dose of 40 mg.
with a UTI [53, 82–83] (LoE 3, 4 and 4).
6.4 Imaging strategies in UTI
6.3.2 Direct radionuclide cystography After a maximum of two UTI episodes
After instillation of MAG 3 into the in a girl and one episode in a boy, more
bladder (by catheter or by suprapubic detailed investigation of the urinary tract
337
should be carried out to clarify the child’s If reflux is seen, then a DMSA scan
risk, but not in asymptomatic bacteriuria would probably be required to assess the
[54, 68, 85–89] (LoE 1b, 2a, 2b, 2b, 2a, 4 extent of any renal damage. The goal of
and 2a). this strategy is early detection of reflux
Initial imaging guidelines from 1999 and prevention of ascending urinary tract
for febrile children up to the age of two infections [93] (LoE 4).
years by the American Academy of
Paediatrics involve a combination of
ultrasound and VCUG or isotope cystog- 7. URODYNAMIC EVALUATION
raphy [15]. UK guidelines from 1991 were
similar for the infant and young child, When voiding dysfunction is suspected,
but also included renal cortical scintigra- e.g. incontinence, residual urine and
phy with DMSA [90]. increased bladder wall thickness, then
During the last few years, efforts have urodynamic evaluation, restricted to
been made to come up with a more risk uroflowmetry, flow- EMG and residual
oriented approach after urinary tract urine should be performed. Furthermore
infections instead of performing sono- fluid intake and bowel movement should
graphic and radiographic studies in be recorded. Video-urodynamic studies,
every child with a first urinary tract including pressure flow studies and elec-
infection. UTI guidelines from the tromyography of the pelvic floor muscles
National Institute of Health and Clinical should be reserved for the evaluation
Excellence (NICE) 2007 put forward a of children with bladder and voiding
selective approach for imaging, accord- problems not responding to standard
ing to risk factors including age, pres- treatment, congenital anomalies and neu-
ence of atypical features (serious illness, rogenic bladders.
poor urine flow, presence of abdominal or
bladder mass, raised serum creatinine
level, septicaemia, non-E.coli organism 8. ENDOSCOPY
from urine culture and poor response
to suitable antibiotics) and presence of Routine cystoscopy has no place in the
symptomatic recurrence, with the aim of evaluation of acute infections. But in the
applying imaging studies to the at-risk final process of diagnosis, some weeks
group of infants in a more focused man- after bacterial eradication, it may be
ner (http://guidance.nice .org.uk/CG054) helpful to clarify the diagnosis in a lim-
[91]. However, while the NICE guidelines ited number of patients. With modern
may help to focus investigations in the imaging techniques the need for endo-
at-risk group, it may result in the under- scopic investigations has been further
diagnosis of significant findings [92]. reduced. Endoscopy is used to manage
Debate continues about optimal imag- VUR, strictures, valves, foreign bodies,
ing strategies after first urinary tract stones etc.
infection [49].
Today, most clinics would recommend
a cystogram if signs, symptoms and his- 9. FURTHER RESEARCH
tory indicate the possibility of reflux e.g.
in children with pyelonephritis, a family Many open questions need to be clarified:
history of reflux or recurrent infections 1. The significance of elimination dis-
associated with signs of bladder dysfunc- orders of bladder and bowel in the
tion, signs for reflux or upper tract dilata- aetiology of UTI combined with the
tion in sonographic studies. various anomalies.
338
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343
|6.4|
Antimicrobial therapy of urinary

tract infections in children
Rolf Beetz, Martin Westenfelder
PD Dr. med. Rolf Beetz, Paediatric Nephrology, Center for Paediatric and Adolescent Medicine
University Medical Clinic, Langenbeckstr.1, 55131 Mainz
Phone +41-6131-17 3937, Fax +41-6131-17 6426, e-mail: beetz@kinder.klinik.uni-mainz.de
Prof. Dr. med. Martin Westenfelder, Zentrum für Kinderurologie und plastisch rekonstruktive Urologie
HELIOS Klinikum Krefeld, Lutherplatz 40, 47805 Krefeld
Tel. +49 2151 32 2281, Fax +49 2151 32 2018, E-Mail: martin.westenfelder@helios-kliniken.de
ABSTRACT factors. In early infancy, a combination of

aminoglycoside/ampicillin or ceftazidime/
The main objectives in childhood urinary ampicillin is commonly recommended
tract infections are rapid recovery from as first line treatment in pyelonephritis.
complaints, prevention of urosepsis and Pyelonephritis in young infants should
infection-related complications as well as always be treated in a paediatric clinic. In
the prevention of renal parenchymal dam- later infancy and childhood, an oral third
age. Calculated antibiotic therapy should generation cephalosporin can be used.
take the local resistance-rates of uropath- Key words: antimicrobial therapy, pro-
ogens into consideration. The current situ- phylaxis, pyelonephritis, cystitis, asymp-
ation of bacterial resistances differs from tomatic bacteriuria, voiding dysfunction,
region to region. In E.coli, resistance rates resistance, recurrence, urinary tract
against cephalosporines, aminoglycosides, infections, children, infants
nitrofurantoin und chinolones have been
relatively low. In contrast, resistance
rates against ampicillin have increased SUMMARY OF RECOMMENDATIONS
over the last 20 years. A similar trend has
been observed for TMP/SMX. The choice 1. In newborns and young infants with
of appropriate antibiotics, the duration pyelonephritis, parenteral anti-
of therapy and the form of application biotic therapy is initiated with a
depend on age, severity of clinical symp- combination of a third generation
toms and the presence of complicating cephalosporin and ampicillin or with
Antimicrobial therapy of urinary tract infections in children | 6.4 |
aminoglycoside and ampicillin (GoR recurrences and the risk of renal scar-
A). Infants of this age should be ring (GoR B).
treated in the hospital (GoR C). 8. Prophylaxis should not be restricted to
2. In infants after the age of two to six the use of antibiotics or other prophy-
months and without further compli- lactic agents but must also include the
cating factors (i.e. urinary tract abnor- efficient management of bladder and/or
malities and neurogenic bladder), bowel dysfunction, as well as the treat-
pyelonephritis can be treated by oral ment of predisposing factors (GoR B).
third generation cephalosporines or
with short courses (two to four days)
of IV therapy, followed by oral therapy 1. INTRODUCTION
[1] (GoR A). However, if enterococci
infection is suspected, amoxycillin or The main objectives in childhood urinary
ampicillin should be added (GoR C). tract infections are rapid recovery from
complaints, prevention of related com-
3. In case of cystitis in older children, plications, such as urosepsis, urolithiasis
oral antibiotic therapy is sufficient and renal abscess, as well as the preven-
(GoR A). It is suggested to use a section of permanent renal parenchymal
ond or third generation cephalosporin damage. To achieve these aims, urinary
as the first line agent (GoR B). tract infections must be recognized and
4. Due to worldwide increasing and quite treated during the early stage of the dis-
high resistance-rates of E.coli against ease. Antibiotics should be both highly
ampicillin, this substance should effective in eliminating usual uropatho-
not be used any longer as first line gens and well tolerated by infants and
medication for urinary tract infections children. This especially applies to
(GoR B). This is also true for co- pyelonephritic episodes. The choice of an
trimoxazole and respectively trimetho- appropriate antibiotic, considering the
prim in regions in which resistance increasing resistance rates against some
rates of E.coli exceed 20% (GoR B). of the conventional agents, is most impor-
5. The duration of antibiotic therapy tant. The unnecessary usage of ‘reserve’
is seven to 14 days in newborns and antibiotics should be avoided in simple
small infants (GoR B), seven to 10 urinary tract infections.
days in the case of pyelonephritis in This part of the chapter focuses on the
older infants and children [2] (GoR therapy and prophylaxis of urinary tract
B), and three to five days in cysti- infections in infants and children.
tis (GoR A). If further diagnostics
(i.e. VCUG, diuretic renography)
are planned after pyelonephritis, 2. METHODS
prophylactic dosages of the appropri-
ate antibiotic should be given until A systematic literature search was per-
the results of the imaging tests are formed for the last 10 years in MEDLINE
available (GoR C). and Cochrane library with the follow-
ing key words: urinary tract infections,
6. Asymptomatic bacteriuria does not usu- therapy, prophylaxis. Limitations were
ally need antibiotic therapy (GoR A). children 0–14 years. An English abstract
7. In children with high grade reflux, had to be available. The authors also had
severe urinary obstruction and fre- continuously observed the relevant litera-
quently recurrent pyelonephritis ture concerning the topic during the last
chemoprophylaxis should be consid- twenty years. Only peer reviewed articles
ered in order to decrease the rate of were included.
345
A total of more than 300 publications should be taken to be able to modify the
were identified, which were screened by therapy, if applicable.
title and abstract, and more than 80 stud- As in adulthood, E.coli are by far the
ies were included in the analysis. most prevalent pathogens of urinary tract
The studies were rated according to the infections in children (Table 1). The path-
level of evidence (LoE) and the grade of ogen probability is dependent on age and
recommendation (GoR) using ICUD gender: the percentage rate of Enterococcus
standards (for details see Preface) [3–4]. infections is higher in early infancy than
at a later age [5–6]. In a recent study, 20%
3. GENERAL ASPECTS OF of uropathogens in boys from birth to four
ANTIMICROBIAL THERAPY years years and 15% in girls at the same
IN CHILDHOOD age were Enterococci [5]. This accounts
inter alia for the combination therapy of
3.1 Choice of antibiotic third-generation cephalosporines, respec-
tively amino glycosides, with ampicillin in
3.1.1 Aspects of calculated therapy the infant age group (LoE 2a).
An acute, symptomatic urinary tract In case of pre-existing abnormalities
infection mostly requires antibacterial or dysfunctions of the urinary tract (so
therapy before the pathogen is known called complicated urinary tract infec-
and the results of a resistance test are tions), after earlier urinary tract infec-
available. Therefore, the selection of the tions, and under antibacterial prophylaxis
antibiotic(s) is “calculated” from the high- non-E.coli strains are more often to be
est pathogen probability. Prior to the reckoned with (Table 1). This is also true
therapy’s initiation, a urine culture (in for nosocomial urinary tract infections.
case of highly feverish infections, fore- In association with secondary urolithi-
most in infancy, also a blood culture) asis (magnesium ammonium phosphate
Table 1 Organisms isolated from the urinary tracts of children in the community and those with an underlying renal problem.
Isolates from children in the Isolates from children with

community underlying renal problems
Escherichia coli 63.0% 40.3%
Proteus spp. 5.8% 3.7%
Klebsiella spp. 3.3% 7.6%
Enterobacter sp.. 1.2% 3.8%
Morganella morganii 0.9% 1.3%
Pseudomonas spp. 2.1% 10.8%
Stenotrophomonas maltophilia 0% 0.7%
Other Gram negative bacilli 1.0% 2.1%
Staphylococcus aureus 0.9% 2.9%
Other staphylococci 0.6% 3.7%
Enterococcus spp. 19.3% 20.2%
Non-faecal streptococci 1.9% 2.8%
from: Ladhani S, Gransden W 2003.
346
calculi), Proteus bacteria are most likely 3.1.2 Specific problems in the choice
to be found. Urinary tract infections with of antibiotic in childhood
Proteus species are more often found in Not all available antibiotics are approved
male infants than in girls because of fre- by the national health authorities in
quent colonization of the prepuce. infancy and childhood. Trimethoprim
The pathogen’s responsiveness to anti- is contraindicated in premature infants
biotics depends on the natural resist- and newborns. Usage limitations exist
ance and the actual resistance situation, for infants under six weeks (due to the
which can differ largely from region to lack of adequate experience). Because of
region. E.coli show the least resistance the danger of haemolytic anaemia, nitro-
against second and third generation furantoin is contraindicated for young
cephalosporines, amino glycosides, nitro- infants until the third month of age.
furantoin and quinolones,. In contrast, In Germany, ciprofloxacin is only
the resistance to ampicillin grew consid- approved for the treatment of compli-
erably in many places over the past 20 cated urinary tract infections from the
years and concerns over 50% of the E.coli age of one to two years onward. The
in some regions. A similar trend becomes American Academy of Paediatrics (AAP)
apparent in childhood concerning co-tri- Committee on Infectious Diseases rec-
moxazole and trimethoprim respectively ommends that the use of ciprofloxacin
[6–15] (Table 2). for UTI in children be limited to urinary
After antibacterial pre-treatment and tract infections caused by Pseudomonas
during antibacterial prophylaxis, the risk aeruginosa or other multi-drug resistant,
of resistant uropathogens is especially Gram-negative bacteria. Circumstances
high [10]. in which fluorquinolones may be useful
Table 2 Resistance rates of E.coli in urinary tract infections in children observed in isolates from different European regions
(in %). The data were collected in different age groups and with first or recurrent UTIs. They are not comparable to each
other. The numbers are useful to demonstrate trends.
Heidelberg, London, Kreta, Innsbruck, Istanbul, Tel Aviv, Toulouse,

Germany England Greece Austria Turkey Israel France
Schmitt CP Ladhani S Anatoliaki M Prelog M Gökce I Marcus N Prere M-F
2007 2003 2007 2008* 2006 2005 2004
Amoxicillin/ 44 51,1 56,4 64,8 62 62 53

Ampicillin
Amoxicillin- 10 15,5 6,9 43 8 7

Clavulanic acid
TMP/Sulfa- 34 27,6 27,3 35,5 33 38 22

methozazole
Cefaclor 5 22,5 2,8** 37**
Cefuroxime 2 0,9 3,1 2,8 19 1
Ceftazidime 0 1,0 0 1
Ceftriaxone 1,6 1,0 9 0 0
Ciprofloxacin 3 0 3
Nitrofurantoin 5,9 2,6 3,4 15 3 7
*only children > 25 months of age.

**Cefazolin.
347
include those in which 1) the infection is with the Schwartz formula (Table 4)
caused by multidrug-resistant pathogens [17–19].
for which there is no safe and effective Drug monitoring is essential in the
alternative and 2) parenteral therapy is deployment of amino glycosides.
not feasible and no other effective oral Nitrofurantoin is not deployable when
agent is available [16] (LoE 4). the GFR is less than 50% of the norm,
The dosage of all substances is depend- because insufficient renal elimination does
ent on age and body weight (Table 3). not allow sufficient urine concentration.
3.1.3 Kidney function 3.2 Form of application

In case of impaired renal function, the The decision for oral or parenteral ther-
dosage is adjusted to the glomerular filtra- apy complies with age, severity of the
tion rate, which can be calculated from the illness, and prerequisites for oral appli-
current serum creatinine and body length cation (Table 5). Because of the increased
Table 3 Frequently used antibacterial substances for the therapy of urinary tract infections in infants and children
up to 12 years.*
Chemotherapeutics Daily dosage Application Comments
Parenteral Cephalosporines
Group 3a, e.g. Cefotaxim 100–200 mg/kg i.v. in 2–3 D
(Adolesc.: 3–6 g)
i.v. in 2–3 D
Group 3b, e.g. Ceftazidim 100–150 mg/kg
(Adolesc.: 2–6 g)
Oral-Cephalosporine
Group 3, e.g. Ceftibuten 9 mg/kg p.o. in 1–2 D
(Adolesc.: 0,4 g)
Group 3, e.g. Cefixim 8–12 mg/kg p.o. in 1–2 D
(Adolesc.: 0,4 g)
Group 2, e.g. Cefpodoximproxetil 8–10 mg/kg p.o. in 1–2 D
(Adolesc.: 0,4 g) p.o. in 2 D
Group 2, e.g. Cefuroximaxetil 20–30 mg/kg p.o. in 3 D
(Adolesc.: 0,5–1 g)
Group 1, e.g. Cefaclor 50–100 mg/kg p.o. in 2–3 D
(Adolesc.: 1,5–4 g)
Trimethoprim or 5–6 mg/kg p.o. in 2 D

Trimethoprim/Sulfamethoxazol 5–6 mg/kg (TMP-Anteil) p.o. in 2 D
(Adolesc.: 320 mg)
Ampicillin 100–200 mg/kgKG i.v. in 3 D Ampicillin and Amoxicillin

are not eligible for calculated
(Adolesc.: 3–6 g) i.v. in 3–4 D
monotherapy
Amoxicillin 50–100 mg/kg p.o. in 2–3 D1
(Adolesc.: 1,5–6 g) p.o. in 2–3 D
348
Chemotherapeutics Daily dosage Application Comments
Amoxicillin/Clavulanic acid 60–100 mg/kg i.v. in 3 D

(parenteral) (Adolesc.: 3,6–6,6 g)
i.v. in 3 D
45–60 mg/kg
Amoxicillin/Clavulanic acid (oral) p.o. in 3 D
(Amoxicillin-fraction)
(Adolesc.: 1500 + 375 mg) p.o.in 3 D
Tobramycin 5 mg/kg i.v. in 1 D Drug monitoring

(Adolesc.: 3–5 mg/kg, max. 0,4 g)
Gentamicin 5 mg/kg
i.v. in 1 D
(Adolesc.: 3–5 mg/kg, max. 0,4g)
Ciprofloxacin Children and adolesc. i.v. in 3 D Approved in most European

(1–17 years of age): 20–30 mg/kg countries as second-or third
(max. D: 400 mg) (parenterally) line medication for compli-
cated UTIs,
Children and adolesc. p.o. in 2 D “reserve-antibiotic“ !
(1–17 years of age): 20–40 mg/kg
(max. D 750 mg) (orally)
Nitrofurantoin 3–5 mg p.o. in 2 D Contraindicated in the case of

renal insufficiency
*Dosage for adolescents in paracentesis, if differing.

1
Infants 2 D, children 1–12 ys. 3 D.
Table 4 Calculation of the glomerular filtration rate according to the Schwartz formula
(Schwartz 1976, 1984, 1985).
Glomerular filtration rate (mL/min x 1.73 m2) = k x L / Crea.S
k = correcting factor (see table); L = body length in cms; Crea S = serum creatinine (mg/dL)
Correcting factors for the Schwartz formula
Age group Age (years) k (mean)* k (mean)**
Term newborns and infants <1 0.45 40
Children 2–12 0.55 48
Female adolescents > 12 0.55 48
Male adolescents > 12 0.70 62
*factor k for Creatinine in mg/dL.

**factor k for Creatinine in mmol/L.
incidence of urosepsis and severe pyelone- cephalosporines enables a relatively safe

phritis, newborns and infants under two oral therapy for urinary tract infections.
months of age are in need of parenteral The cost savings make ambulant therapy
antibiotic therapy (LoE 4). of urinary tract infections attractive and
The intention to convert the recom- it adds to the prevention of nosocomial
mended inpatient initial treatment of infections.
pyelonephritis in later infancy and child- Alternative options to ambulatory man-
hood to ambulant per oral therapy has agement include outpatient parenteral
resulted for various reasons. The avail- therapy for patients with acute pyelone-
ability of potent, orally applicable group 3 phritis. Several studies have demonstrated
349
Table 5 Indications for parenteral application of antibacterial medication in UTI.
• Newborns and young infants (< 4–6 months of age)
• Clinical suspicion of urosepsis
• Critically ill condition
• Refusal of fluids or/and food and/or oral medication
• Vomiting, diarrhoea
• Non-compliance
• complicated pyelonephritis (e.g. urinary obstruction)
that once-daily parenteral administration safety (high efficacy of aminoglycosides,

of gentamicin or ceftriaxon in a day treat- respectively cephalosporines against com-
ment centre is safe, effective and cost- mon uropathogens; enterococcus gap is
effective in children with UTI [20] closed with ampillicin) (LoE 3).
(LoE 1b). When applying amino-glycosides, a
Children with urinary tract abnor- single daily dose is safe and effective
malities have been excluded from all [1, 21–22] (LoE 1a).
randomised studies comparing the equal- After defervescence, and after the
ity of an oral therapy to the parental microbiological resistance results are
treatment. Thus, the responsible pae- known, a parenteral, calculated therapy
diatrician should at least establish by can be changed over to a targeted resist-
ultrasonography whether a urinary tract ance-appropriate medication.
deformity is existent, before dismissing
hospitalization. 4.2 Therapy of pyelonephritis in
late infancy and childhood
In case of pyelonephritis beyond early
4. THERAPY OF PYELONEPHRITIS
infancy, the incidence of parenchymal
scars in DMSA scan after a three-day
4.1 Pyelonephritis in newborns
antibacterial intravenous therapy, fol-
and early infancy
lowed by a five-day oral treatment, equals
In newborns and young infants, a febrile the incidence after an eight-day intrave-
urinary tract infection proceeds consider- nous treatment regimen [23] (LoE 1b).
ably more frequently in the form of uro- According to more recent studies, an
sepsis than in older children. Positive exclusively oral therapy with a group 3
blood cultures are found in approxi- cephalosporin (e.g. cefixim, ceftibuten)
mately 20%. Electrolyte disorders with is equal to the usual two to four days
hyponatremia and hyperkalemia may intravenous therapy followed by an oral
occur; most likely because of temporary treatment. This is true for the duration
pseudo-hypoaldosteronism. For these of fever, as well as for the development
reasons, newborns and infants in the of persistent renal scars [22, 24–25].
first two to six months of life initially Similar data has been shown for amoxi-
require parenteral antibacterial therapy cillin-clavulanate [26] (LoE 1a). However,
under inpatient conditions (Table 6). The amoxicillin-clavulanate is associated with
combination treatment with ampillicin increasing rates of resistance.
and an amino-glycoside (Tobramycin®, Hence, in case of pyelonephritis in
Gentamicin®) respectively a group 3 infancy and childhood, the antibacte-
cephalosporin, achieves great therapeutic rial treatment with an oral group 3
350
Table 6 Recommendations for calculated antibacterial therapy of pyelonephritis dependent on age and
severity of the infection.
Duration of Level of
Diagnosis Proposal Application therapy Evidence
Pyelonephritis during Ceftazidim + Ampicil- 3–7 days parenterally, for 10 (–14) days IV
the first 0–6 months lin1 or Aminoglycoside at least 2 days after after de-
of life + Ampicillin1 vervescence, then oral therapy2
In newborns: parenteral Newborns 14–21
therapy for 7–14 days, then days
oral therapy2
Uncomplicated Cephalosporine Orally (initially parenterally, if (7–)10 days I

pyelonephritis after group 32 necessary)
6 months of age
Complicated pye- Ceftazidime + 7 days parenterally, then oral 10–14 days IV

lonephritis/ urosepsis Ampicillin1 or therapy2
(all ages) Aminoglycoside +
Ampicillin1
after receipt of microbiological findings (pathogen, resistance) adaption of therapy.

1
i.v.: e.g. Cefotaxim; orally: e.g. Cefpodoximproxetil, Ceftibuten, Cefixim.

2
cephalosporin can be carried out after paediatric UTIs with antibiotics for seven
thorough consideration, if a good compli- to 14 days [2]
ance is to be expected and medical sur-
veillance and therapy are warranted, and 4.3 Therapy of complicated
if urinary tract abnormalities have been pyelonephritis
excluded (Table 6) [1].
In complicated UTI non-E.coli uropath-
The conclusion that ambulant treat-
ogens, such as Proteus mirabilis,
ment is to be equated with an inpatient
Klebsiella spp., Indol-pos. Proteus spp.,
therapy cannot be drawn without further
Pseudomonas aeruginosa, Enterococci
consideration. Adequate surveillance,
and Staphylococci are more often to be
medical supervision and, if necessary,
anticipated. Parenteral treatment with
adjustment of the therapy must be guar-
broad-spectrum antibiotics is to be pre-
anteed. To what extent this can be guar-
ferred over oral therapy. A temporary uri-
anteed in everyday practice by ambulant
nary diversion (suprapubic cystostomy
treatment in infancy and childhood, has
or percutaneous nephrostomy) might be
not been investigated so far. If the deci-
required in case of failure in obstructive
sion is made in favour of ambulant treat-
uropathies (i.e. severe pyonephrosis with
ment, the first oral administration of
urethral valves, obstructive megaureter
the antibiotic in the clinic, respectively
or ureteropelvic junction obstruction).
the medical practice, should be applied
in double dosage, to test compliance and
tolerance to the preparation. Also, close 4.4 Acute focal bacterial nephritis
contact with the family is advised in the (“lobar nephronia”)
initial phase of the therapy [27]. Acute focal bacterial nephritis (“lobar
Regarding the optimal duration of ther- nephronia”) is a localized bacterial infec-
apy, a meta-analysis provided an empiri- tion of the kidney presenting as an inflam-
cal basis for the current widespread matory mass without abscess formation,
and recommended practice of treating which may represent a relatively early
351
stage of renal abscess. For the majority cephalosporin in these areas. In principle,
of children, the pathogenesis is related to simple antibiotics should be preferred
ascending infection due to pre-existing to highly effective ‘reserve’ antibiotics in
uropathy, especially vesicorenal reflux or uncomplicated cystitis to avoid further
urinary obstruction. Prolonged intrave- development of resistance in the popula-
nous antibiotic treatment is sufficient in tion (Table 7).
most cases [28]; three weeks of intrave- The recommended duration of therapy
nous and oral therapy tailored to the path- is three to five days. A recent Cochrane
ogen noted in cultures seems to be superior review has shown equivalence of a two to
to shorter treatment [29] (LoE 2 a). four day oral antibacterial therapy com-
pared to a seven to 14-day therapy for
4.5 Therapy of cystitis and lower UTIs [30] (LoE 1a). Single doses or
cystourethritis one-day therapies are accompanied with
higher rates of relapse or recurrence.
Symptomatic nonfebrile UTIs with
dysuria, alguria, pollakisuria, lower
4.6 Therapy of renal carbuncle and
abdominal pain and/or onset of second-
abscess
ary urinary incontinence require a treat-
ment which guarantees high urine levels Renal cortical abscesses (“carbuncles”)
of the antibiotic used. In this respect, are caused by haematogenous spread
nitrofurantoin could be one of the most originating from another focus of bacte-
appropriate substances – it has, however, rial infection (e.g. skin infection such as
limitations due to frequent gastrointes- infected wounds, furunculosis or skin
tinal intolerance reactions. Currently, abscess) the most frequent pathogen being
trimethoprim or trimethoprim/sulfo- staphylococcus aureus. In most of these
methoxazole and related substances are cases urine cultures are sterile. Mostly,
regarded substances of first choice in a prolonged parenteral calculated com-
uncomplicated cystitis. Increasing resist- bination therapy including β-lactamase
ance rates, especially of E.coli against resistant antibiotics targeting staphyloco-
trimethoprim, in some regions justifies ccus aureus is sufficiently effective. More
empirical calculated therapy with an oral rarely, additional percutaneous drainage,
Table 7 Recommendations for antibacterial treatment in cystitis und cystourethritis (Dosages for children up
to 12 years of age).
Chemotherapeutics Daily dosage Application
Oral Cephalosporines
Group 1, e.g. Cefaclor 50 (-100) mg/kgbw p.o. in 2–3 D
Group 1, e.g. Cefalexin 50 mg/kgbw p.o. in 3–4 D
Group 2, e.g. Cefuroximaxetil 20–30 mg/kgbw p.o. in 2 D
Group 2, e.g. Cefpodoximproxetil 8–10 mg/kgbw p.o. in 2 D
Group 3, e.g. Ceftibuten 9 mg/kgbw p.o. in 1 D
Trimethoprim 5–6 mg/kgbw p.o. in 2 D
Trimethoprim/Sulfamethoxazol 5–6 mg/kgbw /TMP-fraction) p.p. in 3 D
Amoxicillin/Clavulanic acid 37.5–75 mg/kgbw (Amoxicillin-fraction) p.o. in 3 D
Nitrofurantoin 3–5 mg/kgbw p.o. in 2 D
352
open surgical revision or nephrectomy are In cases of prolonged fever and failure
required [31]. to recover, one should consider a resistant
Renal corticomedullary abscesses are uropathogen or the presence of a congeni-
sometimes observed as complications of tal uropathy or an acute urinary obstruc-
ascending UTIs with vescicorenal (intra- tion (e.g. due to a urinary calculus), which
renal) reflux or in urinary tract obstruc- urgently demands ultrasonography.
tion. These abscesses often are preceded
by pyelonephritis or by focal bacterial
nephritis (“lobar nephronia”) caused by 6. PROPHYLAXIS
Gram-negative bacteria, e.g. E.coli [32].
6.1 Chemoprophylaxis
4.7 Asymptomatic bacteriuria Early diagnosis and therapy are the most
Infants and children with asymptomatic effective prophylactic measures against
bacteriuria (ABU) have a low risk of renal scarring in every case of pyelone-
developing pyelonephritis. ABU is com- phritis in infancy and childhood.
monly caused by low virulent uropatho- Approximately 1% of boys and 3–5%
gens almost leading to a colonisation of girls suffer from at least one UTI dur-
– not, however, to an infection. They can ing childhood [35]. After their first symp-
even protect the urinary tract from inva- tomatic UTI, 30%-50% are prone to at
sion by bacteria of higher virulence. It least one recurrence [36–37]. The recur-
has been shown that the rate of pyelone- rence rate is directly correlated with the
phritic episodes was higher in girls who number of preceding UTIs [38]. In boys,
were treated for asymptomatic bacteriu- early recurrences are as frequent as in
ria than in those who stayed untreated, girls; later the recurrence rate is much
in spite of bacteriuria [33]. In most cases, lower in boys than in girls. The suscepti-
asymptomatic bacteriuria resolves spon- bility for recurrences is highest within the
taneously after a few weeks or months. first two to six months after a UTI [39].
Asymptomatic bacteriuria in patients The longer the infection-free interval, the
without accompanying uropathy, bladder lower the risk for further recurrences [38].
dysfunction or history of pyelonepritic A long-term antibacterial prophylaxis
episodes does not need antibacterial ther- should be considered in cases of high sus-
apy at all (LoE 2a). If antibacterial ther- ceptibility to UTIs and risk of acquired
apy becomes necessary for other reasons, renal damage. These are, for instance,
e.g. otitis media or pneumonia, a sympto- patients with dilating vesicorenal reflux,
matic UTI can happen thereafter due to a with recurrent pyelonephritic episodes or
shift to a more virulent uropathogen [34]. with significant urinary tract obstruction
(e.g. high grade megaureters, urethral
valves). However, the role of vesicorenal
5. CONTROL OF THERAPEUTIC reflux as a predisposing factor for UTI
SUCCESS recurrence is controversial. Nuutinen
and Uhari found that recurrence-free
Under successful treatment the urine survival was significantly shorter and
usually becomes sterile after 24 hours, recurrent UTIs occurred more often in
and leukocyturia normally disappears the children with grade 3–5 VUR than in
within three to four days. Normal body those with grade 0–2 VUR and concluded
temperature can be expected within 24 to grade 3–5 VUR to be a risk factor for
48 hours after the start of therapy in 90% recurrent UTI [36].
of cases. CRP mostly normalizes after Antimicrobials selected for prophylaxis
four to five days. should fulfil the following demands [40]:
353
• Effectiveness against the majority of reports submitted to the Food and Drug
uropathogens Administration since 1953. There were
• Cause a minimum of serious side only 26 cases of serious reactions to
effects nitrofurantoin in children and adoles-
cents who were younger than 20 years
• Cause minimal bacterial resistance of age in the United States. Neurologic
• Make little ecological impact on indig- and hepatic reactions occurred in seven
enous bacterial flora and nine patients respectively, which
Usually, the substance is given daily in equated to 0.8 and 1.0 cases/million uses
the evening shortly before going to sleep. respectively [43]. On the basis of these
A quarter of the regular therapeutic dos- data and of clinical experience, it may
age is sufficient (Table 8). be concluded that nitrofurantoin is a
For many years, trimethoprim or cot- safe and effective antibiotic for prophy-
rimoxazole and nitrofurantoin have been laxis in children with recurrent UTI.
the substances most used for antibacte- In spite of its potential side effects, the
rial prophylaxis of UTI in children. Due value of nitrofurantoin as an alternative
to the fact that in many countries the use to trimethoprim in children will prob-
of both substances is restricted in early ably undergo a renaissance, since bac-
infancy, oral cephalosporines are pre- terial resistance to trimethoprim has
ferred in this age group. been shown to increase rapidly in many
In comparative studies, nitrofurantoin regions of the world.
produced significantly more side effects
than trimethoprim. The differences were 6.1.1 The problem of non-compliance
due to higher rates of complaints of gas- Patient compliance is one of the big-
trointestinal symptoms like nausea or gest problems with antibacterial proph-
vomiting, as well as of bad taste of the ylaxis. Daschner and Marget tested
mixture [41]. In adults, the use of nitro- compliance with long-term antibiotic
furantoin is limited because of the rela- therapy by checking urine in 93 children
tively high frequency of severe adverse with recurrent UTIs. Only 32.2 % of the
reactions, especially including pulmonary children took the prescribed drugs at
fibrosis and polyneuropathy [42]. The sit- regular intervals, 19% did not take the
uation in childhood appears to be mark- antibiotics at all [44]. Similar results
edly different. Corragio et al. in 1989 have been shown in children with vesi-
reviewed the serious adverse reaction coureteric reflux [45]. Rational and
Table 8 Usable substances for antibacterial prophylaxis.
Substance* Prophylactic dosage (mg/kgbw/d) Limitations in young infants
Trimethoprrim 1 until 6 weeks of age
Nitrofurantoin 1 Until 3 months of age
Cefaclor 10 No age limitations
Cefixim 2 Preterms and newborns
Ceftibuten 2 **
Cefuroximaxetil 5 **
*Substances of first choice are Nitrofurantoin and Trimethoprim. In exceptional cases oral cephalosporine can be used.
**In Germany, Ceftibuten are not approved for infants under 3 months of age.
354
understandable information for parents randomised, controlled, prospective stud-

on the aims and necessity of prophy- ies on antibacterial prophylaxis with
laxis and its control is inevitable for its VUR are in progress [57–58]; (see also
success. chapter “vesicoureteral reflux”).
6.1.2 Current controversies in 6.2 Other agents used for

antibacterial prophylaxis prophylaxis
The efficacy of antibacterial prophylaxis 6.2.1 “Urine disinfectants”
per se has been questioned in several Nitroxolin (5-nitro-8-hydroxyquinoline)
reviews [46–49]. Garin et al came to the is a derivate of nitrochinolinol with
conclusion that “the current available bacteriostatic and bactericide effects
data do not support a role for continuous against many Gram-positive and Gram-
urinary antibiotic prophylaxis in the pre- negative pathogens. In addition, the
vention of renal scars in patients with substance has been demonstrated to
vesicoureteric reflux“ [50]. Likewise, inhibit bacterial adherence to epithe-
Larcombe stated that the long-term lial cells or solid surfaces, probably by
benefits of prophylaxis have not been chelating effects with various metal-
adequately evaluated, even for children lic divalent cations [59–60]. Nitroxolin
with VUR [46]. In an actual Cochrane has been used since 1962 in the treat-
review, Williams et al. concluded that ment of UTI. However, more than half
there is considerable uncertainty about of the very few publications originally
the effectiveness of long-term, low-dose came from France, probably due to the
antibiotic administration for the pre- more popular usage of nitroxolin in that
vention of UTI in children [49]. Finally, country. For children, there is no data
Le Saux et al criticized the low qual- available concerning its prophylactic
ity of available evidence for using anti- efficiency compared to other antibacte-
bacterial prophylaxis to prevent UTI rial substances or to placebo.
in children with normal urinary tracts
or neurogenic bladder [47]. In addition,
they found a surprising lack of evidence 6.2.2 “Urine acidification”
for children with reflux. The bacteriostatic effect of acid urine is
Most of the authors of these articles the main argument for acidifying sub-
criticize the lack of evidence for using stances in UTI prophylaxis, especially
antibacterial prophylaxis due to the low those produced by weak organic acids.
quality of clinical trials and the small L-methionin is the only essential amino
number of patients. Indeed, several acid which contains sulphur. Its metabo-
authors of reviews came to the conclusion lisation to hydrogen sulfide and sulfu-
that it is not clear whether any interven- ric acid sets H-ions free leading to an
tion for children with primary VUR – a acidification of the urine. Another effect
domain for antibiotic prophylaxis – does of L-Methionin is the inhibition of bac-
more harm than good [48, 51]. Therefore, terial adherence at uroepithelial cells
several authors demand new, well- [61]. In children with ammonium mag-
designed randomised trials focusing on nesium phosphate stones due to bacte-
groups with different risk stratifications riuria (e.g. Proteus mirabilis) in alkaline
[47, 51–52]. Recently published results urine, where stone fragments cannot be
of prospective, randomised studies do removed completely, antibacterial prophy-
not support the efficacy of antibacterial laxis in combination with urine acidifica-
prophylaxis in low-grade vesicoureteral tion by L-methionin (urine pH 5.6 to 6.2)
reflux [53–56] (LoE 1b). However, several is most appropriate [62–63].
355
6.2.3 Cranberry to humans so far. However, there is some

Syrup or juice from vaccinium macro- experience with lysates attained from
carpon, a certain cranberry species, has inactivated uropathogenic strains, which
been used for centuries as a homespun are applied orally or parenterally.
remedy for urinary tract infection, and
has undergone a renaissance in UTI 6.4.1 Oral vaccines
prophylaxis over the last 10 years. Its There is some evidence that these prep-
effect is possibly based on the inhibition arations stimulate B-lymphozytes and
of uropathogen E.coli at the uroepithel NK cells as well as cells within the
[64]. In adults, the protective effects of Peyer’s plaques. Stimulation of intesti-
cranberry juice on recurrence rates of nal IgA-secretion is said also to lead to
UTIs is proven [65]. In children, there higher secretory IgA levels in urine. In
are no similar study results available. adults, prophylaxis with Urovaxom®
Two studies in children with neurogenic seemed to be effective in a few placebo-
bladders demonstrated no influence of controlled studies [76]. In children, only
cranberry juice on UTI recurrence rates one controlled, randomized study was
[66–67]. published which showed a protective
effect comparable with that of nitro-
6.3 Treatment of bladder furantoin [77].
dysfunction and obstipation
Normalization of micturition disorders 6.4.2 Parenteral vaccines
or bladder overactivity is a paramount After injection of inactivated uropath-
measure to lower the recurrence rate of ogens, Nayir et al. found increasing
UTIs in a child [68]. If there are signs sIgA-levels in the urine of children.
of bladder dysfunction in infection-free After the first injection the IgA-levels
intervals (e.g. pollakisuria, incontinence, fell but increased again after a booster.
micturition abnormalities), further diag- Children in the vaccinated group suf-
nostics and effective treatment are pre- fered from fewer UTIs than those in the
requisites for therapeutic success [69–70] non-vaccinated group [78]. In Germany,
(LoE 2a). By a standardized history and a parenteral vaccine is on the market
by non-invasive investigations (e.g. blad- (StroVac®), containing 109 inactivated
der and bowel diary, ultrasound including uropathogens (E.coli, Morganella mor-
measurement of residual urine, uroflow- gani, Proteus mirabilis, Klebsiella pneu-
metry, pelvic floor electromyogram), most moniae, Enterococcus faecalis). It is not
types of urinary incontinence and bladder approved for children below the age of
dysfunction in children are easily detect- five years. In children between five and
able [71]. 15 years no sufficient experience exists,
Often, dysfunctional voiding is associ- and experimental data concerning its
ated with constipation. It is well known usage during growth phase in mammals
that treatment of constipation leads to is not available.
decreasing urinary continence and avoid-
ance of UTI recurrences [72–75] (LoE 1b). 6.4.3 Autogene vaccines
These are uropathogens attained from
6.4 Vaccination
the urine of an individual patient with
Experimental trials in animals using an acute urinary tract infection, pre-
vaccines against Pili-antigens of E.coli pared solely for the use in this individual
or blockade of adherence receptors on person. After culture from a urine sam-
uroepithelial cells cannot be transferred ple, and after inactivation, the antigen
356
is injected subcutaneously in increas- three for boys with dilating vesicorenal

ing concentrations in weekly or monthly reflux were calculated in the same study
intervals. Despite being known for over [84] (LoE 1a).
100 years, this method of “autogenic vac- There has never been a recommenda-
cination” is not established. However, in tion for routine circumcision in Western
some countries (e.g. Germany since 2005) European countries. This is also true for
its use is officially approved. Data on chil- the current guidelines of the American
dren do not exist. Academy of Paediatrics [85]. However,
many paediatric urologists consider a
6.5 Primary prevention “prophylactic” circumcision in high risk
male patients, e.g. infants with urethral
6.6.1 Breast milk feeding valves, with high grade VUR or with
Breast milk feeding significantly protects severe neurogenic bladder [86].
against UTIs, at least during the first
months of life. In a case control study,
the protective effect of breast feeding was 7. FURTHER RESEARCH
highest soon after birth and declined to
zero up to the seventh month of life. It Whereas the treatment strategies for UTI
contributed to a diminished rate of UTIs are well established, the problem of effec-
even after weaning, demonstrating a tive prevention in infants and children
prolonged effectiveness [79]. In another susceptible for recurrent UTI’s continues
case control study only 16% of the infants to be unsolved. However, the identifica-
suffering from UTI had been breast-fed tion of children at risk for pyelonephritic
whereas 55% of the control group without scarring is a prerequisite for targeted
UTI were breast-fed at least until three prophylaxis. Genetics, biomarkers and
days before the end of the observation urinary proteomics will play a decisive
period [80] (LoE 3). role in this respect.
Due to the widespread use of antibiot-
ics, resistance rates in uropathogens are
6.6.2 Circumcision growing worldwide. The surveillance of
Circumcised male infants have a three bacterial resistance and the rational use
to 10-fold diminished risk for UTI than of antibiotics to avoid its further increase
non-circumcised boys. Colonisation with in different populations might be one of
uropathogens such as E.coli, Klebsiella- the most important challenges in future
Enterobacter, Proteus mirabilis and research.
Pseudomonas aeruginosa in urethral and Recent advances in the understanding
periurethral swabs from non-circumcised of innate and adaptive immunity of the
boys is much more frequent than in cir- urinary tract have provided new insights
cumcised controls [81]. There is good into the interaction between the urinary
evidence that circumcision lowers the tract and pathogens, which may impact
risk of urinary tract infections, not only clinical practice. Basic research in host
in infants but also in toddlers [81–83]. defence mechanisms and identification
However, the authors of a recent meta- of susceptible patients will enable novel
analysis came to the conclusion that 111 strategies to prevent infections and mini-
circumcisions would be necessary in the mize renal damage [87]. In this context,
whole male newborn population to avoid the influence of bladder and bowel func-
one UTI. The number to treat (NTT) tion on the susceptibility to UTI and
is much lower in high risk patients: a measures for the treatment of their dys-
number of 11 for boys with recurrent function might especially be of clinical
urinary tract infections and a number of interest.
357
8. CONCLUSIONS Agency for Health Care Policy and

Research, 1992: 115–127.
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complaints, prevention of urosepsis and main steps for developing and grading
infection-related complications, and the
2007. 17(3): 681–684.
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362
|6.5|
Non-operative urological
management of urinary tract
infections in children
Stephen Shei-Dei Yang1, Shang-Jen Chang2
1
Professor of Urology, School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan.
Chief of Surgeons, Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan. No. 289 Chienkuo Road, Xindian City,
Taipei, Taiwan. 231. Fax: +886–2-66289009, Tel: +886–2-66289779 Ext: 5708, urolyang@tzuchi.com.tw
2
Lecturer of Urology, School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan, Attending physician,
Buddhist Tzu Chi General Hospital, Taipei Branch, Taiwan. No. 289 Chienkuo Road, Xindian City, Taipei, Taiwan. 231
Fax: +886–2-66289009, Tel: +886–2-66289779 Ext: 5708, krissygnet@yahoo.com.tw
ABSTRACT included behavioural modification (timed

voiding, adequate fluids intake), topical
With growing antibiotics failure due to steroid for phimosis, dietary supplements
emerging resistance of bacteria, non- (breast milk, cranberry, probiotics),
operative management of paediatric biofeedback training for dysfunctional
UTI plays a more and more important voiding, anticholinergics for reducing
role because of its non-invasive char- intravesical pressure, alpha-blockers in
acteristics and little adverse effects. dysfunctional voiding and neurogenic
We searched PubMed (January 1990 bladder, and intermittent catheterization
to February 2009) for management of for children with large PVR. However,
UTI in children other than surgical cor- the published reports usually included
rection and antibiotics. Risk factors for small number of patients, and were
paediatric UTI include poor fluid intake, lacking of randomization and control-
infrequent voiding, constipation, dysfunc- led group. Further well designed studies
tional voiding, phimosis, and VUR. The are warranted to support the concepts of
purpose of non-operative management non-operative management for paediat-
in paediatric UTI mainly aims to reduce ric UTI.
recurrence of UTI. The proposed non- Key words: children, prophylaxis, uri-
operative management of paediatric UTI nary tract infection, treatment
SUMMARY OF RECOMMENDATIONS 1. INTRODUCTION
1. In boys with non-retractile prepuce Because more than 30% of children with
and UTI, topical steroids for phimosis UTI have recurrence of UTI, with most
are recommended (GoR B, LoE 1b). episodes recurring within six months
after the first UTI [1], the aim of non-
2. In children with voiding postponement operative management is to reduce the
and/or infrequent voiding and urinary recurrence of UTI in children following
tract infection, timed voiding schedule antibiotic treatment.
and optimal fluid intake are recom- We did a systematic search of PubMed
mended (GoR B, LoE 2). (January 1990 to February 2009) for the
3. In children with dysfunctional void- management of UTI in children other
ing are at risk of getting urinary tract than surgical correction and antibiotic
infection, biofeedback relaxation of treatment. Recognized risk factors for the
pelvic floor may be helpful in reduc- occurrence and/or recurrence of UTI are:
ing urinary tract infection (GoR B, phimosis, increased post-void residual
LoE 2.). urine (PVR), infrequent voiding, void-
ing dysfunction, and constipation. The
4. In children with neurogenic or
proposed non-operative management of
non-neurogenic bladder with large
paediatric UTI included behavioural mod-
post void residual urine (PVR),
ification (timed voiding, adequate fluid
clean intermittent catheterization is
intake), topical steroid application for phi-
recommended for reducing sympto-
mosis, dietary supplements (breast milk,
matic urinary tract infection (GoR B,
cranberry, probiotics), biofeedback train-
LoE 2).
ing for dysfunctional voiding, anticholin-
5. Although constipation is common in ergics for reducing intravesical pressure,
children, aggressive management alpha-blockers in dysfunctional voiding
of constipation may reduce the risk and neurogenic bladder, and clean inter-
of recurrent urinary tract infections mittent catheterization for children with
(GoR B, LoE 2) large PVR. Details are discussed below.
6. Breast milk feeding reduces the
risk of urinary tract infection in
infants under the age of seven 2. METHODS
months, especially in girls (GoR B,
LoE 2). We performed a literature search in
PubMed from January 1990 to February
7. Dietary supplements including cran- 2009 using the terms: risk factor, prepuce/
berry juice and probiotics have not phimosis, steroid cream/steroid, behavio-
been found to be effective in reduc- ral therapy, urotherapy, biofeedback/pel-
ing urinary tract infection in children vic floor exercise, adrenergic antagonist,
(GoR C, LoE 3), despite the proven anticholinergics, diet/dietary, dysfunc-
efficacy in adult women. tional voiding/dysfunctional elimination
8. Anticholinergics and alpha-block- syndrome, constipation, dietary, clean
ers in children with high voiding intermittent catheterization, probiotics/
pressure have not been found to lactobacillus, cranberry, breastfeeding,
be effective in reducing the recur- breast milk, with infant/child/children/
rence rate of urinary tract infection: paediatrics/paediatrics AND urinary tract
they are recommended as optional infection. Studies included in the review
under the expert’s opinion (GoR C, were limited to human trials published in
LoE 4). English.
364
Non-operative urological management of urinary tract | 6.5 |
The major end point of this review was high risk of UTI [12], while another study
the episodes of UTI development and suggested that circumcision during anti-
recurrence in children. The improvements reflux surgery has no effect on the inci-
in voiding parameters such as decreased dence of postoperative UTI [13].
voiding pressure, decreased post-void Jorgensen and Svensson [14] first
residual urine was the surrogate end- introduced the topical application of ster-
point of the review. With few randomized oid treating phimosis, several authors
controlled trials performed, evidence from subsequently reported success rates
RCTs was given precedence. ranging from 67% to 95%, and little
adverse effects. The fear that topical ster-
2.1 Results of literature search oids would affect the cortisol level in the
children was not observed [15]. Later,
The literature search identified 62 rel- comparable effectiveness of highly and
evant references published in Pubmed moderately potent steroids treating phi-
since January 1990. Case reports and mosis was observed by Yang et al [16]. In
reviews were excluded. Finally, two a small scale, prospective, randomized
Cochrane Database Systemic Reviews, study by Lee et al [3], topical use of
three randomized controlled trials, and hydrocortisone twice daily on non-retrac-
three randomized crossover studies are tile prepuce for two to four weeks reduced
listed in Table 1. The remaining 54 stud- the rate of recurrent UTI in the follow-
ies included were nonrandomized case ing year in infants with UTI (7.1% in the
controlled studies and mostly uncon- treatment group vs. 29.6% in the control
trolled case series. A meta-analysis of the group). Further studies evaluating neo-
studies was not performed due to the het- natal application of steroid on foreskin to
erogeneity of the trials and the diversity reduce the risk of UTI in healthy infants
of the dosage and methods applied. are warranted. The major shortcoming of
topical steroids on phimosis is that the
use of topical steroids in children with
3. TOPICAL STEROIDS FOR PHIMOSIS pathological phimosis, thick scarred pre-
puce or severe balanoposthitis is less
Circumcision reduces UTI, but with a beneficial, and circumcision should be
significant morbidity. Topical steroids considered in these patients [17].
improve phimosis, but their role in the
prevention of UTI needs further study.
In boys, physiologic phimosis is an 4. BEHAVIOURAL MODIFICATION
important factor both in the development
or recurrence of UTI [10]. Children with Clinically, we usually encourage chil-
a non-retractile prepuce had a signifi- dren with UTI and poor fluid intake to
cantly higher rate of recurrent UTI com- increase fluid intake, although relevant
pared to those with a retractile prepuce studies remain scarce. It is assumed that
[11]. Neonatal circumcision has been an increased fluid intake may result in
confirmed to be effective in reducing the shorter stasis time of urine in the blad-
risk of UTI [12]. There was a reduction of der and better wash-out of bacteria from
90% UTI in circumcised boys when com- the bladder. Infrequent voiding, poor
pared with uncircumcised boys. However, fluid intake, functional stool constipation,
complications including haemorrhage and dysfunctional voiding were more fre-
and infection occurred in 2% of patients quently disclosed in girls with recurrent
undergoing circumcision. One meta- UTI than in control girls [18–19]. When
analysis suggested that the clinical bene- managing children with UTI, a frequency/
fit of circumcision is likely only in boys at volume chart may help physicians and
365
Table 1
Subjects and
References Intervention Design Findings and Significance
Pediatr Nephrol. Probiotics prospective The incidence of recurrent UTI did not differ
2007 Sep;22(9): randomized significantly between the two groups (P > 0.05).
Lactobacillus acido-
1315–20 [2] controlled study The development of new renal scar was not
philus 10(8) CFU/g
significantly different between the two groups
1 g b.i.d. vs. antibi-
(P > 0.05).
otics prophylaxis
Pediatr Nephrol. Topical steroid + prospective the recurrent rate of UTI was 7.1% (2/28) in the
2006 Aug;21(8): physiotherapy vs. randomized infants with retractile prepuces, which was signifi-
1127–30. [3] vaseline controlled study cantly less than the rate (29.6%; 8/27) in infants
with nonretractile prepuces (P < 0.05).
Biol Neonate 2002: Seven days of A multicenter Seven days of Lactobacillus GG supplementa-
82(2):103–108 [4] Lactobacillus GG vs. Prospective, tion starting with the first feed is not effective in
placebo randomized- reducing the incidence of UTIs, NEC and sepsis in
controlled study preterm infants.
Paediatrics. 2001 New sterile catheter A prospective, A new, sterile catheter for each void did not
Oct;108(4):E71 [5] for intermittent randomized, decrease the high frequency of bacteriuria in
catheterization crossover trial patients with neurogenic bladder on intermittent
and reuse of a catheterization.
clean catheter
for intermittent
catheterization
J Pediatr. 1999 Cranberry vs. Double-blind, cranberry concentrate had no effect on bacteriuria
Dec;135(6): placebo placebo-controlled, in children underwent CIC
698–702 [6] crossover study
Can J Urol. 1995 Cranberry juice vs. randomized Liquid cranberry product, on a daily basis, at
Jan;2(1):98–102 [7] water single-blind the dosage employed, did not have any effect
cross-over study greater than that of water in preventing UTI in this
paediatric neuropathic bladder population
Cochrane Database Cranberries for pre- Cochrane Review There is some evidence that cranberry juice may
Syst Rev. 2008Jan venting urinary tract decrease the number of symptomatic UTIs over
23;(1):CD001321 [8] infections a 12 month period, particularly for women with
recurrent UTIs. It’s effectiveness for other groups is
less certain.
Cochrane Database Long-term bladder Cochrane Review Intermittent catheterization is a critical aspect of
Syst Rev 2007:(4): management by healthcare for individuals with incomplete emptying
CD006008. [9] intermittent cath- who are otherwise unable to void adequately to
eterization in adults protect bladder and renal health. There is a lack of
and children. evidence to state that incidence of UTI is affected
by use of sterile or clean technique, coated or
uncoated catheters, single (sterile) or multiple use
(clean) catheters, self-catheterization or catheteriza-
tion by others, or by any other strategy.
parents monitor the voiding frequency time of bacteria multiplication in the

and fluid intake in these children. bladder, and increased PVR that was
Increased post-void residual urine frequently observed in urinary bladder
(PVR) has long been linked to the devel- overdistension [21]. Bladder overdis-
opment and recurrence of UTI [20]. tension is defined as a bladder capacity
Infrequent voiding may result in longer (voided volume +PVR) larger than 115%
366
of expected bladder capacity. At a blad- Children with voiding dysfunction and

der capacity reaching overdistension, vesicoureteral reflux usually have a high
more than one-third of voidings resulted breakthrough infection rate of 34% to
in an abnormal uroflow pattern and PVR 43% [28]. Of 37 children with previous
>20ml [21]. A timed voiding schedule is history of UTI, VUR and non-neurogenic
advised in infrequent voiders to decrease voiding dysfunction who underwent a
the urinary stasis time and to avoid blad- biofeedback training program only 19%
der overdistension. However, the optimal had breakthrough UTI during a mean
amount of fluid intake is not known. follow-up of 21 months [29]. Similarly,
Good toilet posture also plays a role, breakthrough infection was reduced to
enabling optimal relaxation of the pelvic 10% after combined conservative medical
floor muscle and hence reducing dysfunc- and computer game assisted pelvic floor
tional voiding and PVR. In postures with muscle retraining program in a mean fol-
adequate bilateral foot support, the relax- low-up period of 24 months [28].
ation was observed in 94% recorded from
the pelvic floor muscles. EMG amplitudes
from the pelvic floor and adductor mus- 6. CLEAN INTERMITTENT
cles were significantly higher in postures CATHETERIZATION FOR LARGE PVR
with unsupported legs compared to pos-
tures with supported legs [22–23]. Since the first introduction of clean inter-
mittent catheterization (CIC) by Lapides
et al [30], CIC has gained wide acceptance
5. BIOFEEDBACK RELAXATION OF in treating patients with a neurogenic
PELVIC FLOOR MUSCLES bladder to improve bladder emptying, to
achieve continence, to prevent upper tract
Children with increased sphincteric damage and avoid symptomatic UTI. It
activity during detrusor contraction, i.e. is also considered a viable therapeutic
dysfunctional voiding, have a higher rate option for the treatment of children with
of UTI recurrence [24–25]. Biofeedback nonneurogenic dysfunctional voiding and
relaxation of pelvic floor muscles is help- large PVR [27]. During the catheteriza-
ful in improving voiding symptoms and tion procedure, some bacteria may be
urodynamic parameters in children with introduced into the bladder and therefore
dysfunctional voiding [26]. In a study of the most common complication of CIC
girls with recurrent UTI who underwent is UTI. In a long term follow-up study
a training program including voiding and of 14 children who were on CIC, 70% of
drinking schedule, pelvic-floor relaxa- urine samples were positive for bacteru-
tion biofeedback, instructions on toilet ria, but only five symptomatic UTIs were
behaviour and biofeedback uroflowmetry, observed during the 323 patient-weeks.
the program was effective in preventing Therefore, the author concluded that CIC
recurrence of UTI in 35 of 42 (83%) chil- may cause asymptomatic pyuria while
dren [27]. In a prospective, randomized reducing the possibility of febrile UTI in
study comparing pelvic floor exercise and children with a neurogenic bladder [30].
biofeedback therapy in treating children The factors affecting UTI were catheteri-
with dysfunctional elimination syndrome, zation frequency and the avoidance of
both groups of patients showed a low rate bladder overfilling. The compliance of
of relapsed UTI (3.8% and 10%). Although CIC was good. In a five-year follow-up in
no differences in effectiveness between 86 children with congenital neurogenic
different programs were detected, only bladder, only four (4.6%) discontinued the
children who received biofeedback ther- CIC program because of discomfort asso-
apy had a significantly reduced PVR. ciated with introducing the catheter.
367
Because there are various techniques Of the 66 with dysfunctional elimination

in practice, and different catheters, a syndrome, 82% needed surgical reim-
recent Cochrane review [9] concluded that plantation, while only 18% had sponta-
there is a lack of evidence to state that neous resolution of reflux. Therefore, the
incidence of UTI is affected by use of ster- importance of managing constipation and
ile or clean technique, coated or uncoated voiding dysfunction concurrently cannot
catheters, single or multiple use cath- be overemphasized. A recent study found
eters, self-catheterization or catheteriza- that children with history of UTI had
tion by others, or by any other strategy. more symptoms of constipation than those
without UTI, although poor correlation
between history of constipation and faecal
7. INTENSIVE BOWEL REGIMEN FOR loading on radiological film was observed.
CONSTIPATION The author found it difficult to define con-
stipation in children. Apart from history
Constipation in children is common. The from parents, the Bristol stool form scale
American Academy of Paediatrics defined had been shown to be appreciated by
constipation as “a delay or difficulty children. In children with recurrent UTI
in defecation, present for two or more and constipation, we should have a bowel
weeks”, while some preferred the Bristol movement diary and a frequency/volume
stool scale in the diagnosis of constipa- chart. Then, physicians and/or parents
tion in children [31]. Others advocated can monitor the condition from the chil-
defining constipation as ≤2 defecations dren and supervise them. Treatment of
per week, the Rome III criteria [32]. It is constipation includes osmotic laxatives,
postulated that chronic retention of faecal stimulant laxatives, increasing fluids
mass above the anal verge makes children intake, biofeedback and psychological
maintain a high anal sphincter tone. The intervention, all are effective in the man-
high anal tone leads to pelvic floor (over) agement of constipation [37].
activity and impaired emptying function
of the bladder and elevated PVR which
is an important factor in developing UTI
8. DIETARY SUPPLEMENT
[33]. Another theory is that constipation
may increase uropathogenic organisms
8.1 Breast milk
in the gastrointestinal tract which then
leads to more UTI [34]. Previous studies The protective role of breast milk may be
have documented a correlation between attributed to the specific contents within
constipation and UTI. Romanczuk et the breast milk, including immunoglobu-
al [35] evaluated 180 children suffer- lin A [38], antiadhesive oligosaccharide
ing from recurrent UTIs and found that [39] and lactoferrin [38]. The antibacte-
treatment of chronic constipation may rial effect and selection of low uropatho-
reduce pyuria, bacteuria and inconti- genic bacteria play the role. Marid et al
nence in these children. In a study of 234 observed that shorter duration of breast-
children treated for chronic constipation, feeding was associated with higher risk of
relief of constipation was obtained in 52% UTI in children [40]. Recently, the same
of patients without urinary tract anom- group concluded that ongoing breastfeed-
aly and resulted in disappearance of UTI ing and a longer duration of breastfeeding
[36]. Koff et al [25] evaluated 143 chil- resulted in a lower risk of infection after
dren with primary vesicoureteral reflux weaning, especially in girls [41]. The pro-
and UTI, 66 had dysfunctional elimina- tective role of breastfeeding was strong-
tion syndrome of which 50% had consti- est directly after birth, then it decreased
pation as the most prominent symptom. after seven months of age.
368
8.2 Cranberry probiotics in the prevention of recurrent

From a meta analysis by Jepson and UTI was largely due to antibiotic failure
Craig, there is some evidence supporting and increased evidence of the efficacy
the use of cranberry in reduction of UTI of probiotics [44]. Several studies have
episodes among women with recurrent shown the effectiveness of some lactoba-
UTI, while there are few randomized tri- cilli strains in reducing UTI in women
als evaluating the effectiveness of cran- through improving vaginal ecology
berry in children [8]. In an open label [45–46]. However, controversy exists over
randomized study, 150 women with uri- the efficacy of probiotics in prevention of
nary tract infection of E.coli were ran- paediatric UTI. Dani et al [4] adminis-
domly allocated to receive cranberry tered Lactobacillus GG in neonates with
juice, lactobacillus drink, or no interven- UTI, sepsis, and necrotizing enterocolitis:
tion. About a 20% reduction in absolute no significant effect of Lactobacillus GG
risk in the cranberry group compared in reduction of UTI was noted. A prospec-
with the control group was observed [42]. tive, randomized controlled study com-
However, the evidence of the role of cran- pared the conventional antibiotics and
berry in prevention of UTI in children probiotics in treating children with pri-
is still inconclusive, although cranberry mary VUR, the incidence of recurrent UTI
juice consumption provides significant was comparable in both groups of chil-
anti-adherence activity against different dren [2]. Long-term effects of probiotics
E.coli uropathogenic strains in the urine in children need further evaluation. Also,
compared with placebo [43]. Schlager et which strains of lactobacillus are more
al conducted a double-blind, placebo-con- helpful in preventing paediatric UTI need
trolled, crossover study to determine the further elucidation [47]. Despite the pos-
effect of cranberry juice on pyuria and sible clinical effects of probiotics on UTI
symptomatic UTI in children with neuro- in children, two cases with bacteremia of
genic bladder needing clean intermittent lactobacilli were reported [48].
catheterization [6]. They found that cran-
berry concentrate had no effect on bacte-
riuria in the study population, although 9. MEDICATIONS OTHER THAN
this may be partly due to host suscepti- ANTIBIOTICS
bility to infection. Foda et al conducted a
randomized single-blind cross-over study 9.1 Alpha-blockers
to compare cranberry juice and water,
and no difference in infection of the inter- There were several studies to show
vention periods were observed [7]. These the effectiveness of alpha blockers to
two studies only enrolled a small number improve voiding dysfunction and reduce
of children. More studies are required to PVR [49–51]. However, none of these
elucidate the role of cranberry in preven- studies correlated the alpha-blockers to
tion of paediatric UTI. reduction of UTI. In children with dys-
functional voiding or neurogenic blad-
der, alpha-blockers may relieve bladder
8.3 Probiotics
outlet obstruction and improve urody-
The term probiotics is defined as “live namic parameters such as uroflow rate
microorganisms which when admin- and post-void residual urine. Yang et al
istered in adequate amounts confer a evaluated the effectiveness of doxazosin
health benefit on the host” [44]. The con- in 16 boys with low flow rate and uri-
cept of probiotics developed from normal nary incontinence. The symptoms and
flora that exist in the gastrointestinal flow rate improved in half of the chil-
tract and genital area. The introduction of dren after medical treatment, although
369
no placebo control group was compared lacks a well-controlled group. In a multi-

[51]. In a randomized, double-blind, center, open-label extension of a 12-week,
placebo-controlled study, doxazosin did double-blind, placebo-controlled study of
not demonstrate a significant objective tolterodine ER in children with urge uri-
benefit (including incontinent episodes, nary incontinence [54] UTI was the most
voiding parameters, and PVR), but pro- commonly reported adverse effect which
duced a significant subjective benefit in occurred in 7% of children during that
the treatment of urinary incontinence open-label treatment. Although only 0.9%
secondary to voiding dysfunction [52]. of UTI was considered by investigator
Yucel et al [53] conducted a small scale, to be treatment related, the role of anti-
prospective, open-label, randomized cholinergics on paediatric UTI needs fur-
study to compare the efficacy of bio- ther evaluation.
feedback therapy and alpha-blockers
for children with dysfunctional voiding
and urinary tract infection. The peak 10. FURTHER RESEARCH
flow rates, PVR, and urge incontinence
improved in both groups without statis-
Despite clinical importance of urinary
tical difference while these patients also
tract infection in children, there is a
received behavioural therapy, anticholin-
lack of large scale, well designed, and
ergics and antibiotics prophylaxis. There
randomized controlled trials on the top-
existed no long-term effects of alpha-
ics about non-operative management.
blocker on paediatric dysfunctional void-
Although some dietary supplements
ing and UTI, further evaluation should
were proven to be effective in adults,
be warranted.
more studies in children are warranted.
Besides, further studies on the impact
9.2 Anticholinergics of life style modification and the optimal
fluid intake on paediatric UTI should be
Theoretically, anticholinergics may
performed.
relieve the symptoms of frequency,
urgency, and urgency incontinence in
children with UTI. However, the fear that
anticholinergics may increase PVR and 11. CONCLUSIONS
hence increase the rate of UTI was still a
major concern for most paediatric urolo- Several non-operative means are avail-
gists [54]. The rationale of anticholiner- able for reducing the recurrence of UTI.
gics in treating children with UTI lies in Except for those with anatomical anom-
the fact that anticholinergics can inhibit aly, non-operative urological management
bladder contractions and reduce bladder for the above mentioned risk factors may
pressure. Some studies advocated add- reduce the recurrence rate of UTI. The
ing anticholinergics in treating VUR with common shortcomings of these studies
bladder overactivity. In their opinion, on non-operative means are small sam-
anticholinergics can reduce bladder pres- ple size, lack of randomization, ill-defined
sure and lower the rate of breakthrough severity of disease and other confounding
UTI [55–56]. In children with spinal factors. Since these non-operative meth-
cord injury, Generao el al [57] suggested ods usually bear little risks to the chil-
early clean intermittent catheteriza- dren, and the long-term sequelae of UTI
tion and use of anticholinergics to pre- may be detrimental, efforts to apply these
vent upper tract deterioration, improve non-operative methods are still recom-
continence and decrease infections. mended to reduce the recurrence of UTI
However, the design of these studies (Table 1).
370
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373
|6.6|
Medical therapy versus surgery

in vesicoureteral reflux from the
view of the paediatrician
Rolf Beetz
Paediatric Nephrology, Center for Paediatric and Adolescent Medicine, University Medical Clinic
Langenbeckstr.1, 55131 Mainz
Phone: +41-6131-17 3937, Fax: +41-6131-17 6426, e-mail: beetz@kinder.klinik.uni-mainz.de
ABSTRACT at least initially, is long term antibacte-

rial prophylaxis to prevent UTI. Another
Up to 30(–50) % of children present- option, presumably indicated in high
ing with their first urinary tract infec- grade VUR, is surgical correction in order
tion (UTI) are subsequently diagnosed to prevent the ascension of bacteria to
with vesicoureteral reflux (VUR) [1–2]. the kidney. Until recently, open surgery
The main goal of any therapy in vesi- was the only treatment option. Currently,
coureteral reflux is the prevention of endoscopic injection with dextranomer/
acquired parenchymal damage by ascend- hyaluronic acid copolymer is widely used
ing urinary tract infections with their [3]. However, in lower to mild reflux
potential sequelae such as hypertension grades no treatment at all seems to be
and/or chronic kidney failure. However, in quite a secure strategy if pyelonephritis
many cases of dilating VUR, renal dam- episodes are promptly treated.
age is already present at diagnosis and is The wide spectrum of treatment
a congenital kidney malformation associ- options provides the opportunity for
ated with VUR rather than an acquired sophisticated therapeutic and prophy-
lesion. lactic strategies. However, in spite of
To prevent future renal scarring, two several national guidelines published or
treatment options are available. Due to being in process no consensus has been
the fact that low to medium grade VUR found yet regarding the best therapy
may spontaneously resolve, the cur- for different grades of reflux and renal
rent standard of care for most children, involvement.
Medical therapy versus surgery in vesicoureteral reflux | 6.6 |
A risk oriented therapy for infants laterality and degree of reflux, bladder
and children with reflux should account function, recurrences of symptomatic
for its complexity. This probably requires UTIs, pre-existing renal scars and the
an extended classification. It should not expectations of parents (GoR B).
only include reflux grades but also fac- 4. VUR grade V is commonly regarded as
tors like bladder dysfunction, age, sex, requiring surgical treatment because
urinary tract infections and scarring spontaneous resolution is very rare
as decision criteria for treatment and (GoR C).
prophylaxis.
To a lesser extent, conservative and 5. If dilating VUR persists during long
surgical concepts should not compete term antibacterial prophylaxis, the
against each other but complement one disadvantages of antibiotics such as
another. Interdisciplinary cooperation side effects or the development of bac-
should result in a differentiated concept terial resistance limit its practicabil-
of therapy and prophylaxis of reflux and ity. In these cases surgery should be
urinary tract infection. considered (GoR C).
Key words: reflux, prophylaxis, 6. Bladder dysfunction increases the
pyelonephritis, voiding dysfunction, risk of urinary tract infections and
resistance, recurrence, urinary tract can lead to significant delay in reflux
infections, children, infants. maturation. Its detection by careful
history and its efficient treatment
therefore is mandatory in affected
SUMMARY OF RECOMMENDATIONS children (GoR B).
7. Therapeutic delay increases the risk
Preliminary note: the following recom- of pyelonephritis and subsequent
mendations apply to cases with the his- renal scarring. Diagnosis and treat-
tory of at least one symptomatic UTI ment of febrile urinary tract infection
before or after the diagnosis of VUR. therefore should be initiated promptly
1. Due to its high spontaneous matura- and effectively (GoR A).
tion rate, most of the children with 8. In patients with VUR, symptomatic
reflux grades I-II should be treated UTI is caused more often by non-E.
conservatively (GoR A). coli than in uncomplicated infections.
2. Antibacterial prophylaxis in low grade This has to be considered with calcu-
reflux (grade I-II according to the lated antibacterial therapy (GoR B).
International Reflux Classification)
is not superior to pure surveillance 1. INTRODUCTION
without medication. In low grade
reflux without frequent recurrences of Scarcely another topic in paediatric urol-
pyelonephritis, antibacterial prophy- ogy has been discussed more controver-
laxis therefore is not generally recom- sially than vesicoureteral reflux. Despite
mended (GoR A). growing knowledge on the interrelations
3. In VUR grade III-IV, surgical reflux between reflux, urinary tract infection
correction and long term antibacte- and renal scars, the significance of reflux
rial prophylaxis show no difference in the pathogenesis of pyelonephritis
regarding the risk of renal damage. and renal damage remains contentious.
The individual decision for surgical Over the last decade vesicorenal reflux
or conservative treatment of dilating and reflux nephropathy have been rec-
VUR should depend on multiple terms ognized as being parts of a multifactorial
and conditions such as age and sex, disturbance of ureterorenal development;
375
“CAKUT“ (congenital anomalies of kid- over the pathogenic importance of VUR in

neys and urinary tract) [4–5]. the development of pyelonephritic scars.
Over 30% of children with urinary Systematic studies using DMSA-scans
tract infection and presenting with a demonstrated that pyelonephritic scars
radiologically detected vesicoureteral can develop in comparable numbers in
reflux (VUR), show renal scars in the infants and children with or without
ipsilateral kidney [6]. In contrast, these reflux [14]. These results throw a new
parenchymal changes rarely exist in the light on VUR: pyelonephritis, not reflux
non-refluxing contralateral kidney of the itself, is the crucial mechanism leading
same child [7–8]. Radiologically detect- to parenchymal damage in acquired renal
able scars have therefore been classified scarring.
as “reflux nephropathy” [9]. The pro- The following factors increase the risk
portion of renal units with reflux neph- for acquired renal damages:
ropathy correlates with the reflux grade.
• Recurrent pyelonephritis
Basically, there are two conditions poten-
tially leading to renal damage in associa- • Therapeutic delay of pyelonephritis
tion with VUR: • High grade vesicorenal reflux
1.1 “Congenital reflux nephropathy” While it is well known that infants and
Approximately one third of newborns young children bear a particular risk for
with sonographically presumed and pyelonephritic damage [15], renal scars
VCUG proven VUR present with paren- can also develop during later childhood
chymal defects in DMSA scans [10–11]. and adolescence [13, 16–17]. In recent
This congenital association of VUR and years it has become obvious that the indi-
renal damage can probably be explained vidual risk for pyelonephritic scars might
by a disorganisation of ureteral develop- be partially genetically determined [18].
ment in early embryonal stage [12]. If From the view of the paediatrician, the
the ureteral bud arises aberrantly from main goal of any therapy is the preven-
its typical origin at the Wolff-duct, it can tion of acquired parenchymal damage by
connect to undifferentiated parts of the ascending urinary tract infections [19].
metanephrogenic blastema, thus inducing Today, there are different ways to achieve
dysplastic renal parenchyma. Dilating this aim. Strategies with the lowest inva-
reflux predominantly is detected in boys, siveness and greatest efficacy in this
with dilating ureters or renal pelvices respect will become accepted in future.
being noticed by ultrasound. As the pro-
portion of renal units with parenchymal
2. METHODS
damage increases with reflux grade, this
might explain why male infants are more
A systematic literature search was
often affected by congenital reflux neph-
performed for the last 10 years in
ropathy than girls.
MEDLINE and the Cochrane library
with the following key words: urinary
1.2 Acquired pyelonephritic renal
tract infections, therapy, prophylaxis.
damage associated with VUR
Limitations were children aged 0–14
The emerging development of renal scars years. An English abstract had to be
is usually associated with the occurrence available. The authors had also continu-
of a pyelonephritic episode [13]. A vesico- ously observed the relevant literature
renal reflux is said to favour the ascen- concerning the topic over the last twenty
sion of uropathogens up to the kidney. years. Only peer reviewed articles were
However, there is growing uncertainty included. More than 300 publications
376
were identified, which were screened by encourages a strategy of “watchful wait-

title and abstract and more than 100 ing“ [26]. Conservative strategies today
were included in this analysis. rely on this concept using antibacterial
The studies were rated according long term prophylaxis to decrease the
to the level of evidence (LoE) and the risk of UTI recurrences as long as reflux
grade of recommendation (GoR) using has not been resolved or downgraded.
ICUD standards (for details see Preface) The indications for antibacterial proph-
[20–21] ylaxis differ from country to country and
from clinic to clinic. The guidelines of
the American Academy of Paediatrics
3. THERAPEUTIC STRATEGIES IN recommend antibacterial prophylaxis
VESICOURETERAL REFLUX independent of reflux grade in all cases,
if there is no absolute indication for sur-
The main goal of therapy is the preven- gical repair [27]. This recommendation
tion of parenchymal damage. In primary was adopted in a recent German consen-
reflux, ascending urinary tract infec- sus paper and advised after diagnosis
tions are responsible for acquired renal of VUR following a pyelonephritis up to
damage. Without urinary tract infection, the fifth year of life in girls and the sec-
primary VUR does not usually cause ond year of life in boys [28]. In a Swedish
scarring. guideline published in 1999, antibacte-
Today, there are two principal thera- rial prophylaxis is used exclusively with
peutic options for primary VUR. The reflux grade III-V and continued for one
“conservative” concept relies on the spon- year. Thereafter prophylaxis is continued
taneous resolution of reflux which mainly if the reflux is not downgraded to grade
depends on reflux grade, but is also influ- 0-II [29].
enced by the presence of bladder func- Today, nitrofurantoin and trimetho-
tional status and age at presentation. prim are the first choice substances used
Surgical therapy relies on the hypothesis for antibacterial prophylaxis of UTI’s.
that the risk for pyelonephritis would be Cefaclor also has its place in long term
significantly lower after the cessation of antibacterial prophylaxis [30].
reflux. However, the reliability of intake is
uncertain. In an observation study, only
two-thirds of the paediatric patients
3.1 Long term observation and
took the antibacterial medication reg-
antibacterial prophylaxis
ularly [31]. A recent analysis of over
For a long time there has been an agree- 35,000 VUR patients evaluated the ratio
ment in principle about the fact that chil- of total days of antibiotic fill over the
dren with pyelonephritis and VUR are at 12-month period following VUR diagno-
risk for developing renal scars and that sis. The average rate of compliance dur-
this risk correlates with the degree of ing this time frame was 41.4%, meaning
reflux [6, 22–23]. This is especially true that, on average, patients had enough
for young infants with dilating vesico- antibacterial therapy to last 41.4% of
renal reflux [24]. The pre-existence of the year [32]. “Breakthrough infections”
parenchymal defects further increases can frequently be ascribed to poor com-
this risk [25]. pliance. Therefore, it is imperative that
The proportion of refluxing ureters parents and patients are fully informed
in the population as well as the degree on the use of antibacterial prophylaxis
of reflux in persistently refluxing renal before commencement and encour-
units decreases with growing age. This aged to continue treatment as long as
phenomenon of “reflux maturation” necessary.
377
3.1.1 Duration of antibacterial become more complicated over the last 10

prophylaxis with vesicoureteral years. It is widely accepted that the risk
reflux for pyelonephritic renal scars decreases
The optimal duration of long-term anti- with increasing age. This has caused a
bacterial prophylaxis is as unclear as recommendation for the cessation of anti-
its indication. Following the rationales bacterial prophylaxis in later childhood,
for antibacterial prophylaxis mentioned despite continuing low grade reflux [29,
above, it should be continued until the 36]. Several recent studies seem to sup-
risk of pyelonephritic recurrences is port this concept with low grade reflux
diminished and/or the risk of renal scars [33, 37–38]. However, the extent of the
is “outgrown”. risk of acquired scarring actually out-
In children with vesicorenal reflux, growing with age remains unclear. There
prophylaxis is usually discontinued after are clinical and experimental data which
resolving reflux, proven by repeated demonstrate the risk of renal scarring in
VCUs, or after successful reflux surgery. later childhood and adolescents [13, 39].
The situation is more difficult in cases The cessation of antibacterial prophy-
with long-lasting, high-grade reflux with- laxis is an individual decision which
out breakthrough infections, and in which must consider the duration of the previ-
continuation of conservative treatment is ous infection-free period, the degree of
intended. reflux, pre-existing parenchymal damage
The decision to discontinue antibacte- and the existence of bladder dysfunction.
rial prophylaxis is quite easy in boys with Last but not least, the decision depends
vesicoureteric reflux. Long-term prophy- on the compliance and reliability of the
laxis in boys over one year of age with family.
conservatively monitored vesicoureteric
reflux has been questioned because the
risk of recurrence is extremely low in 3.1.2 Importance of Bladder Dysfunction
boys at this age [33–34]. in Vesicoureteral Reflux
In girls with vesicorenal reflux, the Vesicoureteral reflux, urinary tract infec-
decision for stopping antibacterial proph- tions and bladder dysfunction are fre-
ylaxis is comparatively more difficult. quently associated [40–42] (Table 1).
The above-average susceptibility for UTIs Overall it is estimated that bladder dys-
often continues over many years into function exists in about 50% of children
adulthood [35]. With growing restraint with VUR [43]. Bladder function influ-
in surgical correction, the situation has ences the spontaneous regression rate
Table 1 Frequency of non-neurogenic bladder dysfunction in children with vesicoureteral reflux

(Diagnosis by urodynamic study).
Types of bladder dysfunction (%)
Source Patients (n) Detrusor-hyperactivity Detrusor-Sphincter-Dyscoordination
Taylor et al. 1982 [104] 37 75 not investigated
Koff u. Murtagh 1983 [105] 62 55 not investigated
Nielsen et al. 1984 [106] 41 50 25
Secura 1989 [107] 53 75 68
Scholtmeijer et al. 1994 [108] 101 40 not investigated
378
of reflux [42, 44–46]. These observations 3.1.4 Effectiveness of antibacterial

support the current trend of a differenti- prophylaxis
ated view of the phenomenon “reflux“: Antibacterial prophylaxis has been shown
not only are reflux grade or the configura- to be safe and has been repeatedly docu-
tion of ureteral insertion into the bladder mented as decreasing symptomatic recur-
crucial prognostic factors in the natural rences of uncomplicated recurrent UTI
history of reflux, but bladder function is in women [49–53]. Most of these studies
also an important predictive parameter show a remarkably consistent re-infection
for spontaneous reflux maturation, sus- rate of 2.0–3.0 per patient year, reduced
ceptibility for pyelonephritic episodes to 0.1–0.2 per patient year with prophy-
and for renal damaging. This awareness laxis (LoE 1a).
has implications for conservative reflux However, the evidence that antibac-
therapy. It must include the treatment terial prophylaxis works in uncompli-
of pre-existing bladder dysfunction to be cated UTI in young women does not
successful in the long run [47]. mean that it is also effective for the
prevention of recurrent UTIs in chil-
3.1.3 Reflux control during observation dren [54]. Furthermore, prophylaxis
Commonly, annual controls of reflux in adults is preferably carried out to
are recommended during conservative reduce the rate of cystitis in women,
treatment. However, the extension of whereas in children efforts are made
these intervals would have no unaccept- to avoid pyelonephritic episodes, which
able influence on the duration of prophy- might lead to renal scars. The question
laxis. Thompson et al. demonstrated via of whether antibacterial prophylaxis is
a mathematical model that two-year effective in children therefore, presum-
intervals with low-grade refluxes would ably has to be focussed on the develop-
decrease the number of VCUs by 42%, ment of renal scars with and without
whereas the duration of antibacterial medication.
prophylaxis would only be prolonged by There is some evidence from a number
16%. In high-grade reflux, a three-year of studies that antibiotics may prevent
interval would decrease the number of recurrent UTI in children, particularly
VCUs by 63%, whereas the duration of during the period of prophylaxis. Previous
prophylaxis would only be prolonged by pioneer trials in children have demon-
10% [48]. Therefore, the frequency of strated the combination of trimethoprim-
repeated VCUs should be based individu- sulfamethoxazole, trimethoprim and
ally on reflux grade with preference to nitrofurantoin to be effective prophylactic
longer intervals. drugs [55–60] (Table 2).
Table 2 Prospective randomised Pioneer Studies on antibacterial prophylaxis in children.
Authors, year of Duration of

publication Age of probands Study design prophylaxis
Stansfeld JM et al, 1975 [60] 6 months-14 years Cotrimoxazole vs. Placebo 6 months
SavageDC et al, 1975[58] 5–7 years Cotrimoxazole or Nitrofurantoin vs. 10 weeks

control
Lohr JA et al, 1977[55] 3–13 years Nitrofurantoin vs. Placebo 6 months
Smellie JM et al, 1978[57] 2–12 years Cotrimoxazole or Nitrofurantoin vs. 6–12 months
control
379
However, in recent years doubts have Initially a DMSA scan was performed
arisen concerning the rationale of the and repeated after six months or after
widespread use of long-term antibac- a febrile urinary tract infection. There
terial prophylaxis in paediatric urol- were no differences between the groups
ogy. The established indications and concerning the recurrence or severity of
the efficacy of antibacterial prophylaxis UTIs, or the development of renal scars.
per se have been questioned in several The authors concluded that neither mild
reviews [61–65]. Williams et al. stated reflux nor antibacterial prophylaxis influ-
in a recent Cochrane review that there is ence the rates of pyelonephritis and renal
considerable uncertainty about whether scarring [66].
long-term, low-dose antibiotic administra- A French working group observed the
tion prevents UTI in children [65]. Most influence of antibacterial prophylaxis
of the authors of these articles criticize with cotrimoxazol on the frequency of
the lack of evidence for using antibac- UTI in 225 children aged one month up
terial prophylaxis, due to the low qual- to three years with vesicoureteral reflux
ity and small patient groups of available grade I-III during an observation period
clinical trials. Indeed, recommendations of 18 months. Concerning sex, age and
offering continuous antibiotic prophylaxis reflux grade there were no differences
in children are based on limited scientific between treated patients and the control
data. group. During the observation period,
Recently published results of a pro- the rate and severity of UTI was not sig-
spective, randomised controlled study nificantly different between both groups.
comparing the effects of antibacterial Only in boys with reflux grade III could
prophylaxis on patients with and with- a significant reduction of recurrences be
out vesicoureteral reflux also question the demonstrated in the treatment group
effectiveness of antibacterial prophylaxis [67]. These results were actually sup-
in children with low-grade reflux [66]. In ported by two Italian studies [68–69]. In
this study, after an acute pyelonephritis, summary, the four randomised control-
218 patients of three months to 18 years led studies cited above allow the conclu-
of age, with or without mild vesicoureteral sion that antibiotic prophylaxis would not
reflux, randomised to a group with and a be indicated for children following a first
group without antibacterial prophylaxis, febrile UTI if no or only mild grade I or II
were followed over a period of one year. reflux is present [70] (Table 3). However,
Table 3 Current prospective randomised studies on antibacterial prophylaxis in children.
Author, year of Characteristics of Antibiotic/control Influence of prophylaxis on

publication probands
UTI recurrence Renal scarring
Garin EH et al, 2006 VUR 0-III TP/MMZ or Nitrofurantoin n.s. n.s.

[66] vs no prophylaxis
Roussey-Kelser G VUR I-III TMP/SMZ vs no n.s. n.s.

et al, 2008 [67] prophylaxis
Pennesi M et al, VUR II-IV TMP/SMZ vs no n.s. n.s.

2008 [69] prophylaxis
Montini G et al, VUR 0-III Amoxy-Clav or TMP/ n.s. n.s.

2008 [68] SMZ vs no prophylaxis
* n.s. = not significantly different from Placebo.
380
for higher grade reflux, no definite conclu- symptomatic urinary tract infections.
sions can be drawn from current studies. Secondary end-points are the develop-
At this time, three randomised pro- ment of renal scars and of bacterial
spective studies are in progress, hopefully resistance. 600 children at the age of
resulting in answers to current questions two to 72 months with reflux grades I-IV
concerning antibacterial prophylaxis with after their first UTI will be included. One
VUR: of the first statements by the authors of
One of these studies has been initiated this study closed with the following sen-
in Sweden by the Gothenburg group. In tence: “It is time that we recognize the
over 200 children under the age of two need to base our decisions on data that
years with reflux grade III and IV, three is obtained from studies relatively free of
treatment options were compared: low- bias. However, until these data are avail-
dose antibacterial prophylaxis, early able, under diagnosis and under treat-
therapy of recurrences in cases with- ment should be approached with caution”
out antibacterial prophylaxis and early [73].
endoscopic reflux correction by subu- Indeed it would be unwise to abruptly
reteral injection of Deflux®. Preliminary leave empirically based and well-prac-
results demonstrate significant superior- ticed, commonly accepted strategies for
ity of antibacterial prophylaxis compared some current study results. Many fac-
to surveillance without prophylaxis tors involved in clinical course and prog-
regarding the risk of new renal scar- nosis must be drawn into consideration
ring (Presentation at the International including age, sex, degree of reflux, asso-
Conference on Vesicoureteral Reflux in ciated malformations, bladder function,
Children, Göteborg, Sweden, June 4–6, bacterial characteristics, localization of
2009). The results are expected to be infection and treatment. This can only
published in late 2009. They will pre- be done by dividing the children into dif-
sumably change established concepts ferent study groups and simultaneously
of reflux treatment in the future [71]. stratifying them according to the most
A second study performed in Australia, important factors [24]. To make antibac-
called PRIVENT-study (Prevention of terial prophylaxis work, excludable pre-
Recurrent urinary tract Infection in disposing factors for recurrent UTI have
children with Vesicoureteric reflux and to be removed or taken into considera-
Normal renal tracts Trial) enclosing tion by careful stratification. This is not
nearly 600 with VUR I-IV in the age of only true for daily practice but also for
two to 72 months has just been finished each prospective study, which aims to
(http://www.kidney-research. org/privent. test the benefit of antibacterial prophy-
php). The third study is the American laxis on UTI recurrence rates and renal
RIVUR study (Randomized Intervention scars. Otherwise, the study results may
for children with VesicoUreteral Reflux) be influenced by more or less meaningful
which was started in 2007 [72]. This susceptibility factors.
multicentric, randomised, placebo-con-
trolled study was designed to examine
the effectiveness of antibacterial prophy- 3.1.5 Treatment of symptomatic urinary
laxis in children with reflux who had suf- tract infection
fered from UTI. The study was initiated In patients with VUR, symptomatic UTI
by the National Institute of Diabetes and more often is caused by non-E.coli than
Digestive and Kidney Disease (http:// in uncomplicated infections. Under anti-
www.rivur.net). 15 clinical centres are bacterial prophylaxis, breakthrough
participating in this study. The primary UTIs are usually caused by resistant
end-point is the occurrence of febrile/ uropathogens. This has to be considered
381
if calculated antibacterial therapy has to in untreated patients [85]. Asymptomatic

be initiated. bacteriuria is commonly a benign condi-
Significant delays in initiating antibacte- tion even with VUR [86]. Treating ABU
rial therapy increase the risk of renal scar- therefore might be rarely indicated even
ring in experimental as well as in clinical in the presence of VUR [86].
settings [13, 74–78]. However, in a recent
study in infants and children one month 3.2 Surgical therapy
to seven years of age who had presented
with acute pyelonephritis proved by paren- The surgical concept is based on the
chymal perfusion defects in DMSA-scans, assumption that ascension of uropatho-
the incidence of persistent scars in a sec- gens to the kidney leading to pyelonephri-
ond DMSA-scan was not dependent on the tis can be avoided by reflux correction, in
start of therapy within a range from < one spite of continuing susceptibility to bacte-
to five days after onset of symptoms [79]. rial growth in the bladder.
This does not mean that delay of therapy Commonly accepted indications for sur-
is without consequences. Indeed, a similar gical reflux correction are:
study performed in infants up to one year • Recurrent pyelonephritis in spite
of age, acute parenchymal changes were of antibacterial prophylaxis (break-
found in 41% of those children who were through infections)
treated within 24 hours and in 75% of the • Poor compliance with antibacterial
cases with a therapeutic delay of more prophylaxis
than four days. In 51% of all of them, per-
• Progression of pyelonephritic scars
sistent renal damage was detected in the
second DMSA-scan independent from the • High grade reflux (grade IV-V) with
start of therapy. This clearly indicates that low chance of spontaneous reflux
early therapy protects against the develop- resolution
ment of severe pyelonephritis. However, if • Persistent high grade reflux in adoles-
pyelonephritic parenchymal changes have cent girls without tendency to resolve
occurred, therapeutic delay is no longer spontaneously
crucial for the risk of renal scarring [80].
• Refusal of antibacterial prophylaxis
In summary, early diagnosis and imme-
by parents and/or patient and desire
diate therapy of UTI might be one of the
for surgical correction with high grade
most effective strategies in the prevention
reflux
of renal scarring in patients with VUR and
UTI recurrences. The principle of all variants in open
reflux correction is the prolongation of
the submucosal section of the refluxing
3.1.6 Should asymptomatic bacteriuria ureter. The success of operation depends,
be treated in patients with amongst other things, on the reflux
vesicoureteral reflux? grade. The success rate of open surgical
Several prospective studies in girls dem- techniques is about 96% in experienced
onstrated that asymptomatic bacteriuria hands [27].
(ABU) leads neither to renal scarring nor Endoscopic reflux correction with sub-
retardation of kidney growth in young ureteral injection of bulking substances
girls in the long term [81–84]. The bac- has become a serious concurrence to open
teria tend to be of low virulence and do reflux correction due to modern material
not harm the kidney. Antibacterial treat- like NASHATM/Dx (stabilized, non-animal
ment of ABU in girls did not have any hyaluronic acid/dextranomer) (Dx/HA,
benefit but was associated with a higher Deflux®, Q-Med AB, Uppsala, Sweden)
incidence of pyelonephritic episodes than and new techniques (subureteral injection
382
techniques = HIT). An important critique procedures, but also to conservative

of this new method is the lower success reflux management, thereby assuming a
rate concerning cessation of reflux. In position between surgical and conserva-
a recent meta-analysis of endoscopical tive strategies. In several centres, endo-
techniques the success rate was 85%, on scopic techniques are even used in very
occasion achieved only with two or more low degrees of reflux. For the paediatri-
repeated injections [87]. However, most cian this situation has become more dif-
of studies included used the bulking ficult than before the Deflux® era: today,
agents polytetrafluorethylene, collagen or the endoscopically treated group consists
other materials. With exclusive usage of of children who formerly would clearly
NASH (Deflux®), extremely experienced have been treated conservatively as well
surgeons achieved growing success rates as children who would have received open
similar to open techniques [88]. The costs surgery. These trends require new algo-
of endoscopic correction are no less than rithms for reflux therapy, which include
with open surgery or long term prophy- the new techniques. Future experience
laxis [89]. will show their significance in relation-
Some reports exist of a decreased inci- ship to traditional strategies.
dence of UTI after Deflux® procedure
[90]. In a retrospective analysis of a
database, significantly fewer UTIs were 4. SIGNIFICANCE OF DIFFERENT
reported after endoscopic injection with THERAPEUTIC STRATEGIES
Dx/HA compared with children receiving
antibacterial prophylaxis [3]. However, Due to high spontaneous resolution rates,
these results should be assessed with conservative treatment is widely accepted
caution. Evident data from prospective- in VUR grade I-II.
randomised studies concerning long term In dilating reflux (grade III-IV), the
results are missing, especially concerning results of randomised prospective stud-
the incidence of postoperative UTI, renal ies demonstrated that conservative and
scarring and late reflux recurrences. surgical therapy were equivalent if renal
Since NASHA (Deflux®) was approved by scarring was taken as an end-point [43,
the FDA (Food and Drug Administration) 92] (Table 4). The closing report of the
in 2001, there is a trend towards increas- International Reflux Study was pub-
ing numbers of surgical reflux correc- lished in 2006 [43]. This study dealing
tions in the USA [91]. Interestingly, this with reflux therapy is the largest to date,
is due to the increasing number of endo- and included infants and children up to
scopic interventions, whereas the number 11 years of age with VUR grade III-IV
of open reflux corrections remains sta- being detected after UTI. One group
ble [91]. Obviously Deflux® injection has was followed with antibacterial proph-
become not only an alternative to open ylaxis, and surgical reflux correction
Table 4 New renal scars detected during an observation period of 5 years in children with VUR grade III-IV who were
randomised to surgical or conservative therapy.
Patients with new renal scars

Study Patients (n)
Surgical Conservative Total
group (n) group (n) (n)
Birmingham Reflux Study [92] 161 4 5 9 (6 %)
International Reflux Study [109] 302 20 19 29 (13 %)
383
was performed in one group. New renal For instance, in a six-year-old girl with
scars were defined as primary end-point. primary VUR grade III detected after her
During the first five year period, 19 new first febrile UTI presenting with no evi-
scars developed in the conservative group dence of renal scarring or kidney involve-
and 21 in the operative group. In the sec- ment, conservative treatment is justified.
ond five year period only two new scars In contrast, in a female infant with febrile
were detected. Renal growth and recur- UTIs in spite of antibacterial prophylaxis
rence rate of UTIs were almost identical. (“breakthrough infections”), high grade
However, more pyelonephritic episodes reflux and renal scarring detected in a
were registered in the non-operated DMSA-scan, surgical correction has to be
group. The incidence of new renal scars recommended.
was similar in both groups despite higher However, in patients with pre-existing
rates of pyelonephritic episodes in the reflux nephropathy and dilating reflux,
conservative group. the main factor that determines outcome
The children included in the Inter- seems to be the extent of renal parenchy-
national Reflux Study were observed with mal reduction and the degree of functional
special care. Breakthrough infections impairment at the time of diagnosis. In a
were treated promptly. To reproduce prospective study in children with bilateral
results in daily practice, high compliance severe VUR and bilateral nephropathy,
by parents and patients, as well as higher Smellie et al. did not find any differences
than average efforts by the doctor respon- in renal growth, function, or scarring at
sible are prerequisites in the conserva- five years, or renal function at 10 years
tive treatment of reflux. Unfortunately, after randomisation between the conserv-
consequent long term follow-up is not atively followed group and the patients
possible in every case. In a retrospective after surgical reflux correction [95].
study with American children, 34% of the
patients were already lost to follow-up
after diagnosis of reflux. 80% were not 5. POST-OPERATIVE TREATMENT
seen again after their one-year follow-up AND CARE AFTER CESSATION OF
visit. Neither specialisation of the phy- REFLUX
sician, nor health insurance, income,
education or living conditions had any Two groups of patients need long-term
influence on compliance. Only the age follow-up even after successful surgical
of the mother correlated positively with correction or spontaneous cessation of
compliance [2]. reflux:
4.1 Which therapy for which 5.1 Patients with continuing

patient? susceptibility for UTIs
The individual decision for surgical or Many patients who have become con-
conservative treatment depends on mul- spicuous with UTI before surgical repair
tiple terms and conditions such as age or spontaneous cessation of reflux, con-
and sex of the patient, bladder function, tinue to suffer recurrences [96]. In a
degree and laterality of reflux, recur- long-term follow-up study with an obser-
rences of symptomatic UTIs, pre-existing vation period of more than 20 years after
renal scars and the expectations of par- surgical reflux repair, more than 70% of
ents [93]. Last but not least, the avail- the patients developed at least one symp-
ability of a paediatric urologist with tomatic UTI. The infection, however,
experience in surgical reflux correction was mostly restricted to the lower uri-
may play an important role [94]. nary tract [35]. Women with a history of
384
previous UTIs have a high incidence of With bilateral severe reflux nephropa-
bacteriuria in pregnancy, and those with thy, the risk of progressive renal insuf-
renal scarring and persistent reflux are ficiency demands repeated controls of
prone to develop acute pyelonephritis serum creatinine and calculated glomeru-
[97]. Because pyelonephritis can lead to lar filtration rate. Adequate treatment of
risks for mother and foetus, special care hypertension and lowering proteinuria by
is recommended during pregnancy, and ACE inhibitors can probably slow down
urine diagnostics are necessary if symp- the progress of functional loss.
toms suspicious of UTI appear.
5.2.3 Complications in pregnancy
5.2 Patients with reflux Reflux nephropathy and increased sus-
nephropathy ceptibility to UTI’s seem to be risk factors
Over 20% of patients have renal scars at for EPH-gestosis during pregnancy [102];
the time of reflux diagnosis. They are at mild renal insufficiency can probably
risk of developing renal arterial hyper- worsen to higher CKD-levels [103].
tension [98]. Girls can also suffer from
complications in pregnancy. Renal insuf-
ficiency can result from severe bilateral 6. FURTHER RESEARCH
reflux nephropathy.
Today, several therapeutic options can be
5.2.1 Arterial hypertension chosen for the therapy of vesicoureteral
reflux. They include long term antibac-
The incidence of renal arterial hyper- terial prophylaxis, open reflux surgery,
tension is about 12–14% in young adults endoscopic therapy and – last but not
with unilateral renal scars and 18% with least- “watchful waiting” without medi-
bilateral changes [7]. With increasing age, cation. However, controversies exist
the incidence can increase up to over 40% about the optimal treatment, especially
[99]. Lifelong control of blood pressure in higher grades of reflux regarding the
and, if necessary, treatment of arterial risk of recurrent pyelonephritis as well
hypertension are therefore recommended as acquired renal scarring. Therefore,
in patients with reflux nephropathy. there is an urgent need for randomized
prospective controlled studies in this
5.2.2 Renal insufficiency field.
In most cases of unilateral reflux neph- In future studies, many factors involved
ropathy, the hypertrophy of non-affected in clinical course and prognosis must be
parenchyma compensates for the loss of drawn into consideration including grade
functioning nephrons in scarred areas of reflux, age, sex, malformations, blad-
resulting in normal or only moderately der function, bacterial characteristics,
reduced whole kidney function [45]. Silva localization of infection and pre-existing
et al. in a retrospective study of 735 renal damage. This can only be done by
patients with primary VUR found that dividing the children into different study
only 3% progressed to chronic renal insuf- groups and, simultaneously, by stratify-
ficiency with an average GFR of 31.2 ml/ ing them according to the most important
min [100]. Interestingly, in a retrospective factors. Another point is the definition of
study performed by the same authors, the risk of recurrence. It is highly depend-
variables independently associated with ent on the number of previous UTIs. This
chronic kidney disease were not only means that the randomisation should
VUR grade V and bilateral renal damage include a stratification of the number of
but also a delay of the diagnosis of VUR recurrences before the start of the study.
more than 12 months after UTI [101]. Information on patient compliance will
385
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|6.7|
Vesico-ureteral reflux: An American

pediatric urologic perspective
Richard Grady1, Martin Koyle2
1
Associate Professor, Department of Urology, The University of Washington School of Medicine, Attending
Pediatric Urologist, Director of Clinical Research, Division of Pediatric Urology, Seattle Children’s Hospital, 4800
Sandpoint Way NE, Seattle, Washington USA 98105, (206) 987–2130 Office, richard.grady@seattlechildrens.org
2
Professor and Chief, Department of Urology, Michael E. Mitchell Endowed Chair of Pediatric Urology, The University
of Washington School of Medicine, Chief, Division of Pediatric Urology, Seattle Children’s Hospital, 4800 Sandpoint
Way NE, Seattle, Washington USA 98105, (206) 987–1461 Office, martin.koyle@seattlechildrens.org
ABSTRACT in distinguishing renal dysplasia from

renal scarring with current imaging
VUR is a heterogenous condition. As a modalities. The available data suggests
result, the sequelae of this condition that a real but modest positive treatment
depend on a variety of factors includ- effect likely exists for the prevention of
ing an affected individual’s underlying end-stage renal disease due to reflux
propensity for UTI and renal scarring. nephropathy when acquired renal scar-
In aggregate, the presence of VUR, espe- ring is the primary cause of renal failure.
cially higher grades of VUR is associated Key words: urinary tract infection, chil-
with an increased incidence of both condi- dren, vesico-ureteral reflux
tions. However, at this point in time we do
not have the ability to stratify risk in this
patient group as well as we would like to SUMMARY OF RECOMMENDATIONS
do. The available data for UTI and VUR
suggests that surgical or endoscopic treat- 1. Use antibiotics to treat acute UTI in
ment of VUR reduces the incidence of children and reconsider the use of
pyelonephritis but does not eliminate it. antibiotic prophylaxis to prevent UTI
The available data for renal scarring sug- in children with recurrent UTI or
gests that surgical correction likely does moderate to low grade VUR (GoR A).
not prevent scar progression or the forma- 2. Surgical intervention should be used
tion of new renal scars. Information on to treat VUR in the setting of recur-
this area is complicated by the difficulties rent pyelonephritis because it has
Vesico-ureteral reflux: An American pediatric urologic perspective | 6.7 |
been shown to decrease the incidence rationale to treat VUR remains the pre-
of pyelonephritis (GoR A). vention of pyelonephritis and its poten-
3. Intervention to treat VUR may have tial consequences, most notably renal
a modest beneficial effect on reduc- scarring. This is especially the case for
ing the incidence of acquired renal younger child with “immature” kidneys
scarring and end-stage renal disease that have been considered at increased
due to this (GoR C). Surgical interven- risk for acquired renal scarring secondary
tion could be used to prevent acquired to pyelonephritis [6].
new renal scarring but no high grade
evidence exists to justify the use of
surgical intervention to prevent new 2. METHODS
renal scarring or end-stage renal
disease. A systematic literature search was per-
formed in Medline from 1969 to 2008
using the following key words: vesi-
1. INTRODUCTION coureteral reflux* AND treatment with
the following limitations: English pub-
This chapter will focus on the diagnosis, lications, human studies, clinical trials,
evaluation and management of vesico- meta-analyses, review, randomized clini-
ureteral reflux ( VUR) in children. The cal trial, comparative study, ages birth to
management of VUR in children has 45 years old.
come under increased scrutiny due to A total of 339 publications were found
concerns of over-treatment and to con- and screened by title and abstract.
cerns regarding lack of efficacy of some Finally 59 publications were included into
current therapeutic options. For exam- this review and supplemented by publica-
ple, recent clinical trials have demon- tions mentioned in the selected publica-
strated that antibiotic prophylaxis does tions or known by the author.
not decrease urinary tract infections in The studies were rated according to
children with a history of low-grade (non- level of evidence and the grade of rec-
dilating) VUR or recurrent UTI [1–2]. ommendation graded according to ICUD
Other studies have failed to demonstrate standards [7–8].
that treatment of VUR impacts long-term
renal scarring. As a result, the treatment
of VUR is in an area of potential sea 3. EPIDEMIOLOGY
change. A number of recent randomized
clinical trials evaluating VUR treatment Urinary tract infections (UTI) are clini-
are now available. These studies signifi- cally significant in children because they
cantly increase the strength of evidence are so common. Up to 8% of children will
available. experience at least one UTI between the
The initial rationale for diagnosis and ages of one month and 11 years. A sig-
treatment of VUR concerned the potential nificant percentage of febrile infections
of ref lux to exert a “water-hammer effect” are associated with VUR, especially in
on the kidney producing renal damage children evaluated before toilet training
even in sterile urine conditions [3–4]. [9]. In the current antibiotic era, the vast
Concerns for a “water-hammer” effect of majority of these infections are treat-
VUR in a child with a relatively normally able. It is important to remember that
functioning bladder have abated and the 100 years ago childhood kidney infec-
concerns regarding VUR largely focus on tions carried a mortality of up to 25%
its association with ascending urinary and left many children with chronic kid-
tract infection [5]. Currently, the primary ney disease. At the turn of the century,
393
Goppert-Kattewitz noted the acute mor- appear to confer the same risk for fur-
tality of pyelonephritis in young children ther UTI [1, 15–16] (LoE 1b). Antibiotic
at 20%. Another 20% failed to recover prophylaxis has been used as a main-
completely and subsequently died, pre- stay of treatment in the setting of VUR
sumably secondary to renal failure [10] for decades. A Cochrane meta-analysis
After sulfonamide antibiotics became in 2006 discussed five placebo control-
available in the 1940s, mortality dropped led studies evaluating the utility of this
to 2% in children hospitalized for non- treatment. Study design was suboptimal
obstructive UTI [11]. Currently, mortal- in these studies but did provide evidence
ity secondary to UTI approaches 0% for to support this practice [17]. Recently
otherwise healthy children in the United Roussey Kesler and their co-investigators
States conducted a randomized controlled study
demonstrating limited therapeutic ben-
efit for antibiotic prophylaxis to prevent
4. UTI IN THE SETTING OF VUR UTI in infant boys and girls with grades
I-III VUR [2]. The North East Italy
Febrile UTI in the setting of VUR is con- Prophylaxis in VUR study group found
cerning in younger children because such no benefit to antibiotic prophylaxis for
kidneys may be more prone to renal scar- children less than 30 months of age with
ring secondary to ascending infections grades II-IV VUR in preventing pyelone-
[9, 12–14]. As a consequence current phritis or renal scarring [18]. In another
management of pyelonephritis focuses randomized controlled trial, Conway et
on prompt diagnosis and treatment to al found limited clinical efficacy of daily
accomplish: antibiotic therapy to decrease the inci-
• Prompt diagnosis and elimination of dence of UTI in children prone to UTI
the acute symptoms of infection [1]. Bacterial antibiotic resistance and
• Prevention of recurrent UTI poor adherence to daily antibiotic ther-
apy remain possible explanations for lack
• Prevention of acquired new renal of efficacy in these two studies. In con-
scarring trast, a recent prospective randomized
• Treatment of associated urologic abnor- controlled study from the prevention
malities including vesicoureteral of Recurrent Urinary Tract Infection
reflux to decrease the risk for future in Children with Vesicoureteric Ref lux
renal infections and Normal Renal Tracts (PRIVENT)
It is this last focal point that is cur- Investigators group in Australia and New
rently used to justify the evaluation of Zealand demonstrated a modest but sig-
children for VUR because approximately nificant decrease in urinary tract infec-
35–50% of children diagnosed with tions in children taking trimethoprim/
pyelonephritis will have VUR. sulfamethoxazole compared to placebo
[19]. The level of evidence surrounding
the use of antibiotic prophylaxis for mod-
5. RATIONALE FOR SURGICAL OR erate to low grade VUR is LoE 1a.
ENDOSCOPIC TREATMENT OF VUR In contrast, surgical treatment of VUR
TO DECREASE PYELONEPHRITIS has been shown to reduce the incidence
of pyelonephritis in the post-operative
Several randomized clinical studies have period compared to a treatment group of
noted moderate to high grade (III-V) patients using antibiotic prophylaxis [20].
VUR to be independently associated A meta-analysis comparing surgical treat-
with an increased risk for recurrent UTI ment of reflux with long-term antibiotic
in children. Lower grades of VUR do not therapy noted a 60% reduction in febrile
394
UTI by five years in the surgical therapy 6. RATIONALE FOR SURGICAL OR

group.[21] This analysis includes two ENDOSCOPIC TREATMENT OF VUR
randomized studies comparing antibiotic TO PREVENT RENAL SCARRING
prophylaxis to surgical correction of VUR
[20, 22] (LoE 1a). A Cochrane analysis in The rationale for treatment of VUR to
2007 also found a modest but significant decrease renal scarring arose from clini-
reduction in episodes of pyelonephritis cal studies demonstrating an increased
after surgical correction for VUR [23]. risk of renal scarring in children follow-
Haggerty et al also found that endoscopic ing pyelonephritis. From the 1960s to the
therapy to treat occult VUR using a dex- present, the perceived risk of significant
tranomer polymer was been associated renal scarring following pyelonephritis
with a decrease in UTI post-injection in childhood has become more controver-
[24]. The latter study, however, was non- sial. Wennerstrom and co-workers pro-
randomized and retrospective in nature spectively followed 1221 children after
(LoE 2b). Elmore and co-workers recently their first UTI. As part of this long-term
reported a series of children successfully study, they evaluated patients with docu-
treated endoscopically for VU reflux who mented scarring by urography later and
had a lower incidence of UTI post-oper- compared this group to an age-matched
atively than a control group of patients control group who had no evidence of
who had undergone ureteral reimplanta- scarring following their first UTI. On fol-
tion suggesting that endoscopic treatment low-up investigation 16 to 26 years later,
of VUR may reduce the risk for UTI after both groups underwent DMSA scans to
VUR correction even more successfully assess scarring and 51Cr-EDTA inves-
than after open ureteral reimplantation tigation to measure glomerular filtra-
[25] (LoE 2b). tion rate (GFR). Median GFRs in these
Prior surgical correction of VUR does two groups were comparable. However,
not eliminate the risk for UTI during patients with initial bilateral renal scar-
pregnancy but may lower it. Bukowski ring demonstrated a significant drop in
and co-workers found renal scarring GFR on follow-up evaluation. The GFR
acted as an independent predictor for of scarred kidneys also declined on fol-
an increased risk for pyelonephritis low-up investigation [29]. Wennerstrom
during pregnancy. Women with renal also evaluated this same group for hyper-
scarring who had undergone previous tension and found no difference between
ureteral reimplantation were at less risk patients with renal scarring and those
than those who had not. However, for without renal scarring. Plasma renin lev-
women without renal scarring no change els, aldosterone, and angiotensin II levels
in pyelonephritis incidence was noted were similarly unaffected although atrial
between adult women during pregnancy natriuretic peptide was significantly ele-
who had undergone correction of VUR as vated in patients with renal scars [29].
children versus those who had persist- These studies demonstrated that global
ent VUR [26]. Other studies have dem- renal function remain intact for patients
onstrated that adult women who had with renal scarring after UTI but that
previously undergone surgical correction the effects of renal scarring do adversely
for VUR as children remain at increased affect kidneys over time. The strength of
risk for UTI during pregnancy [27–28] evidence of these studies is (LoE 3).
(LoE 3). Still, the primary maternal fac- A second report found that scarring in
tor associated with maternal morbid- boys occurred more often in the presence
ity is a pre-existing reduction in renal of VUR (61%) – especially high grade or
function as assessed by glomerular fil- dilated VUR. The parenchymal loss was
tration rate. global in many of the boys. In contrast,
395
girls with renal scarring demonstrated Currently studies with the best level of
focal scarring and only had VUR in 23% evidence (LoE 1b) show a lack of treat-
of the cases. Furthermore, acquired renal ment effect for surgical or endoscopic cor-
scarring only occurred in the setting of rection of VUR to prevent renal scarring.
recurrent febrile UTI [29]. These findings Prospective studies such as the multi-
support the concept that high grade VUR institutional RIVUR study funded by the
is associated with developmental renal National Institutes of Health may help
abnormalities that occur during embryo- provide more robust data in the future
genesis and that VUR in the absence of to determine in surgical intervention
UTI does not damage kidneys. In this improves renal scarring outcomes [33].
setting what may be considered renal
scarring may, in fact, be renal dysplasia.
The data also highlight the increased risk 7. RATIONALE FOR TREATMENT TO
of renal scarring with recurrent febrile PREVENT END STAGE RENAL
UTI in childhood. Other studies have DISEASE SECONDARY TO REFLUX
demonstrated an increased risk for renal NEPHROPATHY
scarring with UTI and VUR independ-
ent of the grade of VUR [9]. Soylu found Two other publications drew different con-
high grade VUR was a predictor of renal clusions about the epidemiology of reflux
scarring but that only previous renal nephropathy. Craig et al retrospectively
scarring was a predictor for the develop- reviewed the dialysis and transplant regis-
ment of new renal scarring [13] (LoE 3). try in Australia and New Zealand between
Importantly, these studies suggest that 1971 and 1998. They found no change in
some children with VUR may have renal the incidence of reflux nephropathy as a
abnormalities such as renal dysplasia cause of end-stage renal disease during
that occur independent of pyelonephritis this time when comparing subjects 25–34
and are may be congenital. years of age, 15–24 years of age and five to
So, while clinical evidence demon- 14 years of age. The authors conclude that
strates an increased association between treatment to prevent UTI in the setting
high grade VUR and renal scarring (per- of VUR has not been associated with the
haps more accurately renal dysplasia), expected decrease in ESRD due to reflux
it is not clear that surgical treatment of nephropathy. They suggest that ESRD
VUR decreases the incidence or number due to reflux nephropathy may represent
of renal scars following treatment. The congenital dysplasia/hypoplasia that are
IRS found no difference in renal scar- not amenable to postnatal intervention.
ring between groups of children treated In contrast, Hansson and colleagues
with antibiotic prophylaxis compared reviewed the results of a quality assur-
to surgical correction based on intrave- ance project in Sweden. This study sug-
nous urographic data for scarring [20, gests that the long-standing interest in
22]. However, some retrospective stud- Sweden in the early detection of UTI
ies using DMSA nuclear medicine stud- in children has led to a high diagnostic
ies show a decreased incidence of renal rate for UTI. This was associated with a
scarring following ureteral reimplanta- decrease in long-term consequences (scar-
tion when compared to historic data [30]. ring and reflux nephropathy-associated
In contrast, other studies using DMSA ESRD) in that country [34]. Hansson’s
renal scinitgraphy to document renal conclusions are supported by Nuutinen
scarring have found no effect of ureteral et al who analyzed the data from chil-
reimplantation or endoscopic injection on dren with acute UTI and compared it to
the progression of existing renal scars or data in the kidney transplant registry for
the formation of new renal scars.[31–32] England, Wales, and Finland [35] (LoE 3).
396
8. FURTHER RESEARCH REFERENCES
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399
Chapter |7|

in nephropathies,
transplant patients and
immunosupression
Chair: Michael C. Bishop
CHAPTER OUTLINE
7.2 Emphysematous pyelonephritis 404
7.3 Renal abscesses 413
7.4 Polycystic renal disease 419
7.5 Urinary tract infections in renal insufficiency and dialysis 426
7.6 Urogenital infections in renal transplant
patients – causes and consequences 438
|7.1|
Introduction
Michael C. Bishop
Prof. Michael C. Bishop, MD,FRCP,FRCS, Consultant Urologist, Nottingham Woodthorpe Hospital,
748, Mansfield Rd., Nottingham NG5 3FZ., Great Britain
mbish@btopenworld.com
The social and economic burden of host defences and immune competence
chronic illness due to progressive renal progressively impaired in uraemia and
disease is considerable and increasing in is there a corresponding loss of bacterial
the industrialised nations, mainly as a virulence factors, as is to be found in the
result of the rising incidence of cardiovas- strains responsible for asymptomatic bac-
cular disease and diabetes. However, the teriuria, and even for the broad category
process may be spreading to the develop- of complicated UTI? Is there loss of epi-
ing World, particularly where there are thelial integrity in the whole urinary
aspirations to adopt a Western lifestyle. tract of the uraemic individual, promot-
Whilst recurrent uncomplicated cystitis ing the development of intracellular bac-
and even severe pyelonephritis will virtu- terial communities and biofilm?
ally never cause permanent renal dam- Fünfstück and colleagues have con-
age some patients with end stage renal sidered what contribution UTI has made
failure will report life-long symptomatic specifically to the cause of chronic renal
UTIs and this could be a preventable disease and whether UTI will hasten the
component of chronic debilitating illness. progression of renal functional impair-
This section examines some important ment. Intuitively, damaged renal paren-
questions on the causative links between chyma from whatever cause would not be
UTI and chronic renal insufficiency, the expected to tolerate recurrent acute infec-
susceptibility of uraemic patients to UTI, tion with the resilience shown by normal
whether it hastens the progression to end adult kidneys. And yet is there evidence
stage renal failure and the significance that UTI is more likely to cause per-
of UTI in relation to graft function after manent injury in patients with chronic
renal transplantation. renal failure than in normal individuals.
The association between UTI and However, the clinician should be espe-
chronic renal disease may be interest- cially vigilant to exclude obstruction
ing from a basic scientific aspect: are which in combination with infection will
predictably cause rapid destruction of to infection and on bladder function,

residual functioning renal tissue. progressive chronic immunological injury,
Other pre-existing non-obstructive potentially nephrotoxic immunosuppres-
structural uropathies and lower urinary sive agents and the relatively frequent
tract dysfunction are obvious risk fac- need for catheters and stents. UTI can
tors in promoting infection but again it be induced by other organisms to which
is questionable if they are more likely to immunosuppressed patients are particu-
cause kidney damage than in the normal larly susceptible (viruses, yeasts) and
individual, with the possible very contro- which may be difficult to identify. They
versial exception of vesicoureteric reflux. may also be more relevant than conven-
Of course, irreversible damage will very tional bacterial pathogens in the context
occasionally occur as part of circulatory of transplant functional deterioration,
multiorgan failure induced by urosepsis. through direct toxic effects and indirectly
The term ADPKD covers a family of by inducing rejection.
systemic disorders characterised by vari- Asymptomatic bacteriuria is a conun-
able but usually inexorable progression to drum, particularly in the small group of
end-stage renal disease and a propensity patients who have undergone enterocysto-
to renal tract infection, within the cysts, plasty and need to void by intermittent
the pelvicaliceal system particularly if catheterisation. As in virtually all other
the cysts cause intrarenal or pelviuret- situations there still seems to be little or
eric obstruction and in the renal paren- no evidence to support long term antibi-
chyma. Perepanova and Apolikhin rightly otic prophylaxis in favour of short course
emphasise the importance of control- high dose treatment of proven infection.
ling this infection well before the patient Finally this section concludes with a
undergoes transplantation and immuno- discussion of the somewhat disconnected
suppression. Very occasionally even bilat- topic of emphysematous pyelonephritis
eral nephrectomy will be indicated, as for (EPN) and renal abscess. Ishikawa has
extreme cases of endstage obstructve and presented an interesting analysis of risk
reflux nephropathy, as a last resort. Some factors which may be predictive of success
of the very limited high level evidence from conservative management, using
available in this section confirms the effi- antibiotics and percutaneous aspiration.
cacy of fluoroquinolones in controlling Much of the data are historic and it is
cyst infection, even when administered likely that contemporary studies would
empirically. show that mortality is much reduced with
Despite good evidence from RCT’s con- better management of sepsis and diabe-
firming the benefits of antibiotic prophy- tes which of course affect the majority of
laxis in the first six months after renal patients with EPN.
transplantation, UTI is still an ongoing To some extent, the old surgical adage
problem. Shoskes and Saad have under- that pus needs to be released urgently
taken a useful detailed analysis of its can be revised, at least for smaller renal
impact on graft function and of the allied abscesses which evidence suggests can
problem of the effect of immunosup- resolve spontaneously with antibiotic
pression on susceptibility to UTI. It is treatment alone. It must not be forgot-
not surprising that the evidence is often ten that EPN and renal abscess can still
confounded by a multitude of co-morbid occur as a result of obstruction and its
factors including diabetes through its relief constitutes one of the few surgical
wide-ranging effects on the host response emergencies in urology.
403
|7.2|
Emphysematous pyelonephritis
Kiyohito Ishikawa
Address of Corresponding Author: Department of Urology, Fujita Health University School of Medicine, 1–98,
Dengakugakubo, Kutsukake, Totoake, Aichi, 470–1192, Japan
e-mail address: kiyo@fujita-hu.ac.jp
ABSTRACT indicator of septic disseminated intravas-

cular coagulopathy (DIC), and bilateral
Emphysematous pyelonephritis (EPN) disease are predictable.
represents a life-threatening infection of Key words: Emphysematous pyelone-
the renal parenchyma by gas-forming bac- phritis, gas-forming bacteria, diabetes
teria. Poorly controlled diabetes mellitus mellitus, sepsis, nephrectomy
is present in up to 90% of patients. It car-
ries a mortality rate of approximately 20%
The literature on EPN has been
reviewed to develop a pathway to guide
management of this rare condition. An
analysis of 23 risk factors has facilitated 1. Diagnosis
the early identification of patients for 1.1 Plain radiography is recom-
whom relatively conservative forms of mended to demonstrate gas
treatment will be appropriate. Rarely, bubbles over the affected kidney
where the disease has an exceptionally in approximately 85% of cases
fulminant course, urgent nephrectomy is (GoR B).
lifesaving. All patients will require vigor-
1.2 Ultrasonography is useful for the
ous intravenous fluid replacement, broad-
diagnosis of urinary tract obstruc-
spectrum antibiotics and diabetic control.
tion, but insensitive for the detec-
Percutaneous drainage (PCD) is some-
tion of renal gas (GoR C).
times urgently required. Paradoxically,
more localized parenchymal infection with 1.3 Modern multislice CT gives bet-
little or no fluid collection (Wan “Type 1”) ter resolution and administration
may be predictive of poor outcome. The of intravenous contrast reveals
sinister implications of two other factors, asymmetric enhancement of renal
thrombocytopaenia, presumably as an tissue (GoR B).
Emphysematous pyelonephritis | 7.2 |
EPN
Initial KUB and renal echography Sussequent abdominal CT scan
Classes 1 and 2 Classes 3A and 3B Class 4
Low risk group (Bilateral) PCD

Fluid, Electrolyte, and
(0 or 1 risk factor)
Glucose control,
Antibiotics and PCD High risk group Failure
(^ 2 risk factors)
Survival Failure Intensive care followed by nephrectomy
Survival or Not
Figure 1 The Flowchart for management of EPN. The diagnostic steps and managements are recommended to [A, IIb], which
means “it is strongly recommended, and they are evidenced from well-designed quasi-experimental study”.
2. Treatment (recommendations are as a result of obstruction of the corre-

based on the classification devised by sponding reno-ureteral unit, debilitating
Huang and Tseng (Figure-1) [1]) alcoholism and immunodeficiency [4–5].
2.1 Class 1 or 2 EPN patients: treat Predictably, EPN is prone to be compli-
with percutaneous drainage (PCD) cated by the mortal effects of systemic
and/or relief of urinary tract sepsis [6]. Four components of gas for-
obstruction (if present) in combi- mation in EPN have been proposed: the
nation with antibiotic treatment presence of pathogenic Gram-negative,
(GoR C). gas-forming facultative bacteria such
as Escherichia coli; a defective immune
2.2 Class 3 or 4 EPN patients with response, e.g. due to diabetes, alcohol-
less than one risk factor: treat ism or cancer, allowing bacterial multi-
with PCD and/or relief of the plication; high tissue glucose levels that
urinary tract obstruction (if help facultative anaerobes to ferment
present) in combination with glucose and produce carbon dioxide and
antibiotic treatment (GoR C). hydrogen; and ischemia of local tissue,
2.3 Class 3 or 4 EPN patients with due to severe inflammation, microan-
more than two risk factors should giopathy or urinary tract obstruction,
undergo timely nephrectomy all of which may impair tissue perfusion
(GoR C). and transportation of gas to the blood
stream, allowing gas accumulation [5].
Escherichia coli (58%), Klebsiella pneu-
1. INTRODUCTION moniae (24%) and mixed flora (10%) have
been cultured from patients with EPN
Emphysematous pyelonephritis (EPN) is [7]. Proteus mirabilis, Enterobacter aero-
a life-threatening necrotizing infection of genes and Candida sp. have also been
the kidney characterized by accumulation implicated [2].
of gas in the renal parenchyma and the During the last three decades there
surrounding tissue [2–3]. It is most com- have been many publications on EPN
monly seen in patients with poorly con- reporting wide variations in mortal-
trolled Type 1 diabetes mellitus (DM) but ity and risk factors [8–11]. We have
not exclusively so. It may also develop attempted to develop recommendations
405
Chapter |7| Urinary tract infections in nephropathies
for management of EPN based on an in- editorial and letters, 3) studies for which
depth analysis of the published work [12]. abstracts were not available, 4) studies
involving paediatric patients, 5) antibi-
otic efficacy studies, 6) studies that were
2. METHODS irrelevant to our specific subjects and 7)
studies written in languages other than
2.1 Data sources English and Japanese. A total of eight
We performed a systematic search of articles were finally used in the analysis.
PubMed (September 1965 to August
2008) to find articles providing data on 2.2 Rating system
risk factors of mortality in patients with The studies were rated according to the
EPN. We used the keywords “pyelonephri- level of evidence and the strength of rec-
tis and (predict or prediction or prognosis ommendations according to the ICUD
or hospitalization or outcome or mortality standards (see preface) [12–13].
or prognostic or risk factor or severity or
survival)” and the search was limited to 2.3 Classification
articles written in English and Japanese.
The three commonly adopted schemes of
The 1503 published reports found were
classification are shown in Table 1.
screened by their title. The full text of
30 selected articles were read and 22
2.4 Statistical Methods
studies in the following categories were
excluded: 1) case reports and case series All-cause mortality was the only outcome
of less than 5 patients, 2) review articles, considered in this analysis. We compared
Table 1 Classification of emphysematous pyelonephritis.
Classification system Basis for classification Defining features
Michaeli et al. (2) Plain film X-ray
Stage 1 Gas present in the renal parenchyma or perinephric tissues
Stage 2 Gas present in the kidney and its surroundings
Stage 3 Extension of gas through Gerota’s fascia and/or bilateral disease
Huang and Tseng (1) CT
Class 1 Gas present in the collecting system only
Class 2 Gas present in the renal parenchyma, without extension into the
extrarenal space
Class 3A Extension of gas or abscess into the perinephric space
Class 3B Extension of gas or abscess into the pararenal space
Class 4 Bilateral EPN, or EPN in a solitary kidney
Wan et al. (18) Radiograpy, US and CT
Type 1 Parenchymal destruction with either lack of fluid collection or

presence of streky or mottled gas
Type 2 Renal or perirenal fluid collection with bubbly or loculated gas

or gas in the collecting system
406
the proportions of patients who died 4. MORTALITY AND RISK FACTORS

according to a list of identifiable risk fac-
tors. Pooled odds ratios and 95% confi- Mortality ranged from 10% to 42% in the
dence intervals were calculated to quantify studies included in the meta-analysis
the risk of mortality for the factors men- (Table 3). Overall 17.3% (62/358) of the
tioned in more than two of the selected enrolled patients with EPN died. The
studies by using the Mantel-Haenszel majority of the selected reports referred
fixed effect [14] and the DerSimonian- to all-cause mortality (1,15–18,20,22).
Laird random effects models. For the risk One Japanese study provided informa-
factors evaluated in one or two studies the tion with regard to the specific end-point
risk of mortality was quantified by using (nephrectomy) for the evaluation of mor-
the chi-square test or Fisher’s exact test tality [22].
with a p-value less than 0.05 considered In Table 3 we present in detail the risk
statistically significant. factors for mortality of patients with EPN
that were analyzed in each of the selected
study cohorts. In Table 4 we show data
3. OVERVIEW OF STUDIES REVIEWED regarding the association between the
specified risk factors and mortality (sum-
In Table 2 we summarize the characteris- mary odds ratio and p-values).
tics of the eight selected studies, compris- Of 23 factors identified from the eligi-
ing 311 patients with EPN, included in ble articles as potentially high risk, seven
the meta-analysis [1, 15–19]. All reports were described in three or more and in
were designed as retrospective cohort our analysis only four factors were asso-
studies. Five of the eight eligible studies ciated with increased risk of mortality.
originated from Asia. These were: conservative mode of treat-
The majority (84.2%) of total 273 ment alone (OR 3.66, 95% CI 2.01–6.66),
patients with EPN were female. In addi- bilateral EPN (OR 5.36, 95% CI 1.41–
tion, 93.3% of total 311 patients had diabe- 20.33), type 1 EPN (OR 2.53, 95% CI
tes mellitus. In three of the eight reports 1.13–5.65), and thrombocytopenia (OR
all patients were diabetic [18, 20–21]. 22.68, 95% CI 4.4–116.32).
Table 2 Main characteristics of studies inclused in the meta-analysis.
No. Pts No. Males/Pts No. Pts With DM/Total

Reference Country Enrolled Enrolled(%) No. Enrolled(%)
Abdul-Halim et al. (15) Kuwait 7 1/7(14) 7/7(100)
Tang at al. (16) Taiwan 21 1/21(5) 21/21(100)
Huang and Tseng (1) Taiwan 48 7/48(15) 46/48(96)
Kuo et al. (17) Taiwan 28 3/28(11) 25/28(89)
Wan et al. (18) Australia 38 Not available 37/38(97)
Shokeir at al. (19) Egypt 20 5/20(25) 16/20(80)
Ahlering et al. (20) United States 13 3/13(23) 13/13(100)
Masago et al. (21) Japan 136 23/136(16) 125/136(91)
Retrosepctive study design for all.
407
Table 3 Risk factors for all cause mortality in patients with EPN inclused in selested studies.
Abdul- Huang Kondo

Halim Tang and Kuo Wan Shokeir Ahlering et al.
et al.(15) et al.(16) Tseng(1) et al.(17) et al.(18) et al.(19) et al.(20) (22)
Conservative 0/0 vs 1/7 2/6 vs 4/15 2/5 vs 7/43 0/0 vs 3/28 6/9 vs 9/29 1/1 vs 3/19 2/6 vs 2/5 12/45 vs
mode of treat- 7/138
ment alone
Bilateral EPN 0/0 vs 1/7 2/4 vs 7/44 0/1 vs 3/27 1/1 vs 3/19 ?/7 vs ?/129
Type 1 EPN 1/7 vs 5/14 5/14 vs 4/34 1/14 vs 2/14 11/16 vs 4/22
DM 1/7 vs 0/0 6/21 vs 0/0 2/25 vs 1/3 5/12 vs 0/0
Thrombocytopenia 1/1 vs 0/6 8/22 vs 1/26 7/7 vs 8/31
Nephrolithiasis 3/12 vs 6/36 0/2 vs 3/26 not significant 0/1 vs 5/11
E. coli or K. 1/20 vs 2/8 13/31 vs 2/7 5/11 vs 0/1

pneumoniae
Comparison of proportions of patients who died among with or without a specific resk factor.
Table 4 Summary risk factors for all cause mortality in patients with EPN.
No. Studies No. Pts in Studies Summary

Reporting Data Reporting Data OR(95%CI) p-value
Conservative mode of 8 358 3.66(2.01–6.66) <0.001

treatment alone
Bilateral EPN 5 116 5.36(1.41–20.33) 0.01
Type 1 EPN 4 135 2.53(1.13–5.65) 0.02
DM 4 69 0.32(0.05–1.99) Not significant
Thrombocytopenia 3 93 22.68(4.4–116.32) <0.001
Nephrolithiasis 3 89 1.25(0.34–4.52) Not significant
E. coli or K. 3 79 0.99(0.29–3.40) Not significant

pneumoniae
Conservative mode of treatment approximately 85% of cases. However,

included fluid resuscitation, administra- this is frequently misinterpreted as bowel
tion of antimicrobial agents and control of gas. There may be a diffuse, mottled
diabetes mellitus. Percutaneous drainage appearance in the affected kidney, with
(PCD) was not considered part of the cat- radially oriented gas, corresponding to
egory conservative treatment alone (GoR the configuration of the renal pyramids.
B, LoE 2b). A crescent-shaped gas collection within
Gerota’s fascia demonstrates extension
into perirenal tissues and indicates an
5. DIAGNOSIS advanced stage of renal necrosis [23].
Ultrasonography is also useful for the
Plain radiography will demonstrate diagnosis of urinary tract obstruction,
gas bubbles over the affected kidney in but is operator-dependent and insensitive
408
for the detection of renal gas. However, severity of vascular insufficiency in the
modern multislice CT gives better resolu- kidney and immunodeficiency especially
tion and nowadays few clinicians would in patients with DM [19] (GoR C, LoE 3).
be confident in taking management deci- We confirmed that Wan’s classification
sions without access to CT [24]. The correlated well with the clinical course
use of intravenous contrast may reveal and was predictive of outcome. However,
asymmetric enhancement of renal tis- the more elaborate classification of
sue or delayed excretion and during the Huang and Tseng [1] was more conven-
nephrogram phase, areas of abscess for- iently applied to a flowchart for manage-
mation or focal tissue necrosis may be ment of EPN (Fig 1) (GoR A, LoE 2b).
identified [23]. A classification system
has been suggested based on CT findings,
and image-guided drainage offers effec- 7. TREATMENT
tive treatment often avoiding emergency
nephrectomy [25]. CT remains the cor- Treatment of patients with EPN remains
nerstone of imaging but new and rapidly a controversial issue. Historically
evolving MR sequences may also contrib- nephrectomy was regarded as the main
ute to the more accurate evaluation of the treatment of patients with this life-
patient with acute pyelonephritis [24], threatening infection [2] to be performed
whilst providing a more cost-effective and as soon as possible after vigorous resus-
radiation-free alternative to CT. citation, administration of antimicrobial
agents, and control of blood glucose and
electrolytes. Early data showed mortal-
6. CLASSIFICATION (TABLE 1) ity for patients who underwent nephrec-
tomy to be 20%, compared with 80% for
A number of staging systems for EPN patients treated solely medically [26].
exist (Table 1). Unlike that of Michaeli Even as recently as the 1990’s the dan-
et al. [2] the system proposed by Huang gers of delayed nephrectomy were re-
and Tseng [1] has important prognos- emphasized [17–18]. These papers still
tic and therapeutic implications. In a describe an accumulated experience
retrospective study of 38 patients, Wan beginning many years before, when
et al. [7] identified two types of EPN patients would not have had the benefit
based on fluid and gas pattern, and cor- of modern intensive care, advanced imag-
related findings with clinical course and ing techniques or interventional radiol-
prognosis (GoR C, LoE 3). The mortal- ogy. Furthermore, patients assigned to
ity rates almost completely matched the a “medical” group will often have been
degree of parenchymal destruction. Type regarded as unfit to undergo major sur-
1 disease had a substantially higher mor- gery and will therefore have had a poor
tality rate (69%), more extensive paren- prognosis at the outset.
chymal destruction and a more fulminant In the last decade the emphasis has
clinical course. Type 2 had a lower mor- changed such that for a proportion of
tality rate (18%) and more indolent clini- patients a more conservative approach
cal course. It is unclear whether these may be appropriate. Mortality as low
two subtypes represent stages in the evo- as 8% has been reported with a staged
lution of EPN or different pathophysi- approach combining CT-guided percutane-
ological responses. ous drainage (PCD) in combination with
Wan et al. hypothesized that the clin- antibiotic and supportive therapy [27].
icopathological differences between types Best and colleagues [28] reported success-
1 and 2 EPN by the pathological findings ful treatment of gas-filled renal abscesses
are probably related to the difference in in diabetic patients with medical
409
treatment alone. Medical therapy is now 8. DISCUSSION

considered a valid alternative to surgical
intervention [29], and management should Our recommendations are based on
be tailored according to disease severity the flowchart for management of EPN
and radiographic findings (GoR C, LoE 3). devised by Huang and Tseng (Fig 1) [1].
There is some indication from the Although there were no significant dif-
Japanese literature that the intro- ferences in the clinical features between
duction of new antibiotics including the categories, there was a progressive
acylaminopenicillins, with more effective tendency toward an increasing likeli-
control of Pseudomonas and resistant hood of failure of PCD and risk of mortal-
Enterobacteriaceae was also of key impor- ity from classes 1 to 4. The patients with
tance in improved results of treatment of class 1 EPN had the best prognosis, and
EPN. Kondo et al. [22] reviewed the out- all of them survived after PCD and/or
come of 183 Japanese patients with EPN relief of the urinary tract obstruction (if
in relation to the introduction of carbeni- present) combined with antibiotic treat-
cillin in 1989, 68 patients treated before ment. In class 2 EPN, all patients treated
1989 (Group 1) were compared with 115 with PCD and antibiotics were cured.
patients treated after 1989 (Table 5). For Therefore, PCD and relief of the urinary
the comparison of prognosis between two tract obstruction combined with antibi-
groups the mortality rate was quanti- otic treatment is the choice of modality
fied by using the chi-square test with a for limited disease (class 1 or 2).
p-value less than 0.05 considered statis- Analysis, particularly of the older lit-
tically significant. Overall mortality in erature, confirmed that patients in the
Group 1 was 16% and fell significantly to category “conservative treatment not
7% for Group 2. including PCD” also had a poor progno-
Huang and Tseng proposed a clinical sis. This can be explained by the fact that
classification which appeared to identify they will have suffered additional co-mor-
categories of patients who might avoid bidity precluding emergency major sur-
nephrectomy except where the disease gery (nephrectomy) and even PCD. Some
is rapidly progressive and fulminant, by might have undergone delayed nephrec-
using the lesser procedure of PCD of the tomy as an act of desperation, no doubt
kidney where it is obstructed and/or of contributing to their death. The delay
the abscess itself [1, 30]. can hardly be regarded as causal and it
Table 5 Treatment and prognosis of EPN: Comparision of Prognosis between early (-1988) and recent period (1989–1999).
Year –1988 1989–1999 P value

No. cases No. death(%) No. cases No. death(%) (X2 test)
Conservative therapy 21 8(38%) 24 4(17%) 0.01
alone
Drainage + 6 0 18 1(6%) 0.56

Nephrectomy
Drainage alone 14 0 24 2(8%) 0.27
Nephrectomy alone 23 2(9%) 49 1(2%) 0.19
Others 4 1
Total 68 11(16%) 115 8(7%) <0.05
410
Table 6 Timing of nephrectomy of reported cases.
Day of nephrectomy (days after the 0–7 8–14 15–21 22–28 >29 Total
initial treatment)
No. patients(%) 24(36) 12(18) 3(4) 8(12) 20(30) 67
would obviously be misleading to derive a and/or where there are two or more iden-
general conclusion from this self- select- tifiable risk factors [A, 2b].
ing group that delayed nephrectomy can
reduce survival chances [17–18].
We reviewed the management of 9. FURTHER RESEARCH
extensive EPN with gas or abscess exten-
sion beyond the renal capsule and bilat- In some articles there is limited evidence
eral EPN (class 3 or 4) in relation to that increased serum creatinine level,
the presence or absence of one or more disturbance of consciousness and hypo-
of the 23 designated risk factors. Our tension (systolic blood pressure less than
study showed that 17 (85%) of the 20 90 mmHg) may also impact the survival
patients with one or no risk were suc- of EPN patients [1, 31]. Thus, further
cessfully treated with PCD combined research on these factors seems warranted
with antibiotic treatment; compared with to confirm the potential detrimental effect
the patients with two or more risk fac- on the outcome of patients with EPN.
tors who had a significantly higher fail-
ure rate (92% vs 15%, p<0.01). For these
patients timely nephrectomy would have 10. CONCLUSIONS
provided the best management outcome.
Table 6 shows timing of nephrectomy of In this study, mortality of EPN was 17.3%
all cases reported [22]. (62 of 358). It also demonstrated that
Bilateral EPN may be reasonably con- whilst a conservative approach to treat-
sidered a more severe infection than uni- ment was generally effective, bilateral
lateral EPN. Data presented in the past EPN, type 1 EPN, and thrombocytopenia
were not sufficient to determine whether were significant risk factors associated
bilateral EPN was necessarily associated with a higher than average mortality. In
with a poor outcome. However, our results such circumstances timely nephrectomy
clearly show that bilateral EPN is a risk might still be preferable as a life-saving
factor predictive of both failure of PCD procedure.
and increased mortality (GoR A, LoE 1a).
Of course co-morbidity is a confounding
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412
|7.3|
Renal abscesses
Kiyohito Ishikawa
Department of Urology, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake,
Totoake, Aichi, 470-1192, Japan
e-mail address: kiyo@fujita-hu.ac.jp
ABSTRACT Keywords: renal abscesses, Gram-

negative bacteria, antibiotic therapy
Renal abscesses result from a severe
infection leading to liquefaction of renal
tissue. They are quite frequently multiple
and arise in areas of interstitial inflam-
mation. An abscess can rupture through Diagnosis
the renal capsule into the perinephric 1. Ultrasonography and CT are helpful
space, forming a perinephric abscess. in distinguishing abscess from other
When it extends beyond Gerota’s fascia, inflammatory renal disease (GoR C).
it may spread throughout the retroperito-
neal space limited anteriorly via the pre- 2. Abscesses are characteristically well
vertebral fascia and point in the inguinal defined on CT both before and after
region or between the paraspinal muscle contrast agent enhancement (GoR C).
masses overlying the kidney below the 3. Rupture of a renal abscess with peri-
12th rib in the costovertebral, renal angle. toneal extension is better appreci-
Patients with diabetes and intravenous ated by MRI (GoR C).
drug abusers are at risk of developing 4. Dilatation of the pelvicaliceal system
renal abscess. may indicate coexisting obstruction
Ultrasonography CT and MRI are (GoR C).
helpful in distinguishing abscess from
other inflammatory renal disease and in Treatment
deciding on the management. Intensive
antibiotic therapy alone may be effec- 5. The management of renal abscess
tive for treatment of renal or perinephric must first include appropriate
abscesses smaller than 5 cm. antibiotic therapy (GoR B).
6. Ampicillin or vancomycin in com- the development of effective antibiot-

bination with an aminoglycoside or ics and better management of disease
third-generation cephalosporin is such as diabetes and renal failure, renal
recommended as antibiotics (GoR B) or perinephric abscesses due to Gram-
7. Antibiotic therapy must be continued positive bacteria are less prevalent;
for at least four weeks (GoR B) whereas those caused by Escherichia coli
or Proteus species are becoming more
8. Coexisting upper urinary tract obstruct common [1–2]. Abscesses forming in
ion is a surgical emergency and requi- the renal cortex are likely to arise from
res drainage, preferably by percutane- hematogenous spread, whereas those at
ous nephrostomy (PCD) (GoR B) the corticomedullary junction are caused
Other management by ascending infection by Gram-negative
bacteria in conjunction with other under-
9. If the patient does not respond with lying urinary tract abnormalities, such as
48 hours of treatment, PCD under stones or obstruction.
CT or ultrasound guidance is indi- 60% of Gram-negative abscesses in
cated (GoR B). adults are associated with renal calculi or
10. The drained fluid should be cultured damaged kidneys. Although the associa-
for the causative organisms (GoR B). tion of pyelonephritis with vesicoureteral
reflux is well established, renal abscess
11. If the abscess still does not resolve, is only rarely a consequence of reflux and
then open surgical drainage or then only in children [3].
nephrectomy may be necessary The differential diagnosis includes
(GoR B). secondary infection in renal cysts which
Follow-up can be simple or part of a complex sys-
temic problem (e.g. adult dominant poly-
12. Follow-up imaging is needed to cystic kidney disease). Occasionally an
confirm resolution of the abscesses abscess can follow secondary infection in
(GoR B) a cystic tumour and it may also form part
13. Evaluation for underlying urinary of chronic infection and inflammation
tract abnormalities, such as stone in the urinary tract e.g. genitourinary
or obstruction, should be performed tuberculosis.
after appropriate antibiotic treat-
ment has been initiated (GoR B).
2. METHODS
1. INTRODUCTION
We performed a systematic search of
A renal abscess results from a severe PubMed (January 1996 to August 2008).
infection leading to liquefaction and per- We used the keywords “renal abscesses
manent loss of renal tissue. It can rup- and (perinephric abscess or retroperitoneal
ture into the perinephric space and then abscess or intravenous drug or antibiotic
extend beyond Gerota’s fascia to spread therapy or prognosis or hospitalization or
widely through the retroperitoneum. outcome or mortality or prognostic or risk
Historically, most renal/perinephric factor or severity or survival)”. The search
abscesses result from hematogenous was limited to articles written in English
spread of staphylococci, in particular and Japanese. 619 published reports were
from infected skin lesions. Diabetes mel- identified and screened by their title. The
litus (DM) and intravenous drug abuse full texts of 16 articles were read and 11
are prominent causative factors. With studies were excluded for several reasons.
414
Renal abscesses | 7.3 |
Table-1 Main characteristics of renal abscesses included in the meta-analysis.
U/C B/C No. Pts

Reference No. Pts positive positive with DM Treatment
Siegel. JF (4) 52 71% 28% 25% 3cm< AB 3-5cm PCD >5 cm Nx
Meng MV (5) 25 72% AB AV=1.8 cm PCD AV=11 cm PCD+Nx 30%
Shu T (6) 70 67% AB 74% PCD 26% Nx 0%
Coelho RF (7) 65 43% 17% 28% AB 25% PCD 37.5% Nx 37.5%
Lee BE (8) 56 45% AB 36% PCD or Nx 64%
U/C: Urine culture B/C: Blood culture DM: Diabetes mellitus

AB: antibiotic therapy alone
PCD: Percutaneus drainage
Nx: Nephrectomy or open surgery
A total of five articles were included into quickest and least expensive method to
the analysis. (Table 1) [4–8]. demonstrate a renal abscess and will
The studies were rated according to the usually be the initial form of imaging
level of evidence (LoE) and the grade of screen. US can reveal either a hyper- or
recommendation (GoR) using ICUD stand- hypoechoic focal mass or complex cystic
ards (for details see Preface) [9–10]. structure. There may be posterior acous-
tic enhancement, although early in
development poor transmission of sound
3. PRESENTATION AND CLINICAL waves can be seen. Demonstrating a
FINDINGS lack of vascularity on Doppler imaging
is important in distinguishing a com-
The most common presenting symp- plex abscess from a malignant process
toms in patients with renal-perinephric [12–13].
abscesses include fever, flank or abdomi- CT appears to be the diagnostic proce-
nal pain, chills, and dysuria. Patients dure of choice for renal abscess, because
sometimes suffer from the effects of an it provides excellent delineation of the tis-
indolent illness for several weeks before sue (GoR A, LoE4). With high sensitivity,
medical advice is sought. A flank mass CT scans can demonstrate an enlarged
is palpable in some patients. Urinalysis kidney with focal areas of hypoattenu-
usually demonstrates white blood cells; ation early on during the course of the
however, it may be normal in approxi- infection. On CT, abscesses are charac-
mately 25% of cases [2]. Urine cultures teristically well defined both before and
only identify the causative organisms in after contrast agent enhancement [14].
about one-third of cases and blood culture Once the inflammatory wall forms around
in only about half of cases [11]. the fluid collection, the abscess appears
as a mass with a rim of contrast enhance-
ment, the “ring” sign. Fluid levels may be
4. IMAGING present with dependent debris. Septation
may be present within the abscess [15].
Ultrasonography (US) and CT are help- CT scans may also demonstrate thick-
ful in distinguishing abscess from other ening of Gerota’s fascia, stranding of
inflammatory renal disease. US is the the perinephric fat, or obliteration of
415
the surrounding soft-tissue planes [16]. [4, 18–21]. Where present, obstruction
Recently, modern multislice CT gives bet- must be relieved by PCD or a stent
ter resolution and few clinicians would be inserted endoscopically.
confident in management decisions with- Response to antibiotic therapy should
out access to CT. The improvements in be obvious from reduction of the dimen-
CT technique and increased use of cross- sions of the abscess. In a review of 55
sectional imaging have facilitated the patients with a renal abscess antibiotic
detection of small or previously undiag- therapy alone was successful in 85.9% of
nosed renal masses. Helical CT technol- cases. Factors predicting a less favorable
ogy will further improve renal imaging outcome were abscess diameter > 5 cm,
with decreasing volume-averaging arti- involvement by more than one organism,
facts, eliminating respiratory misreg- presence of Gram-negative bacilli, dura-
istration artifacts and allowing image tion of therapy less than four weeks, and
acquisition during the peak intravenous use of aminoglycoside as the only anti-
contrast enhancement. Helical CT image biotic [18].
acquisition has also led to improved data Siegel et al. observed successful anti-
sets available for three-dimensional imag- biotic therapy in 5/5 renal abscesses that
ing [17]. were 3 cm or less, in 2/3 renal abscesses
Magnetic resonance imaging, because with a size of 3–5 cm, and in 1/3 renal
of its lack of ionizing radiation, has abscesses larger than 5 cm [4].
recently gained popularity as an imag- Palma et al. recommended that inten-
ing modality in obstetrics and gynecol- sive antibiotic therapy alone could be
ogy. On MRI, a renal abscess is displayed effective for treatment of renal or perine-
as a low-signal intensity inhomogeneous phric abscesses smaller than 5 cm.
mass on T1-weighted images and with However, should clinical response be
increased signal intensity on T2-weighted unsatisfactory, open surgery or PCD
images depending on the presence of pro- drainage should be carried out.
tein, fluid, and cellular debris. Rupture of Several investigators [18–21] empha-
a renal abscess with peritoneal extension size the importance of continuing antibi-
is better appreciated on MRI [15]. otic therapy for at least four weeks, even
Both ultrasonography and/or CT per- when there is excellent clinical improve-
formed as the initial diagnostic investi- ment within a few days (GoR B, LoE 4).
gation will demonstrate dilatation of the
collecting system due to obstruction, and
the presence of other associated abnor- 6. OTHER MANAGEMENTS
malities e.g. renal and ureteric stones.
Occasionally, obstruction must be reli-
eved as a matter of extreme urgency as
5. ANTIBIOTIC THERAPY pyonephrosis may coexist with the paran-
chymal infection. This is more certainly
The appropriate management of renal achieved by percutaneous nephrostomy
abscess must first include appropri- but circumstances may dictate retrograde
ate antibiotic therapy (GoR B, LoE 4). placement of a ureteric catheter.
Because it is often very difficult to iden- The patient who was not obstructed
tify the correct causative organisms from but showing little or no response after
the urine or blood, empiric therapy with 48 hours of treatment, will require PCD
broad-spectrum antibiotics (ampicil- under CT or ultrasound guidance is indi-
lin or vancomycin in combination with cated [4]. The drained fluid should be cul-
an aminoglycoside or third-generation tured for the causative organisms. If the
cephalosporin) is usually recommended abscess still does not resolve, then open
416
Renal abscesses | 7.3 |
surgical drainage or nephrectomy may be 2. Thorley JD, Jones SR, and Sanford JP,
necessary (GoR B, LoE 4). Perinephric abscess. Medicine (Baltimore),
Follow-up imaging is needed to con- 1974. 53(6): 441–51.
firm resolution of the abscesses. These 3. Segura JW and Kelalis PP, Localized
patients will also require evaluation for renal parenchymal infections in children.
underlying non-obstructive urinary tract J Urol, 1973. 109(6): 1029–32.
abnormalities after the infection has 4. Siegel JF, Smith A, and Moldwin R,
Minimally invasive treatment of renal
resolved. Concurrent stone disease will
abscess. J Urol, 1996. 155(1): 52–5.
require interval management particularly
5. Meng MV, Mario LA, and McAninch JW,
if closely associated with development of
Current treatment and outcomes of perine-
the abscess. phric abscesses. J Urol, 2002. 168(4 Pt 1):
The management of infected cysts in 1337–40.
polycystic kidney disease is discussed else- 6. Shu T, Green JM, and Orihuela E,
where in this section (Perepanova et al). Renal and perirenal abscesses in
patients with otherwise anatomically
7. FURTHER RESEARCH normal urinary tracts. J Urol, 2004.
172(1): 148–50.
7. Coelho RF, Schneider-Monteiro ED,
It is unlikely that “Renal Abscess” will
Mesquita JL, Mazzucchi E, Marmo
ever be the subject of a major research Lucon A, and Srougi M, Renal and perine-
endeavour. However, in time a consensus phric abscesses: analysis of 65 consecutive
based on small anecdotal studies will pro- cases. World J Surg, 2007. 31(2): 431–6.
vide useful evidence on the use of more 8. Lee BE, Seol HY, Kim TK, Seong EY,
contemporary antimicrobial agents and Song SH, Lee DW, Lee SB, and Kwak IS,
the appropriate duration of therapy. It Recent clinical overview of renal and peri-
is to be hoped that the need for surgical renal abscesses in 56 consecutive cases.
intervention will continue to diminish. No Korean J Intern Med, 2008. 23(3): 140–8.
doubt new imaging strategies will have 9. Abrams P, Khoury S, and Grant A,
an impact on earlier diagnosis, assist in Evidence – based medicine overview of the
percutaneous drainage and in plotting main steps for developing and grading
the resolution of the abscess. guideline recommendations. Prog Urol,
2007. 17(3): 681–4.
10. U.S. Department of Health and Human
8. CONCLUSIONS Services Public Health Service Agency for
This study shows that renal abscesses of 115–127.
less than 5 cm in diameter can respond 11. Edelstein H and McCabe RE, Perinephric
successfully to antibiotic therapy alone abscess. Modern diagnosis and treatment
without intervention. Larger abscesses in 47 cases. Medicine (Baltimore), 1988.
always need surgical drainage. Evaluation 67(2): 118–31.
for underlying urinary tract abnormali- 12. Kawashima A and LeRoy AJ, Radiologic
ties, such as stone or obstruction, should evaluation of patients with renal infec-
tions. Infect Dis Clin North Am, 2003.
be performed after appropriate antibiotic
17(2): 433–56.
treatment has been initiated.
13. Demertzis J and Menias CO, State of the
art: imaging of renal infections. Emerg
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17. Toprak U, Erdogan A, Gulbay M, 305–8.
Karademir MA, Pasaoglu E, and Akar 20. Rives RK, Harty JI, and Amin M, Renal
OE, Preoperative evaluation of renal abscess: emerging concepts of diagnosis
anatomy and renal masses with heli- and treatment. J Urol, 1980. 124(4): 446–7.
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418
|7.4|
Polycystic renal disease

Tamara Perepanova, Oleg Apolikhin
State S.R. Institute of Urology, Moscow, Russia
Corresponding author: Tamara Perepanova, MD, Professor of Urology, S.R. Institute of Urology in Moscow
3-ja Parkovaja st, h.51, Moscow, 105425, Russia
Tel. +7-495-367.1717, perepanova2003@mail.ru
ABSTRACT therapy can be difficult despite proven in

vitro sensitivity of responsible organisms
UTI occurs in 21–75% of patients with to the agents administered.
autosomal dominant polycystic kidney Key words: Autosomal dominant poly-
disease (ADPKD) during their lifetime. cystic kidney disease (ADPKD) and UTI,
Frequently urinary infection is the first polycystic renal disease, pyelonephritis,
and leading symptom of the disease. The cyst infections, treatment ADPKD.
urinary tract per se, renal parenchyma
and cysts may be involved in the inflam-
matory process. Renal infection is a com- SUMMARY OF RECOMMENDATIONS
mon occurrence in ADPKD and often
leads to serious complications, includ-
1. Uncomplicated lower urinary tract
ing perinephric abscess, septicemia,
infection (cystitis, urethritis) in
and death. Important predisposing fac-
patients with
tors include age, female sex, and recent
instrumentation of the urinary tract. 2. ADPKD should be managed accord-
Renal infections in ADPKD are most coming to the same principles as in
monly caused by Gram-negative enteric patients with normal urinary tracts
organisms. Diagnosis of these infections (GoR B)
may be difficult since some patients do 3. Renal infections of patients with
not have bacteriuria. CT or MRI (or both) autosomal dominant polycystic kid-
may be helpful in some patients with uri- ney disease (ADPKD) should be sub-
nary infection and is often superior to classified as pyonephrosis (infection
sonography for detecting cysts in organs of the upper collecting system), acute
other than the kidney. Eradication of cyst bacterial interstitial infection (infec-
infections with conventional antibiotic tion of the renal parenchyma) or
pyocyst (infection confined to a cyst) urinary tract infections and other com-
(GoR B). plications e.g. hypertension, is higher
4. Of these, pyocysts can be the most for PKD1 gene defects as compared with
diagnostically challenging and, PKD2. Often both kidneys are involved
because of delay in starting effec- in infectious process. Frequently urinary
tive treatment, can generate the infection is the first and leading symp-
most severe infection with risk of tom of the disease. It occurs more often
systemic spread. Therefore, serial in women due to the ascending infec-
cultures of blood and urine are tion of lower urinary tract (urethritis,
essential before starting antibiotic cystitis), similarly to patients without
therapy (GoR B). ADPKD [1–2, 4] (GoR B, LoE 3). The
severity of urinary tract infection var-
5. For the majority of infections com- ies from subclinical bacteriuria, through
mon Enterobacteriaceae also respon- simple cystitis to acute pyelonephritis
sible for cystitis and pyelonephritits and pyonephrosis. The more severe clini-
(eg: E. coli, Klebsiella, Proteus and cal manifestations of upper tract UTI are
Pseudomonas spp.) have to be con- common and tend to occur after instru-
sidered (GoR B). mental intervention and bladder cath-
6. CT imaging, perhaps supple- eterization when there is an increased
mented with MR, is optimal in the risk of colonization by nosocomially
evaluation of the febrile patient acquires hospital polyresistant bacterial
with ADPKD, to detect infected strains [5] (GoR C, LoE4). However, the
cysts, pyonephrosis and perine- overall outcome of ADPKD patients on
phric abscess (GoR B). However, maintenance chronic haemodialysis (HD)
even modern imaging can still be and after renal transplantation is sur-
misleading. prisingly similar to that of HD patients
7. Lipid-soluble antibiotics should be with other primary renal diseases [6]
selected in the treatment of infected (GoR B, LoE 3).
renal cysts. Of these, fluoroqui-
nolones are the most effective and 2. METHODS
should be prescribed empirically
(GoR B). A systematic literature search was
8. Nephrectomy is still occasionally performed in PubMed, Medline, the
necessary to prevent recurrent UTI Cochrane data base and in books, jour-
and its complications, particularly nal articles (in English and Russian)
if transplantation is imminent and with the following key words: “auto-
the infecting organisms are resistant somal dominant polycystic kidney dis-
(GoR B). ease (ADPKD) and UTI, polycystic renal
9. Nephrectomy may also be recom- disease, pyelonephritis, cyst infections,
mended if removal of infective treatment ADPKD” and without limi-
stones is impossible by conservative tation on gender, age, clinical studies.
surgery. Only literature published after 1985 was
reviewed.
A total 368 English publications were
1. INTRODUCTION identified, which were screened by title
and abstract, and three Russian mono-
UTI occurs in 21–75% of patients with graphs. After peer review and exclusion
autosomal dominant polycystic kidney of duplicates a total of 111 were available
disease (ADPKD) [1–3]. The incidence of and included in the analysis.
420
Polycystic renal disease | 7.4 |
The studies were rated according to the 4. DIAGNOSIS

recommendation (GoR) using ICUD 4.1 Clinical symptoms and
standards (for details see Preface) [7–8]. laboratory evaluation
Diagnosis of a simple UTI is made as
usual on the basis of positive bacterial
3. CLINICAL MANIFESTATION analysis of urine in combination with
one or more clinical symptoms – dysuria,
The urinary tract should always be sus- back pain with typical radiation, pyrexia
pected as the most likely source of infec- and even rigors. Pyuria, leukocytosis and
tion in the febrile patient with polycystic bacteriemia are usually present [3] (GoR
renal disease. The urinary tracts per B, LoE 2b). Positive urine culture and
se, renal parenchyma and cysts may be pyuria favour renal parenchymal infec-
involved in the inflammatory process. tion but a positive blood culture with
Urinary tract infection associated with discrete abdominal or flank tenderness,
ADPKD can occur secondarily in associa- sometimes with a negative urine culture
tion with a variety of urological problems is consistent with infection in a cyst.
which are themselves more common in The majority of infections are caused by
ADPKD and can predispose to infection the standard enterobacteriaceae respon-
e.g. nephrolithiasis, recurrent gross hae- sible for cystitis and pyelonephritits (e.g.
maturia requiring repeated endoscopy, E. coli, Klebsiella, Proteus, Pseudomonas)
and obstruction of renal outflow (extrinsi- [2]. Multiresistant strains of Proteus and
cally by cysts, luminally by blood clot and pseudomonas, staphylococcus and strep-
debris). tococcus can be cultured [3, 10–11] (GoR
Renal infections can be subclassified as B, LoE 2b). The presence of anaerobic
pyonephrosis (infection of the obstructed bacteria may relate to the low partial oxy-
upper collecting system), acute bacte- gen pressure in the cyst contents (pO2<40
rial interstitial infection (infection of the mmHg) [1].
renal parenchyma), or pyocyst (infection Cysts can become secondarily infected
confined to a cyst). Pyocysts are poten- by the haematogenous route. S. aureus
tially the most serious of the three as infection from culture of cyst fluid and
diagnosis may be difficult and delayed blood has been reported in an intrave-
by failure of a short course of antibiotics nous drug abuser and after staphylococ-
given empirically to the febrile patient cal peritonitis in a peritoneal dialysis
with nonspecific symptoms to be curative patient [10, 12] (GoR B, LoE 2a)
[3] (GoR B, LoE 2b). Pyocysts are in most
instances accompanied by previously
4.2 Imaging
unreported loin pain and tenderness, and
positive blood cultures. Usually Gram- X-rays and tomograms may reveal evi-
negative enteric organisms are responsi- dence of peri-renal infection and neph-
ble, which suggests an ascending route of rolithiasis. Sonography is commonly
infection. used as a preliminary form of imag-
The relentless substitution of the ing but it can be very difficult to iden-
functioning renal parenchyma with tify the development of an abscess
cysts eventually leads to chronic renal within a complex septate cyst contain-
insufficiency. UTI may play a role in ing echodense proteinaceous deposits
the decline of renal function but the evi- suspended in serosanguinous cystic
dence is surprisingly equivocal [9] (GoR fluid. Invariably modern multislice CT
C, LoE 4). is regarded as mandatory to make the
421
diagnosis and plan further treatment, Much of the detail on antibiotic trans-
though MRI may ultimately prove as port has been derived from studies on
effective without risk of radiation expo- uninfected cysts. Very little is known of
sure [13] (GoR B, LoE 3). In the past, 67 the effect of infection on epithelial func-
Gallium isotope scintigraphy was used tion. Not surprisingly, much of the selec-
to detect areas of inflammation [14–15]. tion of antibiotics has to be empirical and
The value was limited by excretion of occasionally patients with cyst infection
a significant fraction of the dose into may still respond dramatically to tri-
the bowel. Furthermore it was reli- methoprim/sulphamethoxazole and chlo-
able in detecting only 50% of infected ramphenicol where quinolones have been
cysts, though in one study it was help- ineffective.
ful in identifying the focus of persistent After initial efficacy has been con-
UTI in renal transplant recipients with firmed, a prolonged course (four to eight
underlying ADPKD [15]. Sensitivity may weeks) of the antibiotic may be required
be improved with gallium SPECT [16]. to sterilise a pyocyst [3]. Percutaneous
Indium labeled leucocytes may have drainage of antibiotic-unresponsive pyo-
offered advantages as a carrier but cysts may be required to obtain material
these techniques are rarely used except for diagnosis and with a therapeutic aim
in the research environment [17] (GoR [21] (GoR B, LoE 3).
C, LoE 3).
6. NEPHRECTOMY
5. TREATMENT
Nowadays, nephrectomy is rarely required
The efficacy of antibiotic treatment may in the context of infection prevention.
depend on the liposolubility of the agents However, bilateral nephrectomy is still
used and whether or not they are ion- essential in patients whose confirmed
ized at physiological pH. Intracystic pH suppurative pyocysts have not been steri-
determines the extent to which basic lised before renal transplantation and
lipophilic antibiotics accumulate in the immunosuppressive medication is admin-
fluid. Lipid-soluble antibiotics which are istered. The risk of recurrent severe UTI
relatively alkaline may be useful in the and cyst infection occurring after trans-
treatment of infected renal cysts [18–19] plantation is considerable in patients
(GoR A, LoE 2b). with a history of infection pre-transplant
Cephalosporins, gentamicin and ampi- [3, 22] (GoR B, LoE 3). Other indications
cillin, which are standard treatments for include antibiotic resistant infection
acute pyelonephritis are often ineffective in association with renal stones where
for cyst infection, possibly because the clearance cannot be achieved by standard
betalactams and aminoglycazides require minimal access techniques; accelerated
active transport [2, 18]. Fluoroquinolones drug resistant hypertension; acquired
are generally the most effective, as they renal cystic disease with risk of malig-
have high lipid solubility and accumu- nancy and very rarely, persistent heavy
late in gradient cysts [20] (GoR A, LoE 3). haematuria .
Cyst infection is assumed to be present Minimal operative differences were
by default in patients with suspected seen between unilateral or bilateral two-
acute pyelonephritis who do not respond stage nephrectomy or bilateral simultane-
to standard antibiotic regimes. However, ous open or retroperitoneal laparoscopic
increasingly fluoroquinolones are used nephrectomy. The optimal timing is still
non-selectively. debatable [23–25] (GoR B, LoE 3).
422
Patients with ESRF due to ADPKD are responsible, which suggests an ascending
effectively treated by long term dialysis route of infection. Instrumental inter-
and renal transplantation, with graft and vention and bladder catheterization are
patient survival scores similar to that of risk factors of colonization by hospital
the general renal transplant population acquired polyresistant bacterial strains
[26–27] (GoR B, LoE 2a). and can lead to development of severe
UTI [5] (GoR C, LoE4). Cysts can become
secondarily infected via the haematog-
7. EXTRARENAL INFECTION AND enous route.
ADPKD CT imaging, perhaps supplemented
with MR, is optimal to detect infected
Hepatic cysts occur in 58–83% patients cysts, pyonephrosis and perinephric
with ADPKD [28–29]. They are more prev- abscess (GoR B).
alent and tend to be of larger in women Fluoroquinolones are generally the
and in the elderly of both sexes [28] (GoR most effective, as they have high lipid
B, LoE 2a). Cysts are isolated from the solubility and accumulate in gradient
biliary excretion system and therefore cysts [20] (GoR A, LoE 3). Percutaneous
are rarely infected; however, suppuration drainage of antibiotic-unresponsive pyo-
with multiple abscess development is still cysts may be required to obtain material
possible, particularly in renal graft recipi- for diagnosis and with a therapeutic aim
ents [30–31]. If so, bacteraemia is com- [21] (GoR B, LoE 3).
mon and unlike non-cystic pyogenic liver Bilateral nephrectomy is still essential
abscesses, a single bacterial species is in patients whose confirmed suppurative
usually responsible, suggesting a haema- pyocysts have not been sterilised before
togenous origin for the infection. renal transplantation and immunosup-
pressive medication is administered.
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425
|7.5|
Urinary tract infections in renal

insufficiency and dialysis
Reinhard Fünfstück1, Kurt G. Naber2, Michael C. Bishop3
1
Department of Internal Medicine I, Sophien and Hufeland Hospital, Weimar, Germany
2
Technical University Munich, Munich, Germany,
3
Department of Urology, Nottingham City Hospital, Nottingham, UK
Corresponding author: Reinhard Fünfstück, Prof. Dr., Sophien- und Hufeland-Klinikum Weimar,
Klinik für Innere Medizin I, Henry-van-de-Velde-Straße 2, D-99425 Weimar, Germany
Phone: ++49-3643-571100, Fax: ++49-3643-571102,
email: innere1@klinikum-weimar.de, r.fuenfstueck@klinikum-weimar.de
ABSTRACT predisposing factor such as obstruction,

calculus, reflux, abnormalities of the void-
Epidemiological studies demonstrate an ing mechanism, or diabetes mellitus. But
increasing number of patients suffer- a severe acute infection such as pyelone-
ing from a progressive deterioration of phritis or urosepsis may have an adverse
renal function. It may be of some inter- influence on the course of coexisting
est to know whether infection in the uri- chronic kidney disease and enhance the
nary tract (UTI) is more prevalent in such development of renal failure.
patients, but it is of considerable impor- Escherichia coli remains the most com-
tance to establish if UTI enhances the mon infecting microorganism. However, a
rate of renal structural and functional wide variety of other pathogens can also be
deterioration. Predisposing factors for UTI isolated. Urological interventions, cathe-
in renal insufficiency include altered host terization and repeated courses of antibiot-
response and various anatomical and func- ics may increase antimicrobial resistance.
tional abnormalities of the urinary tract The diagnosis of UTI in renal insuffi-
which might be responsible for both renal ciency and in dialysis patients is based on
damage and infection, e.g. vesicoureteral standard clinical and laboratory criteria
reflux, nephro-urolithiasis, obstruction. but these may need modification: pyuria
UTI in patients with normal kidney is more often observed in patients with
function does not often cause chronic oliguria and therefore of less significance.
renal disease in the absence of a major Sometimes low bacterial colony counts
Urinary tract infections in renal insufficiency and dialysis | 7.5 |
(<104 CFU/ml) can also be consistent with 4. It is important to investigate for

clinical infection. specific factors predisposing to UTI
The treatment strategies of UTI in especially for treatable conditions,
renal insufficiency and dialysis are based e.g. upper urinary tract obstruction,
on the same principles as in patients vesicoureteral reflux, urolithiasis,
with normal renal function. However, polycystic kidney disease, prostatic
dosages of drugs cleared renally must be disorders (for details see text) (GoR A)
adjusted to the glomerular filtration rate 5. Consider co-medication commonly
(GFR). Antimicrobials with the potential administered to patients with
to cause systemic toxicity and specifically chronic renal disease which might
nephrotoxicity (e.g. aminoglycosides, predispose them to UTI e.g. immuno-
nitrofurantoin) should be used very criti- suppressive therapy (GoR C).
cally. Antibiotics eliminated by the dialy-
sis procedure must be administered at
the end of the dialysis session. There are Treatment
no randomised trials on the optimal man-
6. The choice of antimicrobial agents is
agement of UTI in renal insufficiency.
similar for patients with or without
Key words: urinary tract infection, chronic renal disease (GoR B)
pyelonephritis, renal/kidney insufficiency, 7. Antibiotics with nephrotoxic adverse
renal dialysis, antibiotic therapy, end effects, should if possible be avoided
stage renal disease but otherwise blood concentrations
must be carefully monitored (GoR B)
SUMMARY OF RECOMMENDATIONS 8. Drug dosing adjustments are neces-
sary in patients with renal insuffi-
Classification ciency and on hemo- and peritoneal
dialysis treatment. (GoR B)
1. In patients with mild and moderate
9. Patients with severe renal disease,
renal insufficiency (without olguria)
particularly those on dialysis, gener-
and with a normal urinary tract, a
ally require longer treatment com-
lower UTI (cystitis) can be classified
pared to patients with lesser degrees
as uncomplicated, because such an
of renal impairment (GoR C), but the
infection has no adverse impact on
optimal duration of treatment is not
renal function.
known.
2. An acute episode of pyelonephritis in
10. Treatment of asymptomatic bacte-
patients with endstage renal disease,
riuria (ASB) should be considered in
where dialysis is imminent or on-go-
patients treated with immunosup-
ing, or with significant urinary tract
pressive therapy as any infection
abnormalities, should be classified as
might increase the rate of progres-
complicated, because such patients
sion of the renal disease. Otherwise
may be particularly susceptible to
treatment is not indicated. (GoR C)
severe urosepsis and hence progres-
sion of renal insufficiency. 11. If symptomatic relapses occur fre-
quently, extended courses of therapy,
Diagnosis or long term suppressive antimicrobial
therapy may be necessary (GoR C).
3. The diagnosis of UTI is mainly based Very occasionally nephrectomy
on typical symptoms, bacteriuria and (+ ureterectomy) is the only option
pyuria, as in patients with normal to control life threatening recurrent
renal function. (GoR A) episodes of pyelonephritis (GoR C).
427
1. INTRODUCTION mellitus and hypertension. Overall the

incidence of ESRD due to glomerular,
Epidemiological studies demonstrate an tubulointerstitial and toxic nephropathies
increasing number of patients suffering remains approximately stable [1, 5]. In
from progressive deterioration of renal general, renal infectious diseases, such as
function [1] (LoE 3), but it is not known chronic pyelonephritis, are summarized
how many of these patients suffer from in the tubulointerstitial diseases without
urinary tract infections (UTI). Although specifying the kind of infection. For 2000
UTI can severely impair renal function, and 2004 the frequencies of ESRD in
this is rare in the absence of a major pre- Germany are listed in Table 1.
disposing factor such as obstruction, cal- In patients with renal insufficiency
culus, reflux, abnormalities of the voiding a wide variety of underlying predispos-
mechanism, or diabetes mellitus [2]. ing factors for UTI has to be considered,
Chronic renal disease is rarely caused by such as age, gender, diabetes mellitus,
UTI, the rate is less than 1 per 5000 per- vesicoureteral reflux, urolithiasis, incon-
sons per year [3] (LoE 3). In infants and tinence, lower urinary tract dysfunction
young children UTI might be expected as in neuropathic disorder, prior instru-
to damage the growing kidney. The inci- mentation of the urinary tract, polycystic
dence is certainly higher than in adults renal disease, and disturbances of spe-
but the level is still modest, at about 1% cific and non specific immune reactions of
[4] (LoE 2a). Other kidney diseases are the host [3, 6] (LoE 2b). In patients with
responsible for the increasing burden of ESRD due to obstructive uropathy, pyo-
end stage renal disease (ESRD) requiring cystis following urinary diversion, pyone-
renal replacement therapy (RRT) reflect- phrosis or perinephric abscess, this may
ing the rising world-wide prevalence of cause recurrent infection, particularly in
chronic systemic degenerative vascular the form of urosepsis, if the source cannot
disease and its association with diabetes be eliminated completely.
Table 1 Incidence rates of different kidney diseases causing end stage renal disease. Results of the German Dialysis Registry
for the years 2000 and 2004 [5].
Incidence rate (%)
Kidney diseases Year 20001 Year 20042
diabetes mellitus type 2 and type 1 36 34
renal vascular diseases (due to hypertension and other causes) 15 22
glomerular nephropathies 15 12
tubulointerstitial nephritis3 10 8
polycystic kidneys (adult type dominant) 6 5
renal disease caused by systemic diseases (vasculitis, lupus erythem.) 4 4
hereditary disease 1 1
unknown causes 9 9
unclassified renal disease 4 5

1
based on 5641 patients
2
based on 6390 patients
3
includes pyelonephritis
428
2. METHODS A total of 421 publications were found

with these keywords and limitations:
A systematic literature search was per- for UTI AND renal/kidney insufficiency
formed in the following data bases: 271 in Medline and 13 in Medpilot; for
Medline and Medpilot (database of the UTI AND dialysis (hemodialysis/perito-
publishers Karger, Kluwer, Springer, neal dialysis) 119 in Medline and 18 in
Thieme and Cochrane Database of Medpilot. The publications were screened
Systemic Reviews). The following key by title and abstract. Finally 32 publica-
words were used: urinary tract infections were considered valid.
tion (UTI) AND renal diseases, kidney The studies were rated according to the
diseases, renal insufficiency, kidney level of evidence (LoE) and the grade of
insufficiency, dialysis (hemo-/peritoneal recommendation (GoR) using ICUD
dialysis); antibiotic treatment in renal standards (for details see Preface) [7–8].
insufficiency; estimation of renal func-
tion. The following limitations were
used: humans (female, male); over 19 3. CLASSIFICATION AND DEFINITIONS
years old; clinical trials; randomised,
controlled trials; meta-analysis; only The typical sign of kidney damage is loss
publications with published abstracts. of renal function. This is diagnosed by
All publications between 1998 and 2008 morphological alterations and by altered
were considered and supplemented by a biomarkers characterizing kidney disease
few earlier key studies considered rel- (Table 2). All diagnostic steps to diagnose
evant for this topic. UTI in renal insufficiency and decisions
Table 2 Biomarkers for kidney damage.
Routine clinical assesment Research assesment
Serum: Urine:
creatinine (and estimation of GFR) Tamm Horsefall protein (THP)
urea Secretory IgA
sodium α1-microglobulin
potassium IgG
acid-base-balance enzymuria, e.g. beta-NAG
glucose asymetric demethyl arginin (ADMA)*
uric acid IL-18*
C-reactiv Protein (CRP) proteomics*
gen polymorphisms of TNF-alpha*
Blood:
monocyte chemoattractant protein-1(MCP-1)*
ESR
leukocytes
Urine:
leukocytes
erythrocytes
proteinuria incl. microalbuminuria
*parameters more typical for glomerulonephritis, only few data available.
429
Table 3 K/DOQI Staging system for chronic kidney disease [6].
Stage Description GFR/ml per minute per 1.73 m2
1 kidney damage with normal or increased GFR > = 90
2 mild decrease in GFR 60-89
3 moderate decrease in GFR 30-59
4 severe decrease in GFR 15-29
5 kidney failure <15 or dialysis
for drug administration depend on the nation with repeated courses of antimi-
level of renal excretory function. The US crobial therapy will increase the risk of
National Kidney Foundation has classi- overgrowth of organisms with increased
fied the degree of chronic kidney diseases antimicrobial resistance. There are no
using the K/DOQI Staging System based studies characterizing the virulence
on the measurement of GFR [9] (Table 3). properties of uropathogens, comparing
In patients with mild and moderate patients with or without renal insuffi-
renal insufficiency and a normal urinary ciency or dialysis, respectively.
tract lower UTI (cystitis) can be classi-
fied “uncomplicated”, because such an
infection has no adverse impact on renal 4.2 Host defence in renal
function. However, any kind of severe insufficiency
infection, such as an acute episode of It is commonly accepted that the immune
pyelonephritis or uroseptic syndrome, status of patients with chronic renal dis-
or UTI in patients with endstage renal ease and ESRF is compromised. One
disease, undergoing dialysis and with measurable effect is of leucocyte dysfunc-
urinary tract abnormalities, such as tion. This may favour infections in general
obstruction, reflux, polycystic disease, [6, 13–14], but has not been shown specifi-
urolithiasis, unstable metabolism e.g. due cally to promote UTI. The activity of the
to diabetes mellitus, should be classified hexose monophosphate shunt pathway in
as “complicated”, because progression of phagocytosis released respiratory burst is
renal insufficiency may be promoted. disturbed [6, 15] (LoE 2b). Phagocytes not
only have the capacity to kill and destroy
bacteria but they also produce cytokines
4. PATHOGENESIS
and activate other components of the
immune system such as lymphocyte sub-
4.1 Uropathogens populations. Alteration of granulocyte
There are only few studies evaluating function, such as impairment of migra-
the uropathogens found in patients with tion, chemotaxis, degranulation and block-
renal insufficiency or undergoing dialysis. ade of glucose uptake will potentially
E. coli remains the most common infect- promote colonisation of the urinary tract
ing organism. A wide variety of other and host invasion. These factors also have
bacteriae, such as Proteus mirabilis, an inverse relationship with the degree of
Pseudomonas aeruginosa, Enterobacter renal insufficiency [13]. It is not known,
spp., staphylococci and enterococci may be to what extent in chronic renal diseases
isolated in these patients [10–13] (LoE 3). the virulence of uropathogens is influ-
Nosocomial exposure, urological inter- enced by urinary variations of substances,
ventions and catheterizations in combi- such as secretory IgA, Tamm-Horsfall
430
protein (THP), β-defensine 1, which nor- microorganisms that are usually respon-
mally inhibit bacterial adherence. sible for contamination. In contamina-
tion, bacterial colony counts are usually
lower than if microorganisms are invasive
5. DIAGNOSIS [17] (LoE 4). Colonization of the urinary
tract is defined as replication of microor-
The diagnosis of UTI is mainly based on ganisms in the urine, not accompanied by
typical symptomatology and quantitation invasion of the adjacent epithelial or sub-
of urinary bacteria and leucocytes (i.e. epithelial tissue. These situations depend
pyuria) or surrogate parameters, such as on the host defence, which may be altered
leucocyte esterase and nitrite reaction. in renal insufficiency, a possible reason
The criteria to diagnose UTI in patients for the increased prevalence of asymp-
with renal insufficiency are similar to tomatic bacteriuria in these patients.
those used in patients with normal renal Bacteruria must be interpreted according
function, but it is necessary to point out to the underlying clinical condition.
some peculiarities. Some patients with renal insufficiency
The typical clinical symptoms of UTI and transient “significant” bacteriuria may
can overlap with symptoms associated not have true infection [17, 19] (LoE 3), but
with kidney related diseases. Pain of in others even a low bacterial colony count
cystitis or of pyelonephritis can be toned with pyuria may represent true infection
down or intensified by complication of [19, 21] (LoE 3). The clinical significance
uremic neuropathy (IV). of specific levels of bacteriuria and pyuria
Guidelines in which pyuria is defined by in patients with decreasing renal function
a white blood cell count of 10 per high field, and in dialysis patients may only be deter-
can generally be applied to the diagno- mined by prospective studies with long
sis of UTI in renal insufficiency. However, term follow-up.
31–53% of dialysis patients have pyuria Recommendations for the diagnosis of
but no UTI [16–18] (LoE 3). Urinary leuco- UTI in renal insufficiency are summa-
cyte count is broadly inversely proportional rized in Table 4. The standard clinical
to the urine volume [16–19] (LoE 2a). and laboratory findings are usually suffi-
This may be due to increased concentra- cient to characterize UTI including unde-
tion of a constant number of leucocytes tected urological disease, e.g. urolithiasis,
secreted from the urothelial surfaces. On upper and lower tract obstruction, poly-
the other hand dilution can also cause cystic renal disease, and to estimate the
misleading reduction in bacterial colony degree of renal insufficiency. Intravenous
counts and negative assessment of nitrites urography has been mainly superseded
on the “Multistix” dip test. Therefore in the by high definition modern ultrasound,
patient with symptoms suggestive of UTI it ultrathin section CT and MRI but it is
is essential not to rely on stick testing but probably contraindicated in patients with
always perform urinary culture and accept CRF due to potential nephrotoxicity of IV
that a count of <100,000 cfu/ml can be contrast [22] (LoE 2b).
pathological, particularly if a single organ-
ism is cultured and leucocytes are present.
Contamination can be suspected if 6. TREATMENT
three or more microorganisms are found
simultaneously in the urine culture or Effective treatment of UTI requires high
if numerous squamous epithelial cells antimicrobial concentration in urine.
are detected on urinalysis [20] (LoE 3). This is usually achieved as many antimi-
Lactobacilli, staphylococci (coagulase-neg- crobials are excreted mainly by glomeru-
ative), corynebacteria and streptococci are lar filtration and tubular secretion [23]
431
Table 4 Recommendations for the diagnosis of UTI in renal insufficiency.
History Routine laboratory measurements:

Clinical symptoms • C-reactive protein (CRP)
Physical examination • erythrocyte sedimention rate
• leukocytes
Urological examination: e.g.
uroflowmetry, urodynamics • Urine:
leucocyturia, bacteriuria
Research assessment:
THP, sIgA, NAG, ACB test,
Adhesion of uropathogens on uroepithelial cells
Imaging:
ultrasound, computer tomography, magnet resonance imaging, DMSA-scan, sometimes micturition
cystourethrography (MCUG)
(LoE 1a). The diseased kidney, however, system). Oliguria only occurs terminally
is insufficiently perfused, therefore lower on dialysis and in acute renal failure.
urinary antimicrobial concentrations are In this context oliguria however, is com-
achieved. This can apply irrespective bined with reduced ability to concen-
of the urine volume in stages 4 and 5 of trate urine (stage 3,4,5/K/DOQI-Staging
renal failure due to chronic renal disease system). This pathophysiology has also
and in patients with acute renal failure. direct implication for antibiotic therapy
(see below).
Dosage of drugs cleared renally should
6.1 Treatment strategies and be adjusted according to GFR as usually
dosage adjustment determined by creatinine clearance [30]
Generally the treatment strategies of (LoE 1a) The calculation of renal func-
UTI in renal insufficiency are based on tion is only valid in a stable situation and
the same principals as in patients with with a constant serum creatinine con-
normal renal function [24–25] (LoE 4). centration. The K/DOQI clinical practice
UTI should respond rapidly, without guidelines advocates using the traditional
recurrence, nor emergence of resistant Cockroft-Gault equation rather than the
pathogens. Modification of Diet in Renal Disease
Acute and chronic kidney diseases can (MDRD) study equation for routine esti-
affect glomerular blood flow and filtra- mation of GFR [9] (LoE 1a). However, In
tion, tubular secretion and reabsorption, patients with a GFR lower than 60 ml per
as well as renal bioactivation and metab- minute per 1.73 m2 and lower than 90 ml
olism. Drug absorption, bioavailability, per minute per 1.73 m2 in older patients,
protein binding, distribution volume, and the MDRD equation is superior to the
non-renal clearance (metabolism) can be Cockroft-Gault equation [31] (LoE 1 a).
altered in renal insufficiency as well as Many antimicrobial agents are elimi-
in hemo- and peritoneal dialysis [26–27]. nated renally and require dosing adjust-
Drug dosing errors are common in these ment. Detailed publications, nomograms
patients and can cause adverse effects and electronic calculators are available for
and poor outcome [28–29]. dose adjustments of antibiotics in patients
Most patients with early chronic renal with chronic kidney disease and on long
failure have normal or increased urine term dialysis treatment. For some antibi-
volumes (stage 1 and 2/ K/DOQI-Staging otics depending on the pharmacological
432
properties a loading dose and maintenance however, depends also on the techniques
dosing are recommended [30, 32] (LoE of extracorporal treatment (hemodialysis,
1a). Dosing adjustments in patients with hemofiltration, hemodiafiltration) and the
chronic renal failure for antibiotics gener- type of dialyzer (membrane type, hydraulic
ally used for treatment of UTI are shown permeability, biocompatibility profile). In
in Table 5. Dialysis treatment requires spe- peritoneal dialysis the treatment modal-
cial attention with regard to dose schedul- ity (continuous technique, tidal dialysis,
ing and the possible need for supplemental nightly peritoneal dialysis) also influences
dosing for agents substantially cleared by the drug levels. The effective antibiotic
dialysis. The dialysability of drugs depends dosage is dependent on the clinical state of
on the molecular weight, water solubility the patient and the dialysis strategy. Often
and degree of protein binding as well as it is difficult to adjust the correct doses
the kind of dialysis treatment. except by carefully timed and interpreted
For general information some exam- blood measurement. In general, antibiot-
ples for dialysability of antimicrobial sub- ics eliminated by the dialysis procedure
stances undergoing hemodialysis are listed have to be administered after the dialysis
in Table 6. The dialysability of drugs, process.
Table 5 Antimicrobial agents: Dosing requirements in patients with chronic renal failure.
Dosage adjustment in percentage of usual dosage

(based on GFR ml/min./1,73 m2)
Drug Usual dosage >50 50-10 <10
Ciprofloxacin 400 mg i.v. 100% 50-75% 50%

500 to 750 mg
orally every 12 hours
Levofloxacin 250 to 750 mg 100% 500 to 750 mg init. dose 500 mg init. dose
every 24 hours then 250 to 750 mg every than 250 to 500
24 hours every 48 hours
Gatifloxacin 400 mg every 24 hours 100% 400 mg initially, then 400 mg initially, then
200 mg dialy 200 mg
Amoxicillin 250 to 500 every 8 hours every 8 hours every 8 hours every 24 hours
Ampicillin/ 1 to 2 g ampicillin and 100% every 12 hours every 24 hours (GFR

Sulbactam 0,5 to 1 g Sulbactam every (GFR 15 to 29) 5 to 14)
(GFR >30)
6 to 8 hours
Cefaclor 250 to 500 mg every 8 hours 100% 50 to 100% 50%
Cefmandole 0,5 to 1 g every 4 to 8 hours every 6 hours every 6 to 8 hours every 8 to 12 hours
Cefazolidine 0,25 to 2 g every 6 hours every 8 hours every 12 hours 50% every 24 to 48
hours
Cefotaxime 1 to 2 g every 6 to 12 hours every 6 hours every 12 hours every 24 hours or

50%
Cefixime 200 mg every 12 hours 100% 75% 50%
Trimethoprim 100 mg every 12 hours every 12 hours every 12 hours (GFR >30%); every 24 hours
every 18 hours (GFR 10 to
30%)
(according to M.Y. Munar et al [23]).
433
Table 6 Dialysability of antimicrobial agents in patients undergoing haemodialysis treatment [32].
Cleared* Partially cleared* Not cleared*
Ampicillin Quinolones Methicillin

Cephalosporin Cotrimoxazole Teicoplanin
Aminoglycoside
Trimethoprim
*by dialysis procedure.
6.2 Choice of antibiotic 6.3 Asymptomatic bacteriuria

The choice of antibiotic depends on the High frequency of asymptomatic bacte-
severity of the symptoms, the causative riuria, ranging from 27–44% has been
microorganisms, the level of renal dis- reported in patients with chronic renal
ease and whether complicating factors failure with and without haemodialy-
are present. sis [17]. It is difficult to determine its
Substances with nephrotoxic side specific cause because of the wide vari-
effects, e.g. aminoglycosides, should be ety of underlying renal diseases, lack
used with caution. Antibiotics without of information on prior instrumenta-
cumulative effects and wide therapeutic tion of the urinary tract and/or poor
range index are preferred. Broad spec- response to antimicrobial therapy.
trum cephalosporins and fluoroquinolo- Patients with progressive renal disease
nes may be effective and are the drugs for whom immunosuppressive agents
of choice in this setting [33–34] (LoE 4). are part of the standard treatment pro-
Nitrofurantoin should be avoided in tocol, e.g. nephrotic syndrome, some
renal failure as the drug is not excreted types of glomerulonephritis, and oth-
and toxic serum concentration may lead ers whose immune responses are likely
to peripheral neuropathy [13]. Patients to be severely impaired, asymptomatic
with diminished renal function are also bacteriuria should probably be treated
susceptible to the nephrotoxic effects of [37–38] (LoE 4) (GoR B). Otherwise it
particular drug combinations e.g. cepha- is not recommended (LoE 4) (GoR B).
losporins with furosemide or ethacrynic However, there is no evidence that clear-
acid [35]. Some antibiotics cause eleva- ance of bacteriuria is beneficial in terms
tion of the serum creatinine by mecha- of slowing down the rate of progression
nisms other than direct nephrotoxicity. of deteriorating renal function.
Trimethoprim can inhibit tubular secre-
tion of creatinine. Tetracycline has an
6.4 Duration of therapy
antianabolic effect in renal failure and
is best avoided but doxycycline may be There are no published data from ran-
used if there is a definite indication, domised trials determining the optimal
e.g. urethritis [36]. No other antimicro- duration of treatment of UTI in renal
bials are specifically contraindicated in insufficiency and in dialysis patients.
renal insufficiency and in dialysis popu- It is customary to treat even uncompli-
lations, although dosage adjustments cated cystitis for at least seven days and
appropriate to the level of renal impair- continue for 21 days or more, accord-
ment will usually be necessary [23] ing to clinical severity and the pres-
(LoE 1a). ence or otherwise of a uropathy [14, 24]
434
(LoE 4). However, the response to even not be cured by nephrectomy. Sometimes
longer courses of antibiotics in higher sampling and culture of urine specimens
dosage may only be transitory. Even obtained by retrograde catheterisation
when the concentration of antibiotic in can be helpful though the result is rarely
urine excreted from the diseased kidney unequivocal.
is adequate, infection may not be eradi-
cated leading to a relapse once antimi-
crobial treatment is discontinued. If 7. FURTHER RESEARCH
symptomatic relapses occur frequently,
extended courses of therapy of six to 12 The contemporary knowledge on many
weeks duration, or long term suppressive aspects of UTI in patients with renal
therapy are recommended but may still insufficiency and/or on dialysis remains
be ineffective [31] (LoE 4). Relapses pre- incomplete. The populations are not
sumably occur due to bacterial regrowth homogeneous and many factors influence
from colonies of non-planktonic bacteria the deterioration of kidney function. The
residing in a protected biofilm environ- specific properties of the infecting micro-
ment which has developed deep within organisms, their geno- and phenotypical
damaged renal parenchymal or urothe- clusters (e.g. presence of fimbriae, alpha
lial tissue, or alternatively from intrac- hemolysin, cytotoxic necrotizing factor)
ellular communities of organisms living as well as the efficacy of the systemic
temporarily as commensals and selected and local host defence mechanisms (e.g.
by antibiotic therapy in the extracellular phagocytosis and bacterial killing activ-
milieu. ity of granulocytes depending on uremic
Ultimately the only available option situation, production of Tamm-Horsfall
is surgical excision of diseased tissues. glycoprotein, attachment capacity of
Bilateral nephrectomy is still very occa- uroepithelial cells) are potentially signifi-
sionally performed in patients with cant but their relative contributions to
incurable relapsing pyelonephritis and the disease process need better clarifica-
end-stage renal failure due to a vari- tion. Also, any studies submitted for pub-
ety of uropathies, particularly terminal lication on patients with UTI and renal
stone disease, scarred kidneys associ- insufficiency and/or on dialysis require
ated with reflux, congenital obstruction complete characterization of the popula-
and adult polycystic disease. Very rarely, tion under scrutiny for the complexity
in the context of chronic renal failure, of this multifactorial disease to be prop-
infection really does seem to be lateral- erly understood. Finally, the outcome and
ised and the response to antibiotics of management of UTI needs to be defined
each recurring episode is substandard. separately for each category of renal
Because of the decreased perfusion of functional impairment (K/DOQI stag-
the affected kidney, the urinary antimi- ing system), if improvements in recom-
crobial concentration is low unilaterally mendations for diagnosis and treatment
and the beneficial effect is not sustained. of UTI in chronic renal failure are to be
The concentration may seem adequate effective.
in urine from the bladder but this
merely reflects excretion from the better
functioning kidney. However, just as in 8. CONCLUSIONS
patients with normal function and uni-
lateral renal disease, relapsing UTI does There is no evidence that lesser degrees
not necessarily originate from a focus in of clinical UTI (e.g. cystitis in a mild or
the affected kidney and therefore may moderate renal insufficiency and with a
435
normal urinary tract) or asymptomatic guideline recommendations. Prog Urol,

bacteriuria increase the rate of neph- 2007. 17(3): 681–4.
ron loss. However, any kind of severe 8. U.S. Department of Health and Human
infection, such as an acute episode of Services Public Health Service Agency for
pyelonephritis or urosepsis, or any UTI Health Care Policy and Research, 1992:
in patients with ESRD, undergoing dialy- 115–127.
sis and with urinary tract abnormalities, 9. K/DOQI clinical practice guidelines for
such as obstruction, reflux, polycystic dis- chronic kidney disease: evaluation, clas-
sification, and stratification. Am J Kidney
ease, urolithiasis, unstable metabolism
Dis, 2002. 39(2 Suppl 1): S1–266.
e.g. due to diabetes mellitus, should be
10. Vaziri ND, Cesarior T, Mootoo K, Zeien L,
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12. Szczepanska M, Szprynger K, and
Adamczyk P, [Effect of urinary tract infec-
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437
|7.6|
Urogenital infections in renal

transplant patients – causes and
consequences
Daniel A. Shoskes, Ismail R. Saad
Corresponding Author: Daniel Shoskes MD, Professor of Surgery, Cleveland Clinic Lerner College of Medicine, Director,
The Novick Center for Clinical and Translational Research, Glickman Urological and Kidney Institute, The Cleveland Clinic,
9500 Euclid Ave, Desk Q10-1, Cleveland, OH USA, 44195
ABSTRACT kidneys. Typical uropathogens are com-

monly involved but UTI’s may also be
Urinary tract infection (UTI) is the most caused by commensal and fastidious bac-
common infectious complication following teria, fungus, mycobacteria and viruses.
kidney transplantation. The incidence Some studies suggest post transplant
in adults is about 20% in the first six UTI has a negative impact on graft sur-
months and 50% in the first three years, vival and function, although causality
despite the common use of antibiotic has not been established. There is a pau-
prophylaxis. Risk factors include more city of prospective controlled data that
intensive immunosuppression (especially can guide UTI prophylaxis or therapy in
the use of depleting induction antibodies terms of agent or duration although most
and sirolimus), extremes of age, diabe- programs will routinely use prophylaxis
tes, prolonged time on dialysis, abnormal for at least six months.
or reconstructed lower urinary tract and Key words: kidney, transplant urinary
prolonged use of urinary catheters and tract infection, bacteriuria
stents. Diagnosis may be complicated by
other conditions causing urinary symp-
toms and fever in transplant recipients,
as well as immunosuppression mask- SUMMARY OF RECOMMENDATIONS
ing the typical presentation and lack
of symptoms in a denervated kidney. 1. Antimicrobial prophylaxis following
Infection may involve the graft or native renal transplantation reduces the
Urogenital infections in renal transplant patients | 7.6 |
incidence of urinary tract infection in 2. METHODS

the first six months (GoR B)
2. While there are kidney and recipient The consensus was reached after a
factors that increase the risk of UTI systematic Pubmed review of reports
post transplant, the value of more published in last 20 years using the fol-
intensive or greater duration prophy- lowing keywords: kidney or renal, trans-
laxis is unproven (GoR C) plantation, complications, (urinary tract
infection, or bacteriuria). This search
3. Post transplant UTI risk can be
yielded 1343 articles of which 155 were
reduced by early removal of urinary
review articles. The studies were rated
foreign bodies (Foley catheter, ure-
according to the level of evidence (LoE)
teral stent) (GoR C)
and the grade of recommendation (GoR)
4. Asymptomatic bacteriuria post kid- using ICUD standards (for details see
ney transplant does not require Preface) [2–3].
therapy beyond standard prophylaxis
(GoR C)
5. Therapy of post transplant UTI 3. DEFINITIONS IN POST
should be guided by culture, sen- TRANSPLANT UTI
sitivities and antibiotic charac-
teristics, favoring bacteriocidal The post transplant UTI literature has
antibiotics with good tissue pene- contributions from many fields outside of
tration (e.g. sulfa drugs, quinolones) Urology and unfortunately the definition
rather than bacteriostatic antibi- of UTI can vary significantly. By strict
otics with poor tissue penetration criteria, the presence of bacteria within
(e.g. nitrofurantoin) (GoR C) the urinary tract is bacteriuria. A uri-
nary tract infection requires pathological
invasion of the urothelium with microor-
ganisms resulting in tissue injury and an
1. INTRODUCTION inflammatory response. This inflamma-
tory response, which may be local and/or
Kidney transplantation has witnessed systemic, produces the clinical syndrome
major advances in surgical techniques of infection. Common signs and symp-
and immunosuppression. Urinary tract toms of UTI may be mimicked by normal
infection (UTI) is the most common infec- post-transplant conditions (e.g. red and
tious complication following kidney trans- white cells in the urine from a urinary
plant [1]. UTI is a potential source of stent, urinary frequency from a small
severe systemic illness. However, its con- defunctionalized bladder) or absent due
tribution to permanent graft dysfunction to therapy (e.g. fever suppressed by ster-
remains controversial. oids, minimal tenderness in a denervated
This chapter aims at discussing the kidney). In reviewing the transplant lit-
classification, epidemiology and pathogen- erature, it is important to distinguish
esis of UTI in renal transplant recipients. articles that define UTI as bacteriuria,
Risk factors for UTI following transplan- symptoms alone or a combination.
tation will be examined in terms of host, Another issue is the diagnostic thresh-
graft, anatomical factors and timing. UTI old for a positive culture. Most labs will
in the pediatric transplant patient will be report a positive urine culture with bac-
discussed considering that ESRD in this terial counts of at least 105 bacteria per
age group is commonly related to ana- ml of fresh unspun midstream urine.
tomical abnormalities and a history or This definition is handed to us from stud-
recurrent UTI. ies in the 1970’s of college age females
439
which tried to find an appropriate cutoff serious infection during the first year
to diagnose pyelonephritis in the absence post-transplant, with mortality rates
of lower urinary tract symptoms. Clearly, approaching 50% [5]. The current infec-
in a symptomatic patient, 102 bacteria tion-related one-yr mortality has been
per ml is a sufficient threshold that does reduced to less than 5%. Nevertheless,
not overly increase false positives, and in UTI’s are still common and while sel-
transplant patients for whom the diagno- dom leading to death can produce signifi-
sis of UTI may be equivocal the lab must cant morbidity and possibly impact graft
be asked to provide the actual numerical survival.
bacterial count and not merely to report Most articles addressing UTI incidence
“no significant growth” [4]. Conversely, after transplant are limited by being sin-
in a patient with a Foley catheter, urine gle center with small numbers and mix
may have counts over 1010 and not be time of follow up, method of diagnosis
infected. and hospitalized vs. outpatient records
Finally, the classification and defini- (LoE 3). In studies of post transplant
tions of repeat UTI give important etio- infections, UTI was the most common at
logic information in transplant recipients. about 45% [6]. In a study of 500 patients
Repeat infections may be unresolved from two centers, the incidence of UTI
(remain active during therapy), persist- was 43% within 42 months [7]. In the one
ent (resolve with therapy but recur soon study that examined a large database
after with the same bacteria) or recur- (USRDS with Medicare billing codes from
rent (resolve with therapy; recur a vari- 1996 to 2000), the cumulative incidence
able time later with different bacteria). of UTI during the first six months after
Unresolved UTI’s usually indicate wrong renal transplantation was 17% (equiva-
antibiotic choice or multiple organisms. lent for men and women) [8]. At three
However, in immunosuppressed patients years the incidence was 60% for women
consideration should also be given to and 47% for men.
antibiotic action, since bacteriostatic The rate of asymptomatic bacteriuria
antibiotics may be insufficient to cure post transplant shows great variation
the infection since the immune system between reports (4% to 60%) [9]. Early
cannot eradicate the dormant bacteria. studies report that up to 90% of post-
Recurrent UTI’s often point to bacterial transplant UTIs were asymptomatic and
re-introduction, often in women follow- diagnosed only on the basis of culture
ing intercourse however in transplant [10]. Graft and patient survival were
recipients it may point to over-immuno- not found to be significantly affected by
suppression. Persistent infections are asymptomatic bacteriuria in the absence
usually a clue to an unresolved bacterial of other complications [11] (LoE 3).
nidus and in transplant patients should Since it is standard practice to use
prompt a search for foreign bodies, inef- antimicrobial prophylaxis periopera-
ficient bladder emptying or a source from tively for the wound (cephalosporins
the native kidneys (e.g. reflux, polycystic in our program) and long term against
kidney disease). Pneumocystis pneumonia (Trimethoprim-
sulphamethoxazole [TMP-SMZ]), most
of the infections within 6 months were
almost certainly “breakthrough infec-
4. EPIDEMIOLOGY
tions” with resistant strains. The inci-
dence of UTI post transplant without any
4.1 Incidence
antibiotic use is unknown, although one
Thirty years ago, 60% of kidney trans- early study found 50% of patients with-
plant recipients developed at least one out prophylaxis developed a UTI during
440
the hospital admission [10]. While we who were younger than 30 years at
presume that prophylaxis is of benefit, we transplantation developed post-trans-
don’t know whether therapy in addition plant UTIs [7]. Older patients may be at
to routine wound and lung prophylaxis, higher risk due to inefficient voiding as
especially in high risk patients reduces a result of poor bladder contractility (e.g.
UTI rates. diabetic cystopathy), outflow obstruc-
tion (e.g. prostatic hypertrophy) or over-
4.2 Timing immunosuppression.
Pediatric renal allograft recipients
Historically, patients were at the high-
represent a special population with
est risk for UTI in the first postoperative
respect to UTI. In this group, ESRD
month [12]. Recent literature indicates
is more likely to be the result of uri-
fewer UTI’s in the early post transplant
nary tract malformations or dysfunc-
period with one study finding 13% in the
tion. Abnormal lower urinary tracts are
first month, 75% between two and six
present in up to 25% of children with
months and 32% after six months [13].
renal failure which is more common than
Late onset UTIs (occurring > 6months
in adults. John et al, in their retrospec-
post transplant) were believed to have a
tive review of three centers found a UTI
benign outcome leading some transplant
rate of 36% (median time one year) and
centers to stop prophylaxis six months
28% of patients had recurrent UTI [15].
after transplantation [14]. The previ-
Even in pediatric patients with neph-
ously mentioned USRDS study found late
rological disease requiring renal trans-
onset UTI associated with increased inci-
plant there is a high incidence of lower
dence of death and graft loss [8]. It was
urinary tract symptoms and post trans-
not clear whether UTI were a cause of
plant UTI.
this complications or whether they were
Gender is a UTI risk factor post trans-
a marker for other comorbid conditions or
plant and females are more likely to
of over-immunosuppression.
develop graft pyelonephritis. In the
report by Chuang et al, 68% of the female
5. ETIOLOGY AND RISK FACTORS transplant patients vs. 30% of the male
transplant patients had at least one UTI
post-transplant with 71% of patients
A combination of etiologies may account
with recurrent post-transplant UTI being
for UTI following renal transplan-
females [7]. In children however, boys are
tation. The pathogenesis is usually
more likely to develop post transplant
multifactorial.
UTI [8] (LoE 3).
Comorbid conditions such as diabetes
5.1 Patient factors
mellitus (DM) may impact the frequency
Age correlates with post transplant UTI’s of infections post transplant particularly
in a bimodal distribution, with the high- UTI [11] (LoE 3). DM recipients had
est incidences in childhood and the eld- higher readmission rate due to infections
erly. In the USRDS retrospective review (45% vs. 32%) [16] and an increased risk
of Medicare claims of adult recipients, of fungal UTI [17].
age was found to be independently asso- Prolonged ESRD with dialysis pre-
ciated with late UTIs (> six months fol- transplant has also been correlated with
lowing renal transplantation) in men higher risk of UTI in renal transplant
>55 years when compared with <55 years recipients [8]. This might be related to a
[8]. Chuang et al reported that 55% of higher incidence of complicated UTI in
the patients who were 65 years or older recipients who had been anuric prior to
at transplantation vs. 38% of patients transplant [18].
441
Increased bacterial colonization and donor and less intensive immunosuppres-

bacteriuria are common in patients sion (see below).
transplanted into a reconstructed lower
urinary tract, but negative sequelae are 5.2.2 Immunosuppression
rare. In a recent case control study of
It is axiomatic that more intensive immu-
children with augmentation cystoplasty,
nosuppression increases the risk of infec-
bacteriuria was more common than in
tion. Unfortunately since there are no
recipients with normal bladders (83%
reliable tests of degree of immune com-
vs. 17%) but graft survival and renal
promise, clinical management of trans-
function was the same [19]. Similarly,
plant recipients based upon drug levels
in a study of patients transplanted into
and weight based dosages will often lead
an ileal conduit, symptomatic UTI’s
to over- and under-treatment, which won’t
developed in 65% (their usual incidence
be evident until acute rejection or infec-
was not quoted) but there was no excess
tion develops. One study which looked at
graft loss or death as a result. Finally,
infectious complications based on drug
the use of clean intermittent catheteri-
selection found more bacterial infections
zation following transplant is not asso-
in patients receiving anti-thymocyte glob-
ciated with excess UTI, graft loss or
ulin (vs. basiliximab) and sirolimus (vs.
patient death [20].
tacrolimus) [1]. In another study, acute
Summary Recipient-Related Risk
pyelonephritis was most strongly corre-
Factors
lated with prior therapy for acute rejec-
tion [21]. It is also possible, although not
• UTI is the most common infec- directly studied, that patients with recur-
tious complication following renal rent UTI may have their maintenance
transplantation (LoE 3). immunosuppression reduced which might
• Age extremes (children and elderly) lead to subsequent acute rejection.
are associated with higher rates of
post transplant UTIs with up to a 5.2.3 Urinary catheters and stents
third being recurrent. Abnormal
All patients following transplant require
LUT and bladder outlet obstruction
bladder drainage, both to closely monitor
account are likely culprits of UTI
urine output and to allow the neo-urete-
in children and elderly respectively
rocystotomy to heal, however bacterial
(LoE 3).
colonization and biofilm formation are
• Patients with augmented LUT inevitable over time. For patients with
present higher rates of asympto- otherwise normal bladders and unevent-
matic bacteriuria and UTI. Graft ful ureteral re-implant, Foley removal
survival is not affected by infection as early as postoperative Day 2 appears
episodes (LoE 3). safe and can reduce the early UTI rate
[22]. For patients whose bladders do not
5.2 Transplant related factors empty, intermittent self catheterization
is preferable to prolonged Foley drainage.
5.2.1 Donor type
Suprapubic catheters may offer advan-
Several studies have suggested that the tages to those who cannot self catheterize
incidence of UTI is lower following living however the microbiologic implications of
donor transplant than cadaveric transplant their use has not been studied in trans-
[6]. This is unlikely due to any issues of plant patients.
donor contamination or ischemia but rather A double J ureteral stent is often
due to shorter waiting times for a living placed at the time of renal transplant,
442
either routinely or in patients consid- organisms (Enterococcus, staphylococcus

ered at higher risk for urologic complica- and streptococcus) and fungi [26] Due to
tions. Meta-analysis of published trials the routine use of post-transplant anti-
confirms that stents reduce the incidence biotics and exposure to hospital acquired
of ureteral complications and simplify organisms, infecting strains are often
their management. However, UTI’s are multiply resistant to commonly used first
more frequent in stented patients, espe- line antibiotics [13].
cially when the stent is left in longer Fungal infections are more common in
than six weeks [23]. Removal of stents immunosuppressed patients, especially
between two and four weeks post trans- those with diabetes and urinary foreign
plant appears to minimize UTI risk while bodies [27]. Fungal UTI can lead to sys-
not compromising ureteral healing [24]. temic spread with significant mortality [1].
Percutaneous nephrostomy tubes are Locally, fungus may form into a ball lead-
also commonly used to manage urologic ing to pelvic or ureteral obstruction [28].
complications after kidney transplant. The BK polyoma virus is an emerging
Prolonged use is associated with multi- pathogen in transplant recipients and
drug resistant bacteria [25] and fungal may cause renal and ureteral injury [29].
infection. BK virus is often found in immunocomp-
Summary of Transplant Related UTI etant patients latently within urothelium
Risk Factors [30]. An early clue to infection and neph-
ropathy is the presence of “decoy cells” on
• Donor type (Living vs. deceased) has urinary cytology [31]. BK may be a cause
conflicting evidence for UTI risk. of hemorrhagic cystitis, although usually
• ATG induction or sirolimus-based,
only in bone marrow transplant recipi-
protocols are associated with higher ents [32]. Low level injury within the
rates of UTI. Treatment of acute transplant ureter may contribute to stric-
rejection raises risk of post trans- ture or necrosis [33].
plant UTI (LoE 3). The parasite Schistosoma haematobium
is endemic in certain African countries.
• Early catheter removal reduces Bacterial UTI, renal stones, and ureteric
early UTI rates (LoE 3). complications were found to be greater
• Routine ureteric stenting is\associ- among kidney transplant recipients with
ated with higher rates of UTI. Early schistosomiasis than among controls.
stent removal (≤4 weeks) and cotri- However this did not impact patient or
moxazole prophylaxis reduced infec- graft outcome [34]. M. tuberculosis myco-
tion rates (LoE 1). bacteria can be contracted by or reac-
tivated in immunosuppressed patients
leading in the urinary tract to UTI, epidi-
6. MICROBIOLOGY OF UTI IN RENAL dymitis or prostatic abscess [35].
TRANSPLANT RECIPIENTS
Bacteria, fungi, virus, parasites and 7. PRESENTATION AND EVALUATION

mycoplasma may all cause post trans-
plant UTI. Bacterial UTI pathogens in Symptomatic UTI after transplant has
renal transplant recipients are similar a wide clinical spectrum including acute
to that in the non-transplantation popu- cystitis, transplant pyelonephritis, and
lation. Gram-negative bacterial infec- pyelonephritis of native kidneys. Typical
tions (Escherichia coli, Enterobacter, signs and symptoms of UTI may be mim-
Pseudomonas and Klebsiella) are most icked by other common post-transplant
common followed by Gram-positive conditions including catheter induced
443
bladder spasm, stent irritation, low vol- of diagnostic studies and systemic antibi-
ume defunctionalized bladder, polyuria otics was also noted but patient and graft
due to early loss of urinary concentrat- survival were not improved by prophy-
ing ability, urinary retention and fever/ laxis [38]. Ciprofloxacin is effective but
graft tenderness from acute rejection. has no prophylaxis against P. carnii,
Furthermore, common UTI features may Nocardia and Listeria species which
not be evident. Immunosuppression can is otherwise provided by TMP-SMZ.
suppress fever, primarily through block- Grade-A recommendation can be drawn
ade of IL-1 and tumour necrosis factor. for routine cost-effective prophylaxis with
Blood WBC counts may not be elevated TMP-SMX in renal transplant recipients
due to bone marrow suppression. The for at least one year.
transplant kidney is denervated and Screening for asymptomatic bacteriuria
may not be tender even in the face of in renal transplant recipients has not been
pyelonephritis. fully evaluated. Moradi et al recommended
Given the high prevalence, uncom- careful follow-up for asymptomatic bac-
mon presentation and microbial diversity teriuria with no therapy as it does not
in transplant UTI, lower urinary tract decrease rate of UTI [40] (LoE 2b).
symptoms, fever and unexplained leuko- Therapy can range from oral outpa-
cytosis should prompt immediate urine tient antibiotics to multidrug inpatient
culture. If fungal infection is suspected, intravenous therapy depending on the
microscopy and cytology may give a more clinical circumstance. Bacteriocidal
rapid result than culture. Blood cultures antibiotics are preferred since the com-
should be included if fever or systemic promised innate immune cells may not
symptoms are present. Lower urinary be able to efficiently clear live bacte-
tract symptoms should be evaluated to ria treated with bacteriostatic drugs.
include assessment of the post void resid- Avoid drugs with primary urinary excre-
ual by ultrasound, especially in diabet- tion and low tissue penetration (e.g.
ics, elderly men and in those with known nitrofurantoin).
urologic abnormalities. Acute prostatitis Predisposing factors should be cor-
should be considered in febrile infections rected if possible (e.g. optimal diabetic
in men and can be confirmed by pros- control, removal or change of stents and
tate exam without prostatic massage. catheters, minimize immunosuppres-
Particularly if the patient was trans- sion based upon drug levels and clinical
planted elsewhere, consider a KUB to course).
ensure that a ureteric stent has not been Interactions exist between antibiot-
inadvertently overlooked. ics used to treat post-transplant UTI and
immunosuppressant drugs. Ciprofloxacin
may raise calcineurin inhibitor (CNI)
8. PREVENTION AND THERAPY levels, but levofloxacin and ofloxacin
usually do not [41]. Erthryomycin and
Antimicrobial prophylaxis reduces the antifungal agents inhibit cytochrome
incidence of post-transplant UTI and its P450 and increase CNI levels. Rifampin,
consequences. It is now standard practice imipenim and cephalosporins can reduce
in most transplant centers [36]. TMP- CNI levels. Nephrotoxic antibiotics (e.g.
SMZ is the most commonly used due to aminoglycosides, amphotericin) may have
its activity against Pneumocystis cari- synergistic effects with CNI’s, increasing
nii. TMP-SMZ was found to significantly renal damage.
reduce post-transplant UTI by 50% in The ideal duration of antibiotic therapy
several prospective randomized trials post transplant is not firmly established.
[37–39] (LoE 1b). A 40% reduction in cost It is suggested that early (≤ six months)
444
relapsing post-transplant UTI be treated and neither impacted patient survival

at least 6 weeks [36] (LoE 3). Lack of [42] (LoE 3). In a study of 110 pediatric
rapid clinical response and relapsing UTI recipients, serum creatinine returned to
should prompt the search for surgically baseline after therapy for UTI and there
correctible causes such as abscess, stones, was no impact on renal function at last
urinary stenosis, reflux or leak and infec- follow up [15] (LoE 3). It is likely that
tion in a poorly functioning native kidney. pathogenic factors of the infecting bacte-
UTI can co-exist with common post- ria play a role in renal injury [43] (LoE
transplant viral illnesses (e.g. cytomega- 2a) which may also account for dispari-
lovirus). Transplant pyelonephritis may ties in published studies.
cause elevated serum creatinine [15],
however reduced renal function should
not be simply attributed to the infec- REFERENCES
tion without ruling out other causes
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ity). Ultimately, lack of response should SA, Morawski K, Garnick J, El-Amm JM,
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authors did state that UTI might simply
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447
Chapter |8|

patients with underlying
urological abnormalities
Chair: Chris F. Heyns
CHAPTER OUTLINE
8.2 Urinary tract infections in obstruction of the urinary tract 452
8.3 Urinary tract infections in patients with urolithiasis 481
8.4 Epidemiology, diagnosis and treatment of urinary tract
infections in patients with spina bifida 497
8.5 Urinary tract infections in patients with neurogenic bladder 507
|8.1|
Introduction
Chris F. Heyns
Professor and Head, Department of Urology, University of Stellenbosch and Tygerberg Hospital, South Africa
Address: Department of Urology, Faculty of Health Sciences, University of Stellenbosch
PO Box 19063, Tygerberg 7505, South Africa
Tel: +27 21 938 9282, Fax: +27 21 933 8010
This chapter deals with urinary tract of solutes in the urine, while the cellular
infection (UTI) associated with structural debris of leucocytes and dead bacteria
or functional abnormalities of the urinary provide a nidus for further nucleation and
tract. The first section focuses on UTI stone formation. Primary UTI caused by
associated with urinary tract obstruction urea-splitting organisms may lead to stru-
due to causes other than urolithiasis and vite stone formation, causing obstruction,
neuropathic bladder dysfunction, and stasis and further infection. The clini-
deals with conditions such as benign pro- cal consequences of this “vicious cycle” of
static hyperplasia (BPH), urethral stric- stones → obstruction → stasis → infec-
ture, and urinary stasis associated with tion → stones are discussed in the chap-
diverticula of the urinary tract. The liter- ter on UTI in patients with urolithiasis by
ature review by Chris Heyns analyses the Gianpaolo Zanetti and Alberto Trinchieri.
evidence which can be used to guide clini- Neuropathic bladder dysfunction in
cally relevant recommendations about the children is most often due to spina bifida
management of UTI associated with uri- (myelomeningocele). The epidemiology,
nary obstruction and stasis. The chapter diagnosis and treatment of UTI in chil-
also discusses interesting new theories dren with this condition are discussed by
that infection or inflammation may have Dan Wood and Christopher Woodhouse.
an etiological role in the pathogenesis of They review the significant advances
BPH and prostate cancer. that have been made with regard to the
Urolithiasis may be a cause as well as management of this disabling condition
a result of UTI. Stone obstruction leads in children, and also discuss the areas of
to urinary stasis, which enables bacteria current controversy.
to adhere to the urothelium and multi- In adults, neuropathic bladder dys-
ply, thus causing UTI. Urinary stasis pro- function may result from conditions such
motes the crystallization and precipitation as traumatic spinal cord or brain injuries,
stroke, cauda equina lesions or multiple recommendations based on the best avail-
sclerosis. The neurogenic bladder remains able evidence.
a common cause of UTI, presenting sev- Despite the large body of literature on
eral challenges in diagnosis and man- these topics, numerous questions remain
agement. Due to improved management to be answered and several controversies
of trauma patients as well as increasing need to be resolved, indicating the neces-
age of the overall population, the preva- sity for well designed, prospective clini-
lence of neuropathic bladder dysfunction cal studies as well as basic laboratory
as a cause of UTI has increased. James research to guide future evidence-based
Salerno and Diana Cardenas review the recommendations on the management of
management of UTI associated with neu- UTI in patients with underlying abnor-
rogenic bladder dysfunction and present malities of the urinary tract.
451
|8.2|

obstruction of the urinary tract
Chris F. Heyns
Professor and Head, Department of Urology, University of Stellenbosch and Tygerberg Hospital, South Africa
Department of Urology, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa
Tel: +27 21 938 9282, Fax: +27 21 933 8010
ABSTRACT volume should predispose to UTI, because

urinary stasis would allow more time for
This chapter examines the association bacterial adherence and multiplication.
between urinary tract infection (UTI) However, there is scant evidence that
and urinary tract obstruction, focusing UTI in the aging male or female popu-
on conditions other than urolithiasis and lation is associated with either PVR or
neuropathic bladder dysfunction, which bladder outflow obstruction (BOO).
are dealt with in other chapters. In men with symptomatic BPH treated
It is one of the axioms of urological with placebo, the cumulative risk of UTI
practice that urinary tract obstruction and at 4 years of follow up is less than 1%.
urinary stasis predispose to UTI. Clinical However, in men undergoing prostatec-
studies confirm that most men with UTI tomy, UTI is the indication for surgery
have an anatomical or functional abnor- in 4% to 12% of cases. Bacteriuria prior
mality of the urinary tract. Experimental to prostatectomy for BPH is very com-
studies indicate that, whereas transure- mon (up to 54% of cases), and bacteria
thral inoculates of bacteria are rapidly can often be cultured from prostatic tis-
eliminated from the normal bladder, ure- sue, especially in those catheterized
thral obstruction leads to cystitis, pyelone- before operation (up to 67% of cases).
phritis and bacteremia. Bacteriuria after prostatectomy despite
Benign prostatic hyperplasia (BPH) sterile urine at the time of the proce-
is, next to urolithiasis, the most common dure is also quite common (up to 40% of
cause of urinary tract obstruction pre- patients).
disposing to UTI. It seems logical that An interesting theory is that inflam-
a large post-void residual (PVR) urine mation is an etiological factor in the
Urinary tract infections in obstruction of the urinary tract | 8.2 |
pathogenesis of BPH, although no causa- ova, leading to upper tract dilatation, uri-
tive bacterial or other antigen has been nary stasis and bacterial superinfection.
identified. Elevated expression of pro- Experimental studies have shown that
inflammatory cytokines in BPH may the kidney is relatively resistant to infec-
induce fibromuscular growth by an auto- tion by organisms injected intravenously,
crine or paracrine loop or via induction of but if a ureter is ligated the obstructed
cyclo-oxygenase-2 expression. Acute and/ kidney becomes infected. Furthermore,
or chronic intraprostatic inflammation ureteric obstruction may cause renal dys-
may be important in the pathogenesis function, so the kidney(s) may not be able
as well as progression of BPH, since the to concentrate antibiotics in the urine,
risk of acute urinary retention (AUR) due making eradication of bacteria difficult.
to BPH is greater in men with prostatitis The most important determinants of UTI
than in those without this condition. caused by resistant strains are previ-
In men with febrile UTI, the prostate ous use of antibiotics and the presence of
is frequently involved. Prostatitis causes underlying urological diseases.
an increased total serum prostate specific In children prenatally diagnosed with
antigen (PSA) and decreased free/total severe hydronephrosis and not on antibi-
PSA ratio, which may be falsely inter- otic prophylaxis, the overall incidence of
preted as a sign of cancer. An interesting UTI during the first 12 months postna-
theory is that bacterial colonization or tally may be as high as 50%, especially in
chronic inflammation of the prostate may those with obstruction at the ureterovesi-
be a cause of prostate cancer. Proliferative cal junction. However, some studies have
inflammatory atrophy is regarded as a shown a cumulative incidence of UTI
precursor to prostatic intraepithelial neo- of only 4% to 8%. The use of antibiotic
plasia (PIN) and prostate cancer. prophylaxis in children with hydroneph-
Urethral stricture remains a com- rosis secondary to upper tract obstruction
mon underlying abnormality in men remains controversial.
with UTI in many parts of the world, In some developing countries renal
and often presents with complications. infection associated with upper tract
Diverticula of the bladder or urethra obstruction remains a common reason for
may occur secondary to obstruction, and nephrectomy, indicating the importance
urinary stasis in such diverticula pre- of early diagnosis and proper treatment
disposes to UTI. Men with BPH plus a of UTIs. Despite the lack of relevant clin-
bladder diverticulum have a higher risk ical studies, it is generally accepted prac-
of UTI as well AUR, probably related to tice that in patients with UTI and upper
the greater PVR and higher voiding pres- urinary tract obstruction, empiric antibi-
sures. Diverticulectomy is recommended otic treatment should be complemented
for BPH-associated bladder diverticula. with urgent intervention to drain the
Urethral diverticula in women present urinary tract (e.g. percutaneous neph-
with UTI in about 30% of cases. The rostomy or double-J ureteric stenting).
management is surgical, with excision of This should be followed with targeted
the diverticulum and closure of the tract antibiotic treatment (according to urine
communicating with the urethra. culture) and definitive surgery to remove
Some studies from tropical countries the cause of obstruction once infection is
have indicated that Schistosoma haema- under control.
tobium infestation predisposes to second- Urinary tract abnormalities may pre-
ary bacterial UTI in up to 30% of cases. dispose to infection with organisms other
This may be related to bladder wall than Escheria coli, and long-term antibiotic
inflammation caused by Schistosomal therapy often leads to bacterial resistance
453
Chapter |8| Urinary tract infections in patients
or fungal superinfection. Urinary tract indicated in patients with negative

obstruction may permit ascending infec- urine culture (GoR A).
tion of E. coli strains with lower adhesive 5. Bladder diverticula do not always
ability that would not be pathogenic in a require surgery, but those associated
normal urinary tract. with recurrent or persistent UTI
In selected patients with UTI, imaging in the presence of BOO should be
of the urinary tract is indicated to detect treated with medical management or
conditions that must be corrected to avoid prostatectomy; there is no clear evi-
rapid deterioration of renal function or dence that diverticulectomy in addi-
systemic sepsis, and to prevent recur- tion to prostatectomy is necessary
rent infections and long-term renal dam- (GoR B).
age. UTI in the presence of urinary tract
obstruction remains a serious, destructive 6. Urethral diverticula associated
and potentially life-threatening process with UTI (in both men and women)
that requires immediate antibiotic treat- should be treated with surgical
ment, supplemented with urgent inter- diverticulectomy (GoR A).
vention to drain the obstructed system, 7. Bladder calculi that are a result and/
followed by surgery to correct the struc- or cause of UTI should be removed
ture and function of the urinary tract. (Grade A). Bladder calculi associated
with BPH are usually an indication
Key words: Urinary tract; infection;
for prostatectomy as well as removal
obstruction; prostate; urethra; stricture;
of the stones; however, endoscopic
hydronephrosis; reflux; diverticulum
vesicolithotripsy and medical treat-
ment of BPH may be an option in
men with major anaesthetic risk
factors (GoR B).
1. There is no clear evidence that a 8. Male urethral strictures increase the
large postvoid residual (PVR) urine risk of UTI and should be treated
volume predisposes to bacteriuria or with dilatation, internal urethrotomy
urinary tract infection (UTI), there- or urethroplasty (GoR A).
fore antibiotic prophylaxis is not 9. Urethrocutaneous fistulae usually
indicated in such patients (GoR B). require suprapubic cystostomy and
2. In men with lower urinary tract subsequent urethroplasty (GoR A),
symptoms (LUTS) due to benign but may be treated with internal
prostatic hyperplasia (BPH) the risk urethrotomy alone (GoR B).
of UTI is very small, therefore anti- 10. Female urethral stricture is
biotic prophylaxis is not indicated extremely uncommon, and there is
(GoR A). no evidence to support the use of
3. Recurrent or persistent UTI in men urethral dilatation as treatment of
with bladder outflow obstruction LUTS or UTI in women (GoR B).
(BOO) and BPH is an indication 11. Schistosoma haematobium infesta-
for medical intervention, i.e. alpha tion may increase the risk for bacte-
blocker and/or finasteride, or prosta- rial UTI, but there is insufficient
tectomy (GoR A). evidence to recommend antibiotic
4. In patients undergoing prosta- prophylaxis in patients with S
tectomy, UTI should be treated haematobium infestation (GoR C).
according to urine culture, and peri- 12. In infants and children with upper
operative antibiotic prophylaxis is urinary tract obstruction, antibiotic
454
prophylaxis to prevent UTI may choice, while computerised tomogra-

be advisable, but the role of antibi- phy (CT) is indicated if more detailed
otic prophylaxis in adults remains information is required (GoR B).
unclear (GoR C). 19. In patients with early recurrent or
13. In patients with UTI and upper persistent UTI, imaging and uro-
urinary tract obstruction, empiric logical investigations should be
broad-spectrum antibiotic therapy performed to identify underlying
should be complemented with urgent abnormalities that may be surgically
intervention to drain the urinary correctable (GoR A).
tract (e.g. percutaneous nephros- 20. In patients with complicated acute
tomy or double-J ureteric stenting) pyelonephritis, blood cultures should
and definitive surgery to remove the be reserved for those with an uncer-
cause of obstruction once infection is tain diagnosis and those who do
under control (GoR A). not respond promptly to treatment
14. Renal calyceal diverticula usually do (GoR B).
not require treatment, but those asso- 21. In patients with bowel in the urinary
ciated with recurrent UTI or stone tract antibiotic prophylaxis is not
formation should be treated with indicated for asymptomatic bacte-
percutaneous, uretero-renoscopic, riuria, but may be indicated in those
laparoscopic or open nephrolithotomy with recurrent symptomatic UTI
to remove stones and obliterate (GoR B).
or remove the diverticulum or to
improve its drainage (GoR A).
15. Emphysematous pyelonephritis with 1. INTRODUCTION
gas in the renal collecting system
or parenchyma only, and those with The prevalence and etiology of urinary
extension of gas into the perinephric tract obstruction in patients with UTI
or pararenal spaces but no risk fac- vary considerably in different reports
tors (thrombocytopenia, acute renal in the literature. In a study of men with
function impairment, disturbance nonbacteremic UTI, identifiable compli-
of consciousness, or shock) can be cations included benign prostatic hyper-
treated with antibiotics and percu- plasia (BPH) in 27% of patients, prostatic
taneous nephrostomy or ureteric cancer in 8%, urethral stricture in 8% and
catheterization instead of urgent neuropathic bladder in 8% (LoE 3) [1].
nephrectomy (GoR C). In a review of patients admitted to a
16. Xanthogranulomatous pyelonephritis urology department with complicated
frequently requires nephrectomy UTI, the underlying abnormality was
in addition to antibiotic treatment urolithiasis in 49%, BPH in 45%, tran-
(GoR A). sitional cell carcinoma of the bladder or
ureter in 6% and renal tumours in 6%.
17. Urinary tract imaging is indicated Mortality due to complicated UTI was
when complicated UTI due to an 3.9% (LoE 3) [2].
underlying abnormality of the uri- In a study of adult men with proven
nary tract is suspected (GoR A). UTI, the diagnosis was bladder outflow
18. Ultrasound with abdominal radiog- obstruction (BOO) in 36%, underactive
raphy is equivalent to intravenous detrusor 7%, bladder diverticulum 7%,
urography (IVU) as screening study chronic retention 4%, urethral stricture
in patients with complicated UTI, 3%, prostatitis 3%, renal stone 3%, ureteric
and is the imaging study of first stone 2%, prostate cancer 2%, pelviureteric
455
junction obstruction (PUJO) 2%, bladder

stone 1%, pelvic kidney 1%, and phimosis
1% (LoE 3) [3].
The aim of this review was to focus
on UTI associated with urinary tract
obstruction due to causes other than
urolithiasis and neuropathic bladder
dysfunction.
2. METHODS
An electronic literature search was per-

formed on PubMed using the key words Figure 1 Cystogram shows trabeculation of bladder wall and
urinary tract infection (UTI) alone and postvoid residual urine with midline filling defect due
in combination with the following terms: to BPH.
benign prostatic hyperplasia, BPH,
hydronephrosis, obstruction, reflux, diver- E. coli and causes more severe renal lesions
ticulum, urethra and stricture. Abstracts in mice challenged with uropathogenic
were reviewed, relevant articles were E. coli (LoE 2b) [7].
studied in full-length version, and further In the presence of a large postvoid
references were obtained from these arti- residual (PVR), even a small bacterial
cles. In total, 520 abstracts were reviewed, inoculum may lead to severe UTI that is
210 articles were studied in detail, and difficult to eradicate. The incidence of bac-
175 were included as references in this teriuria after urodynamic studies is higher
chapter. in men (36%) compared with women
The studies were rated according to the (15%), probably due to larger PVR (LoE 3)
level of evidence (LoE) and the grade of [8]. Mild episodes of UTI can become life-
recommendation (GoR) using ICUD threatening and may lead to systemic
standards (for details see Preface) [4–5]. sepsis when urinary tract obstruction is
present (LoE 3) (Figure 1) [9].
Although it seems logical that a large
3. BENIGN PROSTATIC HYPERPLASIA PVR should predispose to UTI, because
(BPH) urinary stasis would allow more time for
bacterial adherence and multiplication,
A review of more than 200 studies pub- there is little evidence that the occur-
lished between 1954 and 1988 concluded rence of UTI in the aging male population
that most men with UTI have a func- is associated with either PVR or BOO
tional or anatomic abnormality of the (LoE 3) [10]. In elderly men bacteriuria
genitourinary tract. BPH and genitouri- does not appear to correlate with age,
nary instrumentation were the major pre- PVR, or symptoms of BOO (LoE 3) [11].
dispositions to UTI in men (LoE 3) [6]. In elderly women an increased PVR does
An experimental animal model in mice not appear to be associated with bacteriu-
has shown that transurethral inoculation ria (LoE 3) [12].
with a strain of E. coli which is rapidly In older series, acute urinary reten-
eliminated from normal mice will cause tion (AUR) was the indication for surgery
bacteriuria, bacteremia and pyelonephri- in 25% to 30% of men who underwent
tis after reversible urethral obstruction for transurethral resection of the prostate
1 to 6 hours. Urethral obstruction enhances (TURP) and renal failure was present in a
the uropathogenicity of nonpathogenic mean of 14% of cases (range 0.3% to 30%)
456
(Figure 2). In a more recent database of

patients who had upper tract imaging
prior to surgery, 7.6% had evidence of
hydronephrosis, of whom one third had
renal insufficiency (LoE 3) [13–15].
The natural history of untreated
BPH shows that it is not an invari-
ably progressive condition. In 5 studies
of men with lower urinary tract symp-
toms (LUTS) due to BPH followed for
3–6 years the PVR volume increased in
35%, decreased in 37%, and remained
unchanged in 28% of patients (LoE 3)
[10, 16]. In another study of men with
BPH randomized to watchful waiting
and followed for 5 years a PVR >150 ml
developed in only 7% and urinary reten-
tion in 3% (LoE 3) [17].
In older surgical series, UTI was the
indication for surgical intervention in
about 12% of men with BPH (LoE 3)
[18–19]. In a study of men with BPH Figure 2 Excretory urogram shows bilateral hydro-
ureteronephrosis with large post-void residual urine volume
treated at hospitals in Japan, UTI was due to bladder outflow obstruction.
the reason for presentation in 4% (LoE 3)
[20]. In a study of men with BPH in
Spain, the reported prevalence of UTI correlation between the incidence of pre-
was 5.2%, compared to incontinence in operative bacteriuria and the duration of
6.1%, acute retention in 5.1%, haema- catheterization as well as the volume of
turia in 2.5%, renal failure in 2.4%, and residual urine (LoE 3) [25–29].
bladder stones in 0.7% (LoE 3) [21]. In Bacteriuria after prostatectomy has
placebo-treated patients in the Medical been reported in 29% to 40% of patients
Therapy of Prostatic Symptoms (MTOPS) with sterile urine at the time of the pro-
study the cumulative incidence of UTI at cedure, and in 20% of preoperatively
4 years was <1% (95% confidence interval nonbacteriuric patients despite chemo-
0–1%), compared to AUR in 2% (1–4%) prophylaxis. One study reported postoper-
and incontinence <1% (0–1%) (LoE 3) ative bacteriuria in 32% of patients after
[22–23]. However, most of the clinical tri- TURP and in 51% after open prostatec-
als on BPH management have excluded tomy. There was an increased prevalence
subjects with high baseline PVR (>150 ml of Enterococcus and coagulase-negative
to >350 ml), so the natural history of men Staphylococcus isolates from postprosta-
with a high baseline PVR remains largely tectomy compared with preprostatectomy
unknown. Furthermore, it is well known bacteriuria. One study showed a signifi-
that PVR measurement is variable over cant correlation between postprostate-
short intervals of time (LoE 3) [24]. ctomy bacteriuria and meatal cultures,
Bacteriuria prior to prostatectomy in and another study showed an increased
men with BPH has been reported in 28% incidence of bacteriuria with increased
to 54% of cases. The incidence is higher in age (LoE 3) [20, 25, 30–32].
those catheterized before operation (44% Bacteria can be cultured from pros-
to 57%) than in those not catheterized tatic tissue obtained at prostatectomy in
(18%). Several studies have indicated a 21% to 44% of cases (67% in catheterized
457
and 28% in uncatheterized patients) followed for 4.5 years had significantly
(LoE 3) [33]. However, in one study only larger prostates, higher serum pros-
34% of patients with preoperative cath- tate specific antigen (PSA) levels and a
eters had positive prostate cultures, and greater risk of urinary retention. Other
of patients with positive prostate cul- studies have demonstrated elevated
tures 82% had sterile urine cultures pre- expression of pro-inflammatory cytokines
operatively (LoE 3) [34–35]. Histological in BPH. Interleukins 6, 8 and 17 may
lesions indicating prostatitis associated perpetuate a chronic immune response
with BPH were found in 39% of patients, in BPH and induce fibromuscular growth
regardless of the presence or absence of by an autocrine or paracrine loop or via
bacteria in the prostate. Of the patients induction of cyclo-oxygenase-2 (cox-2)
with histologically demonstrated pro- expression (LoE 3) [45].
static inflammation, only 28% had a Histologically, almost all BPH speci-
positive prostatic culture. The microor- mens show inflammatory infiltrates, but
ganisms most frequently isolated from correlation to bacterial or other anti-
the prostate were coagulase negative gens has not been established. In BPH
Staphylococci, E. coli and Enterococcus compared with normal prostate, the
faecalis (LoE 3) [36]. levels of interferon-gamma and inter-
Bacteremia after TURP has been leukin-2 (IL-2) are 10-fold increased,
reported in 23% to 29% of patients and the levels of IL-2 and transform-
despite antibiotic prophylaxis, in 54% of ing growth factor beta are 2-fold ele-
patients with preoperative bacteriuria vated. As BPH nodules develop, IL-4
and 8% without bacteriuria. In 70% to and IL-13 expression increases 2-fold.
81% of cases an identical species was iso- Dysregulation of the immune response
lated from preoperative urine cultures, in BPH may occur via elevated expres-
and in 54% the organism causing bac- sion of IL-17, which stimulates produc-
teremia was identical to that cultured tion of IL-6 and IL-8, thus inducing
from prostatic tissue. Bacteremia was stromal growth in BPH (LoE 3) [44].
significantly more common in patients However, chronic inflammatory pros-
with preoperative UTI, prostatitis on tatitis does not appear to promote ang-
histology, and positive prostatic cultures. iogenesis or increase the microvessel
Staphylococcus epidermidis was the density in BPH cases (LoE 3) [46].
most common organism isolated (LoE 3) Some studies have suggested that pro-
[31, 37]. static inflammation is associated with
It has been suggested that inflam- UTI, prostatic infection, activated comple-
mation is an etiological factor in the ment and downregulated mucosal immu-
pathogenesis of BPH, which may be an nity in BPH (LoE 3) [47]. Acute and/or
immune-mediated inflammatory disease chronic intraprostatic inflammation may
(LoE 3) [38–43]. However, it is not clear if be important in the pathogenesis as well
infection is the primary event for a misdi- as progression of BPH, since the risk of
rected immune response in the prostate. urinary retention due to BPH is greater
No study has shown a single strain of in men with prostatitis than in those
microorganisms present in all BPH sam- without (LoE 3) [48]. It has been shown
ples, and viruses have been detected more that the use of a cox-2 inhibitor in combi-
commonly in association with prostate nation with a 5-alpha reductase inhibitor
cancer than with BPH (LoE 3) [33, 44]. could increase the apoptotic index in BPH
Data from the Medical Therapy of tissue, but the value of cox-2 inhibitor
Prostate Symptoms (MTOPS) study treatment in the prevention of BPH pro-
showed that patients with BPH plus gression has not been evaluated in clini-
chronic inflammation on biopsy who were cal trials (LoE 3) [49].
458
4. PROSTATE CANCER AND 5. URETHRAL STRICTURES

PROSTATITIS
In men with UTI in some countries
In men with febrile UTI, the prostate is (especially in the developing world) the
frequently involved, causing PSA elevation second most frequent underlying abnor-
(LoE 3) [50]. Histological acute and chron- mality, after BPH, is urethral stricture
ic-active prostatitis may induce high PSA (LoE 3) [64]. A study of men with ure-
values via the leak phenomenon (LoE 3) thral strictures treated in a hospital
[51]. PSA elevation is not related to the in Spain reported that 89% presented
extent of inflammation, but to the aggres- with complications, consisting of AUR
siveness of the inflammatory infiltrate, i.e. (57% of patients), bladder obstructive
disruption of epithelial integrity (LoE 3) uropathy (48%), UTI (36%) and vari-
[52–55]. Acute as well as chronic prostati- ous degrees of renal failure (17%). In
tis is associated with a decreased free/total the patients with UTI, 90% were single
PSA ratio (LoE 3) [55–57]. The increased microorganism infections, 44% being
total PSA and decreased free/total PSA caused by E. coli. Risk factors for the
ratio in prostatitis may be falsely inter- development of complications were age
preted as a sign of cancer (LoE 3) [58–60]. >70 years, history of sexually transmit-
The use of empiric antibiotic treatment to ted infections, UTI, previous urethral
decrease the PSA and avoid unnecessary surgery for recurrent stenosis, and PVR
prostate biopsy remains controversial, (LoE 3) [64–65].
and well designed prospective studies are Renal complications were noted in
required to determine the role of antibiotic 21% of men with urethral stricture dis-
treatment (if any) in men with a slightly ease. The complications were renal fail-
elevated PSA and symptoms or signs of ure (36%), hydroureteronephrosis (33%),
prostatitis or UTI. chronic pyelonephritis (16%) and vesico-
There appears to be a correlation ureteric reflux (11%). UTI occurred in
between bacterial colonization or chronic 76% of the men with renal complications
inflammation of the prostate and the devel- (LoE 3) [66]. A recent study from the USA
opment of prostate cancer. Genetic stud- reported that men with urethral stricture
ies support the hypothesis that prostate disease have a high rate of UTI (41%) and
inflammation may be a cause of prostate incontinence (11%) (LoE 3) [67].
cancer development. Proliferative inflam- In a study of men with urethral stric-
matory atrophy is regarded as a precursor tures in the Sudan, 63% had complica-
to prostatic intraepithelial neoplasia (PIN) tions such as inflammatory periurethral
and prostate cancer (LoE 3) [61]. mass, “watering-can perineum” with dis-
It is postulated that during acute or charging sinuses and urethrocutaneous
chronic inflammation in the prostate fistulas, associated urethral calculi, periu-
various cells are activated by chemokines rethral abscesses and urethral diverticula
via different chemotaxin receptors which (LoE 3) [68]. “Watering-can perineum”
then trigger processes in angiogenesis, results from long standing neglected
cellular growth and neoplasia which may inflammatory urethral strictures, there-
lead to prostate cancer. Inflammation is fore prevention requires adequate treat-
thought to incite carcinogenesis by caus- ment of urethritis and urethral strictures
ing cell and genome damage, and by pro- (LoE 3) [69]. Suprapubic cystostomy fol-
moting cellular turnover (LoE 3) [49, 62]. lowed by urethroplasty is the best treat-
A recent study suggested that the pres- ment. However, endoscopic treatment may
ence of Propionibacterium acnes in the also be successful. In a Sudanese study of
prostate was associated with prostate men with a “watering-can perineum” the
cancer development (LoE 3) [63]. fistulae healed completely after a single
459
direct vision internal urethrotomy (DVIU)

in 64% of patients, and in the rest two
or more urethrotomies were required to
resolve the problem (LoE 3) [70].
6. DIVERTICULA
6.1 Bladder diverticula

Bladder diverticula are most often
acquired (also termed secondary) due
to BOO or neuropathic bladder dys-
function, but may also be iatrogenic.
They usually occur after the age of 60 Figure 4 Ultrasound showing two large bladder diverticula.
years, are much more common in men
than women, and are most often associ-
ated with bladder trabeculation, BPH, may predispose to UTI and may impede
prostate cancer or urethral stricture, the eradication of established infection
although obstruction is not present in (LoE 3) [75]. Relapsing or persistent UTI
all cases (Figs. 3,4). The reported preva- unresponsive to antibiotic therapy may be
lence of bladder diverticula in associa- an indication for bladder diverticulectomy.
tion with LUTS is approximately 1% to A study comparing patients with BPH
6% (LoE 3) [71–73]. plus a bladder diverticulum and patients
Congenital bladder diverticula most with BPH only, found that the group with
often present with UTI (LoE 3) [74]. BPH plus a diverticulum had a higher rate
Urinary stasis in a bladder diverticulum of AUR (25% vs. 6% vs.) and UTI (22%
vs. 3%), a larger mean PVR (221 ml vs.
46 ml), a larger bladder capacity (351 ml
vs. 211 ml), more patients voided with
abdominal pressure (50% vs. 24%) and
they had greater urethral resistance. In
patients who underwent TURP with or
without diverticulectomy, urethral resist-
ance parameters and PVR decreased in
both groups. Diverticulectomy showed an
improvement of bladder contractility with
longer detrusor contraction duration, sup-
porting its use in cases of BPH-associated
diverticula (LoE 3) [76].
6.2 Urethral diverticula

Urethral diverticula in women are most
probably caused by infection of the per-
iurethral glands, possibly by Neisseria
gonorrhoeae, although the initial infec-
tion and especially subsequent rein-
fections may be caused by E. coli and
Figure 3 Cystogram showing bladder diverticulum. other coliform bacteria or vaginal flora.
460
Recurrent infection of the periurethral

glands leads to obstruction, suburethral
abscess formation and subsequent rup-
ture of the infected glands into the ure-
thral lumen. Reinfection, inflammation,
and recurrent obstruction of the neck of
the cavity result in enlargement of the
diverticulum. Some urethral divertic-
ula may be noncommunicating (LoE 3)
[77–78].
Urethral diverticula in women typi-
cally present with dysuria, dyspareunia
and post-micturition dribbling (LoE 3)
[79–80]. UTI is the mode of presentation
in about 30% of patients (LoE 3) [81–82]. Figure 5 Retrograde urethrogram shows strictures and diver-
E. coli is the most common organism iso- ticula of male urethra after previous urethroplasty.
lated in patients with urethral divertic-
ula, but other Gram-negative enteric flora
as well as N. gonorrhoeae, Chlamydia, stricture disease or previous urethro-
streptococci, and staphylococci are often plasty) occur in somewhat older men
present. Calculi within urethral divertic- (mean age 35 years) (Figure 5). Most male
ula occur in 4% to 10% of cases and are urethral diverticula require open surgical
most likely due to urinary stasis or infec- repair, although some can be left in situ
tion (LoE 3) [83–84]. if they do not cause severe symptoms or
The management of female urethral complications (LoE 3) [89].
diverticulum is surgical, with excision
of the diverticulum and closure of the
tract communicating with the urethra. In 7. BLADDER CALCULI
women with recurrent UTI and a large
PVR judged to be due to narrowing of Up to 75% of bladder calculi may be
the urethra, dilatation of the urethra to related to BOO, due to BPH, urethral
improve bladder emptying is often per- stricture, bladder neck contracture,
formed, although there is no evidence to neuropathic bladder dysfunction and,
support its efficacy (LoE 3) [85]. in women, urogenital prolapse (LoE 3)
In the USA female urethral dilatation (Figure 6) [90–91]. However, only 1% to
is performed almost as much as treat- 2% of men undergoing surgery for BPH
ment for male urethral stricture disease, will have bladder calculi (LoE 3) [15].
despite the fact that true female ure- A large PVR due to BOO predisposes
thral stricture is an extremely uncommon to UTI, and the combination of urinary
entity (LoE 3) [86]. The most common stasis and UTI promotes bladder stone
etiologies of female urethral strictures formation. Between 22% and 34% of
are traumatic or iatrogenic injury, and bladder calculi are associated with UTI,
inflammatory disease resulting in periu- most often Proteus, but other organ-
rethral fibrosis (LoE 3) [87]. isms such as Pseudomonas, Ureaplasma
Diverticula of the male penile urethra urealyticum, Providencia, Klebsiella,
are rare (LoE 3) [88]. Congenital urethral Staphylococcus, and Mycoplasma species
diverticula usually occur in younger men are also capable of producing bacterial
(mean age 25 years) whereas acquired urease (LoE 3) [90]. The enzyme urease
diverticula (due to trauma, urethral hydrolyzes urea, forming ammonium and
461
bacteria in the urine were Proteus species

(LoE 3) [94].
Bladder calculi associated with BPH
have historically been an absolute indi-
cation for TURP. In a recent report on
23 men with bladder stones secondary
to BPH, who had normal renal function,
no hydronephrosis, no history of AUR
or neuropathic bladder, the stones were
removed endoscopically and the patients
were treated with an alpha-receptor
Figure 6 Plain abdominal X-ray shows spina bifida, staghorn
blocker and/or finasteride. At a mean
calculus on right, and bladder stones; e figure xcretory uro- follow-up of 30 months UTI developed in
gram shows hydronephrosis on right and neuropathic bladder 22%, AUR in 17%, and recurrent calculi
with filling defects (stones)
in 17%. The authors concluded that men
with bladder stones can be successfully
and safely treated with transurethral
carbon dioxide, which increases urine pH. stone removal and medical manage-
Alkaline urine promotes supersaturation ment of BPH (LoE 3) [95]. However,
and precipitation of crystals of magne- it is debatable whether a stone recur-
sium ammonium phosphate and carbon- rence rate of 17% within 30 months is
ate apatite (LoE 3) [91]. acceptable.
In an older review, 92% of bladder cal-
culi occurred in men, 80% in patients
older than 50 years, and BPH was the 8. SCHISTOSOMIASIS
most frequent condition causing incom-
plete emptying (LoE 3) [92]. In a more There is conflicting evidence on the rela-
recent review 80% of bladder calculi tionship between Schistosoma haemato-
occurred in patients older than 60 years, bium infestation and UTI (Figure 7). In
98% were male, and 88% had some form a study from Nigeria, urinary schisto-
of BOO (LoE 3) [93]. In one study the somiasis combined with UTIs was found
disorders associated with bladder stones in 22% of subjects. The most common bac-
were BPH and prostate cancer (48%), teria were E. coli, Proteus, Pseudomonas
neuropathic bladder (12%), and urethral aeruginosa, Staphylococcus epidermidis
stricture (4%) in males, and neuropathic and Staphylococcus saprophyticus. The
bladder (48%), previous hysterectomy authors stated that it is imperative to
(29%), and bladder cancer (6%) in females incorporate the management of UTIs in
(LoE 3) [94]. urinary schistosomiasis control programs
In an older study the major compo- (LoE 3) [96].
nents of vesical calculi were phosphate In a study from a rural area in Nigeria
(59%), oxalate (26%), and uric acid (5%) with prevalence rates of S. haemato-
(LoE 3) [92]. In a more recent study the bium infestation ranging from 64% in
composition of bladder stones were mag- children to 54% in adults, bacteriuria
nesium ammonium phosphate (MAP) in occurred in 30% of study subjects with S
50%, calcium (oxalate and/or phosphate) haematobium infection. The most com-
in 40%, uric acid (urate) in 9%, and cys- mon bacteria on urine culture were
tine in 0.7%. UTI occurred as complica- Klebsiella species, Staphylococcus aureus,
tion in 59% of patients with MAP stones, E. coli and Candida albicans (LoE 3) [97].
in 41% with urate stones and in 20% with However, in another study from Nigeria,
calcium stones. The most often isolated the prevalence of urinary schistosomiasis
462
Figure 7 Plain abdominal X-ray showing calcified bladder wall in patient with Schistosoma haema-
tobium infestation; post-void cystogram shows filling defects due to granulomata and blood clots
in patient with Bilharzia of the bladder.
was 51%, but significant bacteriuria was 9. UPPER TRACT OBSTRUCTION

found in only 0.9% of children with uri-
nary Bilharzia, compared to 1.8% in chil- It is generally accepted that urinary sta-
dren without urinary schistosomiasis sis provides the time and opportunity
(LoE 3) [98]. for bacteria to adhere to the urothelium,
In a study from a region in Kenya multiply, and infect the host (LoE 3)
where the prevalence of S. haematobium (Figure 8) [102]. A contributing factor
infestation was 65%, subjects older may be that ureteric obstruction causes
than 15 years had a greater frequency renal dysfunction, so the kidney(s) may
of hydronephrosis. Among individu- not be able to concentrate antibiotics in
als with bladder calcification, 87% had the urine, making eradication of bacte-
hydronephrosis or hydroureter, com- ria difficult and potentially leading to
pared to 40% in those without bladder bacterial resistance. The most important
calcification (LoE 3) [99]. In a study from determinants of UTI caused by resistant
Mali where the prevalence of S. haema- strains are previous use of antibiotics and
tobium ranged from 77% in adolescents the presence of underlying urological dis-
to 51% in adults, bladder wall enlarge- eases (LoE 3) [85].
ment and irregularities, bladder masses, Hematogenous infection of the kidney
pseudopolyps and dilatation of the upper is rare in normal individuals, but it may
urinary tract were found ultrasono- occur in patients with Staphylococcus
graphically in about one third of infected aureus bacteremia originating from cuta-
individuals (LoE 3) [100]. neous or oral sites. Experimental data
In a study from Nigeria, ultrasound indicate that infection is enhanced when
imaging in volunteers infected with S. the kidney is obstructed (LoE 2a) [103].
haematobium showed bladder wall abnor- In an animal model of hematogenous
malities in up to 70%, residual urine in pyelonephritis, the kidney is relatively
28%, hydroureter in 23% and hydrone- resistant to infection by organisms injected
phrosis in 19% (LoE 3) [101]. It is possi- intravenously, but if a ureter is ligated,
ble that urinary stasis may contribute to the obstructed kidney becomes infected
a higher risk of UTI in subjects with S. (LoE 2a) [104].
haematobium infestation. It seems pru- In an experimental model in rats, tran-
dent to avoid invasive procedures such as sient ureteric obstruction (24 hours) with
cystoscopy in these patients, because it inoculation of E. coli in the bladder after
may introduce infection that may be dif- release of ureteric obstruction predis-
ficult to eradicate. poses to ascending pyelonephritis. It is
463
UTI developed in 19% during 12 months

of follow up – in 84% of those cases
within the first 6 months. UTI devel-
oped in 39% of children with, and in 11%
without obstructive uropathy. High grade
hydronephrosis was associated with an
increased incidence of UTI: 40% in grade
IV hydronephrosis, 33% in grade III,
14% in grade II and 4% in grade I. UTI
occurred more frequently in patients
with, than in those without hydroureter
(47% vs. 13%). The authors recommended
antibiotic prophylaxis in neonates with
obstructive uropathy, severe hydroneph-
rosis or hydroureteronephrosis without
Figure 8 Ultrasound shows hydronephrosis.
VUR (LoE 3) [108].
However, another study of children with
antenatally diagnosed severe hydroneph-
postulated that acute ureteric obstruc- rosis secondary to obstructive megaureter
tion induces foci of medullary necrosis in or PUJO not maintained on prophylac-
the papillae, which may provide a nidus tic antibiotics reported an overall rate of
for bacterial invasion, while altered uro- UTI of only 4.3%. No statistically signifi-
dynamics after the release of ureteric cant difference in the infection rate was
obstruction may promote ascending infec- noted according to sex, obstruction level,
tion (LoE 2a) [105].
There are few clinical studies on the
risk of UTI associated with upper tract
obstruction. In children prenatally diag-
nosed with severe hydronephrosis and
not on antibiotic prophylaxis, the over-
all incidence of UTI during the first 12
months postnatally was 36%, and it was
more common with ureterovesical junc-
tion (UVJ) obstruction than with pel-
viureteric junction obstruction (PUJO)
(50% vs. 31%). Most cases of UTI (93%)
occurred in the first 6 months postnatally
(LoE 3) (Figure 9) [106].
In another study of children with pre-
natally detected renal pelvic dilata-
tion, the estimated cumulative incidence
of UTI was 8% at age 12 months, 13%
at 24 months and 21% at 36 months.
Independent predictors of UTI during fol-
low up were female gender and the pres-
ence of vesico-ureteric reflux (VUR) or
urinary tract obstruction (LoE 3) [107].
Figure 9 Excretory urogram shows right hydro-ureteronephrosis
In a study of children with prenatally due to congenital ureterovesical junction obstruction in a 4-year
diagnosed nonrefluxing hydronephrosis, old child.
464
Despite a surprising lack of relevant

clinical studies, it is generally accepted
practice that in patients with UTI and
upper urinary tract obstruction, empiric
antibiotic treatment should be comple-
mented with urgent intervention to drain
the urinary tract (e.g. percutaneous neph-
rostomy or double-J ureteric stenting).
This should be followed with targeted
antibiotic treatment (according to urine
culture) and definitive surgery to remove
the cause of obstruction once infection is
under control (LoE 4).
9.1 Papillary necrosis

The role of UTI in the development and
progression of renal papillary necrosis
(RPN) is controversial (Figure 11). In
one study, 67% of patients with RPN had
acute or chronic UTI, but in only 15% was
pyelonephritis alone associated with RPN
(LoE 3) [113]. Although there are numer-
Figure 10 Retrograde ureteropyelogram shows pelvi-ureteric ous factors that on their own may cause
junction obstruction.
RPN, the coexistence of multiple factors
(e.g. diabetes mellitus or obstruction and
hydronephrosis grade, or circumcision UTI) increases the risk of developing
status. The authors concluded that antibi- RPN [85]. Therefore, in ureteric obstruc-
otic prophylaxis is unlikely to benefit most tion it is important to prevent UTI and,
children with hydronephrosis secondary if UTI is present, to drain the kidney by
to upper tract obstruction (LoE 3) (Figure ureteric catheter or percutaneous neph-
10) [109]. rostomy (LoE 4) [85, 114].
In some countries, renal infection is still
a common reason for nephrectomy. In a
study from Jordan, infection-related renal
conditions were the reason for nephrec-
tomy in 38% of cases (LoE 3) [110]. In a
report from Pakistan, 77% of nephrecto-
mies were for benign conditions, and in
this group the reason for nephrectomy
was renal stone in 53%, chronic pyelone-
phritis in 20%, neglected PUJO in 16%,
and renal tuberculosis in 8% (LoE 3) [111].
In a study from Nigeria, the indication for
nephrectomy was chronic pyelonephritis in
29% and hydronephrosis in 17% of cases.
The authors emphasised the importance (A) (B)
of early diagnosis and proper treatment of Figure 11 Excretory urogram shows (A) papillary necrosis
UTIs (LoE 3) [112]. and (B) medullary sponge kidney.
465
9.2 Renal calyceal diverticula 85% in those with extension of gas into
Renal calyceal diverticula are often the perinephric or pararenal spaces but
asymptomatic, but may be associated fewer than 2 risk factors (thrombocyto-
with UTI and stone formation in up to penia, acute renal function impairment,
39% of cases (LoE 3) (Figure 12) [115]. disturbance of consciousness, or shock).
However, there appear to be no recent Patients with 2 or more risk factors had
studies reporting the incidence of UTI a significantly higher failure rate (92%
in patients with calyceal diverticula. vs. 15%), indicating that in such patients
The management is usually conserva- immediate nephrectomy is the preferred
tive, but indications for surgery include treatment (LoE 3) [120].
persistent pain, UTI and nephrolithiasis In another study of patients with EPN,
(LoE 3) [116]. Open surgery has been diabetes mellitus was present in all, but
largely replaced by percutaneous, urete- ipsilateral hydronephrosis was found
ro-renoscopic or laparoscopic approaches in only one patient (6%). E. coli was the
to remove stones and obliterate the commonest organism present in urine
diverticulum, or to dilate the connection cultures (52%), followed by Klebsiella
between the collecting system and the pneumoniae (24%) (LoE 3) [121].
diverticulum to improve drainage (LoE 3) Hydronephrosis, renal or perirenal
[117–119]. abscess, and even EPN are often first
treated percutaneously, with surgical
therapy later on, when the patient’s con-
9.3 Emphysematous pyelonephritis
dition has been stabilized (LoE 4) [122].
In a study of patients with emphyse-
matous pyelonephritis (EPN), diabetes
9.4 Xanthogranulomatous
mellitus was present in 96% and hydrone-
pyelonephritis
phrosis in 25% of cases. The most com-
mon pathogens were E. coli (69%) and In a study of patients who underwent
Klebsiella pneumoniae (29%). The mortal- nephrectomy for xanthogranulomatous
ity rate in patients who received antibiotic pyelonephritis (XGP), all had renal cal-
treatment alone was 40%. The success rate culi, the ipsilateral kidney was non-
of management by percutaneous nephros- functioning but enlarged because of
tomy or ureteric catheter combined with hydronephrosis or pyonephrosis in all
antibiotic treatment was 66% in the whole cases and the contralateral kidney was
group, 100% in those with gas in the renal enlarged because of compensatory hyper-
collecting system or parenchyma only, and trophy in 50% (LoE 3) [123].
Figure 12 Intravenous pyelogram showing calyceal diverticulum containing a stone in the

right kidney (seen as a filling defect in the early pyelogram phase on the left).
466
In another study, patients with XGP of the inflammatory mediators inter-

represented 19% of all nephrectomies leukin 6 and 8 in the urine) was markedly
performed for pyelonephritis. CT findings induced only by uropathogenic strains in
included hydronephrosis, kidney enlarge- the urine, but not by nonpathogenic or
ment, poor excretion of contrast medium, anaerobic strains (LoE 3) [132].
and air in the urinary tract. All patients In nonrefluxing enterocystoplasties
had renal calculi, 34% of which were stag- upper tract bacteriuria was demonstrated
horn calculi. The main organism isolated after renal pelvic aspiration of urine
was E. coli (LoE 3) [124]. Nephrectomy in 89% patients. Despite attempts to
and antibiotics are the treatment of choice maintain sterile urine with prophylactic
for XGP. antimicrobial medications, ascending bac-
terial migration was the most plausible
cause for the bacteriuria (LoE 3) [133].
10. BOWEL IN THE URINARY TRACT In a study of patients with an ortho-
topic neobladder after radical cystec-
Bacteriuria is common in all patients tomy, the estimated 5-year probability of
with bowel incorporated into the uri- UTI and urosepsis were 58% and 18%,
nary tract. Asymptomatic bacteriuria in respectively. Urine culture with greater
patients with a continent urinary diver- than 100,000 bacteria and female gen-
sion is generally of no clinical impor- der were the only factors predictive of
tance, because the bacterial strains UTI on multivariate analysis. Urosepsis
growing in the reservoir represent colo- occurred in 12% of patients overall, but
nization rather than infection (LoE 3) 31% of those with a UTI went on to have
[125]. Intestine incorporated into the urosepsis. Recurrent UTI was the only
genitourinary tract remains capable predictor for urosepsis. Hydronephrosis,
of producing a local antibody response ureteric reflux and CISC did not increase
against bacteria (as measured by uri- the risk of UTI or urosepsis. The authors
nary IgA and IgG) (LoE 3).[126–127] recommended prophylactic antibiotics for
After ileocystoplasty, the incorporated patients with recurring UTIs, but not for
ileum may produce larger quantities those with a positive urinary culture in
of IgA than the normal urinary tract, the absence of specific voiding symptoms
thus preventing attachment of E. coli to (LoE 3) [134].
uroepithelial cells and subsequent tis- In another study urine cultures from
sue invasion leading to clinical infection 67% of neobladder patients not on anti-
(LoE 2b) [128–129]. biotic therapy were culture positive, and
Complete emptying seems to reduce half of these contained uropathogenic
the bacterial burden, while clean inter- species, such as E. coli, Klebsiella pneu-
mittent self-catheterization (CISC) and moniae, Pseudomonas aeruginosa, and
residual urine seem to increase it. The Enterococcus faecalis. Bacterial coloniza-
increased rate of bacteriuria indicates tion was strongly correlated with resid-
a lack of antibacterial defenses, and the ual urine. Anaerobic strains were found
symptom-free state of most patients sug- more frequently in urine from ileal than
gests that only a restricted host response colonic neobladders. Patients on prophy-
is triggered (LoE 3) [130–131]. Whereas lactic antibiotics had bacteriuria in 80%
most (>70%) of the urine samples from of the samples, the majority being anaer-
patients with neobladders showed obic strains. The authors concluded that
anaerobic or aerobic bacterial growth, antibiotic prophylaxis does not seem to
and uropathogens were identified in reduce the bacterial burden, but inter-
about 45% of the samples, the local host feres with the bacterial composition (LoE
response (as measured by concentrations 3) [135].
467
A study of patients with orthotopic ileal varies from 0 to 53%, in ileal conduits
neobladders not on antibiotic prophylaxis from 4% to 20%, and in colon conduits
found a steady decrease in the prevalence from 3% to 11% (LoE 3) [141–142].
of positive urine cultures, from 75% to Continent diversions have higher stone
36% to 7% at 1, 6 and 18 months post- rates than freely draining conduits. The
operatively. Bacteriuria was found occa- Indiana pouch has a stone incidence of
sionally in 68% and persistently in 15%, 3% to 13%, the Kock pouch 4% to 43%,
while only 17% had no bacteriuria. E. the Mainz pouch around 8% and the
coli was the commonest organism (77%) cecal reservoir around 20% (LoE 3) [140,
followed by Klebsiella pneumonia (16%). 143–144].
The frequency of nocturnal enuresis (NE) The stone recurrence rate in patients
decreased with time, from 87% to 42% with bowel urinary diversions can be as
to 28% at 1, 6 and 18 months postopera- high as 65% during 5 years of follow up
tively. There was a significant correlation (LoE 3) [145]. Prophylactic measures
between the presence of bacteriuria and include high oral fluid intake, complete
NE during the first 6 months, but not evacuation of the reservoir, regular irri-
after that (LoE 3) [136]. gation of the pouch with saline solution
In a study of patients with an ileal or sterile water to remove mucus and
neobladder 3–9 months after surgery, crystals, and eradication of urea-splitting
recurrent bacteriuria was found in 57%, organisms (LoE 3) [140, 146].
while no bacteriuria occurred in 23%. E. There appears to be no statistically
coli strains were cultured from 80% of significant difference in the incidence of
patients with persistently positive urine. upper tract UTI and renal deterioration
The concentration of leukocytes in the between different types of urinary diver-
urine was higher in those with sterile sion using ileum or colon, or between
urine than in those with asymptomatic antirefluxing versus freely refluxing ure-
bacteriuria (LoE 3) [137]. terointestinal anastomotic techniques in
There is an increased risk of adeno- conduit diversions. However, wide con-
carcinoma of the colon after ureterosig- fidence intervals caused by the small
moidostomy, possibly because bacteria number of studied patients do not rule
catalyse the formation and activation of out important differences (LoE 3) [131,
carcinogens such as N-nitrosamines (LoE 147–148].
3) [138]. However, bacteriuria appears to
be less common in patients with a colonic
conduit (38%) than in those with an ileal 11. BACTERIOLOGY
conduit (73%) (LoE 3) [138].
Bowel (ileum and colon) that is incor- Urinary tract abnormalities may predis-
porated into the urinary tract predisposes pose to infection with organisms other
to stone formation because of bacterial than E. coli, and long-term antibiotic
colonization with urea-splitting organ- therapy often leads to bacterial resistance
isms, urinary stasis, mucus production, or fungal superinfection with Candida
and the presence of foreign bodies (e.g. albicans (LoE 3) [122]. The reported
metal staples). However, bladder augmen- prevalence rates of bacteria isolated
tation with a gastric segment has a lower from serious UTI are: E. coli 21–54%,
incidence of calculus formation, because Enterococci species 6–23%, miscellane-
it produces minimal mucus and secretes ous Gram-negatives 4–20%, Pseudomonas
acid, thereby lowering urine pH and inhib- aeruginosa 2–19%, Providencia spe-
iting bacterial growth (LoE 3) [139–140]. cies 18%, Klebsiella pneumoniae 2–17%,
The incidence of urolithiasis in patients Enterobacter species 2–10%, Proteus mira-
with augmentation enterocystoplasty bilis 1–10%, Citrobacter species 5–6%,
468
coagulase negative Staphylococci 1–4%, Table Indications for imaging of patients with UTI.
group B Streptococci 1–4%, Staphylococcus
aureus 1–2% (LoE 3) [149–150]. In infants • Babies and children
and children with UTI, there is a sig- • Men (see text for exceptions)
nificantly higher association of non-E.
• Patients with history of:
coli disease with VUR, hydronephrosis,
younger age, and previous antibiotic treat- o voiding difficulties
ment (LoE 3) [151]. o urolithiasis
Urinary tract obstruction may permit
o previous renal disease
ascending infection of E. coli strains with
lower adhesive ability. P-fimbriae are o previous urinary tract surgery
mannose-resistant adhesins of uropatho- • Neurological disease/neuropathic bladder
genic E. coli (UPEC) which cause acute
• Poor response to appropriate antibiotic treatment
pyelonephritis (APN). The pap gene (after 3 to 6 days)
cluster (PapGI, -II, and -III) encodes
• Recurrent or unusually severe symptoms
the proteins required for P-fimbrial bio-
genesis [152]. E. coli strains lacking the • Diabetes mellitus or immunocompromised states
P-fimbriae phenotype are more com- • Renal failure
monly associated with APN in children
• Haematuria (macroscopic, or microscopic >1 month
with urinary tract abnormalities (LoE 3) after UTI)
[153]. There is a predominance of papG
Class II allele in infants with APN and • Acute urinary retention
normal urinary tract anatomy (LoE 3) • Infection with urea-splitting bacteria

[154]. In adults the incidence of the papG
class II allele in patients with hydrone-
phrosis is less than in those without uri- important urological abnormalities in
nary tract abnormalities (69% versus men presenting with UTI (LoE 2a) [5].
93%). These findings indicate that struc- Computerised tomography (CT) has
tural or functional abnormalities of the become accepted as a more sensitive
urinary tract may permit infection with modality. CT urography is increasingly
E. coli strains that would not be patho- performed as a comprehensive urinary
genic in a normal urinary tract (LoE 3) tract imaging study. Magnetic resonance
[155]. (MR) imaging is particularly useful in
those with iodinated contrast allergies.
Nuclear medicine has a limited role but is
12. SPECIAL INVESTIGATIONS useful in the assessment of renal function
prior to surgery (LoE 3) [85, 158, 160–
The aim of imaging in UTI is to detect 161]. Imaging with microbubble ultra-
conditions that must be corrected to avoid sonographic contrast agents (USCAs) can
rapid deterioration of renal function or overcome the limitations of conventional
systemic sepsis, and to prevent recurrent B-mode imaging and may become the
infections and long-term kidney dam- modality of choice in the future (LoE 2a)
age. Indications for imaging in patients [162–164].
with UTI are shown in the Table [85, 122, Imaging may not be necessary in all
156–159]. men with febrile UTI. It has been sug-
Intravenous urography (IVU) and ultra- gested that in men younger than 45
sound (US) have traditionally been used years with a first acute UTI no radio-
in the assessment of complicated UTI. logic, endoscopic or urodynamic investi-
US with abdominal radiography (AXR/ gation is required, provided a urethral
KUB) is as accurate as IVU in detecting stricture has been excluded (LoE 3)
469
[165]. Urological evaluation of men with prevent septicemia and recurrent UTI
febrile UTI should primarily be focused (LoE 3) [85].
on the lower urinary tract, especially in In patients with mild to moderate UTI
men with a history of voiding difficulties, (no nausea or vomiting) the recommended
AUR, the presence of microscopic hae- empirical treatment is an oral fluoro-
maturia at follow-up after one month, or quinolone used on an outpatient basis
early recurrent symptomatic UTI (LoE (e.g. norfloxacin, ciprofloxacin, ofloxacin).
3) [157]. Severely ill patients with possible uro-
In women with early recurrent UTI, sepsis should be hospitalized and empiri-
imaging and cystoscopy are usually rec- cal treatment should include intravenous
ommended, although the yield may be ampicillin and gentamicin, or alternatives
quite low, with significant abnormalities such as ciprofloxacin, levofloxacin, ceftri-
being detected in only 8%. The negative axone, aztreonam, ticarcillin-clavulanate
predictive value of normal radiological or imipenem-cilastin. Every effort should
imaging is 99%, suggesting that women be made to correct any underlying urinary
with normal imaging do not need cystos- tract abnormalities that may compromise
copy (LoE 3) [166–167]. treatment efficacy. Therapy is usually
In patients with complicated acute switched from parenteral to oral as soon
pyelonephritis (APN), urine cultures are as possible (LoE 3) [85].
positive in 90–98% of cases and bacter- Empirical therapy of serious UTI
emia may occur in 21–42%, but in only should usually include an intravenous
a small minority (around 1%) the path- antipseudomonal agent. Targeted ther-
ogens found in blood cultures are dif- apy should be initiated once susceptibil-
ferent from those in the urine (LoE 3) ity data are known. Agents commonly
[168–169]. Some authors have suggested prescribed include aminoglycosides,
that blood cultures should be reserved beta-lactamase inhibitor combinations,
for patients with an uncertain diagno- imipenem, advanced-generation cepha-
sis, those who are immunocompromised, losporins and fluoroquinolones. Several
and those who do not respond promptly pivotal clinical trials support the use
to treatment (LoE 3) [170]. However, of fluoroquinolones for serious UTIs,
others recommend that blood cultures with ciprofloxacin the most frequently
should be done in all patients with com- studied drug (LoE 3) [149–150, 171].
plicated APN, because bacteremia indi- Fluoroquinolones which are equivalent to
cates severe disease, which is more likely ciprofloxacin 500 mg twice daily, include
to recur within 6 months in patients with levofloxacin 500 mg once daily and gati-
non-E. coli bacteremia and those with floxacin 400 mg once daily (LoE 3) [172].
urolithiasis or hydronephrosis, especially In a recent study from the USA, 92% of
men (LoE 3) [169]. bacterial isolates from patients with com-
plicated UTI or APN were susceptible to
levofloxacin and ciprofloxacin (LoE 3)
13. ANTIBIOTIC TREATMENT [173–174].
A 7-day course of therapy is recom-
The treatment of UTI in the presence of mended for women with symptoms of 1
urinary tract obstruction requires effec- week or more, men (even those with appar-
tive antibiotic therapy as well as appro- ently uncomplicated cystitis), and indi-
priate Urological intervention to remove viduals with possible complicating factors.
predisposing factors and to restore as For patients with fever or more severe sys-
far as possible the normal anatomy and temic infection, therapy for 10 to 14 days
function of the urinary tract in order to is recommended. Urine cultures should
470
be performed during antibiotic treatment prophylaxis in children with antenatally

and 7–14 days after cessation of therapy diagnosed hydronephrosis secondary to
to determine whether treatment has been upper tract obstruction, prospective, ran-
effective (LoE 3) [6, 85, 165, 175]. domized studies are required in order to
resolve the controversies.
14. FURTHER RESEARCH

15. CONCLUSIONS
Interesting preliminary data indicate
that acute and/or chronic intrapros- The current enthusiasm for evidence
tatic inflammation may be important based medicine requires the ranking of
in the pathogenesis as well as pro- recommendations or guidelines on the
gression of BPH. Further research is basis of levels of evidence, with the high-
required to substantiate or refute this est status assigned to prospective, rand-
theory, and also to determine the possi- omized clinical trials, and the lowest rank
ble role of anti-inflammatory medication assigned to “expert opinion”. However,
in the prevention of BPH as well as its there are certain conditions where pro-
complications. spective randomized trials have never
Most clinical trials of medical therapy been done, largely due to the logic or
for BPH have excluded men with a large “common sense” of expert opinion.
PVR, bladder stones or recurrent UTI, A prime example of this is severe UTI
with the implication that prostatectomy in the presence of urinary tract obstruc-
is indicated for all such patients. Recent tion, e.g. pyocystis or pyonephrosis. Logic
studies have suggested that bladder cal- dictates emergency drainage by means
culi associated with BPH can be managed of transurethral bladder catheterization,
with transurethral stone removal and ureteric stenting or percutaneous neph-
medical treatment of BPH. Prospective, rostomy, and it is unlikely that a rand-
randomised clinical trials are required to omized trial comparing drainage with
establish the role of medical treatment non-drainage will ever be performed. This
in men with complications such as recur- leads to the paradoxical phenomenon of a
rent UTI or bladder calculi associated high grade recommendation based on a
with BPH. low level of evidence.
The observation that prostatitis may The increasing demands for evidence
cause an increased total serum PSA and based medical practice and exhaustive
decreased free/total PSA ratio, which may treatment protocols based on consen-
be falsely interpreted as a sign of prostate sus guidelines should not blind us to the
cancer, indicates the necessity for further imperatives of simple logic or plain com-
research to determine the role of empiric mon sense, or the value of expert opinion
antibiotic treatment in order to avoid based on clinical experience.
unnecessary prostate biopsy. UTI in the presence of underlying uro-
The theory that inflammation of the logical abnormalities provides an excel-
prostate may be an etiological factor lent model for studying the relationships
in the development of prostate cancer between anatomy, physiology, pathology,
should be further investigated, especially microbiology and pharmacology. Although
with regard to the potential use of anti- major advances in the treatment of com-
inflammatory medication to decrease the plicated UTI have been made during the
incidence of prostate cancer. past few decades, many questions remain
In view of the conflicting evidence in unanswered, and much investigative
the literature on the role of antibiotic work still needs to be done.
471
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|8.3|
Urinary tract infections in patients

with urolithiasis
Gianpaolo Zanetti1, Alberto Trinchieri2
1
Assistant Professor, Department of Urology, Fondazione IRCCS Ospedale Maggiore PO.MA.RE, Milan, Italy
2
Director, Urology Unit, Lecco Hospital, Lecco, Italy
ABSTRACT Urease-producing bacteria grow as

biofilm adhering to stone surfaces where
Urease-producing micro-organisms can struvite and calcium phosphate crystals
be cultured from the stone in 48% of precipitate. Damage to the protective
patients with calculi containing magne- layer of glycosaminoglycans (GAG) facili-
sium ammonium phosphate. A negative tates bacterial adherence and further tis-
midstream urine (MSU) culture is not sue invasion by bacteria. High urinary
sufficient to exclude the presence of uri- calcium levels and low citrate levels pro-
nary tract infection (UTI) associated with mote urease-induced crystal precipita-
an obstructing stone. Only culture of the tion. Dissolution of infectious stones can
stone (or of urine obtained from the renal be accomplished by irrigation with acidi-
pelvis) is a good predictor of the risk of fying solutions, but they must be used
post-treatment clinical sepsis. with caution because of the risk of severe
Urinary stones containing struvite side-effects.
or carbonate apatite result from UTI Percutaneous nephrolithotomy (PCNL)
by urease-producing micro-organisms. should be the first treatment utilized for
Proteus, Klebsiella and Staphylococcus removal of high burden infection stones.
species (spp) are the most commonly Extracorporeal shock-wave lithotripsy
encountered urease-producing micro- (ESWL) should be used only for residual
organisms involved in stone formation. stones after PCNL, and as monotherapy
Bacterial urease activity can also be may be considered only in patients with
demonstrated in urine infected by other small volume staghorn stones with nor-
micro-organisms not growing in common mal collecting system.
culture media (Ureaplasma urealyticum, Antibiotic therapy is advisable in
Corynebacterium urealyticum). patients affected by infection stones prior
to and/or after treatment. Antibiotic proph- 4. Dissolution of infection stones can

ylaxis for ESWL and ureteroscopy for be accomplished by irrigation with
uncomplicated stones in the distal ureter acidifying solutions, but they must
should be reserved for high-risk patients. be used with caution, due to the risk
Perioperative antibiotics should be rou- of severe side-effects (GoR B).
tinely administered for ureteroscopy of 5. Eradication of all stones and frag-
stones in the proximal ureter or impacted ments is essential to prevent per-
stones, for PCNL or open stone surgery. sistent infection and recurrence of
Residual stones and fragments cause infection stones (GoR B).
persistent infection and rapid stone
regrowth after surgical and ESWL treat- 6. Antibiotic therapy is advisable in
ment of infected stones. The appropri- patients affected by infection stones,
ateness of chronic low-dosage antibiotic prior to and/or after treatment
suppression treatment and chronic uri- (GoR B).
nary acidification for the prophylaxis 7. Antibiotic prophylaxis for ESWL
of infection stones has not yet been suc- and ureteroscopy of uncomplicated
cessfully demonstrated. Use of citrate as stones in the distal ureter should be
a prophylactic agent for infection stones reserved for risk patients (GoR B).
could be an option. Urease enzyme inhibi- 8. Perioperative antibiotics should be
tors are effective in limiting the change in routinely administered for ureteros-
urinary pH caused by urease-producing copy for stones in the proximal ure-
bacteria, but are associated with frequent ter or impacted stones, for PCNL or
severe side-effects. open stone surgery (GoR B).
Key words: urinary tract infection,
9. Chronic low-dosage antibiotic sup-
urinary calculi, urolithiasis
pression treatment and chronic
urinary acidification for the prophy-
laxis of infection stones may be con-
sidered, but efficacy has not been
proven (GoR C).
1. In the presence of an obstructing
10. The use of citrate as a prophylactic
urinary tract stone, midstream urine
agent for infection stones could be an
(MSU) culture should be obtained,
option (GoR C).
although it is not sufficient to
exclude the presence of urinary tract 11. Urease enzyme inhibitors to limit
infection (UTI) – only culture of the the change in urinary pH caused by
stone, or of urine from the renal urease-producing bacteria can be
pelvis, can predict the risk of post- considered, but severe side-effects
treatment clinical sepsis (GoR B). may occur (GoR C).
2. Percutaneous nephrolithotomy
(PCNL) should be the first-line treat- 1. INTRODUCTION
ment for removal of high burden
infection stones (GoR A). Urinary stone formation and UTI can
3. Extracorporeal shock wave lithot- be associated under different conditions.
ripsy (ESWL) should be used only for UTI can be present in urinary stone
residual stones after PCNL, and as patients as a consequence of obstructive
monotherapy may be considered only uropathy due to a pre-existing stone of
in patients with small volume stag- different origin, or UTI by itself can be
horn stones with a normal collecting the primary cause of modifications of the
system (GoR B). physicochemical composition of the urine,
482
Urinary tract infections in patients with urolithiasis | 8.3 |
promoting crystallization and stone for- decrease over time in relation to the pro-
mation. The former condition is defined gressive increase in the prevalence of cal-
as UTI “associated” with stone disease, cium oxalate stones of metabolic origin.
while the latter is “infectious stone In less developed countries the preva-
disease”. lence is higher in relation to local health
Urinary stones are often associated conditions and to the lower prevalence of
with persistent or recurrent UTIs that other types of renal stones.
can sometimes lead to bacteremia and The presence of urinary calculi is a
urosepsis after endourologic manipulation risk factors for nosocomial acquired uri-
or lithotripsy or persistent urinary tract nary tract infections (NAUTIs) that were
obstruction. “Infectious” or “infection” found associated with urinary stones in
stones are related to UTIs with urease- 20% of patients in the PEP/PEAP study
producing organisms (Proteus, Klebsiella, (2003–2004) (LoE 3) [4].
Providencia and Pseudomonas spp, In general infection stones tend to be
Staphylococcus aureus and Ureaplasma more common in female patients due to
urealyticum) that promote the formation the higher prevalence of recurrent UTIs
of struvite (magnesium ammonium phos- (LoE 3) [5]. Urease-producing microrgan-
phate) and apatite (calcium phosphate) isms could be cultured from the stone in
calculi. 48% of patients with calculi containing mag-
nesium ammonium phosphate (LoE 3) [6].
Renal stones of metabolic origin are
2. METHODS more often associated with infection with
non-urease-producing micro-organisms.
A systematic literature search was per- Of patients with calcium oxalate or cal-
formed in PubMed from October 1998 cium phosphate stones 32% had positive
through September 2008, limited to stud- stone cultures in comparison to only 8%
ies in the English language. In total, 338 of patients with pure calcium oxalate
citations were extracted using the key stones (LoE 3) [6]. Other authors found a
words “urinary calculi” AND “urinary lower rate (5%) (LoE 3) [7].
tract infection”. After screening the titles, On the other hand, this association
35 papers were selected, and after screen- could be underestimated, because MSU
ing the abstracts only 10 studies were cultures often fail to detect stone infec-
included in the final analysis, supple- tion. In a prospective study Mariappan
mented by 74 publications cited in these and Long suggested that in obstructive
references and published before 1998, but uropathy secondary to stone, MSU cul-
considered as “milestones” on this topic. ture is a poor predictor of infected urine
The studies were rated according to the proximal to the obstruction and infected
level of evidence (LoE) and the grade of stones (LoE 3) [8]. Among the patients
recommendation (GoR) using ICUD who developed urosepsis after stone
standards (for details see Preface) [1–2]. removal, stone culture was positive in
25% and pelvic urine culture was positive
in 66%, but MSU culture was negative in
3. EPIDEMIOLOGY all patients [8].
In a similar study in 54 patients under-
The incidence of infection stones in dif- going PCNL, MSU culture was positive
ferent accounts and different countries only in 5.6% of the patients (LoE 3) [9].
varies widely. In Western developed Patients with infected stones and pelvic
countries, “infection” stones represent urine carried a four-fold risk of develop-
approximately 10–15% of all urinary ing urosepsis. Similarly, Margel et al.
stones (LoE 3) [3], but this rate tends to have shown that MSU culture is a poor
483
predictor of upper urinary tract colo- formers who develop chronic renal failure
nization, but stone culture is the only suffer from infectious stones (LoE 4) [15].
parameter that may predict the risk of
developing post-treatment clinical sepsis
(LoE 3) [10]. 5. PATHOGENESIS
Infection urinary stones develop as a

4. CLINICAL EVALUATION/RISK result of persistent infections caused by
ASSESSMENT urease-producing bacteria and are often
associated with urinary tract obstruction
Infection stones present as casts of the (LoE 4) [16–17].
collecting system that can be partial or
complete with a “staghorn” configura- 5.1 Urea-splitting bacteria
tion. Bladder stones are commonly asso-
Urease splits urea into ammonia and car-
ciated with outlet obstruction and UTI.
bon dioxide, which are hydrolysed to ammo-
Struvite stones are characterised by
nium ions and bicarbonate, thus increasing
their exceptionally rapid growth (infec-
the pH. In the alkaline urine, phosphate
tion stones can form within 4–6 weeks)
is precipitated in the form of magnesium
(LoE 4) [11].
ammonium phosphate (struvite). Struvite
Cases of gas-containing renal stones
precipitation starts at a pH of 6.7–6.8,
associated with E. coli UTI have been
peaks at around pH 7.5 and then declines
reported (LoE 3) [12]. The gas-containing
markedly at higher pH (LoE 4) [18].
stones were visible on computed tomog-
Infection stones also consist of monoam-
raphy (CT) scans, ultrasound (US) and
monium urate and/or carbonate apatite
intravenous urography (IVU) and were
in relation to the urinary concentration of
radiolucent.
other available cations (LoE 4) [16].
Patients with struvite stones do not
Proteus, Klebsiella and Staphylococcus
typically present with colic, unless a
spp are the most commonly encoun-
stone fragment passes down the ure-
tered urease-producing micro-organisms
ter after prior manipulation. Infection
involved in stone formation (Table 1).
stones should be suspected as the source
Others such as Pseudomonas spp are less
of recurrent or persistent UTIs in the
likely to produce urease and are therefore
presence of mild recurrent flank pain.
less frequently connected with struvite
Assessing urinary pH is critical in help-
stone formation (LoE 3, LoE 4) [3, 18].
ing to determine the presence of struvite
Bacterial urease activity can be dem-
calculi that form in a urinary environ-
onstrated in the urine by a fast colori-
ment with a pH of at least 7.2, whereas
metric test (LoE 3) [3]. A recent study
normal urinary pH lies in the range of
further documented the pivotal role of
5.8–6.0. Persistently alkaline urine there-
urea-splitting bacteria in the formation of
fore suggests the presence of a struvite
struvite calculi: experimental instillation
calculus (LoE 4) [13].
of urease-negative Proteus into murine
Clinical sepsis can be seen following
bladders failed to produce encrustation,
stone surgery secondary to endotoxemia,
whereas wild-type Proteus spp rapidly
even without bacteremia. Some patients
formed encrustations containing bacteria
who develop clinical sepsis can have neg-
in the stone matrix (LoE 2b) [20].
ative cultures but exceedingly high lev-
els of endotoxin in the stone itself (LoE
5.2 Ureaplasma urealyticum
2b) [14].
Although end-stage renal disease is now U. urealyticum frequently colonizes the
rare in renal stone disease, most stone lower urinary tract in sexually active
484
Table 1 Frequency of urease-producing pathogens (modified from Bichler et al. [19] ).
Organism Total (N) Urease positive (N) Urease positive (%)
Proteus spp 54 54 100
Klebsiella spp 31 26 84
Staphylococcus spp 67 37 55
E. coli 142 2 1.4
Pseudomonas spp 20 1 5
Providencia spp 1 1 100
M. morganii 1 1 100
Total 423 122 28.8
individuals. It may also invade the upper transplant recipients may cause graft
urinary tract and induce stone formation loss (LoE 3) [29].
in the kidneys by its urease activity.
Experimental studies demonstrated 5.4 Nanobacteria
that U. urealyticum is able to induce a
The possible role of nanobacteria as the
urinary pH increase and crystallization in
initial nidus for stone formation has been
vitro (LoE 2b) [21] and to produce rapid
described by Kajander et al. (LoE 3) [30].
concretion formation after inoculation
Nanobacteria are the smallest bacte-
into the rat bladder in vivo (LoE 2b) [22].
ria with cell membranes, being 10–100
Its presence has been demonstrated as
times smaller than bacteria known so far
the only urease-producing micro-organ-
(LoE 3) [31]. Kajander et al. demonstrated
ism in the urine of patients with infection
that nanobacteria are able to excrete bio-
stones (LoE 3) [23–27]. U. urealyticum
genic apatite (carbonate apatite) through
can be overlooked by routine investiga-
their cell cover, and found them in 90% of
tion, since it is not detected by stand-
human kidney stones examined, claim-
ard urine cultures and its presence in
ing their important potential as nidus for
the stone is less well reflected by urine
stone development.
culture.
However, other authors were not able
to confirm the presence of nanobacteria in
5.3 Encrusted pyelitis and
urinary stones, nor phosphate excretion
corynebacteria
by these organisms (LoE 3) [32]. A recent
Encrusted pyelitis (EP) is an infectious study investigating the presence of nano-
disease characterized by encrustation of bacteria in stone patients with negative
the collecting system. Corynebacterium conventional urinary cultures demon-
group D2 is the most common urea- strated the presence of nanobacteria in
splitting micro-organism involved in the only 0.5% (LoE 3) [33].
pathogenesis of EP that can be treated The small organisms can be difficult to
conservatively with intravenous vanco- identify, or the previously positive find-
mycin and percutaneous acidification ings published may have been caused by
of the renal collecting system (irriga- contamination of the sample or of the cul-
tion with Thomas’ acid solution) (LoE 3) ture media. In an in vitro study, inhibi-
[28]. Mortality directly associated with tion of nanobacteria by tetracycline was
infection by this organism is not fre- measured by a modified microdilution
quent, but encrusted pyelitis in kidney method (LoE 2b) [34].
485
5.5 Biofilm Distal renal tubular acidosis (RTA I)

The growth of bacteria on stones as biofilm can result from chronic pyelonephri-
is a naturally occurring phenomenon that tis, which damages the distal tubular
has significant implications for antibiotic cells, with acidification disturbances and
resistance or minimum inhibitory con- reduced excretion of citrate as well as
centrations of drugs required for effective higher calcium excretion and partially
therapy (LoE 4) [35]. Urease-producing increased phosphate excretion [3] (LoE 3).
bacteria adhere to stone surfaces where This condition predisposes to urinary
struvite and calcium phosphate crystals stone formation by pH changes and espe-
preferentially precipitate in the alkaline cially low citrate excretion.
urine environment and deposit on the bio- E. coli infection depletes the urinary
film. As a consequence the calculi grow content of citrate, a powerful inhibitor of
rapidly with the addition of more bacte- calcium stone formation (LoE 3) [41].
ria, matrix production and further deposi-
tion of crystals, and may eventually form 5.8 Urine composition
a staghorn calculus (LoE 2b) [36]. Several urine components, but most signif-
Antimicrobial agents are ineffective in icantly citrate, have been shown to influ-
eradicating the infection, because bac- ence urease-induced precipitation (LoE
teria are protected by bacterial extracel- 2b). [42–45] A low native urine pH and
lular matrix. For this reason complete high urinary phosphate (by its relevant
stone clearance is mandatory to eradicate buffering effect of urine) reduce the risk of
UTI and to prevent rapid recurrence of alkalinisation of urine and consequent for-
staghorn calculi. mation of struvite crystals (LoE 3) [46].
On the other hand, high urinary cal-
5.6 Bacterial adherence cium levels promote urease-induced pre-
cipitation (LoE 3) [46]. High urine citrate
Ammonia damages the protective layer
is associated with reduced concretion
of glycosaminoglycans (GAG) which acts
production, owing to its inhibitory activ-
as a defence against bacterial adherence
ity of nucleation and crystal aggregation,
and infection, so facilitating bacterial
although urine pH increases (LoE 2b)
adherence and further tissue invasion by
[44–45, 47].
the bacteria (LoE 4) [37]. Experimental
damage of this protective layer increases
the adhesion of struvite crystal to the 6. RISK FACTORS
rat bladder by five to six times compared
with an intact bladder (LoE 2b) [38–39]. Risk factors for the development of infec-
Also other uropathogens could facilitate tion stones are urinary tract obstruction,
stone formation by inducing an inflam- urinary diversion, presence of catheters
matory reaction that can damage the proin the urinary tract, neurogenic bladder,
tective GAG layer. renal transplant, and medullary sponge
kidney (LoE 4) [3, 48].
5.7 Other infection-related
mechanisms of calcium stone
formation 7. TREATMENT
Non-urease-producing micro-organisms
7.1 Medical treatment
can facilitate urine crystallization and
formation of calcium-containing stones, Dissolution of infection stones could theo-
acting as a nucleus for epitactic crystal- retically be accomplished by acidifying
lization (LoE 2b) [40]. the urine. Suby’s Solution G, consisting of
486
citric acid, magnesium oxide and sodium to the collecting system and the complete
carbonate, can be used to dissolve kidney removal of all stones. ESWL should be
stones containing carbonate-apatite and used only for residual stones after PCNL,
struvite via nephrostomy or a ureteric and as monotherapy may be considered
catheter (LoE 3) [49]. only in patients with small volume stag-
Other medications proposed for stone horn stones with normal collecting sys-
dissolution are Renacidin (Hemiacidrin). tem (LoE 1a) [55].
Renacidin is similar to Suby’s Solution
G, but contains additional magnesium 7.3 Infection stone removal and
and D-gluconic acid (LoE 3) [50]. It has antibiotic treatment
proved effective to dissolve ureteral and
kidney stones with no side-effects (LoE 3) Antibiotic therapy is advised in patients
[51–53]. On the other hand, side-effects affected by infection stones prior to and/or
and even death after Renacidin treat- after treatment. Antibiotic therapy signifi-
ment have been reported (LoE 3) [54]. In cantly reduces the bacterial load, although
order to prevent the risk of side-effects, urine does not always become sterile.
Renacidin irrigation should be avoided in Besides decreasing the risk of sepsis, anti-
the case of UTI or concomitant flank pain, biotics prevent recurrence or re-growth of
and magnesium serum levels must be stones after treatment.
monitored to prevent hypermagnesemia. In the literature, different schedules of
targeted antibiotic therapy are reported,
sometimes in association with urease
7.2 Surgical treatment
inhibitors (Table 2) (LoE 3) [10, 56–58].
Successful treatment of struvite infec- According to the 2007 guidelines of the
tion stones requires complete clearance European Association of Urology (EAU)
of all stone material. Current treatment (LoE 4) [59], antibiotic therapy should be
options are PCNL and ESWL. Less inva- combined with complete stone removal by
sive methods are preferable and open all possible treatments, including PCNL,
surgical procedures should be limited to ESWL, and open surgery (Table 3).
cases with giant stones or associated with
abnormalities of the urinary tract.
7.4 Antibiotic prophylaxis for stone
The treatment of high burden infec-
procedures (all types)
tion stones is best accomplished via the
percutaneous route. Single or multiple There is controversy in the literature with
percutaneous punctures with or without respect to the use of antibiotic prophylaxis
adjuvant flexible endoscopy (nephroscopy for stone procedures. Its role, expediency,
or ureteroscopy) allow for complete access and duration in relation to the various
Table 2 Antibiotic treatment for infection stones.
Streem et al. [56] 1 or 2 weeks of pre-operative targeted antibiotic therapy + broad-spectrum IV therapy
intra- and post-operatively
Wang et al. [57] Targeted antibiotic therapy + urease inhibitors as completion of the PCNL + ESWL treatment
Margel et al. [10] 2 weeks of targeted antibiotic therapy prior to treatment (referring to the most recent positive
urine culture)
Sharifi Aghdas et al. [58] 1–2 days of antibiotic prophylaxis prior to treatment
487
Table 3 Treatment of complete or partial staghorn stones.
Type of stone Procedure Grade of recommendation
Infection stones and stones with Antibiotics + PCNL A

infection
Antibiotics + PCNL + ESWL A
Antibiotics + ESWL + PCNL A
Antibiotics + ESWL + local chemolysis B
Antibiotics + open surgery
Table 4 Perioperative antibiotic prophylaxis for stone procedures (modified from EAU Guidelines).
Procedure Pathogens Prophylaxis Antibiotics Remarks
ESWL Enterobacteriacae No Cephalosporins 2nd-3rd generation Only in risk

patients
Enterococci TMP+/-SMX
Aminopenicillin/BLI
Ureteroscopy (uncomplicated Enterobacteriacae No Cephalosporins 2nd-3rd generation Only in risk

distal stones) patients
Staphylococci Aminopenicillin/BLI
Fluoroquinolones
Ureteroscopy (proximal Enterobacteriacae All patients Cephalosporins 2nd-3rd generation Short course
stones or impacted stones)
PCNL
Staphylococci Aminopenicillin/BLI
Fluoroquinolones
Open surgery Enterobacteriacae Recommended Cephalosporins 2nd-3rd generation Single pre-

operative
dose
Staphylococci Aminopenicillin/B
surgical procedures are still debated. stones in the distal ureter only in high-
Differences in the way infective complica- risk patients (e.g. when ureteric stent or
tions are classified (fever, SIRS (Systemic a nephrostomy is present). Perioperative
Inflammatory Response Syndrome), antibiotics should be routinely adminis-
symptomatic UTI, asymptomatic bacte- tered for ureteroscopy of stones in the
riuria) makes it difficult to compare the proximal ureter or impacted stones, for
results of various studies. PCNL or open stone surgery (Table 4).
The guidelines of the EAU for the The EAU guidelines give no definite
management of urinary and male geni- indication as to the duration of antibi-
tal tract infections strongly recommend otic prophylaxis and whether prophy-
peri-operative prophylaxis for the pre- laxis must necessarily lead to continuous
vention of infection related to surgical therapy. For this reason endourology
procedures[59] (LoE 4). These guide- centres often develop internal guidelines
lines suggest antibiotic prophylaxis for according to their own clinical practice
ESWL and ureteroscopy of uncomplicated (Table 5).
488
Table 5 Antibiotic prophylaxis/treatment before and after different procedures for stone removal.
Authors Procedure Prophylaxis/Therapy Results
Charton et al. [62] PCNL No prophylaxis 35% UTI
Cadeddu et al. [61] PCNL Prophylaxis + Therapy 16% fever

(>38°C)
(Gentamicin + Ampicillin
or Cephalosporins)
Margel et al. [10] PCNL Prophylaxis 22% SIRS

(Cephalosporins 2 generation 1 g one shot)
nd
Sharifi Aghdas et al. [58] PCNL No prophylaxis 25.8% fever

(>38°C)
Mariappan et al. [64] PCNL Prophylaxis 3% SIRS

(Ciprofloxacin 500 mg x 2/day orally for 1 week)
Dogan et al .[65] PCNL Prophylaxis 20% fever

(Ofloxacin 200 mg IV one shot)
Dogan et al. [65] PCNL Therapy 21% fever

(Ofloxacin 400 mg/day orally)
Knopf et al. [67] ULL Prophylaxis 1.8% bacteriuria

(Levofloxacin 250 mg one shot)
Knopf et al. [67] ULL No prophylaxis 12.5%

bacteriuria
Tenke et al. [68] ULL Continuous therapy 12% UTI

(Levofloxacin 500 mg x 2/day for 18–21 days)
Tenke et al. [68] ULL Intermittent therapy 12% UTI

(Levofloxacin 500 mg x 2/day for 7+3 days)
Costantino et al. [69] ULL Prophylaxis + Therapy 14% UTI

(Levofloxacin 500 mg 4h pre-operatively
+ Levofloxacin 500 mg for 5 days)
Dincel et al. [71] SWL Prophylaxis 2–17% UTI
Petterson and Tiselius [74] SWL No prophylaxis (urine culture negative prior to treatment) 8–15% UTI
Bierkens et al. [73] SWL No prophylaxis (urine culture negative prior to treatment) 4–12% UTI
Zanetti et al. [75] SWL No prophylaxis (urine culture negative prior to treatment) 7.3% UTI
7.5 Percutaneous lithotripsy certainty that the urine is sterile. Several

Although the presence of turbid urine authors have shown an increase in septic
by renal puncture is not predictive of risk (including fatal risk) with the place-
infected stone or urine, it is custom- ment of instruments in an infected cal-
ary, when undertaking PCNL, to leave iceal system (LoE 3) [9].
a nephrostomy in place if there is evi- The incidence of urosepsis does not
dence of potentially infected urine, and increase with an increase in the number
to postpone the procedure until there is of punctures of the pelvi-caliceal system
489
during PCNL, nor does there seem to be a Knopf et al. compared two groups
close correlation between the duration of of patients who underwent endoscopic
the procedure and the occurrence of infec- removal of ureteric stones: the first
tive complications (LoE 3) [60–61]. group received prophylaxis with one-shot
In patients with negative pre-opera- levofloxacin 250 mg orally an hour prior
tive urine culture who did not undergo to treatment, while the second did not
any antibiotic prophylaxis, Charton et al. receive any prophylaxis. No acute infec-
observed a 35% incidence of UTI (LoE 3) tive complication was observed in either
[62]. Several authors have shown how of the groups, but a relevant reduction in
prophylaxis, associated with antibiotic bacteriuria was observed in patients who
therapy, markedly reduces the incidence had received prophylaxis. Levofloxacin
of UTIs and post-operative hyperpyrexia therefore proved useful in minimizing pos-
(LoE 3) [61, 63]. sible infective complications caused by the
In the presence of proven pre-operative surgical procedure (LoE 1b, 2b) [67–69].
UTI, targeted antibiotic therapy should
be administered until the urine culture
7.7 Extracorporeal shock wave
is negative, or a cycle of broad-spectrum
lithotripsy (ESWL)
antibiotic should be administered prior to
surgery (LoE 3) [10]. Renal and vascular trauma caused by
Recently, the use of fluoroquinolo- ESWL treatment can lead to the passage
nes has been proposed (LoE 3) (LoE 2a) of bacteria present in the urine into the
[64–65]. Antibiotic prophylaxis was systemic circulation. Skolarikos et al.
administered one week prior to sur- found post-ESWL bacteriuria in 7–23%
gery for patients with staghorn stones of patients, bacteremia in 14% with evo-
(>20 mm) and/or pyelocaliceal dilata- lution toward urosepsis in less than 1%
tion. The results were compared with of cases (but for infection stones this per-
those of a group of patients with the centage rose to 2.7%). The risk of sepsis
same characteristics, but who did not increases in the presence of positive pre-
receive any prophylaxis (control group). treatment urine culture and/or urinary
In the patients who had prophylaxis, a obstruction (LoE 4) [70].
3-fold lower risk of upper UTI and SIRS Currently, the role of antibiotic prophy-
was observed, and a considerably lower laxis for ESWL is controversial. Although
number of positive pelvic and stone cul- some authors support the usefulness
tures were found. of routine prophylaxis (LoE 3) [71], the
most recent studies have not shown any
significant advantage in the prevention
7.6 Ureterolitholapaxy (ULL) of infection in the absence of pre-existing
During this procedure, the hydrostatic UTIs or infected stones. There is, instead,
pressure generated by the irrigation agreement on the use of prophylaxis or
fluid causes migration of bacteria and antibiotic treatment in infection stones in
endotoxins into the systemic circulation. the presence of positive urine culture, in
This process is apparently amplified in patients with history of recurrent UTIs,
the presence of urinary tract obstruc- and in patients who undergo treatment
tion, because of the greater permeability with stents or nephrostomies (LoE 3)
of the blood and lymphatic vessels of the [70–75].
renal pelvis. Therefore, the incidence of
systemic infection can be reduced with
7.8 Prophylaxis
low-pressure irrigation or using a flexible
ureterorenoscope with a ureteral access After treatment residual stone fragments
sheath (LoE 3) [66]. may settle in the dependent calices and
490
therefore lead to an increased recurrence periods (LoE 4) [3]. Vitamin C admin-

rate. Residual stones and fragments istration only results in lowering the
cause persistent infection and rapid stone urine pH to alkaline levels. Oral intake
regrowth in 61% of cases after surgical of citrate has been suggested in order
therapy (LoE 3) [76] and in 65–78% after to prevent struvite crystal formation and
ESWL (LoE 3) [77–78]. aggregation by increasing urinary citrate
Antibiotics eliminate bacteriuria, but levels, although there has been a reluc-
the persistence of stones or residual frag- tance in relation to the potential increase
ments compromises the possibility of in urinary pH. Successful use of citrate as
eradicating the infection. The presence of a prophylactic agent for infection stones
persistent UTI increases the risk of stone has been described by some authors
recurrence. In patients with infected (LoE 1b) [80].
staghorn stones treated by Meretyk et al.,
stone recurrence was present in 33.3% of 7.9 Urease enzyme inhibitors
cases post-ESWL and in 22% after PCNL
Urease inhibition can limit the change in
(LoE 1a) [79].
urinary pH produced by urease-produc-
Complete eradication of the stones is a
ing bacteria. Urease enzyme inhibitors
pre-requisite for successful prophylaxis
such as acetohydroxamic acid have been
of infection calculi. Similarly, the pres-
developed (LoE 3) [81–83], but frequent
ence of concomitant obstruction of the
neurological, dermatological and haemo-
urinary tract should be addressed to pre-
tological side-effects have limited long-
vent persistence of infection and stone
term efficacy (LoE 1b) [84].
recurrence. Despite broad-spectrum anti-
Aceto-hydroxamic acid (AHA) causes a
biotic use, little success can be obtained
complete non-reversible, non-competitive
with eradication of infection and recur-
inhibition of the enzyme urease. Other
rent stone formation in the presence of
urease inhibitors are hydroxyurea, bio-
residual stones or urinary stasis due
suppressin (hydroxycarbamide), and furo-
to obstruction related to urinary tract
semide. Other enzyme inhibitors with
abnormalities.
fewer side-effects may be more useful in
Patients should be strictly followed up
the future.
for recurrent UTI and stone recurrence.
Urine specimens for bacteriological cul-
ture should be routinely collected and 8. FUTURE RESEARCH
imaging of the urinary tract should be
obtained at each follow-up visit. In case of In in order to expand further understand-
newly arising infections, antibiotic ther- ing, future research is required:
apy based on results of sensitivity testing • to find new methods of diagnosing and
should be given. Chronic low-dosage anti- quantifying biofilm infection
biotic suppression treatment for several
months has been recommended, but the • to develop new strategies of antibiotic
appropriateness of chronic treatment is treatment more effective against bac-
debated. teria in the biofilm mode (higher doses,
Alternative treatments have been longer duration of treatment, combina-
proposed, such as chronic urinary acidi- tion of antibiotics)
fication or alkalisation of urine with cit- • to gain an understanding of the uri-
rate. Chronic urinary acidification has nary components involved in biofilm
not yet been successfully demonstrated. formation and of the mechanism of
Ammonium chloride can be used only for interaction between stone surface and
short-term treatment, whereas ammo- bacteria in order to engineer alterna-
nium sulphate can be used over longer tive non-antibiotic treatments aiming
491
to interfere with microbial adherence gender of patients: a multivariate epi-

to stone surfaces demiological approach. Urol Res, 2004.
32(3): 241–7.
• to find new diagnostic tools to iden-
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8. Mariappan P and Loong CW, Midstream
The prevention and treatment of infec- urine culture and sensitivity test is a poor
tion associated with urinary stones still predictor of infected urine proximal to
remain unresolved problems. Our knowl- the obstructing ureteral stone or infected
edge of bacterial biofilms is limited, stones: a prospective clinical study. J Urol,
2004. 171(6 Pt 1): 2142–5.
making treatment difficult and often
unsatisfactory. For treatment and preven- 9. Mariappan P, Smith G, Bariol SV,
Moussa SA, and Tolley DA, Stone and
tion of infection stone recurrence, com-
pelvic urine culture and sensitivity are
plete stone clearance by endourological better than bladder urine as predictors of
or surgical procedures still remains cru- urosepsis following percutaneous neph-
cial in order to obtain complete bacterial rolithotomy: a prospective clinical study.
eradication. J Urol, 2005. 173(5): 1610–4.
10. Margel D, Ehrlich Y, Brown N, Lask D,
Livne PM, and Lifshitz DA, Clinical
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|8.4|
Epidemiology, diagnosis and

treatment of urinary tract
infections in patients with
spina bifida
Dan Wood1*, Christopher Woodhouse2
1
Consultant in Adolescent and Reconstructive Urology, University College London Hospitals.
2
Professor of Adolescent Urology, University College London Hospitals.
*Corresponding author: 1Mr Dan Wood PhD FRCS(Urol) Consultant in Adolescent and Reconstructive Urology, University
College London Hospitals.
ABSTRACT emphasised. The recognised complica-

tions of cystoplasty are discussed.
This section examines the aetiology, diag- There is little consensus about how to
nosis and treatment of urinary tract infec- manage asymptomatic bacteriuria and
tions (UTIs) in patients with spina bifida. little in the way of high level evidence
The incidence of spina bifida has decreased to guide strategies for prophylaxis. This
due to preconception administration of chapter aims to explain the potential
folic acid and in some cases termination application of recognised strategies as
of affected pregnancies. Aggressive early well as describing those that are less well
management offers improved renal and established in clinical practice.
continence outcomes. Advanced reinnerva- Key words: myelomeningocele, spina
tion strategies may offer further hope for bifida, urinary tract infection, sepsis,
an improved functional quality of life for cystoplasty
affected children.
The correct diagnosis of UTIs is impor-
tant in management of these patients, SUMMARY OF RECOMMENDATIONS
particularly those who have been previ-
ously augmented. The importance of cor- 1. There is no indication for antibiotic
relating symptoms and investigations is prophylaxis in patients who are
asymptomatic, have no vesico-ureteric those affected. However, improvements

reflux and are able to self-catheterise are relative - with a survival at 35 years
(GoR B). of 50%. This has lead to greater empha-
2. In patients suffering with UTIs anti- sis on secondary problems such as those
biotic prophylaxis strategies should within the urinary system.
be discussed as an optional treatment If one could establish efficient, normal
(GoR C). voiding, all secondary urological manifes-
tations would be eliminated – including
3. Intravesical hyaluronic acid may UTI. The work of some groups in correct-
offer some benefit in recurrent UTIs ing the anatomical deformity in utero
(GoR C). has shown some promise in dramati-
4. We can make no recommendation cally reducing neuromotor defects [5].
regarding perineal treatments, or Carr’s 2007 review was extended with
alternatives such as acupuncture or further data at the American Academy
cranberry juice (GoR C). of Paediatrics 2008. Early data suggest
normal voiding behaviour in infants and
early childhood – the long-term success
1. INTRODUCTION of this treatment will take years to fully
understand.
Spina bifida and its association with dam- Questions remain about the residual
age to the urinary tract create a lifelong neural dysplasia despite ‘anatomical’ clo-
management problem for both physicians sure. In functional terms the long-term
and patients. Worldwide incidence of safety of the upper tracts will need careful
spina bifida is 0.3–4.5 per 1000 live births. evaluation in order to accept such work
In the last 60 years the medical profes- as the progress that it may represent.
sion has moved between extremes. Sixty The potential for re-innervation by anas-
years ago before the description [1] and tomosing somatic with autonomic nerves
popularisation of the ileal conduit [2] [6] (LoE 3) and restoring voiding through
or the use of clean intermittent self- subsequent neurostimulation (a thigh
catheterisation (CISC) [3–4] the outcome scratch) also offers hope for the future.
following a diagnosis of spina bifida in a
newborn infant was nearly always fatal.
Many would succumb to overwhelming 2. METHODS
infection or progressive hydrocephalus
and death in early childhood. The most up to date and relevant refer-
Modern medicine has seen a dramatic ences were identified using the keywords:
fall in the number of live births with myelomeningocele, spina bifida, urinary
spina bifida – for two reasons: tract infection, sepsis, and cystoplasty with
the following limitations: peer reviewed
1. The introduction of pre-conception publications (abstract only publications
folic acid supplements for planned were excluded) and English language
pregnancies. papers were included and a manual review
2. Improvements in antenatal diagnosis of references was performed. This identified
and subsequent termination. 357 papers. These were reviewed by title
and abstract, leaving a total of 47 papers
Better understanding and manage- for analysis as described. A level of evi-
ment of spina bifida, such as early clo- dence (LoE) was ascribed to each and key
sure of the lesion and shunting, has lead points were distilled. Recommendations
to increased survival and a reduction in were focused and chosen with relevance to
physical and intellectual problems of the remit of the chapter.
498
Epidemiology, diagnosis and treatment of urinary | 8.4 |
The studies were rated according to the been closed. Data have suggested it is
level of evidence (LoE) and the grade of important to distinguish between asymp-
recommendation (GoR) using ICUD tomatic bacteriuria in the absence of
standards (for details see Preface) [7–8]. reflux, bacteriuria with reflux and those
suffering with periodic and systemic bac-
terial UTI (LoE 4) [12].
3. EARLY MANAGEMENT The literature indicates that there is
no indication for antibiotic prophylaxis
The major priorities in the first phase of in bacteriuric patients who are asympto-
management are the reduction of risk to matic, do not have vesico-ureteric reflux,
the upper tracts and protection against and are on self-catheterisation (LoE 3).
infection. In those patients who have an
acontractile pelvic floor and are there-
fore incontinent the upper tracts are safe. 4. CONSEQUENCES OF
Closure of the lesion may lead to conver- AUGMENTATION
sion to an overactive pelvic floor within
2–3 months[9] (LoE 4) creating detrusor The indications to augment the blad-
sphincter dyssynergia and consequently der in a neuropathic bladder may have
high bladder pressures. Hence it is sen- changed slightly with the evidence to
sible not to evaluate the urodynamics support the use of botulinum toxin A in
until this has had a chance to develop. paediatric patients. Data from short-term
Thus many patients have an aggressive cohort studies suggest a 65–73% improve-
early regime to include an anticholiner- ment in continence and improvements
gic, self-catheterisation and antibiotic in bladder capacity of 59% and a signifi-
prophylaxis. cant reduction in mean detrusor pressure
It has been argued that maximal (LoE 3) [13–14].
treatment of all patients will be over- It remains common practice to aug-
treatment for many (LoE 4)[10]. However, ment the bladder of neurogenic patients
there is evidence that aggressive manage- for two major indications:
ment yields high success – 92% kidneys
1. Incontinence
with normal imaging and 77% continence
rate (LoE 3) [9, 11]. The acknowledged 2. Protection of the upper tracts
predictability of a call for a randomised
controlled trial becomes important in The controversies over who, how and
establishing the correct balance for these when patients should be augmented are
complex patients. well rehearsed but beyond the scope of
It is reflex behaviour for paediatric this chapter. It may be that we shall see
urologists to prescribe antibiotic prophy- less augmentation over coming years,
laxis for all spina bifida patients. There is as selection criteria are refined (LoE 3)
little scientific evidence for this – however [15]. It can be a successful treatment on
it is regarded as safe practice to give its own (LoE 4) [16]. However, it remains
2 mg/kg trimethoprim antibiotic prophy- a major decision to augment a bladder –
laxis. The major objective is to prevent the consequences are discussed below.
renal scarring secondary to reflux and
infection. This is an important distinc- 4.1 Perforation
tion. All patients with neuropathic void- In their review Greenwell et al. show a
ing dysfunction at this age will enter a number of series with a range of perfora-
programme of self-catheterisation, prob- tion from 0–9% (LoE 3) [17]. This is the
ably with anticholinergic medication to most dangerous of all complications with
be initiated once the spinal lesion has a mortality of up to 25% (LoE 3) [18–20].
499
4.2 Stones arises as a result of absorption of ammo-

The rate of stone formation following aug- nia and net loss of bicarbonate. It proba-
mentation varies between urethral and bly has no direct association with UTI or
Mitrofanoff drainage, from 8% for ure- stone formation.
thral drainage to 21–100% for Mitrofanoff
drainage (LoE 3) [21–25]. Other series 4.4 Malignant change
have suggested little difference between Opinions vary widely over the need for
the two (6% vs 10%) respectively. Hamid surveillance of patients with cystoplasty.
et al. demonstrated that urinary citrate The majority of centres appear to agree
and 24 hour urine volumes were both sig- on the need for follow-up in neuropathic
nificantly lower (173% and 41%) respec- and other higher risk groups. It is true
tively in those patients who formed that in patients with bacteriuria there
stone [26]. Stone formers also had signifi- are higher N-nitrosamine levels. This
cantly higher urinary calcium excretion does not prove an association but may
(5.2 vs 2.78 mmol/l) – these factors cor- suggest a possible link (LoE 3) [27].
related with a significantly higher risk of
both calcium oxalate and calcium phos-
phate stone formation in the stone form-
5. PREGNANCY
ing group (LoE 3) [26].
Whilst many authors have speculated
that UTI may be causative in stone for- There are very few data relating to the
mation, it appears that urinary stasis is a care of patients with neuropathic blad-
positive risk factor and bladder irrigation ders, reconstruction and pregnancy.
protocols may reduce risk. Patients with Two series have sought to examine this
stones may present with an increased within the last few years (LoE 4) [22, 28].
incidence of UTI with organisms such Pregnancy must be established using a
as Proteus mirabilis [22] (LoE 2b) or a serum hCG test as the urine test gives a
change in continence. There is little evi- 57% rate of false positive diagnosis (LoE
dence to support a direct link between 2b) [27].
bacteriuria or urinary sepsis and stone These patients need to be carefully
formation. With this evidence in mind it monitored and shared care is impor-
is clear that a diagnosis of either upper tant through their pregnancy. The inci-
tract or reservoir stones must be consid- dence of UTI ranges from 53% to 91% in
ered in patients with enterocystoplasties pregnancy[28–30]. Therefore, they should
who present with a change in symptoms, be on antibiotic prophylaxis (LoE 3). In
particularly an increase in UTIs. those who have had ileal conduits an
The most important method of pre- expanding uterus may compress the con-
venting stone formation is probably to duit, affecting emptying and therefore
increase daily fluid intake [26] (LoE 3). increasing the risk of UTIs. In those that
Bladder irrigation is also an important have ureteric rerouting the possibility of
means of achieving this [22] (LoE 2b). extrinsic compression by the uterus and
Other strategies may also be helpful – therefore hydronephrosis needs to be
including the addition of potassium considered.
citrate. Some expectant mothers with Mitrofanoff
channels will run into difficulty with cath-
eterisation and emptying as their preg-
4.3 Metabolic changes
nancy progresses. As this may represent an
All patients with enterocystoplasty will additional risk for UTIs some will need an
have a degree of metabolic acidosis – indwelling catheter during their pregnancy.
for the majority this is subclinical. This This can be removed following delivery
500
and a normal CISC regime re-established then be possible to avoid unnecessary anti-
(LoE 4). biotics for some and institute one of the
following schemes of treatment for others.
6. DEFINITION OF UTI WITH AN

AUGMENTED BLADDER 6.1 Management of UTIs
Any patient presenting with recurrent
There is an unfortunate tendency for UTIs to a urology clinic can appear as a
patients and family doctors to ascribe a frustrating and clinically difficult prob-
wide range of symptoms to UTI, including lem to treat.
smelly urine, malaise, increased mucus The first priority must be to establish
production and back pain. All of these a definition and diagnosis. Treatment
have other possible causes and are com- should be reserved for patients who
mon in those with augmented bladders. present with symptomatic UTIs.
However, once the idea takes root that There is little clear consensus as to the
UTI is the cause, courses of antibiotics are management and follow-up of asympto-
requested by the patient and prescribed matic bacteriuria. In patients with neuro-
by the doctor with little further thought. pathic bladders who are self-catheterising
Correlation of the symptoms with the 76.8% have been demonstrated to have
investigative findings is as important bacteriuria, with E. coli being the most
as in any other clinical situation, even common bacterial pathogen identified
though it may be difficult. (70%) (LoE 3) [31].
The history may be sufficient to exclude A survey of urological clinics suggested
infection as a cause – UTI does not give follow-up with surveillance ultrasound
intermittent symptoms and generally and urinalysis in 59% and urine culture
they persist unless treated. Fever is a in 49%. Only 14% suggested that they
common accompaniment. The smell of would perform baseline radio-isotope
urine from an augmented bladder is often evaluation of the kidneys. The authors
pungent. The subjective view of mucus of this survey go on to suggest that age,
by a patient is very unreliable, especially grade of vesico-ureteric reflux and abnor-
when there is no comparator other than mal renal function do not appear to affect
personal experience. Furthermore, mucus treatment decisions. Most would wait
will appear to be increased when urine is until a symptomatic presentation before
concentrated. beginning treatment. In the presence of
Stick tests for ‘infection’ are commonly fever 69% of clinics would begin empiri-
positive as white cells and nitrites may cal antibiotic treatment, 64% would treat
only be measures of inflammation or of with flank pain (LoE 4) [32].
insignificant bacteriuria. Bacteria do not It is clear that patients need to be
carry enough protein to make a stick test watched closely since renal deterioration
positive – the presence of protein is not is seen in 18% and 30% before and after
an indicator of infection. puberty, respectively, without diversion
It is essential that the symptoms are (LoE 4) [33]. In those who have under-
correlated with urine culture. In doubtful gone cystoplasty and long term follow-up
cases it may be necessary to culture the around 20% will show deterioration in
urine monthly and compare the results renal function. It seems unlikely that renal
with a symptom diary. It is, in the long deterioration can be attributed solely to
term, a worthwhile, though often difficult, cystoplasty. Therefore the management of
exercise to establish the pattern of symp- other factors including infection becomes
toms that are indicative of significant increasingly important (alongside stones
infection for an individual patient. It will and non-compliance) (LoE 3) [34].
501
7. AVOIDING INFECTION 7.1 Prophylaxis strategies

Many patients develop an established
The first principle with all those who pattern of proven UTIs. They can be dis-
have spina bifida should be to avoid infec- tressing and uncomfortable for patients.
tion where possible – where achievable For those with ventricular shunts sys-
this is a major victory. It is also vital to temic sepsis carries the risk of shunt
have an overview of the whole patient. and CNS infection. There is little evi-
This will include factors such as bowel dence to support any significant change
management. Faecal incontinence or con- in management. However, in a report of
stipation may create major difficulties 3 patients who had UTIs all were shown
with the control of UTIs. In patients who to have temporary dysfunction of their
do not respond to laxatives, the MACE shunt that settled with treatment of the
procedure can be used to improve con- underlying UTI. There was no evidence of
tinence (LoE 3) [35]. The association shunt infection in any case. The authors
between poor bowel function and UTIs is of this small case series emphasised the
well established and should be rigorously need for close monitoring of patients in
applied in this group. this situation (LoE 4) [39].
The need to establish regular and Therefore management needs to cen-
complete bladder emptying has already tre on the degree and regularity of the
been discussed and is important in infection. Depending on the antibiotic
these patients for a number of reasons. used, they may reduce the bacterial load
Community based studies have looked at either directly within the urine or indi-
colonisation with resistant organisms – rectly within the gut, perineum or vagina
there was a lower level of colonisation (LoE 3) [40]. The strategies that can be
in those who were continent and self- adopted are the same as those used for
catheterising (LoE 3) [36]. other patients with UTIs.
Recent data have suggested that this
may be of fundamental importance. A study
7.1.1 Expectant treatment on the
from Game et al. suggests that in those neu- basis of symptoms and confirmed
rogenic patients who show a urodynamic microbiology
response to Botox A there is a significant
reduction in the number of UTIs. In this This involves a patient awaiting symptoms
study, prior to injection the mean number of of a UTI and presenting to a physician for
symptomatic UTIs over 6 months was 1.75 urinary culture and antibiotics – these
± 1.87. After injection, the mean was 0.2 ± may be empirical initially and subse-
0.41 (p=0.003) (LoE 3) [37]. quently adjusted, as necessary, on the
Editorial comment on the paper basis of microbiological cultures.
acknowledged that detailed information
had been collected on the patients and 7.1.2 Off the shelf treatment for
the differences appeared to be significant. patients with an established
This is an original finding. However, it pattern of infection who are
was a small group and the findings could able to recognise their own
not be widely accepted or used as jus- symptoms
tification to standardize this as a form This enables patients to take their own
of treatment for this effect in isolation urine sample at home and initiate treat-
(LoE 4) [38]. Since UTI is a common phe- ment immediately – without the need
nomenon in these patients and many are to wait and see a doctor before doing so.
now undergoing Botox injections as a This is useful in patients for whom an
treatment for bladder dysfunction, it may established infection may result in either
be a fortuitous bystander effect. prolonged treatment or severe sepsis and
502
hospital admission for treatment. The prophylactically colonised patients’ blad-

more applied version of this relates to the ders with Escherichia coli 83972 – they
use of antibiotics around the time of trig- found a reduction from 3.1 symptomatic
gers such as intercourse. infections per year to 0 infections over
18.4 patient years (LoE 3) [45]. Hyaluronic
7.1.3 Low dose daily antibiotic acid may be applicable in patients with
strategies difficult to treat recurrent UTIs.
Low dose daily antibiotic strategies are
employed in many patients and they 7.3 Perineal treatments
have a well established track record and Zarate et al. have suggested that the
evidence basis with a significant reduc- use of Lactobacillus paracasei CRL1289
tion in comparison with placebo (LoE 2) (a human vaginal strain) in pessary
[41]. These can be used in cutting down form may be a means of reducing recur-
the number of infections but they do not rent UTIs. This was tested in a murine
prevent all. Some patients suffer with model (LoE 4) [46]. A phase 1 trial
breakthrough infections which need to be using Lactobacillus crispatus has sug-
managed with urine culture and appropri- gested that this may be safe treatment
ate treatment. Some will develop resist- in humans but there are no data to sup-
ant infection and therefore need to change port the suggestion that it may clinically
their form of prophylaxis. In undertaking affect the number of UTIs (LoE 1) [47].
this strategy caution needs to be exercised We make no recommendation for the use
in the use of nitrofurantoin. The risks of of these treatments.
pulmonary and hepatic dysfunction are
numerically small but they exist and fol-
lowing recent successful litigation in the 8. ALTERNATIVE TREATMENTS
UK, patients should certainly be warned
of this potential (LoE 4) [42]. The creation of vaccines for the treatment
There is no evidence that one of the of recurrent UTIs in young women may
strategies is better than another and create hope for groups of patients such
their usage will come down to a combina- as those with significant reductions in
tion of physician and patient preference E. coli infections seen in a phase two trial
or motivation. It is our recommendation of vaginal mucosal vaccine (LoE 1) [48].
that these treatment decisions be dis- Acupuncture has been ventured as an
cussed with the parents/patient and the alternative treatment and when com-
strategy is adapted as best as possible pared to sham and control groups a
to the individual. There is little evidence Scandinavian trial suggested a signifi-
to support this but it is widely accepted cant effect (LoE 1) [49].
practice. Whilst many people have talked about
the use of cranberry juice in preventing
7.2 Intravesical treatments UTIs, when its effect on bacteriuria was
assessed there was no significant effect
Hyaluronic acid (Cystistat) has been (LoE 3) [50]. We make no recommenda-
shown to reduce infections by 85% when tion for the use of these treatments.
given in a protocol once per week for
4 weeks and then once per month for
5 months (LoE 3) [43]. Murine studies 9. Future research
have suggested that intraurethral instil-
lation of Lactobacillus casei is a potent The outcome of phase II trials with
treatment for UTI [44]. In a trial with Lactobacillus is currently awaited and
spinal cord injured patients Hull et al. will be important in establishing efficacy
503
as well as safety. Vaccine research may of a somatic-autonomic reflex pathway

also offer opportunities to improve man- procedure for patients with spinal cord
agement for patients with recurrent injury or spina bifida. Eur Urol, 2006.
UTIs, which may be applicable to spina 49(1): 22–8; discussion 28–9.
bifida patients. It would be desirable, but 7. Abrams P, Khoury S, and Grant A,
remains unlikely that resources would be Evidence – based medicine overview of the
available to support credible trials of dif- main steps for developing and grading
ferent prophylaxis strategies.
2007. 17(3): 681–4.
10. CONCLUSIONS
115–127.
Our treatment recommendations are 9. de Jong TP, Chrzan R, Klijn AJ, and
based around aggressive early treatment Dik P, Treatment of the neurogenic
with CISC, anticholinergic treatment bladder in spina bifida. Pediatr Nephrol,
and antibiotic prophylaxis. Urodynamic 2008. 23(6): 889–96.
assessment of the bladder will differen- 10. Woodhouse CR, Progress in the manage-
tiate the type of neurogenic dysfunction ment of children born with spina bifida.
and will dictate the management course. Eur Urol, 2006. 49(5): 777–8.
Preservation of renal function remains 11. Dik P, Klijn AJ, van Gool JD, de Jong-de
the priority. Some patients will still Vos van Steenwijk CC, and de Jong TP,
require augmentation but with increas- Early start to therapy preserves kidney
ing options this need may reduce. For function in spina bifida patients. Eur
UTIs treatment is largely on the basis Urol, 2006. 49(5): 908–13.
of symptoms when the bladder has been 12. Ottolini MC, Shaer CM, Rushton HG,
augmented. For those with recurrent or Majd M, Gonzales EC, and Patel KM,
persistent infection prophylactic strate- Relationship of asymptomatic bacteriu-
ria and renal scarring in children with
gies are often necessary.
neuropathic bladders who are practic-
ing clean intermittent catheterization.
J Pediatr, 1995. 127(3): 368–72.
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506
|8.5|
Urinary tract infections in patients

with neurogenic bladder
James Salerno*, Diana D. Cardenas
University of Miami, Miami, Florida,
Corresponding author: James Salerno, MD,
*University of Miami Leonard M. Miller School of Medicine, Department of Rehabilitation Medicine, 1611 NW 12
Avenue, Bantle Rehabilitation Center, Basement, Room L105, Miami, FL 33136, (305) 585-1431 (o), (303) 585-1340 (f),
jsalerno@med.miami.edu
ABSTRACT than an indwelling catheter, to reduce

rates of UTI (GoR A).
Proper management of urinary tract infec- 3. Diagnosis of UTI should be supported
tion (UTI) in the neurogenic bladder popu- by appropriate laboratory data includ-
lation involves a comprehensive approach. ing urinalysis and urine culture, as
This includes preventive measures coupled symptoms may not coincide with
with management of the underlying dys- actual infection (GoR A).
function. Understanding the dysfunction
4. Antimicrobial prophylaxis should not
and choosing the optimal management
be used in catheterized patients due to
technique, which varies from patient to
risk of antimicrobial resistance (GoR A).
patient, are vital. If an infection develops,
one should use a recommended regimen 5. Treat UTI with appropriate antimicro-
guided by laboratory data. bial regimen for seven days initially,
and for fourteen days if response is
Key words: Neurogenic bladder, urinary delayed (GoR A).
tract infection
1. INTRODUCTION
SUMMARY OF RECOMMENDATIONS Traumatic spinal cord and brain inju-
ries, strokes, cauda equina lesions and
1. Ensure bladder volumes do not exceed other diseases such as multiple sclerosis
500 mL (GoR A). are established risk factors for the devel-
2. Clean intermittent catheterization opment of neurogenic bladder [1]. While
should be used, when possible, rather the location and severity of the injury
determine the degree and duration of the 3. ETIOLOGY

dysfunction, nearly all of these patients
will experience bladder dysfunction with The various etiologies of a neurogenic
its resulting increased risk of urinary bladder are worth exploring in an effort
tract infections (UTIs). to help differentiate specific disease types
Due to improved techniques for man- to guide overall treatment and discuss
aging acute injuries at times of trauma prognosis with a patient. Prior to a brief
as well as increasing age of the overall explanation of some of these etiologies,
population, the prevalence of neurogenic discussion of the general classification of
bladder has increased [1]. A concurrent upper motor versus lower motor neuro-
increase in UTIs has also been seen. genic bladder is worthwhile.
Overall prevalence in Europe has been An upper motor neuron neurogenic
stated as 15.6% of men and 17.4% of bladder typically results from disrup-
women. In Asia, women make up 53.1% tion of the sensory and motor bladder
of those with neurogenic bladder. In the pathways in the spinal cord above the
United States, the prevalence has been sacral segments. This will usually result
estimated at 16% for men and 16.9% for in detrusor overactivity. The majority of
women [2]. Incidence of UTIs in patients these patients will also experience dys-
with spinal cord injuries has been stated synergy of bladder function (concurrent
at 2.5 episodes per patient per year [3–4]. contraction of the sphincter and detru-
sor). Injuries involving sacral segments
can result in detrusor denervation and
2. METHODS an areflexic bladder. While catheteriza-
tion is used in both conditions, medica-
In examining the data on this subject, tions to reduce detrusor hyperactivity
PubMed was initially searched. A search can be useful in the upper motor neuron
on Google Scholar was also performed. patient.
The key words “neurogenic”, “bladder”, Spinal cord injuries are commonly
and “urinary tract infection” were placed related to traumatic events. However,
into the search bar in different combina-
tions. All publications with a pertinent
title and available abstract were exam-
ined. No year or language restriction
was made, as long as an English trans- Pontine micturition
Supraspinal
lation was available. This produced 307 center
results on PubMed and approximately
7,500 results on Google Scholar. The
list of abstracts was filtered after read-
ing them, based on pertinence to the Suprasacral
chapter. In total, 72 papers were then
obtained and examined. Appropriate
ones were included. Other research
known to the authors from experience
was also included. The pertinent infor- Conal S2, 3 and 4
mation from Braddom’s textbook was

also examined. Infrasacral Autonomic
neuropathy
level of evidence (LoE) and the grade of Cauda equinal
recommendation (GoR) using ICUD Pelvic
standards (for details see Preface) [5–6]. Figure 1.
508
Urinary tract infections in patients | 8.5 |
a spinal cord injury can also be due to population [14]. This has been supported
Schistosomiasis mansoni infection, which by evidence that restoring the normal
is an endemic fluke in South America, low-pressure reservoir function of the
the Caribbean, and Africa. Infection of bladder aids the prevention of UTI in
the spinal cord, such as acute transverse those with neurogenic bladder [15].
myelitis, is a well-recognized complica- As a complication of UTI, certain
tion [7]. Along the line of acute transverse patients with neurogenic bladders, such
myelitis, Human T-Lymphotrophic Virus as those with multiple sclerosis, can
Type I (HTLV-I) as a causal organism is experience a decline in neurologic func-
also documented [8]. tion [16].
Of the subset of patients with spinal
cord injury, patients with black ethnic-
ity, poor personal hygiene, and less-than- 4. MICROBIAL ORGANISMS
daily condom catheter changes have an
increased incidence of UTI, as do those While a patient with neurogenic bladder
with complete functional dependence can suffer UTI due to the same organ-
and vesicoureteral reflux [3–4]. However, isms as any other patient, the specific
bladder drainage method, age, years since incidence varies [15]. Posted rates are:
injury, income, education, sex, neurologic Escherichia coli 60% to 65%, Proteus
level, and administration of prophylactic mirabilis 14%, Klebsiella pneumoniae
antibiotics are reportedly not correlated 10%, Staphylococcus species 4%, and then
with increased risk of UTI [3]. other enterobacteria [17–18]. Variation
Of note, it has been revealed that spi- between men and women has also been
nal cord injury patients possess the same reported with the predominant organ-
neutrophil phagocytic and opsonic activity ism in women being E. coli and in men,
as those without injury [9]. Therefore, the Gram-positive cocci [19].
data suggest that the bladder dysfunction Of note, it has been identified that E. coli
with compensatory catheterization is the colonization does not confer an increased
etiology of the increased incidence of UTI risk of symptomatic disease or deterio-
in this population. The inability to clear ration of the upper urinary tract [20].
urine from the bladder creates a medium However, certain E. coli clones did confer
for the growth of bacteria. Furthermore, an increased risk of colonization [20].
factors common to the neurogenic blad-
der population such as outlet obstruction,
high pressure voiding, and the presence 5. MANAGEMENT
of stones in the urinary tract are gener-
ally accepted risk factors for UTI. Clean intermittent catheterization (CIC)
Other causes of neurogenic bladder is a preferred method for managing neu-
include chronic 3,4-methylenedioxymeth- rogenic bladder in many patients. The
amphetamine (MDMA) use [10]. Post- ability for a patient and/or family to per-
partum patients are subject to transient form the procedure is typically what pre-
urinary retention [11]. Aseptic and Listeria cludes use of this technique. Data support
meningitis have also been reported to it as an excellent procedure for minimiz-
result in neurogenic bladder [12–13]. ing urinary tract complications, which
Overall, the importance of a neurogenic include UTI [19]. The volumes to target
bladder in the development of UTI has are less than a maximum of 500mL [21–
been documented. The risk of UTI has 22]. Volumes less than 100mL generally
been reported to increase when only 2 or do not require CIC [21].
more ultrasound PVR readings are more Indwelling catheters are also used in
than 150mL in the stroke rehabilitation patients with neurogenic bladders to
509
reduce bladder volumes. These are used examination to verify effective emptying
in the acute patients to closely monitor of the bladder is necessary to lower the
fluid balances. Patients with chronic inju- risk of UTI [30].
ries who cannot perform CIC, due to poor Animal studies have started to point
skills, difficulty with fluid management, towards the use of a micturition alert
failure of other methods, and limited device to compensate for a neurogenic
assistance may require use of an indwell- bladder [31]. These data suggested such a
ing catheter as well [22]. device may be able to reduce bladder vol-
Regarding the method of indwelling umes, reducing the risk of UTI [15].
catheterization used, suprapubic cath- Use of cranberry extract tablets in
eterization has lower rates of UTI when reducing the rate of UTIs remains con-
compared to urethral catheterization in troversial. Some data did not show a
select populations [23]. However, urethral benefit to its use [32–33]. However, it has
catheterization and suprapubic catheteri- been suggested that cranberry extract
zation are both felt to be superior to other tablets may be beneficial, especially in
forms of urinary management, excluding patients with a higher glomerular filtra-
CIC, especially compared to using vari- tion rate (GFR) [34]. Similar conflicting
ous methods at different times [24]. This data surround the use of methenamine.
includes, but is not limited to, the use of Evidence revealed methenamine can
condom bag systems, diapers, and manu- reduce the rate of UTIs for the inpatient
ally increasing bladder pressure. population [35]. This does not necessar-
Adoption of a closed catheter system ily hold true for the outpatient popula-
has been shown to reduce the rate of UTI tion [32].
[25]. This has included the addition of a Initial data were also not definitive
urine sampling port in the drainage tub- regarding use of antibiotic prophylaxis
ing and the use of a preconnected cathe- [36]. Recent data have revealed that use
ter/collecting tube system [26–27]. of a weekly oral cyclic antibiotic pro-
Evaluation of sterile versus nonsterile gram decreased the rate of symptomatic
(or clean) urethral catheterization in an UTIs from 9.4 per patient-year with 197
observational study revealed a significant episodes of febrile UTIs and 45 hospi-
cost variance. The rate of UTI was higher talizations to 1.8 per patient-year with
in the nonsterile group (28.6% compared 19 episodes of febrile UTIs [37]. Also, a
to 42.4%) with an increased cost due to weekly regimen did not result in any new
antibiotic use at 43%. The increased base cases of multi-drug resistant bacteria dur-
cost of the sterile kits was 371% coming the two year follow-up in this study
pared to the nonsterile kits. The authors [37]. However, it has been established
estimated the overall increased cost of that antibiotic prophylaxis does result in
the sterile kits was 277% compared to resistance in the general population, as
nonsterile, after factoring in antibiotic well as those with neurogenic bladders
related costs [18]. [38]. Also, it has been shown that a sup-
Hydrophilic-coated catheters have been pressive antibiotic regimen does not pre-
shown to decrease the rate of UTI from vent clinical UTI [39–41].
82% to 64% over a 12 month period [28]. Conversely, inoculation with nonpatho-
Use of silver hydrogel urinary (SHU) genic Escherichia coli 83972 in patients
catheters has been recently explored. with a neurogenic bladder improved UTI
Preliminary data suggest a positive effect rates. The inoculated patients experi-
of using SHU in prevention of UTI [29]. enced a 63-fold decrease in UTI rates
Condom catheters have also been used during colonization versus a prestudy
in patients who can reflex void or at period of the same subjects and a 33-fold
least micturate to some degree. However, decrease when compared to a population
510
not successfully colonized [42]. This was performed with a lack of response
method of control has also been demon- in either bladder or bowel pres-
strated to be safe [42–43]. sure indicating an irreversible blad-
der myopathy [46]. If no response, the
patient would be ruled out as a candi-
6. MODULATING THE UNDERLYING date. A successful response suggested
DYSFUNCTION that the patient may respond to sacral
neurostimulation.
In an effort to improve rates of UTI and Surgeons have also tried to recon-
overall prognosis, new techniques have struct the reflex pathway by anastomos-
been developed to return the patient to as ing the spinal roots. This was performed
close to normal function as possible. This in patients with history of a traumatic
has been approximated by modulating lesion of the conus medullaris. Functional
risk factors common to patients with neu- T11 ventral roots, being above the lesion,
rogenic bladder. were transected and anastomosed to
To aid in the micturition process, pos- S2 ventral roots unilaterally by use of
terior tibial nerve stimulation has been a nerve graft. The T11 dorsal root was
implemented with significant improve- left intact as the trigger for micturition
ment in volume reached prior to invol- after axonal regeneration. Overall, 70%
untary voiding and mean maximum of patients reported satisfactory bladder
capacity [44]. control within 18–24 months. This 70%
Anterior root stimulation, placed intra- did not experience any UTI during the
durally, coupled with sacral deafferen- follow-up period [47].
tation resulted in a decline in UTI rate Bladder augmentation can also aid
from 6.3 per year to 1.2 per year [45]. The those patients with bladder dysfunc-
procedure helped to restore the reservoir tion due to intractable involuntary blad-
function of the bladder and achieve con- der contractions causing incontinence.
tinence, known to decrease UTI rates [15, The bladder is opened widely and then
45]. Autonomic dysreflexia was reported a section of bowel is added to increase
to have nearly disappeared in most cases the capacity and reduce pressure. This
and accurate adjustment could result in is used in conjunction with intermit-
low resistance micturition [45]. tent catheterization programs, typi-
In an effort to assess in which patient cally through a stoma in the abdominal
sacral stimulation would be effective, a wall [22]. In this population, pyuria
detrusor contractility test was devised. and bladder stones are common, but
Electrostimulation of the sacral nerves symptomatic infections rare. Also, an
increased risk of bladder cancer has
been reported, but a causal relation-
Table 1 ship has not yet been determined [22].
Of note, patients who undergo this pro-
Generally accepted risk factors cedure must be compliant with CIC to
Over-distention of bladder avoid overdistention.
Vesicoureteral reflux
In male patients with detrusor-exter-
nal sphincter dyssynergia, sphincterot-
High pressure voiding omy can be performed to permit effective
Large post-void residuals bladder drainage resulting in lower blad-
der volumes, thereby reducing UTI rates
Presence of stones in urinary tract
[22]. A mesh wallstent has been shown
Outlet obstruction (detrusor-sphincter dyssynergia, to be an acceptable long-term alterna-
enlarged prostate)
tive to sphincterotomy with similar
511
low bladder volumes and no significant is taken. However, it has been shown
interference with erectile function [48]. that patients with a spinal cord injury
However, stents should be avoided in are not accurate in predicting when they
patients who cannot manage a condom have a UTI based entirely on symptoms
catheter, have urethral abnormalities, [1, 57–58]. In an effort to further assess
and are female [22]. for UTI, laboratory data are used. In a
Recently, botulinum toxin serotype A spinal cord injury patient who complains
(BoNT-A) has been investigated to treat of typical UTI symptoms, lack of pyuria
neurogenic detrusor overactivity. Data reasonably predicts the absence of UTI
support its use in spinal cord injuries [57, 59].
and multiple sclerosis where there is Furthermore, while the symptoms of
reported efficacy and improved quality a typical UTI may not correlate with an
of life [49–52]. However, its use in neu- actual infection in this population, the
rogenic detrusor overactivity for patients complaints themselves may represent
with stroke damage, Parkinson’s disease, psychological distress related to the use
and other central disorders has not been of CIC [60]. Patients with spinal cord
fully delineated. Also, the available data injury due to HLTV-1 infection are par-
are limited, with the optimal dose not yet ticularly prone to having urinary symp-
proven [51]. tomatology without the presence of a true
Capsaicin and resiniferatoxin have UTI [8].
also been examined. Studies have overall In treating patients with UTI, exam-
pointed to capsaicin as generally supe- ining precipitating antibodies against
rior to placebo, with 3.8 less episodes of urinary tract pathogens (PAU) may be
urinary incontinence over 30 days [50]. an indicator of need for more aggressive
Resiniferatoxin was felt to be comparable treatments [61]. While this practice is not
to capsaicin [50] and effective in refrac- standard, it may represent an area for
tory patients [53–54]. future research. Also, it may have clinical
Tolterodine 2mg taken twice a day utility in the future.
has been shown to improve catheteriza- In determining which patients do have
tion volumes and reduce incontinence a UTI, urine culture, urine analysis, and
when compared to placebo [55]. Also, plasma white blood cell counts are reli-
this dosing of tolterodine has a reduced able tests [62]. The presence of pyuria is
side-effect profile when compared to oxy- significantly associated with fever and
butynin [55]. chills [3]. Of note, Gram-negative bac-
As a result of the neurogenic bladder teria are relatively more pyogenic than
and related repetitive infections, the uri- Gram-positive bacteria [3].
nary tract itself can become mechanically
disturbed. This pathology is represented
by erosions, strictures, diverticula, ure- 8. TREATMENT
throcutaneous fistulas, or combinations of
these processes. Surgical reconstruction The effective treatment of UTI is para-
in patients with neurogenic bladders can mount to minimize long term complica-
improve functional outcomes with limited tions. While use of urine cultures is vital
morbidity [56]. to directing antibiotic therapy, initial
treatment is still based on treatment
protocols.
7. ASSESSMENT Current guidelines recommend three
days of trimethoprim/sulfamethoxazole
In an effort to delineate which patients as a first line agent in treating UTI.
have UTI, a history of presenting illness Second line agents include three days
512
of a quinolone or seven days of nitro- for future research. Re-establishing

furantoin, amoxicillin, or a first genera- proper bladder function may lead to a
tion cephalosporin [26]. However, these reduction in UTI rates. Also, research
guidelines are for uncomplicated UTIs, into the relationship between asympto-
and the presence of a neurogenic bladder matic bacteriuria and UTI is required.
complicates the diagnosis. Further development of a first line as well
For the neurogenic bladder popula- as definitive antibiotic regimen, including
tion, initial consideration can be made agent and length of treatment, represents
to utilize trimethoprim/sulfamethoxazole another avenue open to investigators.
or quinolone therapy at longer courses
of treatment. Some sources recommend
courses of seven to fourteen days, depend- 10. CONCLUSIONS
ing on the clinical picture [63]. Courses
of treatment longer than twenty-eight While the etiology of a neurogenic blad-
days have been shown to increase resist- der and its management vary, UTI is a
ance without improving clinical outcomes common complication in this population.
[64]. If the patient has been recently Use of proven techniques as well as inves-
discharged from a long term care facil- tigation into promising data are vital to
ity, is severely ill, or received quinolones successful treatment of this condition,
recently, consideration should be given to thereby reducing UTI rates. When UTI
using cefepime, ceftazidime, imipenem, does occur, proper utilization of antibiot-
meropenem, or piperacillin-tazobactam ics is vital in reducing acute and chronic
[63]. Also, if the culture reveals Gram- complications.
positive cocci in a severely ill patient,
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517
Chapter |9|
Device associated urinary

tract infections
Chair: Peter Tenke
CHAPTER OUTLINE
9.2 Urinary catheters and drainage systems: definition,
epidemiology and risk factors 522
9.3 Urinary catheters and drainage systems:
prevention and treatment of urinary tract infections 532
9.4 Evolution of catheter material for prevention of
catheter-associated urinary tract infections 541
9.5 Infections associated with the artificial urinary sphincter 549
9.6 Infections associated with penile prostheses 554
|9.1|
Introduction
Peter Tenke
Peter Tenke, MD, PhD, Head, Department of Urology, Jahn Ference Del-Pesti Korhaz,
Köves utca2-4, H-1204 Budapest, Hungary
Tel 0036-1-289.6200, tenkep@chello.hu; tenke.peter@jahndelpest.hu
The use of urological devices, especially diagnostic results (e.g. urine cultures),
urinary catheters, forms the basis of the and the choice of antibiotic and also the
daily praxis in urological departments, length of the therapy can differ from the
and also has a great importance in every convectional ones.
medical discipline. Using a foreign body Clinicians should always consider
always increases the risk of infectious alternatives to indwelling urethral cath-
complications. Approximately 40% of eters that are less prone to causing symp-
nosocomial infections originate in the uri- tomatic infection. In appropriate patients
nary tract, and most patients with nosoco- suprapubic catheters, condom drainage
mial urinary tract infections (UTIs) have systems and intermittent catheterisation
permanent urethral catheterisation or can be preferable to indwelling urethral
other urinary foreign body. Catheter asso- catheterization.
ciated urinary tract infections (CAUTI) Urinary catheters are of varying
are the most common nosocomial infec- design and material. There are still great
tions worldwide. Although largely asymp- efforts to develop catheter materials and
tomatic, they are reservoirs for antibiotic coatings witch can decrease or inhibit
resistance and contribute to morbidity in CAUTIs.
hospitals and long term care facilities. In the first part of the section the
When UTI occurs in a catheterized authors summarise the definition, epide-
patient it always requires special atten- miology and risk factors of catheter asso-
tion and knowledge. Due to biofilm for- ciated urinary tract infections, present
mation there are different causative evidence-based recommendations for the
pathogens with different sensitivities prevention, diagnostic and treatment of
from what we see in the urinary tract CAUTIs, and also compare the available
without foreign body. The present of a catheter materials and the different alter-
CAUTI needs special evaluation of the native methods of urine drainage.
With the design revisions, engineering of penile prostheses - different coatings

changes and improvements of surgical have been developed to prevent or treat
techniques the non-infectious complication infections.
rates of urological devices, such as artifi- In the second part of the section the
cial urinary sphincters and penile prosthe- authors summarise the pathogenesis
ses significantly decreased. As urological and epidemiology of the infections of
devices are now expected to function for artificial urinary sphincters and penile
many years post implantation, infection prostheses, and present evidence-based
has become a more significant problem. recommendations for the prevention
Different conservative treatment modali- and treatment of device associated
ties, surgical techniques, and - in case infections.
521
|9.2|
Urinary catheters and
drainage systems: definition,
epidemiology and risk factors
Paul A. Tambyah1, Dariusz P. Olszyna1, Peter Tenke2, Bela Koves2
1
Department of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074
2
Corresponding author: Paul Ananth Tambyah, MBBS, Dip ABIM (Inf Dis), Associate Professor, Consultant Infectious
Disease Physician, Department of Medicine, Yong Loo Lin School of Medicine, National University Hospital, 5 Lower Kent
Ridge Road, Singapore 119074
Tel.: 0065-6779.5555, Fax.: 0065-6779.4112, mdcpat@nus.edu.sg; ptambyah@pacific.net.sg
ABSTRACT catheterisation should be considered if

possible including intermittent catheteri-
Catheter associated urinary tract infec- sation, use of condom catheters, suprapu-
tions (CAUTI) are the most common noso- bic catheterisation.
comial infections worldwide. Although Key words: Urinary catheter Risk fac-
largely asymptomatic, they are reservoirs tor Epidemiology Nosocomial infection
for antibiotic resistance and contribute to
morbidity in hospitals and long term care
facillities. A recent European and Asian SUMMARY OF RECOMMENDATIONS
guideline on CAUTI recommended a
threshold of 105 CFU/ml for the diagnosis 1. The duration of indwelling cathterisa-
of CAUTI in asymptomatic patients and tion should be minimised (GoR A).
102 CFU/ml in patients with symptoms
related to the urinary tract. The most 2. The use of nurse-based or electronic
important risk factor for the development reminder systems to remove unneces-
of CAUTI is prolonged duration of cath- sary catheters can decrease the dura-
eterisation, others include female gender, tion of catheterization and the risk of
insertion of the catheter outside the oper- CAUTI (GoR B).
ating room, diabetes mellitus and other 3. Alternatives to indwelling catheteri-
patient factors. Alternatives to indwelling sation should be considered where
Urinary catheters and drainage systems | 9.2 |
possible including condom catheters, insertion due to inadequate preparation

intermittent catheterisation and of the meatus or perineum. Up to 20%
supra-pubic catheterization (GoR B). of individuals will be colonised immedi-
4. There is insufficient evidence of cost ately after catheterisation [9] (LoE 2a-3).
effectiveness at this time to recom- Subsequently, more bacteria can enter the
mend antiseptic or antimicrobial bladder through the lumen of the cathe-
coated catheters (GoR C). ter by reflux of urine from contaminated
drainage bags or ascend from the urethra
along the extraluminal catheter-urethral
surface [10]. In males the predominant
1. INTRODUCTION route of invasion is the intraluminal, sug-
gesting an exogenous source. It is dem-
Urinary catheters are among the most onstrated that the intraluminal ascent
commonly used devices in nursing homes of bacteria is faster (32–48 h) than the
and hospitals especially in peri-operative extraluminal route (72–168 h) [11]. The
and intensive care unit patients. Recent normal host defence mechanisms that
data show that more than 80% of patients result in rapid clearance of introduced
undergoing major surgery receive peri- microorganisms with voiding in non-
operative indwelling urinary catheters catheterized individuals are bypassed by
[1]. Overall, up to 25% of all patients the presence of the indwelling urinary
admitted to hospital can expect a urinary catheter.
catheterization performed at some time In addition, the presence of a biofilm
during their stay for a variety of indica- on the surfaces of the catheter provides
tions [2]. The most common complication a favourable environment for bacterial
associated with indwelling urinary cath- invasion and proliferation via the extra-
eters is urinary tract infection (UTI). luminal route; thereby it is a major con-
Hospital acquired UTIs amount to tributor to the pathogenesis of UTI in
approximately 500,000 cases a year catheterized patients. Biofilm is defined
in the United States alone [3] and are as an accumulation of microorgan-
responsible for 42% of all hospital – isms and their extracellular products
acquired infections [4]. They result in that form a structured community on
extension of hospital stay on average of a solid surface. Biofilms are ubiquitous
one day and are a major reservoir for and have been demonstrated on cath-
antibiotic-resistant pathogens [5]. eters, drainage bags and other foreign
Urinary catheters have long been bodies and prostheses [12]. Biofilm is
recognized as the major risk factor for composed of three layers: (i) the linking
developing healthcare associated UTIs. film, attached to the surface tissue or
The presence of a urinary catheter has biomaterial; (ii) the basal layer; and (iii)
been associated with up to 80% of noso- the surface film adjacent to the lumen,
comial UTIs [3]. In more recent studies from which planktonic organisms can be
conducted hospital-wide [6] or in urology released. Organisms within the biofilm
departments [7], the association of cath- are well protected from mechanical flush-
eters with nosocomial UTIs remains high ing by urine flow, other host defences and
with at least two thirds of nosocomial antibiotics or antiseptics. Conventional
UTIs associated with indwelling urinary microbiologic laboratory testing can eas-
catheters. Every additional day of cath- ily detect planktonic free-floating bacte-
eterization is associated with a further ria within the urine or occasionally in the
3–10 % risk of developing bacteriuria [8]. tissue. However, sessile pathogens from
Bacteria can be introduced to the the biofilm will not be detected with rou-
urinary tract at the time of catheter tine methods [12].
523
Chapter |9| Device associated urinary tract infections
2. METHODS patients without bacterial colonisation

[15]. Further analysis showed that such
We surveyed the extensive literature symptoms have low predictive value of
regarding the definition and epidemiol- UTI in catheterized patients as the pres-
ogy of catheter-associated UTIs using the ence of catheter alone can result in com-
following key words “urine” “catheter” plaints resembling dysuria. The study
and “infection” and the following limita- also showed that the presence of periph-
tions “English language”, “Human” and eral leucocytosis is also not predictive of
“review”. We systematically searched for UTI in this group. It has been proposed
meta-analyses of randomised controlled that the presence of urinary catheter
trials available in Medline by giving pref- actually limits the symptoms of dysuria
erence to the Cochrane Central Register in the presence of bacteriuria [13]. There
of Controlled Trials and also considered is also no convincing evidence that fever
other relevant publications until March is a reliable symptom of catheter-related
2008. Studies were identified through a UTI, especially in elderly patients [16].
PubMed search. More than 600 publica- It is thus very difficult to distinguish
tions were found, which were screened asymptomatic catheter-associated bacte-
by title and abstracts and finally 51 were riuria from symptomatic catheter associ-
included into the analysis. ated urinary tract infections.
The studies were rated according What is clear, is that it is not possible
to the level of evidence (LoE) and the to have a symptomatic catheter associated
grade of recommendation (GoR) using UTI without significant bacteriuria. The
ICUD standards (for details see Preface) degree of bacteriuria that is considered
[13–14]. significant is also controversial. A recent
European and Asian guideline on cath-
eter associated urinary tract infections
3. DEFINITIONS OF CATHETER determined that a qualitative count ≥105
ASSOCIATED UTI cfu/ml with one or more uropathogens
isolated in urine specimen should be used
The presence of an indwelling urethral to define significant catheter-associated
catheter inevitably leads to bacteriuria. bacteriuria in asymptomatic patients
However, bacteriuria leads to bacter- with indwelling urethral, suprapubic or
emia in less than 5% of the catheterized intermittent catheterisation, and a quali-
patients [15]. Symptoms of dysuria in tative count ≥102 cfu/ml in the presence
combination with pyuria help clinicians of symptoms traditionally associated
in diagnosing a UTI in patients without a with UTI. To define significant catheter-
urinary catheter. Traditionally, these clin- associated bacteriuria in case of condom
ical tools have also been used to help dis- catheter a qualitative count ≥105 cfu/ml
tinguish between bacterial colonization of should be used in asymptomatic patients,
the catheterized urinary tract or asymp- and a qualitative count ≥103 cfu/ml in
tomatic bacteriuria and symptomatic UTI symptomatic patients [17].
in catheterized patients. However, the
roles of dysuria, pyuria and even fever in
patients with suspected catheter-related
4. RISK FACTORS OF CATHETER
UTI have been questioned. A prospective
ASSOCIATED UTI
study of 1497 newly catheterized patients
showed that fewer than 10% of patients
4.1 Duration of catheterization
who developed bacteriuria reported
symptoms normally associated with UTI, The length of catheterization is an
a number not different from catheterized established risk factor for developing
524
bacteriuria and a subsequent UTI with immediate removal after operation,

[18–19]. Every day of continuing cathe- but there is some evidence that there is
terization is associated with an increased less need for re-catheterisation following
risk of approximately 3–10% of develop- hysterectomy if there is a short period of
ing bacteriuria [18] and long term cath- continuous drainage. Eleven trials con-
eterized patients will inevitably have the sidering the duration of catheterisation
presence of bacteria in the urine by day after surgery showed considerable heter-
30 of catheterization [1, 20]. Wald et.al. ogeneity and did not prove that any one
performed a large retrospective cohort policy was better than another. In gen-
study of 35,904 patients undergoing a eral, fewer UTIs occurred when the cath-
major surgery which showed that the eter was removed as soon as possible.
risk of developing a documented physi- Removal of the indwelling urinary
cian treated UTI was doubled after two catheter before midnight may be bene-
days of catheterization [1]. The same ficial (GoR C). There are some resource
study showed that as many as 50% of implications but their magnitude is
patients who underwent a major surgery not defined. Patients stay in hospital
stayed catheterized for longer than two for a shorter period of time after early,
days. In another, randomized study of rather than delayed catheter removal,
patients undergoing an abdominal sur- but the effects on other outcomes are
gery catheterization duration of longer unclear [18].
than seven days was found to carry an Physicians are often unaware that their
increased risk of developing UTI (rela- patients have a urinary catheter. The use
tive risk of 3.4) [16]. These observations, of nurse-based or electronic reminder sys-
however, are not limited to surgical tems to remove unnecessary catheters
patients. A study in neurological patients can decrease the duration of catheteriza-
without previous infection who received tion and the risk of CAUTI [19–21] (LoE
a urinary catheter for at least one week 2a, GoR B).
showed that the length of catheterization Other risk factors identified have
was the major risk factor for developing included [22–25] (IIa): (i) colonisation of
a UTI [17]. the drainage bag, catheter and periure-
The evidence shows clearly that the thral segment; (ii) diabetes mellitus; (iii)
duration of catheterization is the major female gender; (iv) older age; (v) renal
risk factor for developing a catheter function impairment; (vi) poor quality of
associated UTI (LoE 2a-3) and the con- catheter care including insertion outside
tinuing indication for keeping a cath- of an operating room; and (vii) lack of
eter should be reassessed by clinicians antimicrobial therapy.
regularly.
Although there is extensive literature 4.2 Type of catheterization
on the type, maintenance and techniques
for the insertion of urinary catheters, lit- 4.2.1 One-time single (straight)
tle attention is paid to their removal. The catheterisation
importance of urethral catheter manage- After single (straight) catheterisation,
ment is recognised; however, there is no bacteriuria develops in less than 5% of
consensus about the optimal time and cases [22–23] (LoE 3). The risk of infec-
method for removal of indwelling ure- tion is increased in female patients,
thral catheters. patients with urinary retention, in peri-
According to the Cochrane database partum catheterisation, in men with pro-
[18], there is not sufficient evidence of the static obstruction, in diabetes mellitus
benefit of using a catheter for a period and in debilitated and elderly patients
after operation (such as 24 h) compared [18] (LoE 3).
525
4.2.2 Short-term catheterisation Despite the high level of bacteriuria in

Short-term catheterization is usually patients with long-term indwelling cath-
defined as having a catheter in place for eters, symptomatic manifestations, either
less than seven days [26]. Indications through ascending infection or through
for short-term bladder catheterisation bacteraemia, are uncommon. Studies in
are to monitor urine output (i) in acutely a long-term facility identified UTIs as
ill patients, (ii) for urinary obstruction a source of febrile episodes in less than
and (iii) in the perioperative period. The 10% of patients [27] despite near uni-
majority of studies have been done on versal bacteriuria (LoE 3). It is therefore
short term catheterization in identifying extremely important to rule out other
the risk factors described above. sources of fever (GoR A).
Most episodes of short-term catheter- Although, asymptomatic bacteriuria is
associated bacteriuria are asymptomatic common during initial catheter insertion
and are caused by single organisms; up or during catheter exchange in chroni-
to 15% may be polymicrobial [5] (LoE cally catheterised patients [33], the risk of
3), reflecting the prevailing flora in hos- bacteraemia during catheter exchange is
pital or community environments. The low [34]. Chronic catheterisation can lead
most common organism causing UTIs to obstruction of the lower urinary tract
in patients with short term urinary owing to catheter blockage as well as to
catheters is Escheria coli. Other organ- urinary tract stones, epididymitis, pros-
isms that are increasingly identified tatitis and scrotal abscess [35–37] (LoE
include Klebsiella spp, Pseudomonas 2a-3). Up to 50% of patients undergoing
spp, Acinetobacter spp, Enterobacter spp, catheterisation for more than 28 days
Candida spp and enterococci [22, 24]. experience recurrent encrustation and
catheter blockage (LoE 2a). Intermittent
4.3.3 Long-term catheterisation urinary retention can also lead to vesi-
coureteral reflux and ascending compli-
When indwelling catheterisation lasts cated infection. Infecting organisms often
for more than 28 days it is defined as include P. mirabilis, a potent urease pro-
‘long-term’ or ‘chronic’. Unfortunately, ducer, which promotes the development
there is no consensus on the classifica- of struvite stones by hydrolysis of urea to
tion or nomenclature for indwelling cath- ammonium (LoE 2b-3).
eters in place for 8–29 days. The risk of As indwelling urethral catheters are
bacteriuria with at least one strain is prone to cause symptomatic infection, cli-
universal in patients with a long-term nicians should always consider alterna-
indwelling catheters, whilst most patients tives. In appropriate patients, suprapubic
are infected with two or more strains of catheters, condom drainage systems or
bacteria [27–28] (LoE 2b). The common- intermittent catheterisation are prefera-
est infecting organism is E. coli, followed ble to indwelling urethral catheterisation
by Providentia stuartii, Pseudomonas, (GoR B).
Proteus, Morganella and Acinetobacter,
Enterococcus and Candida spp. Bacte-
riuria is polymicrobial in up to 95% of 4.3.4 Transurethral versus suprapubic
urine specimens from long-term catheter- catheters
ised patients [29–31] (LoE 2b-3). One- Transurethral indwelling catheters are
quarter of organisms in catheter urine the most commonly used catheters in both
are not present in urine simultaneously hospitals and nursing homes. Suprapubic
obtained by suprapubic bladder puncture, catheters have long been an alternative
suggesting that some organisms colonise to the transurethral indwelling cath-
the catheter only [32] (LoE 2b). eterisation. The issue whether they are
526
associated with fewer UTIs than tradi- patients [42–43] (LoE 3). There are no
tional catheters has not been resolved well-designed studies investigating the
until today. A number of studies have significance of bacteriuria or symptomatic
been performed, mainly in patients under- UTI in correlation with various urethral
going surgical procedures to compare the inserts and stents in comparison with
risks of developing a UTI between the two other drainage methods.
methods of catheterisation.
A meta-analysis of six randomized con- 4.3.6 Coated catheters
trolled trials in patients after abdominal A meta-analysis of 11 trials comparing
surgery found that transurethral cath- antiseptic impregnated urinary catheters
eterisation was associated with more sig- to standard catheters suggested that sil-
nificant bacteriurias than suprapubic ver alloy coated catheters may carry a
catheterisation [38]. A Cochrane analy- lower risk for UTI. The beneficial effect of
sis by Niël-Weise of studies comparing combination of minocycline and rifampin
suprapubic and transurethral catheters in was less clear [44].
surgical patients also found that the lat- A more recently published Cochrane
ter were associated with higher rates of analysis also suggested that silver alloy
bacteriuria [39]. In another meta-analysis catheters or antibiotic – impregnated
which included patients undergoing a uro- catheters may be beneficial in preventing
genital surgery, four randomized trials bacteriuria in selected groups of adults
were analyzed [40]. The data were incon- with short term indwelling catheters.
clusive. It has been noted that patient However, a cost-benefit analysis of such
comfort is higher with supra-pubic cath- devices has yet to be performed [45].
eterisation than with urethral catheterisa-
tion (LoE 3).
4.3.7 Condom catheters
Most of the studies that were included
in the meta-analyses defined a catheter- Condom catheters are usually used for
associated UTI as a presence of bac- reliable monitoring of urine when there
teriuria only. In contrast, a study by is no urinary tract obstruction or urine
Baan et al. compared suprapubic and retention or when patient has problems
transurethral catheters after an abdom- reaching the toilet or other urine col-
inal surgery and found no difference in lection device. Although they are less
incidence of symptomatic urinary tract reliable than indwelling catheters in
infections [41]. measuring urine output due to leakage,
In summary, despite a number of ran- condom catheters cause less discomfort
domized trials and at least three meta- to the patients. However, condom drain-
analyses, we cannot conclusively state age may be unsatisfactory in confused or
that suprapubic catheterization is supe- uncooperative patients or where there is
rior to urethral catheterization in reduc- obesity and/or a short penis. Skin mac-
ing the incidence of UTIs. eration and ulceration can occur. Daily
changing of the condom catheter is rec-
ommended, although changes every other
4.3.5 Urethral stents day are not associated with increased
Urethral stents/prostheses are often infection rates [46]. Data on UTIs asso-
inserted into the prostatic urethra for ciated with condom catheters are scarce.
a variety of indications, including neu- Small studies have suggested that they
rogenic bladder dysfunction, preven- are associated with lower rates of UTI
tion of strictures, treatment of urinary provided manipulation of the catheter by
retention. Bacteriuria, which is usu- staff or the patient was kept to minimum
ally asymptomatic, occurs in 10–35% of [47–48] (LoE 3).
527
4.3.8 Intermittent catheterisation 6. CONCLUSIONS

Clean intermittent catheterisation is pop-
ular in the management of voiding dys- Catheter associated urinary tract infec-
function due to a wide variety of causes, tions are a major problem in hospitals
including a neuropathic bladder, women and nursing homes worldwide. The defi-
with incontinence caused by uncontrolled nition of these infections is complicated
reflex detrusor contraction, women and as the symptoms of urinary tract infec-
men with urinary retention due to inef- tion are protean in patients with ind-
fective or absent detrusor contraction and welling catheters and bacteruria is very
males with bladder outlet obstruction who common in patients with prolonged cath-
are not fit for surgery [49]. Bacteriuria eterization. The most important risk fac-
is acquired at the rate of approximately tor for catheter associated urinary tract
1–3% per catheterisation, however, this infection is the duration of catheteriza-
might be transient and not cumulative tion and strategies are being developed
[48–51]. Complications include bleeding, to reduce catheterization using elec-
urethral inflammation, stricture, false tronic and other reminders. Alternatives
passage, epididymitis, bladder stone and to indwelling urethral catheteriza-
hydronephrosis. tion should also be considered where
Three trials compared indwelling ure- possible.
thral catheterisation with intermittent
catheterisation. In two trials there were
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531
|9.3|
Urinary catheters and

drainage systems: prevention
and treatment of urinary tract
infections
Peter Tenke, Bela Koves, Karoly Nagy
Corresponding author: Peter Tenke, MD, PhD, Head, Department of Urology, Jahn Ference Del-Pesti Korhaz,
Köves utca2-4, H-1204 Budapest, Hungary
Tel 0036-1-289.6200, tenkep@chello.hu; tenke.peter@jahndelpest.hu
ABSTRACT Healthcare workers should be constantly

aware of the risk of cross-infection between
We surveyed the extensive literature catheterised patients. They should observe
regarding the prevention and treatment protocols on hand washing and the need
of catheter-associated urinary tract infec- to use disposable gloves. While a catheter
tions (CAUTIs). The clinician should be is in place, systemic antimicrobial treat-
aware of two priorities: the catheter sys- ment of asymptomatic catheter-associated
tem should remain closed and the duration bacteriuria is not recommended, except
of catheterisation should be minimal. In for some special cases. Routine urine cul-
case of short-term catheterisation routine ture in an asymptomatic catheterised
prophylaxis with systemic antibiotics is patient is also not recommended because
not recommended. There are sparse data treatment is in general not necessary.
about antibiotic prophylaxis in patients Antibiotic treatment is recommended only
on long-term catheterisation, therefore for symptomatic infection. After initia-
no recommendation can be made. For tion of empirical treatment usually with
patients using intermittent catheterisa- broad-spectrum antibiotics based on local
tion routine antibiotic prophylaxis is not susceptibility patterns, the choice of anti-
recommended. Antibiotic irrigation of the biotics may need to be adjusted accord-
catheter and bladder is of no advantage. ing to urine culture results. Long-term
antibiotic supportive therapy is not effec- clinically indicated in patients on

tive. In case of asymptomatic candiduria, long-term catheterisation are sparse.
neither systemic nor local antifungal Therefore no recommendation can be
therapy is indicated, but removal of the made (GoR D).
catheter or stent could be considered. In 9. There is little evidence suggest-
case of candiduria associated with urinary ing that antibiotic prophylaxis
symptoms or if candiduria is the sign of a decreases bacteriuria in patients
systemic infection, systemic therapy with using intermittent catheterisation,
antifungals is indicated. therefore it is not recommended
Key words: urinary, infection, catheter, (GoR B).
UTI, CAUTI, prevention, prophylaxis, 10. Long-term indwelling catheters
treatment, bacteriuria, candiduria should be changed in intervals
adapted to the individual patient,
but must be changed before blockage
SUMMARY OF RECOMMENDATIONS is likely to occur, however there is
no evidence for the exact intervals of
General aspects changing catheters (GoR B).
1. Health care workers should observe Diagnostics
protocols on hand hygiene and the
need to use disposable gloves between 11. Routine urine culture in asympto-
catheterised patients (GoR A). matic catheterised patients is not
recommended (GoR B).
Catheter insertion and choice of 12. Urine, and in septic patients also
catheter blood for culture must be taken
2. An indwelling catheter should be before any antimicrobial therapy is
introduced under antiseptic conditions started (GoR A).
(GoR B). 13. Febrile episodes are only found in
3. Urethral trauma should be minimised less than 10% of catheterised patients
by the use of adequate lubricant and living in a long-term facility. It is
the smallest possible catheter caliber therefore extremely important to rule
(GoR B). out other sources of fever (GoR A).
Prevention and prophylaxis Treatment
4. The catheter system should remain 14. Whilst the catheter is in place, sys-
closed (GoR A). temic antimicrobial treatment of
asymptomatic catheter-associated
5. The duration of catheterisation should bacteriuria is not recommended,
be minimal (GoR A). except in certain circumstances:
6. Topical antiseptics or antibiotics especially prior to traumatic urinary
applied to the catheter, drainage bag, tract interventions (GoR A).
urethra or meatus are not recom- 15. Antimicrobial treatment is recom-
mended (GoR A). mended only for symptomatic infec-
7. In case of short-term catheterisation tion (GoR B).
routine antibiotic prophylaxis is not 16. Elderly female patients may need
recommended (GoR A). treatment if asymptomatic bacteriu-
8. The data comparing antibiotic prophy- ria does not resolve spontaneously
laxis to giving antibiotics when after catheter removal (GoR B).
533
17. Chronic antibiotic suppressive ther- written guidance on catheter care on

apy is generally not recommended evidence-based grounds.
(GoR A).
18. In case of symptomatic CAUTI it
2. METHODS
may be reasonable to replace or
remove the catheter before starting
antimicrobial therapy if the indwell- We surveyed the extensive literature
ing catheter has been in place for regarding the prevention and therapy
more than 7 days (GoR B). of catheter-associated UTIs through a
PubMed search using the following key
19. For empiric therapy broad-spectrum words in different combinations: catheter,
antibiotics must be given based on infection, urinary, UTI, CAUTI, preven-
local susceptibility patterns (GoR A). tion, treatment, bacteriuria. We system-
20. After culture results are available atically searched for meta-analyses of
antibiotic therapy has to be adjusted randomised controlled trials available
according to sensitivities of the path- in Medline by giving preference to the
ogens (GoR A). Cochrane Central Register of Controlled
21. In case of asymptomatic candiduria, Trials and also considered other rele-
neither systemic nor local antifungal vant publications until March 2008. The
therapy is indicated (GoR A). publications were screened by title and
abstracts and after exclusion of duplicates
22. In case of asymptomatic candiduria a total of 50 publication were included
removal of the catheter or stent could into the analysis.
be considered (GoR C). The studies were rated according to the
23. In case of candiduria associated with level of evidence (LoE) and the grade of
urinary symptoms or if candiduria recommendation (GoR) using ICUD stand-
is the sign of a systemic infection, ards (for details see Preface) [6–7].
systemic therapy with antifungals is
indicated (GoR B).
3. PREVENTION OF BACTERIURIA
AND PROPHYLAXIS
1. INTRODUCTION
3.1 Prevention of bacteriuria
Approximately 40% of nosocomial infec-
tions originate in the urinary tract. The following recommendations are com-
Most patients with nosocomial urinary monly used [8–10] (LoE 3). A closed-
tract infections (UTIs) have either had catheter system with ports in the distal
genitourinary or urological manipula- catheter for needle aspiration of urine
tion (ca. 10–20%) or permanent urethral should be used (GoR B). An indwell-
catheterisation (ca. 80%), or both [1–5] ing catheter should be introduced under
(LoE 3). antiseptic conditions (GoR B). Urethral
The aim of this chapter is to give evi- trauma should be minimised by the use
dence based recommendations for the of adequate lubricant and the smallest
prevention and treatment of catheter- possible catheter (GoR B). A limited study
associated bacteriuria and urinary indicates that the risk of bacteriuria is
tract infection (UTI) for all medical equally high if a sterile or clean tech-
disciplines, with special emphasis on nique or an antiseptic gel is used [11–12]
urology where catheter care is an impor- (LoE 2a). The drainage bag should be
tant issue, and to assist and to encour- always kept below the level of the blad-
age urological departments to establish der and the connecting tube [13] (GoR B).
534
The clinician should be aware of two pri- that antibiotic prophylaxis compared to
orities: the catheter system must remain giving antibiotics when clinically indi-
closed (GoR A) and the duration of cath- cated reduced the rate of symptomatic
eterisation has to be minimal (GoR A). UTIs in female patients with abdominal
There is a resurgence of interest in surgery and a urethral catheter for 24
the use of the convenient flip valve as a hours. There was limited evidence that
replacement for the daytime catheter prophylactic antibiotics reduced bacteriu-
bag. It is expected that the risk of coloni- ria in non-surgical patients [18] (LoE 1a).
sation of such a device will be a problem, Therefore in case of short-term catheteri-
although a randomised controlled study of sation routine prophylaxis is not recom-
100 patients comparing the use of cathe- mended (GoR A).
ter valve with standard drainage systems According to the Cochrane database
showed no difference in the incidence of the data comparing antibiotic prophylaxis
UTIs [14]. Adequate urine flow must be to giving antibiotics when clinically indi-
ensured. The patient should receive suf- cated in patients on long-term catheteri-
ficient fluids given orally to maintain sation are sparse [19] (LoE 1a). Therefore
an output of more than 50–100 mL/h. no recommendation can be made (GoR D).
Bacteraemia is not prevented by topical For patients using intermittent catheteri-
antiseptics or antibiotics applied to the sation, there is limited evidence suggest-
catheter, urethra or meatus. ing that antibiotic prophylaxis decreases
There is no consensus as to the time the rate of bacteriuria (asymptomatic and
in which routine catheter changes have symptomatic) [19]. Therefore it is not rec-
to be made. This may be dictated by the ommended (GoR B). Possible benefits of
manufacturer’s instructions and condi- prophylaxis must be balanced against cost
tions for indemnity. Shorter periods may and adverse effects, such as development
be necessary if there is catheter malfunc- of antimicrobial resistance. Cycling of
tion or leakage. In general, long-term ind- antibiotics on a weekly basis can be pos-
welling catheters must be changed before sible way to reduce the risk of resistance,
blockage occurs or is likely to occur. The but further research is needed before a
time differs very much from one patient recommendation can be made [20].
to another. Some patients form deposit in
the catheter lumen very quickly [10, 15]. 3.3 Additional methods of
These individuals (‘blockers’) need to have prevention
catheter changes more frequently than
According to a recent Cochrane review of
‘non-blockers’, i.e. weekly or even twice
randomised controlled trials cranberry
weekly [16–17]. Some authors advise
products (juice or tablets) did not reduce
leaving the catheter out for at least one
significantly the incidence of catheter-
hour, but no longer than two hours,
associated bacteriuria or CAUTI in
when a long-term indwelling catheter is
patients with neurogenic bladder requir-
changed, to allow the urethral glands to
ing intermittent or indwelling cath-
drain [10]. However, this method has no
eterisation [21]. Therefore they are not
evidence-based support.
recommended (GoR A). There is no avail-
able data on the use of cranberry prod-
3.2 Prophylaxis with systemic
ucts for prevention of catheter-associated
antibiotics
bacteriuria or CAUTI in patients without
In a recent Cochrane review of anti- neurogenic bladder, therefore no recom-
biotic policies for short-term catheter mendation can be made (GoR D).
bladder drainage in adults the authors Methenamin salts (methenamine man-
concluded that there was weak evidence delate or methenamine hippurate) reduced
535
the incidence of asymptomatic bacteriuria bacteriuria will either not be eradicated

and symptomatic UTIs in post-surgical or will return rapidly. However, antimi-
patients without renal tract abnormali- crobial therapy may contribute to the
ties with an indwelling catheter for no selection of resistant organisms and to
more than one week [22–23] (LoE 1b). adverse reactions. There is no evidence
Benefits from antiseptic substances, such that antimicrobial therapy decreases
as oral methenamine have never been morbidity or mortality from UTI in cath-
established in patients with intermittent eterised patients [18], therefore systemic
catheterisation. antimicrobial treatment of asymptomatic
Catheter irrigation with antiseptics catheter-associated bacteriuria is only
(povidone–iodine or chlorhexidine) or recommended in the following circum-
antibiotics are not effective in prevent- stances [8–9, 29–30, 36–37]: (i) patients
ing catheter associated bacteriuria in undergoing urological surgery or implan-
patients with indwelling catheterisation tation of prostheses (GoR A); (ii) treat-
[24–25], therefore they are not recom- ment may be part of a plan to control
mended (GoR A) There is some evidence nosocomial infection due to a particularly
that catheter irrigation with antisep- virulent organism prevailing in a treat-
tics may prevent bacteriuria in surgical ment unit (GoR B); (iii) patients who have
patients undergoing short-term catheteri- a high risk of serious infectious complica-
sation [26–27] (LoE 1b). Administration tions, e.g. patients who are immunosup-
of antimicrobials in the drainage bag is pressed (GoR C); (iv) in case of pregnancy
not recommended [28] (GoR A). (GoR B); and (v) infections caused by
strains causing a high incidence of bacter-
3.4 Prevention of cross-infection aemia, e.g. Serratia marcescens (GoR B).
If the catheter drains properly, routine
Healthcare workers should be constantly
urine cultures in asymptomatic catheter-
aware of the risk of cross-infection
ised patients are also not recommended
between catheterised patients. They
(GoR B) because treatment generally is
should observe protocols on hand wash-
not necessary. Also, it has not been shown
ing and the need to use disposable gloves
that a uropathogen cultured from an
(GoR A). The periurethral bacterial flora,
asymptomatic patient will be the causa-
surfaces of the catheter system and the
tive organism when a symptomatic episode
persistent, huge reservoir of contami-
occurs. Following catheter removal in ca.
nated urine as well as the skin of the
one-third to one-half of cases, the urinary
patient are sources for contamination
tract will clear bacteria spontaneously [10,
of the hands of medical personnel who
30] (LoE 3). Spontaneous clearance occurs
may carry the bacteria to other patients
more commonly in women under 65 years
[29–32] (LoE 2b-3). This may be reduced
of age or when S. epidermidis is the infect-
by treating the catheterised urinary tract
ing organism [10]. However, one study
as an open wound. It is therefore essen-
shows that elderly females may need
tial to use gloves after hand washing in
treatment if bacteriuria does not resolve
antiseptic solutions [33–35] (LoE 2a-3).
spontaneously [38] (LoE 2a) or if sympto-
matic infection occurs.
4. TREATMENT
4.2 Treatment of symptomatic UTI
4.1 Treatment of asymptomatic
The most frequent clinical manifestation
bacteriuria
of symptomatic UTI in catheterised resi-
Generally, asymptomatic bacteriuria dents is fever. Some patients may also
should not be treated (GoR A) because become septic with at least two of the
536
followings symptoms: hypothermia, tach- Although there are no adequate clini-

ycardia (> 90/min), tachypnoea (>20/min cal studies to guide the length of therapy
and/or pCO2 <33 Hgmm), leucocytosis for catheter-related symptomatic UTI,
(>12/nl) or leucopenia (<4/nl). Since antimicrobial treatment usually var-
patients with long-term indwelling cath- ies from 5 days to 21 days depending on
eters always have positive urine cultures, the organism, co-morbid conditions and
a definite diagnosis of the source of infec- patient response [33, 38, 44] (LoE 1-3).
tion remains problematic in a febrile or In patients with CAUTI, who are not
septic catheterized patient without local- severely ill, a 5-day regimen of a fluoro-
ising genitourinary symptoms and if not quinolone should be considered [45–46]
bacteraemic due to the same urinary (GoR B). Chronic antibiotic suppressive
pathogen. UTI may be the source of fever; therapy is not effective and generally
if there are no localising features such as not recommended (GoR A). Catheterised
obstruction, haematuria or costovertebral urine cannot be permanently sterilised
angle tenderness, alternative diagnoses [8–9, 31, 33, 39, 47] (LoE 2a-3). For
must be considered (GoR A). Observation, women age 65 or younger who develop
rather than immediate antimicrobial CAUTI without upper tract symptoms
therapy, should be considered when the after the catheter has been removed, a
patient is clinically stable and the fever 3-day antimicrobial regimen is recom-
is of low grade [39]. mended (GoR C).
Antibiotic treatment is recommended Occasionally, the culture shows candi-
only in symptomatic infection (bacter- duria, which is usually asymptomatic and
aemia, pyelonephritis, epididymitis, often resolves without treatment. In this
prostatitis) (GoR B). In catheterized case neither systemic nor local (bladder
patients the presence or the degree of irrigation) antifungal therapy is indicated
pyuria should not be used to differenti- [48–49] (LoE 1b, GoR A), but removal of
ate catheter-associated bacteriuria from the catheter or stent could be considered
CAUTI [40–41] (GoR B), and it is not an (GoR C). If the infection is associated
indication for antimicrobial treatment. with urinary symptoms or candiduria is
Systemic antibiotics should be used for the sign of a systemic infection, systemic
catheterised patients who are febrile and therapy with antifungals is indicated
appear to be ill, because of the possibility [50–52] (LoE 2a, GoR B).
of UTI-related bacteraemia or pyelone-
phritis (GoR B). Owing to the likelihood
of bacteria sequestered in a biofilm on the 5. FURTHER RESEARCH
catheter surface, it may be reasonable
to replace or remove the catheter (if the However there are prospective, ran-
indwelling catheter has been in place for domised studies regarding the most
more than 7 days) before the therapy of aspects of the prevention and treatment
symptomatic catheter-associated bacte- of CAUTIs, there are still some unan-
riuria [10, 33, 42–43] (GoR B). After ini- swered questions, such as the need of
tiation of empirical treatment usually antibiotic prophylaxis in patients on
with broad-spectrum antibiotics based on long-term catheterisation, the length of
local susceptibility patterns, the choice therapy for catheter-related symptomatic
of antibiotics may need to be adjusted UTIs, or the time in which routine cathe-
according to urine culture results ter changes have to be made. Prospective
(GoR A). Therefore, urine, and in septic studies and long-term follow up are
patients also blood for culture, must be needed to answer these questions and to
taken before any antibacterial therapy is make evidence-based recommendations
started (GoR A). about them.
537
6. CONCLUSIONS A prospective microbiologic study of bac-

teriuria in patients with chronic indwell-
The urinary tract is the commonest ing urethral catheters. J Infect Dis, 1982.
source of nosocomial infections, and one 146(6): 719–23.
of the leading risk factors is urethral 9. Warren JW, Catheter-associated urinary
tract infections. Int J Antimicrob Agents,
catheterisation. Therefore the evidence-
2001. 17(4): 299–303.
based prevention and treatment of cath-
10. West DA, Cummings JM, Longo WE,
eter associated UTIs are very important
Virgo KS, Johnson FE, and Parra RO,
in the daily practice. Written catheter Role of chronic catheterization in the
care protocols are necessary to decrease development of bladder cancer in patients
the number of nosocomial infections, with with spinal cord injury. Urology, 1999.
special emphasis on urology departments. 53(2): 292–7.
11. Carapeti EA, Andrews SM, and
Bentley PG, Randomized study of sterile
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540
|9.4|
Evolution of catheter material for
prevention of catheter-associated
U-Syn Ha, Yong-Hyun Cho
Department of Urology, Catholic University of Korea, Medical College, Seoul, South Korea
Corresponding author: Yong-Hyun Cho, Department of Urology, Catholic University of Korea,
Medical College, Seoul, South Korea
Tel: 82-2-3779-1024, Fax: 82-2-761-1626, cyh0831@catholic.ac.kr
ABSTRACT and antibiotic-coated catheters may pro-

vide promise for the control of CAUTIs.
Nosocomial urinary tract infection is Silver alloy coated catheter significantly
the most common infection acquired in prevent asymptomatic bacteriuria in the
both hospitals and nursing homes and is short-term (at both less and more than
usually associated with catheterization. one week of catheterization) catheter-
These catheter-associated urinary tract ized patient in comparison with standard
infections (CAUTIs) have been reported catheter. Antibiotic-impregnated cathe-
to increase the mortality rate and consid- ters reduce the asymptomatic bacteriuria
erable economic impact. Currently, there in hospitalized adults who are catheter-
are many types of catheters available, ized up to one week in comparison with
which try to alter the catheter material standard catheter. For more than one
in order to inhibit CAUTIs. Many sub- week there was no significant effect.
stances are being challenged for their There is no trial in comparison between
potential as catheter material or coat- antiseptic impregnated catheters or
ings. There are still no trials and con- between antibiotic impregnated cathe-
sensus which provide sufficient evidence ters. More basic research at the level of
to suggest whether or not any of the pathogenesis and catheter substance is
standard catheters results in a decreased needed to design novel strategies.
rate of bacteriuria compared to another
standard catheter. However, among these Key words: catheter material, catheter,
catheters, recently developed antiseptic evolution, urinary tract infection
SUMMARY OF RECOMMENDATIONS irritation and allergic reaction may occur

[1] (LoE 2a). Silicone catheters are more
1. There are still no trials and consen- biocompatible and obstruct less than
sus which provided sufficient evi- normal latex ones and therefore are bet-
dence to suggest whether or not any ter choices for long-term usage. However
of the standard catheters results in teflon- or silicone-coated latex catheters
a decreased rate of bacteriuria com- in patients are prone to catheter encrus-
pared to another standard catheter. tation which is thick and condensed bio-
Therefore no recommendation con- film, occluding the inner or outer surface
cerning any preference can be made of the catheter [2–3] (LoE 2a). Polyvinyl
(GoR D). chloride is a strong material that often
2. Silver alloy coated catheter signifi- composes the three-way catheters used
cantly prevent asymptomatic bac- for bladder irrigation and wash-out. On
teriuria in the short-term (at both the other hand, there is not enough evi-
less and more than one week of cath- dence to define whether any standard
eterization) catheterized patient in catheter was better than another in terms
comparison with standard catheter. of reducing the risk of UTI in adults hos-
Therefore, this kind of catheter could pitalized short-term, although silicone
be useful, if short-term prevention of catheters may be less likely to cause ure-
asymptomatic bacteriuria is impor- thral side effects in men. There are still
tant, e.g. before a urological interven- no trials and consensus which provide
tion (GoR C). sufficient evidence to suggest whether or
not any of the standard catheters result
3. Antibiotic-impregnated catheters in a decreased rate of bacteriuria com-
reduce the asymptomatic bacte- pared to another standard catheters [4].
riuria in hospitalized adults who Many innovations have been tried in
are catheterized up to one week in clinical settings to prevent CAUTI. These
comparison with standard catheter. have included the use of antiseptic lubri-
For more than one week there was cating gel at catheter insertion [5], the
no significant effect. Therefore, this use of a tape seal applied to the catheter
kind of catheter could be useful, if drainage tubing junction [6], anti-reflux
short-term prevention of asympto- valves, anti-infective irrigation of the
matic bacteriuria is important, e.g. bladder or instillation of antiseptics in
before an urological intervention the collection bag [7–8]. However, com-
(GoR C). pared with the closed drainage system,
4. There is no trial in comparison all of these have failed to show significant
between antiseptic impregnated cathe- benefits.
ters or between antibiotic impregnated Biofilm formation on the urinary cath-
catheters. Therefore, no recommen- eter may play a key role in the pathogen-
dation concerning preference can be esis of CAUTIs and in the resistance of
made (GoR D). CAUTIs to management. Renewed inter-
est has therefore arisen in altering and
coating the catheter surface to inhibit
1. INTRODUCTION biofilm formation. A recent approach to
solve some of the problems associated
Indwelling urinary catheters are of with CAUTI has been the application of
varying design and material. The most a range of different coatings to the sur-
common standard catheters include poly- face of the catheter. The results have
vinyl chloride, latex, teflon and silicone. been varied but the problems remain
Latex catheters are relatively cheap but unsolved.
542
Evolution of catheter material for prevention | 9.4 |
2. METHODS 3. Antibiotic impregnated urethral cath-

eters versus antiseptic impregnated
2.1 Systematic literature search indwelling urethral catheters;
We surveyed the extensive literature 4. One type of antiseptic impregnated
regarding the development and mate- urethral catheter versus another type
rial of catheter-associated UTIs. We sys- of antiseptic impregnated indwelling
tematically searched all randomized and urethral catheter;
quasi-randomized controlled trials com- 5. One type of antibiotic urethral cath-
paring types of indwelling urinary catheter versus another type of antibiotic
eters available in Medline via Pubmed by impregnated urethral catheter.
giving preference to the Cochrane Central
Register of Controlled Trials and also con-
sidered other relevant publications until
October 2008. The search strategy used 3. ANTISEPTIC IMPREGNATED
terms: catheter, catheterization, urethra, URETHRAL CATHETERS VERSUS
urinary tract, combined with the terms: STANDARD URETHRAL CATHETERS
infection or bacteriuria. For the purpose
of this review a total of 111 possibly eligi- There were two types of antiseptic cath-
ble publications were found, which were eters compared with a standard catheter:
screened by title and abstracts and finally silver oxide and silver alloy.
22 publications [9–30] were included into
the analysis. The limitations for this lit-
erature search were language problems 3.1 Short-time catheterization
(among 22 trials, four eligible trials 3.1.1 Silver oxide
[10, 23, 29–30] were not fully reviewed
Three trials compared silver oxide coated
because just only abstracts were written
catheters with a standard catheter [12,
in English). Short-term catheterization is
21, 23].
defined as catheter in place up to 14 days
Johnson et al reported that silver-coated
and long-term was defined as more than
catheters reduced the incidence of UTI
30 days. There were no eligible trials that
only among women not receiving antimi-
provided data concerning indwelling cath-
crobial agents in a prospective clinical
eters in place for 15–29 days.
trial involving 482 hospitalised patients
[12] (LoE 2a). In a clinical trial involving
1309 hospitalised patients, Riley et al. [21]
recommendation (GoR) using ICUD stand-
not only failed to demonstrate the efficacy
ards (for details see Preface) [31–32].
of silver-coated catheters in the prevention
of CAUTI, as suggested in prior studies,
2.2 Analysis but also showed a significantly increased
We compared the effect of the type of the incidence of bacteriuria in male patients
urinary catheter on the risk of urinary (LoE 2a). This study found that silver-ox-
tract infection in hospitalized adults as ide impregnated urinary catheters were
follows: not effective in preventing CAUTI. Until
now, the use of more expensive silver-
1. Antiseptic impregnated urethral coated catheters to prevent CAUTI has
catheters versus standard indwelling not been supported by quality data, and
urethral catheters; resistance to silver was likely to become a
2. Antibiotic impregnated urethral problem with widespread use.
catheters versus standard indwelling Pooling the results of all three tri-
urethral catheters; als using a fixed effects model by The
543
Cochrane Review did not provide enough a standard silicone coated catheter [29].
evidence to show whether or not there This trial defined infection as patients
was a reduction in risk of developing bac- with catheters in situ > 30 days had bac-
teriuria (Relative Risk (RR) 0.89, 95% teriuria greater than 105 CFU/ml. There
Confidence Interval (CI) 0.68 to 1.15) [4] were no significant differences between
(LoE 1a). There was no statistically sig- the different types of catheters in terms
nificant difference in the number with of urinary tract infections because all the
bacteriuria between groups. participants had UTIs.
3.1.2 Silver alloy

4. ANTIBIOTIC IMPREGNATED
Six trials have compared silver alloy cath-
URETHRAL CATHETERS VERSUS
eters with a standard catheter [15–18,
STANDARD URETHRAL CATHETERS
25, 27, 33] (LoE 2a). All the trials defined
infection as bacteriuria greater than 105
CFU/ml. The timing of the outcome meas- 4.1 Short-term catheterization
urement varied considerably between tri- Reid et al. [34] reported that pre-
als so results were analyzed as outcomes treatment of urinary silicone latex
in two time periods (less than one week catheters in vitro with ciprofloxacin sig-
and greater than one week). Pooling the nificantly reduced the adhesion and sur-
results of all three trials using a fixed vival of the clinical isolate Pseudomonas
effects model by The Cochrane Review aeruginosa. Results of these in vitro stud-
indicated that at less than one week of ies suggest that there could be a clinical
catheterization the risk of asymptomatic role for antibiotics in preventing CAUTI
bacteriuria was statistically significantly associated with bacterial adherence to
reduced in the silver alloy group (RR prosthetic devices. Further research
0.54, 95% CI 0.43 to 0.67) [4] (LoE 1a). has continued into the use of various
Beyond one week the estimated effect was antibiotics, including gentamicin, nor-
smaller but the risk of asymptomatic bac- floxacin, nitrofurazone and minocycline
teriuria was still less in the silver alloy with rifampicin for impregnated mate-
group (RR 0.64, 95% CI 0.51 to 0.80). In rial. Among these trials, there were two
summary, these studies provide the evi- types of antibiotic coated catheters exam-
dence that a catheter coated with silver ined by randomized controlled trials.
alloy significantly decreased the risk of The trials for each were analysed in two
infection during short term period (within subgroups depending on the type of inter-
two weeks). For those catheterized for vention catheter and grouped into sepa-
less than one week the estimated risk of rate outcomes dependent upon duration
asymptomatic bacteriuria was at least a of catheterisation.
half of that with a standard catheter.
4.1.1 Minocycline and rifampicin
3.2 Long-term catheterization There was only one trial (n=124) that
3.2.1 Silver oxide compared a minocycline and rifampicin
impregnated catheter with a standard
No trials were found that addressed this
catheter [11]. Outcome measures included
comparison.
bacteriuria (greater than 104 cfu/ml) at day
three, day seven and day 14, and sympto-
3.2.2 Silver alloy matic UTI (timing not stated) as defined
Only one very small trial, in which 12 by the health care provider. Patients who
participants were enrolled, compared a received the antimicrobial-impregnated
type of silver alloyed Foley catheter with catheters had significantly lower rates of
544
bacteriuria than those in the control group silicone catheter group (seven of 77 [9.1%]
both at day seven (15.2% versus 39.7%) vs. 19 of 77 [24.7%]; incidence per 1000
and at day 14 (58.5% versus 83.5%) after catheter-days, 13.8 vs. 38.6 (adjusted
catheter insertion. Patients who received risk 0.31, 95% CI 0.14 to 0.70). Onset of
the antimicrobial-impregnated catheters CAUTI was also delayed in the nitrofura-
had significantly lower rates of gram- zone group and nitrofurazone catheters
positive bacteriuria than the control group led to fewer instances of new or changed
(7.1% versus 38.2%; P<0.001) but similar antimicrobial therapy (adjusted risk 0.27,
rates of gram-negative bacteriuria (46.4% 95% CI 0.10 to 0.69) [22].
versus 47.1%) and candiduria (3.6% ver- Pooling the results of all three tri-
sus 2.9%). Catheters impregnated with als using a fixed effects model by The
minocycline and rifampin significantly Cochrane Review indicated that at less
reduced the rate of gram-positive catheter- than one week of catheterisation the risk
associated bacteriuria up to two weeks. of asymptomatic bacteriuria was statis-
tically significantly reduced in the nitro-
furazone impregnated catheter group (RR
4.1.2 Nitrofurazone 0.52, 95% CI 0.34 to 0.78) [4]. As with
Three trials compared nitrofurazone- minocycline and rifampicin impregnated
impregnated catheters with standard catheters, at greater than one week the
catheters [9, 14, 22]. Al Habdan used a benefit from nitrofurazone impregnated
latex catheter as the standard catheter catheters in preventing bacteriuria was
whilst Lee and Stensballe both used sili- inconclusive, but the numbers were small
cone catheters as the comparison. (RR 0.31, 95% CI 0.06 to 1.66).
All outcome measures included bacte- In addition to above results, the
riuria (defined as greater than 103 cfu/ml) Cochrane Review reported the overall
and, in one trial, associated funguria [22]. effect for antibiotic impregnated cath-
Lee et al reported that the inci- eters (irrespective of antibiotic type)
dence rate of CAUTI was lower in the compared to a standard control was a sig-
nitrofurazone-coated catheter group nificant reduction in the risk of asympto-
compared with the control group [14]. matic bacteriuria at less than one week of
When the catheters were maintained catheterisation (RR 0.47, 95% CI 0.33 to
for >5 days but <7 days, the incidence 0.67). However, for more than one week,
rate of CAUTI was statistically signifi- there was no statistically significant dif-
cantly lower in the experimental group ference in the incidence of asymptomatic
compared with that in the control group. bacteriuria (RR 0.85 95% CI 0.76 to 0.96).
Considering that the incidence rate of
CAUTI is very low within five days of 4.2 Long-term catheterization
catheter insertion, provided the cath-
No trials were found that addressed this
eter was inserted aseptically and a
comparison.
closed drainage system was maintained
[35], this result is clinically important
since the effect of inhibiting CAUTI was
proven during the clinically important 5. ANTIBIOTIC IMPREGNATED
period of CAUTI expression between URETHRAL CATHETERS VERSUS
five and seven days of catheterization ANTISEPTIC IMPREGNATED
[14]. In other study, 1190 urine cultures URETHRAL CATHETERS
were obtained over 1001 catheter-days.
Catheter-associated bacteriuria and fun- No trials were found either for short- or
guria occurred less frequently in the long-term catheterization that addressed
nitrofurazone catheter group than in the this comparison.
545
6. ONE TYPE OF ANTISEPTIC needed to produce ideal urinary catheters

IMPREGNATED URETHRAL for control of CAUTI.
CATHETER VERSUS ANOTHER TYPE
OF ANTISEPTIC IMPREGNATED
URETHRAL CATHETER
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|9.5|
Infections associated with the

artificial urinary sphincter
Alexander von Bargen1, Margit Fisch2
1
Department of Urology, Asklepios Hospital Harburg, Eißendorfer Pferdeweg 52, 21075 Hamburg, Germany
2
Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D – 20246 Hamburg, Germany
Corresponding author: Dr. med. Alexander von Bargen, M.B.A., Asklepios Hospital Harburg, Eißendorfer Pferdeweg 52,
21075 Hamburg, Germany, a.bargen@asklepios.com
ABSTRACT of the device. Additionally, a special

passport handed out to the patient gives
The artificial urinary sphincter (AUS) information on the device in emergency
AMS 800 is still the most effective ther- situations. If an infection of the AUS
apy in patients with severe urinary stress occurs, removal of all components of
incontinence. Continence rates and satis- the device is required. A systemic ther-
faction of patients are high. Despite the apy with a broad spectrum antibiotic
fact that the artificial sphincter is well drug including the usual gram-positive
accepted by physicians and patients, skin flora and the predominant patho-
there are significant number of com- gens of the urogenital tract should be
plications and reoperations associated started immediately and frequent clini-
with the device. A remarkable number of cal checks should be performed. In case
infections – also known from other inter- of simultaneous erosion into the urethra
ventions using alloplastic material – are a transurethral or suprapubic catheter is
noted with the AUS (up to 12%). To avoid essential to ensure an optimal healing of
infections several important points have the urethra. A reimplantation of an AUS
to be considered. First, a strict antimicro- should not be performed before three
biotic intra- and perioperative manage- months after explantation.
ment is needed. Furthermore, intensive
education of the patient but also physi- Key words: Infection, arrosion, com-
cian involved in patients care is manda- plication, artificial sphincter, artificial
tory to prevent iatrogen damage of the urinary sphincter, ams 800, prosthesis,
AUS subsequently leading to an infection implant, urogenital
SUMMARY OF RECOMMENDATIONS satisfaction (more than 95%) are high.

Since the introduction of the narrow back
1. To avoid the infection of an AUS a cuff in 1987, mechanical durability has
strict antimicrobiotic intra- and periop- significantly improved. Nevertheless, a
erative management is needed (GoR B) significant number of complications can
2. To prevent iatrogen damage of the occur [3]. A reoperation rate up to 35%
AUS an intensive education of has been reported due to mechanical and
patients and physicians is important non-mechanical failure [4]. The typical
(GoR B) reason for mechanical failure is leakage
of one of the parts of the device, most
3. The patient should store a special common leakage of the cuff. An impor-
passport and x-rays of the device in the tant non-mechanical reason is the atro-
purse in case of emergency (GoR C) phy of the urethral tissue below the cuff
4. In case of infection of the AUS imme- which leads to recurrent incontinence.
diate removal of all components of the Recurrent incontinence can have different
device is necessary (GoR B) mechanical or non-mechanical reasons. A
5. In case of simultaneous arrosion of the rare but severe complication is the infec-
urethra a transurethral or suprapubic tion of the device. It is known from many
catheter is essential (GoR B) other alloplastic implants that the risk
of infection is high. Precautions must be
6. A broad systemic antibiotic therapy taken to keep the rate of infections low
including the usual gram-positive and in case of an infection of the device
skin flora and the predominant patho- a strict management is necessary to pre-
gens of the urogenital tract must be vent further damage to the patient.
started immediately in case of infec- This guideline should help to avoid
tion (GoR B) infections of an artificial urinary sphinc-
7. A reimplantation of an AUS should ter and present a concept to handle this
not be performed within three months complication if it occurs.
after explantation (GoR C)
2. METHODS
1. INTRODUCTION
A literature search was done by PubMed.
Urinary stress incontinence is more com- The time horizon was defined with 30
mon than expected. Besides medical prob- years, but the focus was laid on the last 15
lems it presents a severe social handicap, years. The search was performed by using
which can lead to total social isolation of the following key words in different com-
the respective person [1]. binations: infection, arrosion, complica-
In cases of severe urinary stress incon- tion, artificial sphincter, artificial urinary
tinence or failure of less invasive thera- sphincter, ams 800, prosthesis, implant.
peutic options the artificial urinary Within the last 15 years more than 200
sphincter (AUS) still represents the gold publications were identified which were
standard especially in men. The main screened by the two authors by title and
indication in men is post-prostatectomy abstract. Finally 22 publications were eval-
incontinence. Postoperative urinary uated, but eight of them had to be excluded
incontinence affects 5–30% of patients because the infection of the device as a
undergoing radical prostatectomy, with special complication was not worked out
a significant effect on their quality of life clearly enough in these studies.
[2]. Success rates related to social conti- The studies were rated according to the
nence (range 61–96%) and to patient’s level of evidence (LoE) and the grade of
550
Infections associated with the artificial urinary sphincter | 9.5 |
recommendation (GoR) using ICUD may show accumulation of fluid around the
standards (for details see Preface) [5–6]. infected parts of the device. In severe cases
Within the 14 relevant publications an abscess can be found. Blood leucocytes
there was however no prospective com- and c-reactive protein can be elevated. In
parative study on this subject (LoE 1) the case of erosion a urethroscopy confirms
nor any level 2 studies. Most of the stud- the diagnosis. A retrograde urethrogramm
ies were level 3 studies (12 of 14 studies). may also be helpful.
The remaining two studies are expert Risk factors for a higher rate of infec-
opinions (LoE 4). Additionally the expe- tion are diabetes [13], a complex history
riences, results and studies of our own and irradiation [11, 14].
department were included. During any type of revisional sur-
gery with complete or partial change
of the device smears of the balloon, the
3. DEFINITION OF THE DISEASE tubes, the cuff and the pump should be
taken. If the microbiologic investigation
Infection of the device is a rare but severe reveals any bacterial contamination a
non-mechanical complication and is specific targeted antibiotic therapy is
defined as the bacterial colonisation of initiated.
the device. There are two main reasons
for an infection of an artificial sphincter.
During surgery bacterial contamination 5. TREATMENT
may occur. Symptoms usually present
within the first days or weeks after To avoid the infection of an artificial
implantation. These infections may be sphincter a strict antimicrobiotic periop-
induced by atmospheric pathogens, unrec- erative management should be followed:
ognized urinary tract infections and skin The clinical investigation should
pathogens [3]. In rare cases an unnoticed exclude any infection of the skin e.g. myco-
intraoperative arrosion of the urethra or sis. The urine culture must be sterile. One
vagina is responsible for the infection of day prior to surgery the patient himself
the device. In contrast to this early infec- disinfects the area of the lower abdomen
tion late infection may occur. They are and external genitalia with an antiseptic
mainly caused by iatrogenic manipula- spray. Parenteral broad spectrum antibi-
tion, for example traumatic catheteriza- otic treatment is started one day before
tion or surgery (e.g. internal urethrotomy, the operation and continued until the fifth
herniotomy) in the area of the device. The postoperative day. Immediately before
rate of infections ranges between 2–12% surgery the lower abdomen and external
in the literature [3, 7–12]. However, com- genitalia is washed for 10 minutes with
parability between all these studies is an antiseptic soap, followed by routine
limited because of different follow-up, dif- disinfection. The components of the device
ferent cuff locations, different number of are stored in an antibiotic solution before
study attendees, different indications and implantation (not required for coated
complexity of patient histories. devices) (LoE 4, GoR B).
To avoid postoperative erosion with
subsequent infection, an intensive edu-
4. CLINICAL EVALUATION/RISK cation of patients and physicians is
ASSESSMENT important (LoE 4, GoR B). Furthermore
the patient has to be able to handle the
Clinical symptoms of infection are: scro- sphincter mechanism and should be
tal, perineal or abdominal pain, reddening, able to deactivate the system. He has to
tumescence, dysuria, fever. Ultrasonography be informed that the system has to be
551
deactivated before any transurethral (one Klebsiella, one Enterobacter, one

manipulation (catheterisation, urethros- Pseudomonas species). Cultures of the
copy) is performed. For emergencies a periprosthetic fluid were not available
special passport with x-rays of the device in two patients and they were sterile in
filled with contrast medium is handed two patients. These data support the
over to the patient. Patient should carry need for a broad antibiotic therapy if
this passport all the time with him the pathogen is unknown (e.g. a cepha-
(LoE 4, GoR C). losporin of the second or third generation
If erosion or infection occurs immediate combined with gentamycin). The course
removal of all components of the device is of healing is monitored by clinical exami-
required (LoE 3, GoR B). Reimplantation nations, investigation of infection param-
should be performed at a later stage eters in the blood and ultrasonography.
[3–4], preferably after three months A reimplantation of the AUS should not
(LoE 4, GoR C). During explantation, rec- be performed within three months after
ommendations for septic surgery must infection or erosion [16] (LoE 4, GoR C).
be followed. Antibiotic lavage, wound
debridement, sufficient drainage of the
whole area and keeping the wound open 6. FURTHER RESEARCH
may be indicated. In patients with ero-
sion of the device into the urethra urinary Attention should be paid to the reasons
diversion with suprapubic cystostomy for the large varieties of infections in dif-
or transurethral catheter is required [4] ferent studies after the implantation of
(LoE 3, GoR B). Time of urinary diversion an artificial urinary sphincter. For early
depends on the extent of the defect and infections particularly, it could be possible
should be continued for a minimum of two to detect the causes within the different
weeks. Before voiding is initiated com- perioperative managements. Determining
plete closure of the defect should be docu- and respecting the important parts of this
mented by voiding cystogram. management should lead to a reduction
When infection is suspected or con- in the rate of infection.
firmed, systemic antibiotic therapy must Further technical developments in
be started immediately. As the pathogenic antimicrobial surface coating will hope-
organism initially is unknown, antibiotic fully decrease the rate of infections.
drugs given should be effective against
the usual Gram-positive skin flora but
also against the typical predominant 7. CONCLUSIONS
organisms of the urogenital tract (LoE
3, GoR B). Bryan et. al [15] described Infections of the artificial urinary sphinc-
these two origins of bacteria for infec- ter after implantation still occur in a
tions found during salvage procedures significant number, varying in different
for non eroded artificial urinary sphinc- studies. Early infections can be reduced
ters. An older study on periprosthetic by strictly following a broad antimicro-
infections [13] investigated the respon- bial protocol. Late infections after sev-
sible agents for infections in 15 artificial eral months or years are mostly caused
urinary sphincters and inflatable penile by iatrogenic manipulation. Intensive
prostheses out of a total of 556 implanta- education of all participants is impor-
tions. Eight patients had infections with tant to avoid these complications. In
Gram-positive organisms (five S. epider- the case of an infection, an immediate
midis, one S. aureus, one Staphylococcus explantation of the system is necessary.
species, one Enterococcus species) and A re-implantation is possible with a time
three had Gram-negative infections interval of several months.
552
Infections associated with the artificial urinary sphincter | 9.5 |
REFERENCES atrophy. J Urol, 2002. 167(5): 2075–8;

discussion 2079.
1. Welz-Barth A, [Incontinence in old age: a 9. Kowalczyk JJ, Spicer DL, and
social and economic problem]. Urologe A, Mulcahy JJ, Long-term experience with
2007. 46(4): 363–4, 366–7. the double-cuff AMS 800 artificial urinary
2. Peyromaure M, Ravery V, and Boccon- sphincter. Urology, 1996. 47(6): 895–7.
Gibod L, The management of stress 10. O’Connor RC, Gerber GS, Avila D, Chen
urinary incontinence after radical AA, and Bales GT, Comparison of out-
prostatectomy. BJU Int, 2002. 90(2): comes after single or DOUBLE-CUFF
155–61. artificial urinary sphincter insertion.
3. Hussain M, Greenwell TJ, Venn SN, and Urology, 2003. 62(4): 723–6.
Mundy AR, The current role of the artifi- 11. Walsh IK, Williams SG, Mahendra V,
cial urinary sphincter for the treatment Nambirajan T, and Stone AR, Artificial
of urinary incontinence. J Urol, 2005. urinary sphincter implantation in the
174(2): 418–24. irradiated patient: safety, efficacy and
4. Raj GV, Peterson AC, and Webster GD, satisfaction. BJU Int, 2002. 89(4): 364–8.
Outcomes following erosions of the arti- 12. Dalkin BL, Wessells H, and Cui H, A
ficial urinary sphincter. J Urol, 2006. national survey of urinary and health
175(6): 2186–90; discussion 2190. related quality of life outcomes in men
5. Abrams P, Khoury S, and Grant A, with an artificial urinary sphincter for
Evidence – based medicine overview of the post-radical prostatectomy incontinence.
main steps for developing and grading J Urol, 2003. 169(1): 237–9.
guideline recommendations. Prog Urol, 13. Montague DK, Periprosthetic infections.
2007. 17(3): 681–4. J Urol, 1987. 138(1): 68–9.
6. U.S. Department of Health and Human 14. Gomha MA and Boone TB, Artificial
Services Public Health Service Agency for urinary sphincter for post-prostatectomy
Health Care Policy and Research, 1992: incontinence in men who had prior radio-
115–127. therapy: a risk and outcome analysis.
7. Raj GV, Peterson AC, Toh KL, and J Urol, 2002. 167(2 Pt 1): 591–6.
Webster GD, Outcomes following revi- 15. Bryan DE, Mulcahy JJ, and Simmons
sions and secondary implantation of the GR, Salvage procedure for infected non-
artificial urinary sphincter. J Urol, 2005. eroded artificial urinary sphincters.
173(4): 1242–5. J Urol, 2002. 168(6): 2464–6.
8. Guralnick ML, Miller E, Toh KL, and 16. Webster GD and Sherman ND,
Webster GD, Transcorporal artificial Management of male incontinence follow-
urinary sphincter cuff placement in cases ing artificial urinary sphincter failure.
requiring revision for erosion and urethral Curr Opin Urol, 2005. 15(6): 386–90.
553
|9.6|
Infections associated with

penile prostheses
Bela Koves, Peter Tenke, Karoly Nagy
Corresponding author: Bela Koves, MD, Department of Urology, South-Pest Hospital, 1 Koves Str., H-1204 Budapest,
Hungary, bkoves@gmail.com
ABSTRACT appropriate preoperative preparations.

Antibiotics should be administered one
Inflatable penile prostheses have been to two hours prior to surgery and con-
available since the 1970s. Designs revi- tinued for 36–48 hours postoperative. To
sions and engineering changes have decrease the infectious complications of
reduced the mechanical malfunctions penile prosthesis implantations, the use
associated with these prostheses to less of antibiotic impregnated penile pros-
than 5%. As penile prostheses are now theses can be recommended. Although
expected to function for an average of preliminary data using hydrophilic coat-
eight to 12 years post implantation, infec- ing device shows promise, long-term fol-
tion has become a more significant prob- low-up and prospective studies are not
lem. The majority of prosthesis infections yet available, therefore no recommenda-
occur secondary to bacterial seeding at tion can be made. In case of subclinical
the time of surgery, Staphylococcus spe- infection initial trial of oral antibiotic
cies, especially Staphylococcus epider- therapy using long-term antibiotics can
midis are the most common pathogens be recommended. If pain fails to resolve
found in penile prostheses infection. or rapidly returns after antibiotics, sur-
Known risk factors are urinary tract gical intervention is appropriate. In case
infection, infections elsewhere in the body of clinically apparent infection surgical
and hematogenous spread. The role of intervention along with antibiotics is of
diabetes mellitus and spinal chord injury critical importance. The traditional treat-
as risk factors of penile prosthesis infec- ment is the immediate removal of all the
tion are contradictory. Because in most components followed by delayed reim-
cases bacterial contamination occurs at plantation two to 12 months later. To
the time of surgery, it is essential to use avoid complications of late reinsertion the
Infections associated with penile prostheses | 9.6 |
salvage protocol is a treatment alterna- 6. If pain fails to resolve or rapidly

tive of traditional delayed reimplantation. returns after antibiotics, surgical
In patients with life-threatening systemic intervention is appropriate (GoR A).
conditions such as septicemia, or dia- 7. In case of clinically apparent infec-
betic ketoacidosis, or in whom necrotizing tion surgical intervention along with
infections of penile skin is occurring sal- antibiotics is of critical importance
vage procedure is not recommended. (GoR A).
Key words: penile prosthesis, infection, 8. To avoid complications of late rein-
complication, antibiotic impregnation, sertion the salvage protocol is a
salvage treatment alternative of traditional
delayed reimplantation (GoR B).
9. In patients with life-threatening sys-
temic conditions such as septicemia,
or diabetic ketoacidosis, or in whom
Prevention necrotizing infections of penile skin
1. Washing the genital region with is occurring salvage procedure is not
strong soap in the days before the recommended (GoR B).
procedure, preoperative shaving and 10. There is no significant benefit of
an aggressive scrub of the operat- delayed salvage procedure compared
ing area with povidone-iodine in the to immediate salvage protocol, there-
operating room should be performed fore it is not recommended (GoR B).
(GoR C).
2. Prophylactic antibiotics should be
administered 1–2 hours prior to sur- 1. INTRODUCTION
gery and continued for 36–48 hours
postoperative (GoR B) Phosphodiesterase type 5 (PDE-5)
3. To decrease the infectious com- inhibitors have achieved widespread
plications of penile prosthesis acceptance in the treatment of erectile
implantations the use of antibiotic dysfunction. However, penile implants
impregnated penile prostheses can be are still a popular choice, especially in
recommended (GoR A) patients who have failed to successfully
achieve erections by chemical enhance-
4. Although preliminary data using
ment or in those who have considerable
hydrophilic coating device shows
scar tissue in the penis resulting in erec-
promise, long-term follow-up and
tion deformalities [1].
prospective studies are not yet avail-
The types of prosthesis most commonly
able, therefore no recommendation
implanted are the three-piece inflatable
can be made (GoR D)
device, the two-piece inflatable device,
and the soft and malleable prosthesis. In
Treatment the last few years the three-piece inflat-
5. In case of subclinical infection initial able device has been used for prefer-
trial of oral antibiotic therapy using ence, as it improves the erection with the
long-term antibiotics (ciprofloxacin most acceptable cosmetic and functional
500mg twice daily) can be recom- results [2–3].
mended. Following initiation of Inflatable penis prostheses have been
antibiotics, pain suppression should available since the 1970s. Designs revi-
suggest continuing antibiotics for sions and engineering changes have
10–12 weeks (GoR C). reduced the mechanical malfunctions
555
associated with these prostheses to less different combinations: penile prosthesis,

than 5% [4–5]. As penile prostheses are infection, complication, bacteriuria, coat-
now expected to function for an average ing, salvage. The identified publications
of eight to 12 years post implantation, were screened by title and abstract,
infection has become a more significant after exclusion of duplicates a total of
problem. The incidence of infection has 33 publications were included into the
been reported to range from 0.5–17.7% analysis. The studies were rated accord-
[6–7] usually about 1–3% in case of pri- ing to the level of evidence (LoE) and the
mary implantation, and about 10–13% in grade of recommendation (GoR) using
case of revision or reimplantation [8]. ICUD standards (for details see Preface)
Penile prosthesis infection is tradition- [10–11].
ally treated by systematic and local anti-
biotics application with the removal of
the device followed by reinsertion within 3. PATHOGENESIS/EPIDEMIOLOGY
two to 12 months. However, removal of
the device along with inflammation from Staphylococcus species, especially
the infectious process leads to corpo- Staphylococcus epidermidis are the most
real fibrosis and scarring, which almost common pathogens found in penile pros-
always results in penile shortening and theses infection, isolated from 35–56% of
may make dilation of the corporeal bod- infected penile prostheses patients [12].
ies very difficult, resulting reinsertion of Gram-negative enteric bacteria including
a new device more complicated and some- Proteus mirabilis, Pseudomonas aerugi-
times impossible [1, 9]. nosa, Escherichia coli and Serratia mar-
To reduce the risk of device associ- censes may also be pathogens, accounting
ated infections and to avoid the difficul- for 20% of infections [8]. In severe infec-
ties associated with late reinsertions tions Gram-negative bacteria can com-
many modifications have been developed bine with anaerobic organisms, such
such as antibiotic or hydrophilic coated as Bacteroides species, and lead to gan-
devices and immediate replacement of the grene of the penis. Fungi, mycobacteria
infected prosthesis (salvage techniques). and Neisseria gonorrhea have also been
The aim of this chapter is to summa- reported as etiological agents in penile
rize the different methods of preven- prosthesis infections [8, 13].
tion and treatment of penile prosthesis The majority of prosthesis infections
infections. occur secondary to bacterial seeding at
the time of surgery. Prosthetic materials
attract bacteria and support subsequent
2. METHODS biofilm formation. In a multicenter study
culture positive bacteria were found in
We surveyed the extensive literature 70% of patients with clinically uninfected
regarding the prevention and treatment penile prostheses during revision surgery
of penile prosthesis infections. We sys- for mechanical malfunction, with 90%
tematically searched for meta-analyses growing Saphylococcus species [14], which
of randomised controlled trials available have an enhanced ability to produce gly-
in Medline by giving preference to the cocalyx biofilm.
Cochrane Central Register of Controlled Penile prosthesis infections can be
Trials and also considered other rel- divided into clinically apparent and sub-
evant publications until February clinical infections. Most of the infections
2009. Studies were identified through occur within the first 12 months follow-
a PubMed search. The search was per- ing implantation [15]. Clinical infec-
formed by using the following items in tions present with fever, penile pain,
556
erythema, induration, purulent drain- 5.2 Perioperative antibiotic

age from the wound and extrusion while prophylaxis
subclinical infections most often mani- Athough the effectiveness of prophylactic
fest by chronic prosthesis-associated perioperative antibiotics for implanta-
pain. tion of penile prosthesis has never been
proven in prospective series their use
has become established and favored by
4. RISK FACTORS most urologists. Antibiotics should be
administered one to two hours prior to
Known risk factors for penile prosthesis surgery and continued for 36–48 hours
infection include urinary tract infection, postoperative (LoE 3, GoR B). Most com-
infections elsewhere in the body and mon pathogenic organisms most likely
hematogenous spread [16–17] (LoE 3). to produce infections must be targeted
There is an increased incidence of infec- when choosing prophylactic antibiotics.
tion among patients undergoing primary Therefore traditional prophylaxis include
implantation with penile reconstruction a parenteral aminoglycoside for Gram-
or secondary prosthesis revision com- negative and a first- or second generation
pared to primary implantation alone, cephalosporin or vancomycin for Gram-
probably due to the increased dura- positive organisms coverage [22–23].
tion of surgery [7, 18] (LoE 3). The role Schwarz et al found in a randomized
of diabetes mellitus and spinal chord prospective trial of 20 patients that oral
injury as risk factors of penile prosthe- fluoroquinolone (ofloxacin) administered
sis infection are contradictory [18–19] 2 hours before surgery achieved signifi-
(LoE 3). cantly higher intracavernosal levels and
was more cost-effective than the combi-
nation of gentamicin and cefazolin [22]
5. PREVENTION (LoE 1a). To estimate the safety and effi-
cacy of this prophylaxis modality, further
5.1 General aspects studies with similar settings, but bigger
sample size should be performed.
Because in most cases bacterial contam-
ination occurs at the time of surgery, it
5.3 Antibiotic impregnation
is essential to use appropriate preopera-
tive preparations. Short preoperative Early efforts in device impregnation
hospital stays have been documented to focused on coating catheters with anti-
maintain low virulence [12]. It is impor- biotics. In 1995 Raad et al reported that
tant to eliminate skin infections and in in vitro studies catheters coated with
to have sterile urine prior to surgery. a combination of rifampin and minocy-
Washing the genital region with strong cline provided significantly better inhibi-
soap in the days before the procedure, tory activities against S. epidermidis,
preoperative shaving and an aggres- S. aureus and E. faecalis than catheters
sive scrub of the operating area with coated with either drug alone or vanco-
povidone-iodine in the operating room mycin [24]. After additional in vitro and
should be performed [1, 20] (LoE 3–4, in vivo studies in 2001 the US Food and
GoR C). Drug Administration approved the use of
During surgery adequate sterile tech- penile prosthesis coated with a combina-
nique, short operating time, minimal tis- tion of rifampin and minocycline called
sue devitalization along with effective InhibiZone. The concentrations of the
wound closure can all decrease the rate of antibiotics, while adequate for decreas-
perioperative infections [21] (LoE 3–4). ing colonization, provided only minimal
557
serum levels of the agents [5]. Coated experience with the device [30], the infec-
inflatable penile prostheses are implanted tion rate for 2357 coated penile prosthe-
in a fashion similar to those without anti- ses was 1,06 % compared to 2,07 % in 482
biotic treatment except that the devices uncoated penile prostheses implanted
are not soaked prior to implantation [5]. over the same time period (LoE 3).
In a retrospective study of more than Although preliminary data using this
4,000 prostheses, Carson et al reported device shows promise, long-term fol-
61.7% decrease in perioperative infection low-up and prospective studies are not
with InhibiZone compared to controls [25] yet available; therefore no recommenda-
(LoE 3). In 2007 Wilson et al. began a tion can be made (GoR D).
prospective randomized study comparing
the infection rate of rifampin and mino-
cycline coated implants with implants 6. TREATMENT
without impregnation [26] (LoE 1b). After
it became evident that the infection rate Subclinical infections may be more com-
was less with the impregnated group mon than clinically apparent infections
they abandoned the other arm because of [31]. These infection which most often
ethical considerations and compared they manifest by chronic prosthesis-associated
results with the previously published pain, are difficult to diagnose and even
series of the same surgical team with more challenging to treat. Parsons et al.
noncoated implants [6, 27]. The use of recommend initial trial of oral antibiotic
antibiotic coated inflatable penile prosthe- therapy using long-term antibiotics (cip-
sis resulted in a statistically significant rofloxacin 500mg twice daily) [31] (LoE
reduction in the infection rates compared 4, GoR C). Following initiation of antibi-
with the historical data in nondiabetic otics, pain suppression should suggest
virgin implant patients (p=0,0024), dia- continuing antibiotics for 10–12 weeks.
betic virgin implant patients (p=0,0141) The authors reported a 60% success rate
and in revision patients in whom wash- with conservative treatment of subclini-
out with antiseptic solutions was used cal penile prosthesis infections. The use
(p= 0,0095). Revision without washout of oral cephalosporins (cefalexin and
had the same infection rate (10%) as cephradine) has also been suggested for
with noncoated implants. To decrease the 10–12 weeks, although success rates are
infectious complications of penile pros- lower at 25–30% [12, 32] (LoE 4). If pain
thesis implantations the use of antibiotic fails to resolve or rapidly returns after
impregnated penile prostheses can be rec- antibiotics, however, surgical interven-
ommended (GoR A). tion is appropriate (GoR A). Parsons et al.
have reported 90% success rate in treat-
ing these prostheses with an exchange
5.4 Hydrophilic coating
protocol including systemic antibiotics for
In 2002 a hydrophilic penile prosthesis 24–48 h using vancomycin. The suspected
coating was developed which has been infected prosthesis is then removed and
shown to decrease bacterial adherence in a combination of vancomycin and pro-
vitro and in animal models [28]. Further, tamine was used for antibiotic irrigation
this coating absorbs surgeon chosen prior to reimplantation of a new prosthe-
intraoperative antibiotics that can elute sis. Patients are maintained on vancomy-
into surrounding tissues over 24–72 h to cin and parental antibiotics for one week
further decrease infection [29] (LoE 2b). [12, 31].
Clinical data on the hydrophilic coated In case of clinically apparent infection
inflatable penile prosthesis is limited. surgical intervention along with antibiot-
Wolter et al. presented their one-year ics is of critical importance (GoR A). The
558
traditional treatment is the immediate The delayed salvage procedure con-

removal of all the components followed by sists of placement of a drainage tube after
delayed reimplantation 2–12 months later removal of the prosthesis; antibiotic solu-
[20, 33]. The advantage of this solution is tion is irrigated through the drain and a
that the new implant is scheduled only new prosthesis is placed about 3 days later.
when the infection has completely cleared. In a retrospective review of 41 patients
However, removal of the device along with reported by Knoll there was no statistically
inflammation from the infectious process significant difference between immediate
leads to corporeal fibrosis and scarring, and delayed salvage procedure [35] (LoE 3),
which almost always results in penile therefore it is not recommended (GoR B).
shortening and may make dilation of the
corporeal bodies very difficult, resulting
reinsertion of a new device more compli- 7. FURTHER RESEARCH
cated and sometimes impossible [1, 9].
To avoid difficult reinsertion and main- Prospective studies and long-term follow
tain as much penile length as possible, a up are needed to make stronger recom-
salvage protocol was instituted in 1991. mendations about the different methods
The salvage procedure involves remov- in the prevention or treatment of penile
ing all parts of the infected prosthesis, prostheses infections, especially about the
washing the wound, and replacing the hydrophilic coated penile prosthesis.
device at the same procedure. Mulcahy
et al. recommend a sequence of irrigating
solutions including kanamycin (80 mg/l) 8. CONCLUSIONS
and bacitracin (1 g/l) in normal saline
followed by half-strength hydrogen per- The efforts to apply more effective meth-
oxide, half-strength povidone/iodine solu- ods of prevention and the new develop-
tion, 5 l of pressurized normal saline ments of prosthesis coatings resulted a
containing vancomycin (1 g) and gen- significant reduction of the infectious
tamicin (80 mg), half-strength povidone/ complications of penile prosthesis implan-
iodine, half-strength hydrogen peroxide, tation. Further improvements of surgical
and finally another kanamycin/bacitracin procedures and prosthesis materials and
solution [34]. Gloves, instruments, gowns, coatings can lead to further decrease of
and drapes are changed and a new inflat- the infection rates in the future.
able penile prosthesis is immediately
implanted. Postoperatively, patients are
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2. Bettocchi C, Ditonno P, Palumbo F,
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Lucarelli G, Garaffa G, Giammusso B,
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and Battaglia M, Penile Prosthesis: What
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In patients with life-threatening sys- Urol, 2008: 573560.
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ommended [1, 9] (LoE 4, GoR B). 97(1): 129–33.
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Efficacy, safety and patient satisfaction hematogenous infection of penile prosthe-
outcomes of the AMS 700CX inflatable ses. J Urol, 1988. 139(1): 50–2.
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Group. J Urol, 2000. 164(2): 376–80. penile implants during invasive dental
5. Carson C, Antibiotic impregnation of procedures: a national survey of urolo-
inflatable penile prostheses: effect on gists. J Urol, 1992. 148(6): 1801–4.
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6. Wilson SK and Delk JR, 2nd, Inflatable 402–4.
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561
Chapter |10|
Healthcare associated
Chair: Truls E. Bjerklund Johansen
CHAPTER OUTLINE
10.2 Criteria for health care associated urinary tract
infections: an update on current definitions 567
10.3 Epidemiology, treatment and prevention of
healthcare-associated urinary tract infections 575
10.4 Urinary tract infections in long term care patients 589
|10.1|
Introduction
Truls E. Bjerklund Johansen
Urology Department of Urology, Århus University Hospital, Skejby, Aarhus University, Århus, Denmark
Corresponding author: Truls E. Bjerklund Johansen, MD, PhD, Chairman and Professor, Urology Department,
Århus University Hospital, Skejby, Aarhus University, Brendstrupgårdvej 100, DK-8200 Århus N, Denmark
Tel office: (45) 89 49 59 00, tebj@ki.au.dk
Without effective antimicrobial treatment is clear. In asymptomatic bacteriuria

urinary tract infection (UTI) can create (ASB), and when patients cannot
big problems in urology. Without effective communicate about symptoms, the
antimicrobial prophylaxis most of mod- situation is more complex. Because of
ern urological surgery would be high risk outpatient procedures and sometimes
surgery. Even today with effective anti- very short hospitalisation, observa-
biotics available in most countries, the tion time to define HAUTI (usually 48
prevalence of healthcare associated UTI hours in the past) has to be revisited
(HAUTI) in urology departments is on (see chapter 10.2).
average about 10% [1] and UTI accounts 2. There are very few situations when
for more than 40% of all health care asso- screening for and treating ASB is evi-
ciated infections [2]. dence based, such as in pregnancy and
In this section several important before invasive urological procedures
aspects are discussed: [4]. In most other situations detection
1. Healthcare associated urinary tract of ASB may lead to administration
infection (HAUTI) means an infection of antibiotics that are not indicated.
caused by a healthcare event, whether Considering ASB an infection creates
during hospital admission, accommo- a dilemma when the prevalence of
dation in nursing homes or during an HAUTI is used as a quality indica-
outpatient visit. To diagnose HAUTI tor. For these reasons ASB should be
there must be no evidence that the regarded as colonisation, probably as
infection was present or incubating a risk factor under certain circum-
at the time of admission [3]. In case stances, but no longer as an infection,
of a negative culture and no sympto- which unfortunately is not so clearly
matic UTI at admission the situation stated in the CDC criteria [3].
3. In many developing countries there antimicrobial prophylaxis as well as

is poor availability of antibiotics, the number of blood and urine cul-
and in some regions even in Europe tures taken.
today there are countries where 6. HAUTI should be prevented with
available antibiotics are no longer all measures available. Basic hygi-
effective. Modern urological surgery enic and surgical principles must be
has to rely on effective antimicro- adhered to. Antimicrobial prophylaxis
bial prophylaxis otherwise UTI can never compensate for poor surgi-
will become a severe problem. Most cal technique. Risk factors for HAUTI
HAUTIs are complicated infections, must be analysed and avoided.
although the group is not very homo- Urinary catheters are the most impor-
geneous. Furthermore, HAUTIs are tant factor, and biofilm is a key issue
frequently caused by other patho- [7]. Antimicrobial treatment of HAUTI
gens than those found in community in urology departments should be
acquired UTI, and these pathogens based on close collaboration between
often show reduced antimicrobial urologists, microbiologists and infec-
susceptilibility. tious disease specialists as well as
4. It is suggested that ASB should no knowledge on pharmacological proper-
longer be recognised as infection but ties of antibiotics.
only as a risk factor under certain Because of the importance especially
circumstances. Several years of regis- in urology an international prevalence
tration of NAUTI and HAUTI in the study on HAUTI in urology departments
GPIU-studies have shown that ASB is has been run on an annual basis since
the most common type of UTI reported 2003 by the European Association of
(>30%) [5]. We also know that in Urology/European Section on Infections
hospitals urinary pathogens are fre- in Urology in collaboration with many
quently transferred between patients other national and international scientific
[6]. ASB is thus still important, but societies. This global prevalence study on
probably more as a source of informa- infection in urology (GPIU) is fully spon-
tion about the bacterial environment sored by EAU. A research group of more
in urology departments and intensive than 100 hospitals is established. More
care units, than as a basis for treat- than 20 000 patients have been screened
ment. Monitoring ASB is probably and a database with detailed informa-
important for learning how to tailor tion from more than 2000 patients with
antimicrobial prophylaxis in each HA-UTI has been built. An extensive
urology department. evaluation is ongoing.
5. Because the prevalence of HAUTI
has become an important quality
REFERENCES
parameter, hospitals and clinical
departments are often compared. The
1. Bjerklund Johansen TE, Cek M, Naber
prevalence of HAUTI depends on the
K, Stratchounski L, Svendsen MV, and
type of surgery, the hygienic meas- Tenke P, Prevalence of hospital-acquired
ures and the antimicrobial prophy- urinary tract infections in urology depart-
laxis. For this reason key urological ments. Eur Urol, 2007. 51(4): 1100–11;
interventions should be established discussion 1112.
for comparison and the prevalence 2. Gastmeier P, Kampf G, Wischnewski N,
of HAUTI should be related to the Hauer T, Schulgen G, Schumacher M,
types of surgery being undertaken Daschner F, and Ruden H, Prevalence of
in a department, the extent of nosocomial infections in representative
565
Chapter | 10 | Healthcare associated urinary tract infections
German hospitals. J Hosp Infect, 1998. from PEP and PEAP-studies. Int J Antimicr
38(1): 37–49. Agents, 2006. 28(Suppl): S91-S107.
3. Horan TC, Andrus M, and Dudeck MA, 6. Wagenlehner FM, Krcmery S, Held
CDC/NHSN surveillance definition of C, Klare I, Witte W, Bauernfeind
health care-associated infection and cri- A, Schneider I, and Naber KG,
teria for specific types of infections in the Epidemiological analysis of the spread of
acute care setting. Am J Infect Control, pathogens from a urological ward using
2008. 36(5): 309–32. genotypic, phenotypic and clinical param-
4. Nicolle LE, Asymptomatic bacteriuria: eters. Int J Antimicrob Agents, 2002.
review and discussion of the IDSA guide- 19(6): 583–91.
lines. Int J Antimicrob Agents, 2006. 28 7. Tenke P, Kovacs B, Bjerklund Johansen
Suppl 1: S42–8. TE, Matsumoto T, Tambyah PA, and
5. Bjerklund-Johansen TE, Cek M, Naber KG, Naber KG, European and Asian guide-
Stratchounski L, Svenden MV, and lines on management and prevention of
P T, Hospital acquired urinary tract infec- catheter-associated urinary tract infec-
tions in urology departments: pathogens, tions. Int J Antimicrob Agents, 2008. 31
susceptibility and use of antibiotics. Data Suppl 1: S68–78.
566
|10.2|
Criteria for healthcare associated

urinary tract infections: an EAU/
ESIU update on current definitions
Truls E. Bjerklund Johansen1, Henry Botto2, Mete Cek3, Magnus Grabe4, Peter Tenke5, Florian M.E.
Wagenlehner6, Kurt G. Naber7
1
Urology Department of Urology, Århus University Hospital, Skejby, Århus University, Århus, Denmark
2
Department of Urology, Hopital Foch, Suresnes Cedex, France
3
Department of Urology, Taksim Teaching Hospital Istanbul, Istanbul, Turkey
4
Department of Urology, Malmö General Hospital, University of Lund, Malmö, Sweden
5
Department of Urology, Jahn Ference Del-Pesti Korhaz, Budapest, Hungary
6
Department of Urology, University of Giessen-Marburg, Giessen, Germany
7
Corresponding Author: Truls E. Bjerklund Johansen, MD, PhD, Chairman and Professor, Urology Department,
Århus University Hospital, Skejby, Aarhus University, Brendstrupgårdvej 100, DK-8200 Århus N, Denmark
ABSTRACT infections in urology, because the same

criteria have to be used if data of differ-
Healthcare associated infections (HAI) ent institutions are collected/compared
have a high impact not only on the indi- and if the efficacy of any intervention has
vidual patient but also on the total to be tested.
healthcare system. Healthcare associated Key words: healthcare associated infec-
urinary tract infections (HAUTI) are the tions, nosocomial infections, urinary tract
most frequent HAI in a general hospital. infections, asymptomatic bacteriuria
The EAU/ESIU recommends in general
the CDC/NHSN criteria for HAI and espe-
cially HAUTI. However, the ESIU has SUMMARY OF RECOMMENDATIONS
adapted and modified the CDC/NHSN
criteria for special usage in urology and The EAU/ESIU recommends in general
especially when urologists are taking part the CDC/NHSN criteria for HAI and espe-
in the annual global prevalence study on cially HAUTI [1]. The ESIU has adapted
Received 03 Febr 2010-CorrTi-05–02–10-Na-05–02–05

and modified the CDC/NHSN criteria for traumatizing urological interventions

usage in urology, especially when urolo- of the urinary tract, because treat-
gists are taking part in the annual GPIU ment of ASB has to be initiated before
study. any such interventions (GoR A).
In the following only recommendations 7. Health care associated asympto-
are mentioned which are either clarifica- matic bacteriuria (HAASB) should
tions or modifications of the CDC/NHSN be considered as colonisation, prob-
criteria for HAUTI [1], which are com- ably as risk factor under certain
pletely listed in Table 1. circumstances, but not as infection
1. The time interval is no longer a cri- (GoR B).
terion for the definition of a HAUTI. 8. If differentiation between sympto-
It should be replaced by a negative matic HAUTI (SHAUTI) and HAASB
urine culture on admission and a is difficut, e.g. intensive care medi-
careful clinical evaluation that there cine, the diagnosis should be based
was no UTI present on admission on clinical judgment by experienced
(GoR B). specialists (GoR B).
2. During the study time (month) all 9. For routine surveillance we rec-
patients should have at least one ommend that the time interval
(in case of ASB without indwelling for diagnosing HAUTI or HAASB
catheter urine two) culture(s) follow- should be seven days after the
ing any urological intervention to intervention, or in case of ongoing
improve the diagnosis of HASUTI/ antibiotic therapy seven days after
HAASB, not depending too often on the end of antibiotic therapy, or in
surrogate parameters only (GoR B). case of an indwelling urinary cath-
3. An exacerbation from ASB to a eter seven days after removal of the
symptomatic UTI after any interven- catheter (GoR B).
tion has to be considered healthcare 10. Continuous surveillance of regular
associated caused by an endogenous urine cultures results should be the
source (GoR A). rational basis for tailoring antimicro-
4. Any extension of infection already bial prophylaxis (GoR B).
present at admission with a change 11. Key urological interventions should
in pathogen, including emergence be established for comparison and
of resistance, has to be considered the prevalence of HAUTI should be
healthcare associated (GoR A). related to the types of surgery being
5. Screening for HAASB may not be undertaken in the department as
necessary routinely because treat- well as the extent of the antimicro-
ment is not indicated in general bial prophylaxis (GoR B).
(GoR C). Since HAASB can con- 12. Physicians/institutions responsible
tribute to the environmental flora for the interventions have to inform
by cross contamination/infection in not only the patient, but also the
certain time intervals screening for following treating physician about
HAASB should be included into the the specific risk of HAI in a specific
surveillance of HAI (GoR B). This patient and the following treating
is also necessary during the GPIU physician has to inform the physi-
study period (GoR A). cian/institution responsible for the
6. Screening for ASB is always nec- intervention about any occurrence of
essary before all the mucosa HAI in this specific patient (GoR A).
568
Criteria for healthcare associated urinary tract infections | 10.2 |
Table 1 Summary of CDC/NHSN criteria of healthcare associated urinary tract infection (HAUTI)
according to Horan et al 2008 [1].
General criteria of healthcare associated infection (HAI) and HAUTI

1. (For the diagnosis of an HAI) “there must be no evidence that the infection was present or incubating at the time of
admission to the acute care setting”.
2. HAIs may be caused by infectious agents from endogenous or exogenous sources.
3. Infections are not considered HAI if associated with complications or extensions of infections already present on admis-
sion, unless a change in pathogen or symptoms strongly suggests the acquisition of a new infection.
4. The following conditions are not infections:
4.1 Colonization, which means the presence of microorganisms on skin, on mucous membranes, in open wounds, or in
excretions or secretions but are not causing adverse clinical signs or symptoms; and
4.2 Inflammation that results from tissue response to injury or stimulation by non-infectious agents,
such as chemicals
5. HAUTI comprises healthcare associated symptomatic UTI (HASUTI), asymptomatic bacteriuria (HAASB), and other infec-
tions of the urinary tract (HA-OUTI), such as kidney, ureter, bladder, urethra, or tissue surrounding the retroperitoneal or
perinephric space.
I. Symptomatic urinary tract infection (HASUTI)

A symptomatic urinary tract infection must meet at least 1 of the following criteria:
1. Patient has at least 1 of the following signs or symptoms with no other recognized cause: fever (>38°C), urgency, fre-
quency, dysuria, or suprapubic tenderness (in patient <1 year of age signs and symptoms with no other recognized
cause: fever (>38°C), hypothermia (37°C), apnea, bradycardia, dysuria, lethargy, or vomiting)
and
patient has a positive urine culture, that is, >105 microorganisms per cc of urine with no more than 2 species of
microorganisms.
2. Patient has at least two (in patient <1 year of age one) of the following signs or symptoms with no other recognized
cause: fever (>38°C), urgency, frequency, dysuria, or suprapubic tenderness (in patient <1 year of age signs and
symptoms with no other recognized cause: fever (>38°C), hypothermia (37°C), apnea, bradycardia, dysuria, lethargy, or
vomiting)
and
at least 1 of the following
a. positive dipstick for leukocyte esterase and/ or nitrate
b. pyuria (urine specimen with >10 white blood cell [WBC]/mm3 or >3 WBC/highpower field [HPF] of unspun urine)
c . organisms seen on Gram’s stain of unspun urine
d. at least 2 urine cultures with repeated isolation of the same uropathogen (gramnegative bacteria or Staphylococcus
saprophyticus) with >102 colonies/mL in non-voided specimens
e. >105 colonies/mL of a single uropathogen (gram-negative bacteria or S. saprophyticus) in a patient being treated with
an effective antimicrobial agent for a urinary tract infection
f. physician diagnosis of a UTI
g. physician institutes appropriate therapy for a UTI
II Asymptomatic bacteriuria (HAASB)

An asymptomatic bacteriuria must meet at least 1 of the following criteria:
1. Patient has had an indwelling urinary catheter within 7 days before the culture
and
patient has a positive urine culture, that is, >105 microorganisms per cc of urine with no more than 2 species of
microorganisms
and
patient has no fever (<38oC), urgency, frequency, dysuria, or suprapubic tenderness.
2. Patient has not had an indwelling urinary catheter within 7 days before the first positive culture
and
patient has had at least 2 positive urine cultures, that is, >105 microorganisms per cc of urine with repeated isolation of
the same microorganism and no more than 2 species of microorganisms
and
patient has no fever (<38oC), urgency, frequency, dysuria, or suprapubic tenderness.
continued
569
Table 1 Summary of CDC/NHSN criteria of healthcare associated urinary tract infection (HAUTI)
according to Horan et al 2008 [1] – cont’d
III. Other infections of the urinary tract (HA-OUTI)

(kidney, ureter, bladder, urethra, or tissue surrounding the retroperitoneal or perinephric space)
Other infections of the urinary tract must meet at least 1 of the following criteria:
1. Patient has organisms isolated from culture of fluid (other than urine) or tissue from affected site.
2. Patient has an abscess or other evidence of infection seen on direct examination, during a surgical operation, or
during a histopathologic examination.
3. Patient has at least two (in patient <1 year of age one) of the following signs or symptoms with no other recognized cause:
fever (>38oC), localized pain, or localized tenderness at the involved site (in patient <1 year of age signs and symptoms with
no other recognized cause: fever (>38oC), hypothermia (37oC), apnea, bradycardia, dysuria, lethargy, or vomiting)
and
at least 1 of the following:
a. purulent drainage from affected site
b. organisms cultured from blood that are compatible with suspected site of infection
c. radiographic evidence of infection (eg, abnormal ultrasound, computerized tomography [CT] scan, magnetic
resonance imaging [MRI], or radiolabel scan [gallium, technetium], etc)
d. physician diagnosis of infection of the kidney, ureter, bladder, urethra, or tissues surrounding the retroperitoneal or
perinephric space
e. physician institutes appropriate therapy for an infection of the kidney, ureter, bladder, urethra, or tissues surrounding
the retroperitoneal or perinephric space.
Comments
A positive culture of a urinary catheter tip is not an acceptable laboratory test to diagnose a UTI
a
Urine cultures must be obtained using appropriate technique, such as clean catch collection or catheterization.
b
In infants, a urine culture should be obtained by bladder catheterization or suprapubic aspiration; a positive urine culture
from a bag specimen is unreliable and should be confirmed by a specimen aseptically obtained by catheterization or
suprapubic aspiration.
1. INTRODUCTION (LoE 3). For daily practise and especially

for this study it is important to use the
Healthcare associated infections (HAI) commonly accepted criteria. Otherwise
have a high impact not only on the indi- data of different institutions cannot be
vidual patient but also on the total collected/compared and interventions
healthcare system. At 42.1% health- cannot be tested for effectiveness.
care associated urinary tract infections
(HAUTI) are the most frequent HAI in
general German hospitals [2] (LoE 2a). 2. AIM AND METHODS
Urologists have become more and more
concerned about minimizing the rate of For surveillance of healthcare associated
HAI in their institutions. Since 2003 the infections (HAI) the EAU/ESIU recom-
EAU/ESIU in collaboration with many mends in general the CDC/NHSN defini-
scientific societies has performed every tions for HAUTI as updated in 2008 [1]
year a worldwide (global) prevalence (LoE 4). The results are summarized in
study on infections in urology (GPIU) Table 1. However, some clarifications or
with special emphasis on HAUTI. In this modifications will be discussed and rec-
study it was found that the prevalence ommended for special usage in urology,
of HAUTI in urological departments is especially when urologists are taking part
about 10% but with very wide variations in the annual global prevalence study on
between countries and institutions [3–4] infections in urology.
570
3. DISCUSSION close to two days in many departments,

this definition makes no sense any more.
In the CDC/NHSN document the term “noso- The time interval is no longer a criterion
comial” was replaced by “healthcare associ- for the definition of a HAUTI. It should
ated” to indicate that all infections have to be replaced by a negative urine culture on
be considered as HAI whether acquired in admission and a careful clinical evaluation
an outpatient or in an institutional (hospi- that there was no UTI present on admis-
tal) acute care setting. HAIs may be caused sion (GoR B, LoE 4).
by an infectious agent(s) or its toxin(s)
from endogenous or exogenous sources. 3.2 Infections not considered HAUTI
Unfortunately it is not mentioned whether The CDC/NHSN document states that
infections acquired by patients living in infections associated with complications
long-term facilities, e.g. nursing homes, or extensions already present on admis-
should also be considered as HAI. The sion are not considered healthcare asso-
reason for that may have been that these ciated, unless a change in pathogen or
infections were not in the scope of the sur- symptoms strongly suggest the acquisi-
veillance recommended by the CDC/NHSN. tion of a new infection [1].
Under the diagnosis of healthcare How should a patient with asympto-
associated UTI (HAUTI) the CDC/NHSN matic bacteriuria (ASB) or presumed
incorporates three different entities: ASB, e.g. in case of an infection stone or
i) symptomatic UTI; ii) asymptomatic bac- indwelling urinary catheter, at the time of
teriuria; iii) other infections of the urinary admission followed by an exacerbation of
tract (kidney, ureter, bladder, urethra, or infection with the same pathogen in asso-
tissue surrounding the retroperitoneal or ciation with any kind of healthcare provi-
perinephric space). To comply with these sion, e.g. change of catheter, be classified?
guidelines, the following problems have to In this situation we strongly suggest that
be considered or clarified, respectively. HAUTI has to be diagnosed as caused by
an infectious agent from an endogenous
3.1 Rule out UTI at admission source (GoR A, LoE 4) .
How should a patient admitted with an
To diagnose HAUTI “there must be no
acute pyelonephritis due to an obstruc-
evidence that the infection was present
tive urinary stone and incomplete stone
or incubating at the time of admission”
removal, who experience extension of infec-
according to the CDC/NHSN definitions
tion leading to prolonged antibiotic therapy
for HAUTI as updated in 2008 [1] (LoE 4).
and emergence of resistance of the same
It is not difficult to achieve this require-
pathogen be classified? In this situation we
ment in an otherwise healthy patient
also strongly suggest that HAUTI has to be
undergoing an elective urological opera-
diagnosed as caused by a resistant patho-
tion/intervention, who has no signs and
gen, although the pathogen may belong to
symptoms of UTI, was not treated with
the same type/species, but emergence of
antibiotics during the last week and
resistance was associated with antibacterial
whose urine culture shows no growth.
therapy (GoR A, LoE 4).
However, the guidelines do not provide
any recommendations on what minimal
3.3 Diagnosis of healthcare
investigations are required to exclude the
associated symptomatic
presence of UTI/bacteriuria at admission.
UTI (HASUTI)
Often a 48 hour delay from admission to
start of symptoms is thought to be required The diagnosis of symptomatic HAUTI is
to qualify for a HAI, including HAUTI. based on two principles: i) symptoms and
With an average period of hospitalisation ii) the presence of bacteriuria
571
There is no problem if in association urinary catheter within seven days before

with any healthcare provision the patient the first urine culture (two cultures with
has experienced (suddenly) at least one >105/ml with no more than two uropatho-
typical urinary symptoms of the upper or genic species are required).
lower urinary tract and a positive urine It is appreciated that in the defini-
culture with a high bacterial load (cfu tion of HAASB the term “infection” is not
>105/ml) with no more than 2 species of used. However, in the document ASB is
(uropathogenic) microorganisms can be subclassified to HAUTI and it is not men-
documented. tioned as one of the conditions which are
However in case no urine culture was not an infection. This is misleading and
taken or the culture only showed a low not in line with the most recent IDSA
bacterial load (cfu <104/ml) according guidelines [5–6] (LoE 1a) which strongly
to the CDC/NHSN document surrogate advise not to consider ASB as infection
parameters have to be taken to diagnose and therefore not to treat ASB except in
HAUTI, such as pyuria, leukocyte este- two situations (because of risk factors):
rase, nitrite test, repeated urine cultures, i) during pregnancy and ii) before the
effective antimicrobial therapy, physi- mucosa traumatizing interventions of the
cian’s diagnosis and/or antibiotic therapy urinary tract (GoR A). Therefore, HAASB
for UTI. Whether the requirement of two should be considered as colonisation,
urinary symptoms (instead of one urinary probably as risk factor under certain cir-
symptom as above) in conjunction with cumstances, but not as infection (GoR B,
one surrogate parameter will improve the LoE 1a). There is probably no difference
diagnosis, remains questionable, espe- whether a mucous membrane is colonized
cially since after many urological inter- after intubation or the bladder mucous
ventions patients will experience urinary membrane after catheter insertion. This
symptoms, like dysuria, frequency and change of paradigm will have therapeutic
urgency, and for example, pyuria may and probably also legal implications.
only reflect an inflammatory and not The IDSA guidelines [5–6] (LoE 1a)
necessarily an infectious process of the imply that in general screening for ASB
urinary tract. Unfortunately in such a is not indicated, because treatment is
situation many urologists nevertheless not necessary. In the context of HAASB
diagnose HAUTI and recommend antibi- we face the problem that if screening for
otic therapy “just to be on the safe side”. HAASB is not recommended, HAASB will
According to the CDC/NHSN criteria a not be diagnosed. However we know that
physician’s diagnosis and appropriate uropathogens, especially from patients
therapy for UTI are also accepted as cri- with indwelling urinary catheter, can cause
teria for HAUTI, which also can be con- cross contamination/infection in other
sidered as surrogate parameters. patients [7–8] (LoE 2a). Therefore surveil-
lance of HAASB may also be an important
issue and quality parameter. The CDC/
3.4 Diagnosis of healthcare
NHSN document does not give any advice,
associated asymptomatic
how this dilemma could be solved.
bacteriuria (HAASB)
We recommend that at least in certain
According to the CDC/NHSN document time intervals a screening for HAASB
HAASB is diagnosed in an asymptomatic should be performed in each institution
patient i) who had an indwelling urinary (GoR B, LoE 4). The results should, how-
catheter within seven days before the ever, be analysed separately from the
culture (one culture with >105/ml with HASUTI. The data will supplement the
no more than two uropathogenic species assessment of the bacterial spectrum and
is sufficient) or ii) who had no indwelling the susceptibility pattern in a certain
572
environment (ward), which may have compared. The prevalence of HAUTI

implications for antibiotic usage for treat- depends on the type of surgery, the hygiene
ment and prophylaxis. measurements and the antimicrobial
There are situations, in which SUTI prophylaxis. For this reason key urologi-
and ASB cannot easily be differentiated cal interventions should be established
especially when systemic symptoms, like for comparison and the prevalence of
fever etc, are missing. This is always the HAUTI should be related to the types of
case in unconscious patients, e.g. inten- surgery being undertaken in the depart-
sive care medicine, but it is also often ment as well as the extent of the antimi-
difficult in patients with indwelling cath- crobial prophylaxis (GoR B, LoE 4). The
eter, whether the “urinary symptoms” are effect of prophylaxis depends on the local
caused by the foreign body or by a UTI, environment. Continuous surveillance of
and in patients with atypical urinary regular urine cultures results should be
symptoms, e.g. neurogenic bladder distur- the rational basis for tailoring antimicro-
bances. In such situations the diagnosis bial prophylaxis (GoR B, LoE 4).
should be based on clinical judgment by
experienced specialists (GoR B, LoE 4). 3.8 Observation period to diagnose
HAUTI/HAASB
3.5 Diagnosis of other healthcare Because of the short hospitalisation period
associated infections of the nowadays and the increased number of
urinary tract (HAOUTI) outpatient procedures many patients will
The EAU/ESIU definitions of HAOUTI fol- be discharged from the institution (hospi-
low the CDC/NHSN definitions of surgical tal or outpatient clinic) before any HAUTI/
site infections, that a physician diagno- HAASB can be diagnosed. Therefore a
sis of infection can be derived from direct minimal observation time needs to be
observation during surgical operation, defined when an infection should still be
endoscopic examination, or other diagnos- considered healthcare associated. For
tic studies or from clinical judgment. practical reasons we recommend that this
time should be seven days after the inter-
vention, or in case of ongoing antibiotic
3.6 Diagnosis of urosepsis therapy seven days after the end of anti-
The GPIU studies have shown an increas- biotic therapy, or in case of an indwelling
ing proportion of urosepsis reported as urinary catheter seven days after removal
HAUTI (LoE 3). Diagnosing urosepsis in of the catheter (GoR B, LoE 4).
urology departments represents a diag- Physicians/institutions responsible for
nostic dilemma because many patients the interventions have to inform not only
will have SIRS after undergoing urologi- the patient, but also the following treat-
cal surgery, and transient bacteriaemia ing physician about the specific risk of
is common, especially after transurethral HAI in a specific patient and the follow-
resection of the prostate [9] (LoE 3). Thus ing treating physician has to inform the
there is a risk for overdiagnosis which physician/institution responsible for the
will increase with the number of blood intervention about any occurrence of HAI
cultures taken. in this specific patient (GoR A, GCP).
3.7 Comparison of departments 4. FURTHER RESEARCH

and hospitals
Because the prevalence of HAUTI has Especially in patients in whom symptoms
become an important quality parame- cannot be registered, e.g. intensive care
ter, hospitals and departments are often medicine, or with atypical symptoms, e.g.
573
young children, elderly, patients with spi- P T, Hospital acquired urinary tract infec-
nal cord injury, differentiation between tions in urology departments: pathogens,
symptomatic UTI and ASB is almost susceptibility and use of antibiotics.
always impossible. Determination of bac- Data from PEP and PEAP-studies.
terial virulence factors could probably Int J Antimicr Agents, 2006. 28(Suppl):
S91-S107.
help to differentiate between an invasive
4. Bjerklund Johansen TE, Cek M, Naber
infection and colonisation.
K, Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
5. CONCLUSIONS urinary tract infections in urology depart-
ments. Eur Urol, 2007. 51(4): 1100–11;
discussion 1112.
Since HAUTI is common in urology, urol-
5. Nicolle LE, Bradley S, Colgan R, Rice JC,
ogists have a high responsibility to care Schaeffer A, and Hooton TM, Infectious
about this kind of infection and minimise Diseases Society of America guidelines for
it as much as possible. Widely accepted the diagnosis and treatment of asympto-
criteria like the CDC/NHSN criteria matic bacteriuria in adults. Clin Infect
should be applied when data from differ- Dis, 2005. 40(5): 643–54.
ent institutions are collected and com- 6. Nicolle LE, Asymptomatic bacteriuria:
pared. However, some modifications are review and discussion of the IDSA
necessary to adapt them specifically to guidelines. Int J Antimicrob Agents,
urological needs. 2006. 28 Suppl 1: S42–8.
7. Wagenlehner FM, Krcmery S, Held
C, Klare I, Witte W, Bauernfeind
REFERENCES A, Schneider I, and Naber KG,
Epidemiological analysis of the spread of
1. Horan TC, Andrus M, and Dudeck MA, pathogens from a urological ward using
CDC/NHSN surveillance definition of genotypic, phenotypic and clinical param-
health care-associated infection and cri- eters. Int J Antimicrob Agents, 2002.
teria for specific types of infections in the 19(6): 583–91.
acute care setting. Am J Infect Control, 8. Naber KG, Witte W, Bauernfeind A,
2008. 36(5): 309–32. Wiedemann B, Wagenlehner F, Klare I,
2. Gastmeier P, Kampf G, Wischnewski N, and Heisig P, Clinical significance and
Hauer T, Schulgen G, Schumacher M, spread of fluoroquinolone resistant
Daschner F, and Ruden H, Prevalence of uropathogens in hospitalised urological
nosocomial infections in representative patients. Infection, 1994. 22 Suppl 2:
German hospitals. J Hosp Infect, 1998. S122–7.
38(1): 37–49. 9. Grabe M, Antimicrobial agents in
3. Bjerklund-Johansen TE, Cek M, Naber transurethral prostatic resection.
KG, Stratchounski L, Svenden MV, and J Urol, 1987. 138(2): 245–52.
574
|10.3|
Epidemiology, treatment and

prevention of healthcare-associated
Florian M.E. Wagenlehner1, Mete Cek2, Hiroshi Kiyota3, Truls E. Bjerklund-Johansen4
1
Department of Urology, University Giessen, Germany
2
Department of Urology, Taksim Teaching Hospital, Istanbul, Turkey
3
Department of Urology, Jikei University Affiliated Aoto Hospital, Tokyo, Japan
4
Urology Department, Århus University Hospital, Skejby, Århus University, Århus, Denmark
Corresponding author: F.M.E. Wagenlehner, Clinic of Urology, Pediatric Urology and Andrology, Justus-Liebig-University,
Giessen, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany.
Tel: +49/ 641-99 44518; Fax : +49/ 641-99 44509 ; E-mail: Wagenlehner@AOL.com
ABSTRACT of HA-uropathogens are provided. The

treatment of HAUTI encompasses treat-
Healthcare associated (HA) urinary tract ment of the complicating factors as well
infections (UTI) are the most frequent as the antimicrobial chemotherapy. At
healthcare associated infections (HAI) least in serious UTI adequate initial anti-
in a general hospital. They are almost biotic therapy results in lower mortality.
exclusively complicated UTIs, although Therefore the initial antibiotic regimen
the complicating factors are very heter- must provide sufficient antibiotic cov-
ogenous. HAUTIs are mainly catheter erage. This can only be achieved if the
associated. Most of them are asympto- bacterial spectrum and antibiotic resist-
matic and do not need antimicrobial ther- ance patterns of uropathogens in the
apy. However, cross-contamination and own institution is followed continuously.
cross-infection may contribute to the Provisional microbiological findings, such
distribution of resistant uropathogens. as reports on Gram-stain or certain bio-
The bacterial spectrum of HAUTI is chemical results can lead to early strati-
broad and antibiotic resistance is com- fication of pathogens and allow a more
mon. The results of international and taylored empiric antibiotic therapy.
national surveillance studies on the bac- Antibiotic therapy of HAUTI has to con-
terial spectrum and antibiotic resistance sider two different aspects: i) therapeutic
success in the individual patient, and ii) 8. Antibiotics with best performance in
prevention of emergence of antibiotic resist- biofilm infection should be selected
ant mutants. For both aspects adequate and the dosage should be sufficiently
drug selection and dosing are paramount. high when treating HAUTI (GoR B).
Since most of the HAUTI are catheter asso- 9. Prevention of catheter associated
ciated UTI (CAUTI), prudent catheter man- UTI (CAUTI) is the gold standard for
agement and prevention of CAUTI should prevention of HAUTI (GoR A).
be considered high priority in urology.
10. For prevention of HAUTI in short-
Key words: Healthcare associated UTI, term catheterization the following
Nosocomial UTI; antibiotic treatment of recommendations are to be consid-
UTI; emergence of antibiotic resistant ered: i) staff education about catheter
uropathogens management; ii) catheterization only
when indicated and prompt removal
of indwelling catheters; iii) hand-
washing; iv) catheter insertion with
aseptic technique and sterile equip-
ment, and v) maintenance of a closed
1. All urinary tract infections (UTI)
urinary drainage system (GoR A).
acquired in an outpatient or in an
institutional care setting, should be 11. For prevention of HAUTI in long-
considered as healthcare-associated term catheterization the following
UTI (HAUTI) (GoR B). recommendations should be consid-
ered: i) hydration; ii) appropriate
2. Healthcare associated asymptomatic
catheter exchange; iii) no antimicro-
bacteriuria (HAASB) should not be
bial prophylaxis (GoR B).
treated with antimicrobials, except
before the mucosa traumatizing 12. For avoidance of long-term bladder
interventions of the urinary tract catheterization the following meth-
and in pregnant women (GoR A). ods should be considered:
3. In HAUTIs a wide spectrum of fre- 12.1. in case of incomplete emptying
quently also multiresistant uropath- of the bladder: i) medications
ogenic bacteria has to be considered for complete emptying the
(GoR B). urinary bladder, such as
cholinergic drugs and/or
4. For rational empiric therapy the
alpha-1 adrenergic inhibitors;
local susceptibility pattern of the
ii) operative deobstruction for
uropathogens must be continuously
benign prostatic hypertrophy
followed and considered (GoR A).
(BPH); iii) clean intermittent
5. A urine specimen and in case of catheterization (GoR B).
urosepsis also a blood specimen for
12.2. in case of incontinence: i.)
culture must be obtained before initia-
medications for incontinence;
tion of any antibiotic therapy (GoR A).
ii) operative treatment of
6. Antibiotic treatment should be initi- incontinence (GoR B).
ated after the results of the suscepti-
bility testing are available, whenever
possible (GoR B). 1. INTRODUCTION
7. If empiric antibiotic treatment is
warranted, it should be tailored after A healthcare associated infection (HAI) is
the results of the susceptibility test- defined as a localised or systemic condi-
ing are available (GoR B). tion that results from an adverse reaction
576
Epidemiology, treatment and prevention | 10.3 |
to the presence of an infectious agent or therapeutic study was found, in which

its toxin, and was not present or incubat- only patients with nosocomial UTI were
ing prior to the initiation of a healthcare treated or such patients were substrati-
encounter [1–2]. The term “healthcare fied. Only one study investigated the
associated infection” incorporates the effect of antibiotic prophylaxis at urinary
term “nosocomial” or “hospital acquired”, catheter removal, which was included
which refers to infections that occur as into this review and one study investi-
a result of hospital care, but also any gated the effect of an antibiotic coated
infection occurring in an institutional urinary catheter on prophylaxis of noso-
(long-term facilities, nursing home) or comial UTI, which was included into this
outpatient care settings. Healthcare asso- review. These publications were aug-
ciated urinary tract infections (UTI) are mented with publications known by the
the most frequent healthcare associated authors.
infections (HAI) and account for more The studies were rated according to the
than 40% of all HAI in a general hospital level of evidence (LoE) and the grade of
[3–5] (LoE 2b). They are mainly catheter- recommendation (GoR) using ICUD
associated [3–4, 6] (LoE 2b). Bacteriuria standards (for details see Preface) [8–9].
develops in up to 25% of patients who
require a urinary catheter for seven days
or more, with a daily risk of 5% [6] (LoE 3. EPIDEMIOLOGY
3). Most of the catheter associated bac-
teriuria are asymptomatic (CAASB) [7] The incidence of HAIs has stayed more
(LoE 3) and therefore do not need antibi- or less stable over the last one to two dec-
otic therapy. However, the pathogens are ades. However, certain aspects of patient
fully exposed to the healthcare setting care have changed during this period. As
(nosocomial) environment, including the minimally invasive techniques develop
selective pressure of antibiotic or antisep- and patient care improves, patients are
tic substances. HAUTIs comprise perhaps being treated either on an outpatient
the largest institutional reservoir of anti- basis or they stay in hospitals for shorter
biotic-resistant pathogens [6] (LoE 3). periods. Particularly in urology there is a
wide range of operations which allow the
patient to be discharged within 48 hours
2. METHODS of operations. This has two important
implications on the incidence of HAIs: 1)
This review is based on a systematic liter- More elderly patients with comorbidities
ature search for the last 10 years (2000– are hospitalised [10–11]. Shorter hospital
2009) in PubMed. Two searches were stays make it difficult to assess the true
performed: i) surveillance AND suscepti- frequency of healthcare associated infec-
bility AND nosocomial urinary tract infections. The incubation periods of certain
tion (for search the term “nosocomial” infections (e.g. surgical site infections)
was used instead of “healthcare associ- are sometimes longer than the hospital
ated”); and ii) randomized clinical trials stay of patients. It is thus more prefer-
AND nosocomial urinary tract infection able to calculate the incidence of HAIs
AND antibiotic therapy. The first search on the basis of patient days, rather than
revealed 55 publications. There were sev- actual number of admissions [12]. The
eral local or national surveillance stud- denominator can also be the number of
ies, but only three multinational studies patients at risk, or days of indwelling
were found and used for this review. The catheterisation [13]. The rate of nosoco-
second search revealed 15 publications. mial infections per 1000 patients’ days
No prospective controlled, randomized in the United States of America was
577
calculated to be 9.8 in 1995 [12–13]. More there was a significantly increased risk
recent estimates (for 2002) for all infec- of having a Candida sp., Klebsiella sp.,
tions combined are not comparable to pre- or Pseudomonas sp. as a causative path-
vious overall estimates [5]. On the other ogen, when compared to those patients
hand, the incidence of nosocomial urinary with three or less risk factors.
infections in European countries was Another recent study also found strong
found to be 3.55 episodes/1000 patient- evidence between HAUTI and prolonged
days and the prevalence was estimated to length of stay, urinary catheter and
be 10.65/1000 [14]. female sex [18]. Other factors found sig-
The prevalence of HAUTI in urologi- nificant in this study were e.g. spinal
cal departments was 10% in the Pan injury or fracture/dislocation, transfer to
European Prevalence (PEP) study, another hospital, underlying neurologic
14% in the Pan Euro-Asian Prevalence disease, some assistance required prior
(PEAP) study, and 11% in the combined to admission, and previous stroke sug-
analysis [15]. The largest group was gesting chronic health problems and
asymptomatic bacteriuria (29%) followed reduced health status which needs to be
by cystitis (26%), pyelonephritis (21%), further elucidated. Studies suggested
and urosepsis (12%). The prevalence of also the severity score of hospitalised
HAUTIs was found to be 14.7% in the patients as an important risk factor
Global Prevalence Study on Infections for the development of HAUTI [11, 19].
in Urology (GPIU) 2008 (unpublished On the other hand, immmunosupressant
data). Another finding which raises con- therapy within 14 days, history of malig-
cern is the rising percentage of urosep- nancy, cigarette smoking in the past and
sis from 9.3% in 2006 to 21.8% in 2008 male sex, are shown to be risk factors for
while the prevalence of HAUTI stayed nosocomially urinary tract related bacter-
more or less stable around 14% in the emia [20].
same period. This suggests that pro-
phylactic measures in various urology
clinics may not be appropriate and the 5. BACTERIAL SPECTRUM
choice of prophylactic antibiotics is still
not optimal [16]. Whereas community acquired UTI are
often uncomplicated, almost all HAUTIs
are complicated infections with structural
4. RISK FACTORS or functional abnormalities within the
urinary tract, such as indwelling cath-
Several characteristics related to the eters or some kind of urinary obstruc-
healthcare provider, the patient and the tion. The bacterial etiology of UTI differs
procedures are known to increase the risk markedly between uncomplicated and
of NAUTI. The most important risk fac- complicated UTIs.
tors for HAUTI are an indwelling catheter
and the duration of catheterisation [17].
5.1 Bacterial spectrum in
Other significant risk factors are i) UTI
complicated HAUTI
during the previous 12 months; ii) urinary
tract obstruction; iii) urinary stones; iv) The bacterial spectrum of complicated
previous antibiotic usage within the last 3 HAUTIs comprises a wide range of Gram-
months and v) hospitalisation within the negative and Gram-positive species. The
last six months due to any reason [17]. bacterial spectrum can vary geographically,
The study also showed that for patients over the time and between distinct special-
having more than three risk factors, ities at the same institution [21] (LoE 3).
578
5.1.1 Bacterial spectrum of HAUTI in 5.1.3 Bacterial spectrum of HAUTI

North-America (SENTRY study) in urological patients in Europe
The SENTRY antimicrobial surveillance (PEP-study)
program, initiated in 1997, has chrono- A European multi-center one-day preva-
logically examined urinary pathogens lence study on HAUTI in urology tested
collected from hospitalized patients 320 uropathogens from 232 urological
from different hospital departments departments throughout Europe [17] LoE
across North America and thus provides 3). E. coli was responsible for 35% of UTIs,
insight into pathogen frequency and followed by Pseudomonas spp. (13%),
resistance rates [22] (LoE 3). A surveil- Klebsiella spp. (10%), Proteus spp. (7%)
lance study based on 1998 data encom- and Enterobacter spp. (3%). With Gram-
passed 31 North American institutions positive uropathogens Enterococcus spp.
which examined 1,510 urinary isolates was isolated in 9% and Staphylococcus
from hospitalized patients from differ- spp. in 4%. Candida spp. was isolated in
ent departments. Approximately 25% of 3% (Table 1).
these isolates were HA-strains, of which
20% were isolated from intensive care
6. ANTIBIOTIC RESISTANCE
units [23].
For Gram-negative organisms, E. coli
Since antibiotics have been introduced
was responsible for 47% of UTIs, followed
into clinical medicine, antibiotic resistant
by Klebsiella spp. (11%), Pseudomonas
bacteria have evolved. The epidemiology
spp. (8%), Proteus spp. (5%), Enterobacter
of antibiotic resistant bacteria, however,
spp. (4%), and Citrobacter spp. (3%)
varies from region to region, from speci-
(Table 1). The most commonly isolated
ality to speciality, from infection type to
Gram-positive uropathogens from this
infection type and from time to time.
cohort of hospitalized patients were
Enterococcus spp. (13%), coagulase-
6.1 Antibiotic resistance in
negative staphylococcus (3%), and S.
complicated HAUTI
aureus (3%) (Table 1).
HA-uropathogens are frequently subject
to antibiotic pressure and cross-infec-
5.1.2 Bacterial spectrum of HAUTI in tion [25] (LoE 2b). The influence of these
Europe (ESGNI-003 study) parameters can vary between regions and
A European multi-center one-day preva- specialities [21] (LoE 3). Different species
lence study on HAUTI of patients from of uropathogens show distinct abilities to
different hospital departments tested 607 develop antibiotic resistance.
uropathogens from 228 hospitals through-
out Europe [24] (LoE 2b). Patients from 6.1.1 Antibiotic resistance in HAUTI in
different departments throughout the North America, Latin America and
hospital were evaluated. E. coli was Europe (SENTRY study)
responsible for 36% of UTIs, followed by In the SENTRY study a central refer-
Klebsiella spp. (8%), Proteus spp. (8%), ence laboratory was employed using
Pseudomonas spp. (7%), Enterobacter NCCLS (National Committee for Clinical
spp. (4%), and Citrobacter spp. (2%). With Laboratory Standards) criteria [23]
Gram-positive uropathogens Enterococcus (LoE 3). Strains were sent from the local
spp. was isolated in 13%, coagulase- microbiology laboratories. Global resist-
negative staphylococcus in 2% and S. ance rates (combined resistance of E. coli,
aureus in 2%. Candida spp. was isolated Klebsiella spp., P. aeruginosa, and ente-
in 9% (Table 1). rococci) in North America for Ampicillin,
579
Table 1 Bacterial spectrum of nosocomial uropathogens (≥ 2%) from distinct surveillance studies.
Name of study SENTRY [29] SENTRY [29] SENTRY [29] ESGNI-003 [24] PEP-study [17]
Regions of the world North America Latin America Europe Europe Europe
Year of surveillance 2000 2000 2000 2000 2003
Type of surveillance longitudinal longitudinal longitudinal Cross section Cross section
Origin of samples Microbiology laboratories Microbiology laboratories Microbiology laboratories Different departments in the hospital Urology departments
Number of pathogens n=1,466 n=531 n=783 n=607 n=320
Species %
E. coli 43% 60% 46% 36% 35%
Klebsiella spp. 12% 12% 9% 8% 10%
Pseudomonas spp. 7% 6% 9% 7% 13%
Proteus spp. 6% 7% 10% 8% 7%
Enterobacter spp. 3% 4% 4% 4% 3%
Citrobacter spp. 4% 2% 2% 2% n.r.
Enterococcus spp. 16% 4% 13% 16% 9%
Staphylococcus spp. 6% 3% 3% 4% 4%
Resistance rates of antibiotics %
Ampicillin 59%e 62%e 65%e 66%a 51%
e e e a
Ampicillin + BLI 31% 36% 36% 29% 30%
e e e a
TMP/SMZ 43% 38% 48% 32% 45%
Ciprofloxacin 29%e 32%e 29%e 17%b 34%
Gentamicin n.r. n.r. n.r. 18% 34%
c
Ceftazidime n.r. n.r. n.r. 13% 17%
Amikacin n.r. n.r. n.r. 19%c 14%
Piperacillin/Tazobactam n.r. n.r. n.r. n.r. 15%
Imipenem n.r. n.r. n.r. 14%c 7%
d
Vancomycin n.r. n.r. n.r. 1% n.r.
a b c d e
n.r. – not reported; – Gram-negative bacteria excluding P. aeruginosa; - Gram-negative bacteria; – P. aeruginosa; – enteroccoci.; – E. coli, Klebsiella spp., P. aeruginosa, enterococci.
Amoxicillin/ clavulanate, Trimethoprim/ 6.1.3 Antibiotic resistance in HAUTI

Sulfamethoxazole and Ciprofloxacin were in urological patients in Europe
59%, 31%, 43% and 29%, respectively. (PEP-study)
Global resistance rates in Latin America The PEP-study also evaluated resistance
for Ampicillin, Amoxicillin/ clavulanate, rates of uropathogens causing HAUTI in
Trimethoprim/ Sulfamethoxazole and urological patients [17] (LoE 3). However,
Ciprofloxacin were 62%, 36%, 38% and there was no reference laboratory and dif-
32%, respectively. Global resistance rates ferent standards were employed for test-
in Europe for Ampicillin, Amoxicillin/ cla- ing of the strains (178 hospitals employed
vulanate, Trimethoprim/ Sulfamethoxazole NCCLS criteria, 34 DIN (Deutsches
and Ciprofloxacin were 62%, 36%, 38% Institut für Normung) criteria, and 20
and 32%, respectively (Table 1). other criteria) and not all hospitals have
tested all antibiotics. Global resistance
rates for the total bacterial spectrum were
6.1.2 Antibiotic resistance in HAUTI
as follows (Table 1): Ampicillin 51%, amp-
in Europe (ESGNI-003 study)
icillin + beta-lactamase-inhibitor 30%,
The European Study Group on Nos- piperacillin 21%, piperacillin/ tazobactam
ocomial Infections (29 countries) also 15%, cefazolin 44%, cefuroxime 25%,
evaluated antimicrobial susceptibility ceftazidime 17%, cefepime 21%, imipenem
against hospital-acquired urinary isolates 7%, gentamicin 34%, amikacin 14%, cipro-
[24] (LoE 2b). Sensitivity assays were not floxacin 34% and TMP/SMZ 45%.
performed in a central laboratory and In all these studies increasing resist-
local results of susceptibility testing were ance rates were found for some species
taken at face-value. During 1999, 607 like E. coli, but not for all uropathogens.
organisms from 522 patients with HAUTI However, resistance rates may vary sub-
were tested. Resistance rates were for E. stantially between regions. Therefore
coli comparable to those observed from local, hospital based surveillance of the
the North American SENTRY experience bacterial spectrum and antibiotic sensi-
(Table 1): TMP/SMX (28%), ampicillin tivity is paramount for a rational empiric
(55%), ciprofloxacin (9%), and gentamicin therapy.
(6%). However, it is worth noting that
non-European Union countries tended
to have higher rates of E. coli resistance 7. TREATMENT OF HAUTI
than European union countries.
In particular, amikacin, ceftazidime, As mentioned earlier, HAUTI are mainly
and cefepime were the most active catheter associated. Most of them are
agents (>90% susceptible), imipenem asymptomatic and do not need antibiotic
and tobramycin were moderately active therapy according to the current guide-
(>85% susceptible), and ciprofloxacin lines, except before an traumatizing
and gentamicin were the least active intervention of the urinary tract and in
(~75% susceptible). In contrast, P. aeru- pregnant women [26] (LoE 1a). However,
ginosa isolates from non-European Union by cross-contamination and cross-infec-
countries (e.g. Estonia, Serbia) showed tion healthcare associated asymptomatic
resistance rates of over 50% for fluoro- bacteriuria (HAASB) may also contrib-
quinolones and non-amikacin aminogly- ute very much to the distribution of
cosides. The authors speculated that this resistant uropathogens throughout the
high rate of resistance to pseudomonal institution (nursing home, hospital) [25]
strains might be explained by the lack of (LoE 2b) and also throughout the com-
strict antimicrobial policies in hospitals munity in case of an outpatient care
within non-European Union countries. setting. Therefore, HAASB may be an
581
important factor for the spread of resist- many cases of complicated UTIs biofilm
ant uropathogens and should therefore infection is predominant. In a biofilm, the
be included into a systematic (not rou- pathogens adhere to anatomical structures
tine) surveillance. But in general, anti- of the urinary tract - stones, foreign materi-
biotic therapy should only be considered als or necrotic tissue - and are embedded in
for symptomatic HAUTI. In some situa- organic (exopolysaccharide) and anorganic
tions, however, the distinction between (phosphate) material [30–31] (LoE 3). This
HAASB and symptomatic HAUTI may leads to reduced susceptibility of the patho-
be difficult, e.g. intensive care medi- gens and therefore it is necessary to elevate
cine, patients with spinal cord injury, antibiotic concentrations by 10- to 100 fold
physically and mentally handicapped in order to inhibit or kill the pathogens [32]
(geriatric) patients or children in young (LoE 2b). Such increased antibiotic con-
age. Careful consideration of all clinical centrations are often not clinically achiev-
parameters is necessary before antibiotic able. Fluoroquinolones and macrolides
therapy is initiated. (only effective against Gram-positive bacte-
ria) exhibit a specific effect on the biofilm
7.1 General aspects of antibiotic formation, which, however, is usually not
therapy of UTI sufficient to eradicate the pathogens [33]
(LoE 3). Therefore, antimicrobial therapy
In the antimicrobial treatment of uncom-
in complicated UTIs may only kill the bac-
plicated UTIs the rapid elimination of the
teria dissolved from the biofilm (planctonic
pathogen is most important. In compli-
form) and thus inhibit spread of the infec-
cated HAUTIs, the primary goal of anti-
tious process. An accompanying urological
biotic therapy is to contain the spread of
therapy must aim to remove the biofilm.
infection and prevent the emergence of
In any case, antibiotics with best perform-
resistant mutants.
ance in biofilm infection should be selected
Drusano and Craig determined four
and the dosage should generally be high
parameters for the rational dosing of an
when treating complicated HAUTIs [34].
antibiotic in a population [27]:
The dosage should even be sufficiently
1. the minimal inhibitory concentration high enough to eradicate also the first step
(MIC) of the clinical isolates. resistant mutants [35] (LoE 3).
2. the pharmacokinetic (PK) profile. At least in severe UTIs, adequate
3. the pharmacodynamic (PD) profile. initial antibiotic therapy results in
lower mortality compared with inad-
4. the protein binding of the applied equate antibiotic treatment [36] (LoE 3).
antibiotic. Susceptibility testing should be carried
The distribution of the MIC values of out in any case of HAUTI, and if possi-
nosocomial clinical isolates is the great- ble the results should be awaited before
est variable parameter and the MICs treatment. However, in severe infections
vary geographically and by time [28–29] an initial empiric therapy must be insti-
(LoE 2b). The other three parameters are gated immediately after microbiologi-
usually determined from Phase I to III cal sampling. Susceptibility testing can
studies. There is, however, a surprisingly serve in these cases to narrow the antibi-
high interindividual variation. Certain otic coverage. Provisional microbiological
subgroups, however, are not studied and findings, such as reports on Gram-stain
recommendations for antibiotic therapy or certain biochemical results, such as
must be extrapolated from the results of oxidase, coagulase, catalase, can lead
other related groups. to early stratification of pathogens and
An additional 5th parameter is extremely allow a more taylored empiric antibi-
important for the treatment of HAUTI. In otic therapy [37] (LoE 3). Prudent use of
582
antimicrobials may also help to reduce HAUTI are CAUTI, optimal management
the selection of resistant pathogens to a of any indwelling catheter and prevention
minimum (see chapter 4.7) of CAUTI should be of highest priority in
urology. Some principles are listed here,
7.2 Antibiotic selection for but for more details see Section 11.
therapy of complicated
HAUTI and urosepsis 8.1 Prevention of HAUTI in short-
term indwelling catheterization
Antibiotics with an enlarged antibac-
terial spectrum are necessary for ini- According to CDC guidelines prevention
tial empiric treatment [38] (LoE 4). The of catheter-associated urinary tract infec-
empiric parenteral treatment could start tions (CAUTI) is the gold standard for
with a cephalosporin group 3a, a fluo- prevention of HAUTI [39]. The following
roquinolone with good renal excretion or have to be considered:
with an aminopenicilline in combination i. staff education about catheter
with a betalactamase-inhibitor (recom- management,
mended dosages see Table 2). If clinical
ii. catheterization only when indicated
improvement fails after two to three days,
and prompt removal of indwelling
treatment should be switched to a pseu-
catheters,
domonas active acylaminopenicilline/
betalactamase-inhibitor, a group 3b cepha- iii. handwashing,
losporin or a group 1 carbapenem. Other iv. catheter insertion with aseptic tech-
reasons for treatment failure, such as per- nique and sterile equipment, and
sistent complicating factors, other infec- v. maintenance of a closed urinary
tions or noninfectious sources, should also drainage system,
be taken into account and be re-evaluated.
Regional variations in resistance must be vi. silver- or antibiotic coated uri-
also considered for empiric treatment. nary catheter may reduce the risk
The use of parenteral antibiotics is for CAUTI [40–41] (LoE 1b), but
determined by the general condition of whether this also holds true for epi-
the patient (e.g., nausea, vomiting) and sodes of symptomatic CAUTI, needs
the severity of the infection; oral anti- to be shown,
biotics can be continued as soon as the vii. a short term antibiotic prophylaxis
clinical situtation has improved. After the at urinary catheter removal may
results of the susceptibility testing have prevent UTI after short-term ind-
arrived, the antibiotic treatment should welling catheterization [42] (LoE 1b),
be aligned accordingly. Treatment dura- however may increase the total anti-
tion should continue for at least three to biotic selection pressure.
five days beyond defervescence, depend-
ent on the removal of the complicating 8.2 Prevention of HAUTI in long-term
factor. However, this recommendation indwelling catheterization
does not hold true for the treatment of The CDC guidelines mentioned earlier have
pyelonephritis with abscess formation or been developed only for the patients with
chronic bacterial prostatitis, which should short-term indwelling urethral catheteriza-
usually continue for several weeks. tion. Catheter-associated bacteriuria (CA-B)
is ultimately not avoidable in patients with
8. PREVENTION OF HAUTI long-term indwelling catheterization. Since
most CA-Bs with long-term indwelling
The best treatment is prevention; this catheterization are asymptomatic [43] (LoE
is also true for HAUTI. Since most of 3), prevention of symptomatic episodes is
583
Table 2 Bacterial spectrum of nosocomial uropathogens (≥ 2%) from distinct surveillance studies.
Antibiotic group Substance Dosage
oral IV
Aminopenicillin + BLI Ampicillin/Sulbactam 0.750g bid 0.75–3g tid
Amoxicillin/Clavulanic acid 1g bid or 0.625g tid 1.2–2.2g tid
Acylureidopenicillin + BLI Piperacillin/Tazobactam - 2.5–4.5g tid
Piperacillin/Combactam - 5g tid
Cephalosporine Gr. 1 Cephalexin Prophylaxis only -
Cephalosporine Gr. 2 Cefuroxime axetil 500mg bid -
Cefuroxime - 0.75–1.5g tid
Cefotiam - 1–2g b/tid
Cephalosporine Gr. 3 Cefpodoxime proxetil 200mg bid -
Ceftibuten 200–400mg qd -
Cephalosporine Gr. 3a Cefotaxime - 1–2g b/tid
Cetriaxone - 1–2g qd
Cephalosporine Gr. 3b Ceftazidime - 1–2g b/tid
Cephalosporine Gr. 4 Cefepime - 2g bid
Carbapenem Gr. 1 Imipenem - 0.5–1g q6–8h
Meropenem - 0.5–1g tid
Doripenem 0.5g tid
Carbapenem Gr. 2 Ertapenem - 1g qd
Fluoroquinolone Gr. 2 Ciprofloxacin 500–750mg bid 400mg bid

Ciprofloxacin XR 1000mg qd -
Fluoroquinolone Gr. 3 Levofloxacin 500–750mg qd 500mg qd
the aim to look for. The following practical frequency of catheter exchange
points are recommended, but the level of depends on the individual patient,
evidence is low (LoE 4). because the catheter encrustation
i. Hydration - the increase of urine sometimes happens in shorter
volume by hydration results in periods. In these cases, catheter
wash-out of bacteria from the exchange should be performed more
urinary bladder and thus inhibiting frequently.
bacterial growth in the urinary iii. No antimicrobial prophylaxis (AMP)
bladder. Hydration also prevents - AMP can delay the occurrence
obstruction of the urethral catheter of CAB. However, the incidence of
due to encrustation. drug-resistant bacteria increases in
ii. Catheter exchange - routine catheter the presence of AMP. Therefore AMP
exchange is usually performed every should be avoided
4 to 6 weeks. However, the optimal [6] (LoE 4).
584
8.3 Avoidance of long-term HAASB should not be treated with anti-

indwelling catheterization microbials except before traumatizing
To prevent CAUTI long-term indwell- interventions of the urinary tract and in
ing catheterization should be avoided pregnant women. Besides of an adequate
at the first place. There are two fre- antibiotic therapy the complicating factors
quent indications for long-term bladder need to be treated effectively. For initial
catheterization: empiric therapy the regional susceptibility
profile of common uropathogens such as
– incomplete emptying of the bladder E. coli must be known to choose the most
and appropriate antibiotic. In case of severe,
– non-obstructive incontinence. bacteremic UTIs it has been shown that
In both indications attempts, such as an inadequate initial antibiotic regimen
i) medications for complete emptying the has an elevated mortality. Before initia-
urinary bladder, ii) operative techniques tion of antibiotic therapy a urine speci-
such as deobstruction in case of pros- men for culture must be obtained to be
tatic obstruction in males, or pelvic floor able to adapt the antibiotic regimen to the
reconstruction in case of pelvic floor dis- susceptibility profile. Increasing antibiotic
orders, such as cystocele formation, iii) resistance requires a more prudent use of
clean intermittent catheterization (CIC) antimicrobial drugs also in the treatment
or iv) urethral stent for benign pros- of HAUTIs.
tatic enlargement (BPE) [44–45] (LoE
3), [46–47] (LoE 3) may be considered.
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|10.4|

long term care patients
Lindsay E. Nicolle
Professor, Department of Internal Medicine and Medical Microbiology, University of Manitoba, Health Sciences Centre,
Room GG443 – 820 Sherbrook Street, Winnipeg, MB R3A 1R9
ABSTRACT should not be interpreted as urinary tract

infection. Pyuria is expected with both
Urinary tract infection is one of the symptomatic and asymptomatic infec-
most common problems encountered in tion, and is not an indication for anti-
residents of long term care facilities. microbial therapy. For residents with
Asymptomatic bacteriuria is present in long term indwelling catheters, the most
25–50% of women and 15–40% of men common presentation is fever by itself
without a chronic indwelling catheter, and without localizing genitourinary find-
is associated with incontinence of blad- ings. Prophylactic antimicrobial therapy
der and bowel and increasing functional should be given prior to invasive geni-
impairment. Asymptomatic bacteriuria tourinary procedures likely to be associ-
appears to be benign, and antimicrobial ated with mucosal bleeding, to prevent
treatment does not improve outcomes. post procedure sepsis. Removal of a long
Symptomatic urinary tract infection in term indwelling catheter whenever feasi-
the resident without a chronic indwell- ble, avoiding catheter trauma, and early
ing catheter is diagnosed when localiz- identification of obstruction will likely
ing genitourinary signs or symptoms are prevent symptomatic urinary infection.
present and a urine culture is positive. Other strategies effective to limit asymp-
Impaired communication, chronic comor- tomatic or symptomatic urinary tract
bid symptoms, and the high prevalence infection have not yet been identified.
of bacteriuria interfere with diagnostic
precision. Non-specific decline in resident Key words: elderly, nursing home, long
function or nonlocalizing signs and symp- term care, bacteriuria, urinary infection,
toms, even with a positive urine culture, chronic urinary catheter
Chapter | 10 | Health care associated urinary tract infections
SUMMARY OF RECOMMENDATIONS to diagnose symptomatic urinary

tract infection, and is not an indi-
Diagnosis cation for antimicrobial therapy
(GoR B) [1, 3].
Clinical diagnosis
9. Urine specimens for culture should
1. The diagnosis of symptomatic uri- be collected, wherever possible, by a
nary infection for residents of long clean catch technique (GoR B).
term care facilities without a chronic
10. For women who cannot cooperate for
indwelling catheter should be made
specimen collection, a urine speci-
only when acute localizing genitouri-
men should be obtained by in and
nary signs or symptoms are present
out catheter (GoR C).
(GoR B) [1–2].
11. For men with voiding managed by
2. For residents with a chronic indwell-
external condom catheters, a urine
ing catheter, a diagnosis of sympto-
specimen can be obtained following
matic urinary infection requires the
cleaning of the glans and meatus and
presence of fever, acute confusion,
after application of a freshly applied
rigors, or costovertebral angle pain
clean condom catheter and drainage
or tenderness without an alternate
bag (GoR B) [4–5].
source, with or without other localiz-
ing genitourinary signs or symptoms 12. For residents with chronic indwell-
(GoR B) [1–2]. ing catheters, the indwelling cath-
eter should be removed and replaced
Laboratory diagnosis with a urine specimen for culture
obtained through the newly inserted
3. Screening of asymptomatic residents catheter prior to institution of anti-
for bacteriuria, with or without an microbial therapy (GoR A) [2, 6].
indwelling catheter, is not recom-
mended (GoR A) [1, 3]. Treatment
4. A quantitative count of ≥ 105 cfu/ml
is appropriate for the microbiologic 13. Asymptomatic bacteriuria should
diagnosis of urinary infection in resi- not be treated in residents of long
dents with or without an indwelling term care facilities whether or not
catheter (GoR B). a chronic indwelling catheter is
present (GoR A) [1, 3].
5. For individuals with localizing geni-
tourinary symptoms, lower quantita- 14. Antimicrobial therapy is selected
tive counts may also be consistent considering the known or suspected
with symptomatic infection (GoR C). infecting organism, patient toler-
ance, prevalence of antimicrobial
6. For urine specimens collected from resistance in the institution, and doc-
external condom catheters in men, umented effectiveness of the agent in
the appropriate quantitative count is urinary tract infection (GoR C)
≥105 cfu/ml (GoR B) [4–5].
15. Parenteral antimicrobial therapy
7. For specimens obtained by in and should be initiated for patients
out catheter, ≥ 103 cfu/ml is the with hemodynamic instability, who
quantitative criteria for bacteriuria are unable to tolerate or absorb
(GoR C) [3]. oral medication, or with known or
8. The presence of pyuria with bac- suspected resistant organisms for
teriuria without localizing clinical which oral therapy is not available
signs or symptoms is not sufficient (GoR C).
590
Urinary tract infections in long term care patients | 10.4 |
16. For symptomatic infection in men or 26. Intermittent catheterization should

suspected renal infection in women be used rather than chronic ind-
the treatment course should be 7–10 welling catheters where possible
days (GoR B). (GoR B).
17. Women with symptoms of acute cys- 27. Intermittent catheterization should
titis should be treated with a short use a clean technique (GoR A) [13].
course of antimicrobial therapy 28. For residents with chronic indwell-
appropriate for the antimicrobial ing catheters, catheter care must
used (GoR A) [7]. minimize mucosal trauma and iden-
18. For men with suspected chronic tify catheter obstruction promptly
bacterial prostatitis manifesting as (GoR C).
recurrent acute cystitis, retreatment 29. Routine catheter changes are not rec-
with 6–12 weeks antimicrobial ther- ommended to prevent symptomatic
apy may be considered (GoR B) [8]. urinary tract infection (GoR C).
19. For residents with chronic indwell- 30. Antimicrobial therapy at the time of
ing catheters, duration of therapy catheter change is not recommended
should not exceed 7 days when there (GoR B) [14–15].
has been a prompt clinical response
31. Routine use of antimicrobial or silver
following institution of antimicrobial
coated catheters is not recommended
therapy (GoR C).
(GoR B) [1].
Prevention
20. Residents with asymptomatic bacte- 1. INTRODUCTION
riuria should receive antimicrobial
prophylaxis prior to genitourinary Urinary tract infection is the most com-
interventions where mucosal bleed- mon infection which occurs in long term
ing is anticipated (GoR A) [3]. care facilities [16]. The majority of these
infections are asymptomatic, and benign
21. Use of cranberry juice is not recom- (3). However, symptomatic infection does
mended for the prevention of symp- occur, and urinary infection is a frequent
tomatic urinary infection (GoR A) [9]. indication for antimicrobial therapy in
22. Topical estrogen is not recommended these settings [2]. Clinical ascertain-
for the prevention of asymptomatic ment of symptomatic infection may be
or symptomatic urinary tract infec- problematic given chronic genitourinary
tion (GoR B) [10–11]. symptoms, difficulties in communica-
23. Indwelling urethral catheters should tion and atypical presentations [2, 17].
be used only with clear indications This uncertainty, together with the high
(GoR C). prevalence of bacteriuria, leads to anti-
microbial overuse and the accompanying
24. The need for an indwelling urethral problems of adverse effects from anti-
catheter should be reviewed on a microbials and increased antimicrobial
continuing basis, and the catheter resistance.
discontinued as soon as feasible This guideline provides recommen-
(GoR C) dations for the management of urinary
25. For men, an external condom cath- infection in residents of long term care
eter should be used when possible facilities. It addresses both asymptomatic
rather than an indwelling urethral and symptomatic urinary tract infection,
catheter (GoR B) [12]. and includes patients with and without
591
long term indwelling catheters. The dis- 4. EPIDEMIOLOGY

cussion is relevant to residents without
a chronic indwelling catheter unless spe- 4.1 Prevalence of bacteriuria
cifically noted to address the catheterized
Studies consistently report a prevalence
individual.
of asymptomatic bacteriuria in women in
long term care facilities of 25–50%, and
2. METHODS in men from 15–40% [3, 16, 20]. A recent
study of residents of long term care facili-
ties in three municipal areas of Sweden is
This document incorporated and updated
consistent with earlier reports. The preva-
the 2005 Infectious Diseases Society of
lence of bacteriuria was 43% in women and
America Guideline for the management
30% in men, with 23% and 16% remaining
of asymptomatic bacteriuria [3] and the
bacteriuric on a second consecutive urine
2001 SHEA Guideline for urinary tract
specimen [20]. The mean age of these resi-
infections in long term care facilities
dents was 84.6 years, and 47% of residents
[1]. These were updated using a sys-
in these facilities were excluded because of
tematic literature search performed in
severe incontinence or dementia. As incon-
MEDLINE, Cochrane, and Embase. The
tinence and dementia is strongly associ-
key words used included urinary infec-
ated with bacteriuria, the prevalence in
tion, bacteriuria, nursing homes, and
the full population would have been even
long term care facility. The limitations
higher than reported [1, 16].
included adult clinical studies, English,
Bacteriuria in long term care facility
and peer reviewed. A total of 145 pub-
residents is dynamic [21]. Repeated prev-
lications were identified, and screened
alence surveys report that individuals
by title and abstract. After exclusion
who are initially not bacteriuric become
of duplicates, a total of 8 were included
positive, and residents with bacteriuria
in the review. The information identi-
may become negative, often following
fied through the literature review was
antimicrobial therapy. Some residents
supplemented by citations in published
have persistent infection with the same
reports as well as other papers identified
organism for months or years, while oth-
by the author.
ers have repeated reinfections with new
organisms [22–23].
recommendation (GoR) using ICUD stand-
4.2 Incidence of symptomatic
urinary infection
Symptomatic urinary infection occurs
3. DEFINITION OF THE DISEASE infrequently relative to the high preva-
lence of bacteriuria. Rates of sympto-
Urinary tract infection is the isolation of matic urinary infection vary from 0.1 to
bacteria or yeast from the urine in counts 2.4/1,000 resident days [16]. This varia-
meeting accepted quantitative criteria. tion reflects underlying differences in the
Asymptomatic urinary infection, or bac- populations studied, as well as different
teriuria, is present when microbiologic definitions used for case ascertainment
criteria are met but there are no acute [16, 24]. A mean of 0.6 symptomatic uri-
signs or symptoms referable to the urinary infections/1,000 residents’ days was
nary tract. Symptomatic infection may be reported in a group of facilities in one US
restricted to the bladder (cystitis), affect state when uniform surveillance meth-
the kidneys (pyelonephritis) or, in men, odology, including consistent definitions,
the prostate. was used [24].
592
4.3 Risk factors isolated. Repeated prior antimicrobial

The prevalence of asymptomatic bacteri- exposure and opportunities for transmis-
uria increases with increasing functional sion of organisms within the long term
disability [16, 21]. Long term care facil- care setting promote isolation of organ-
ity residents with incontinence of bladder isms of increased antimicrobial resist-
or bowel, dementia, and who score poorly ance [27–28].
in measures of functional ability have an
increased prevalence. Voiding abnormal- 4.5 Chronic indwelling urethral
ity which accompanies the chronic neu- catheter
rologic diseases which often precipitate
institutional care likely explains the high From 4–7% of residents of long term care
prevalence observed. Oral [10] or topical facilities have voiding managed with a
[11] estrogen therapy does not influence chronic indwelling catheter [29]. The
the frequency of bacteriuria or symp- limited indications for use of long term
tomatic urinary infection in women. In catheters include obstruction, to assist
men, an additional contributing factor is with healing of a pressure ulcer and,
prostatic hypertrophy and chronic pros- uncommonly, in managing incontinence
tatitis [8]. Men with continence managed for patient comfort or end of life care.
using external condom catheters have a Individuals with a chronic indwelling
higher incidence and prevalence of bac- catheter are always bacteriuric, usually
teriuria, with the highest risk observed with 2–5 organisms isolated at any time
when there is obstruction or manipula- [30]. There are a wide variety of organ-
tion of the condom or drainage tubing isms isolated, with urease producing
[12]. Cross-sectional [25] and prospective organisms such as Proteus mirabilis and
[26] studies have not reported any associ- Providencia stuartii over-represented.
ation of bacteriuria or symptomatic infec- Bacteria produce and grow on the inter-
tion with increased post-void residual nal and external catheter surfaces within
urine volume in men or women. Other a biofilm which incorporates protein and
risk factors for development of sympto- metal ions from the urine. This provides
matic urinary infection, other than the a protected environment which limits
presence of a chronic indwelling catheter, exposure to host defenses as well as anti-
are not well defined. microbials in the urine [31].
The presence of a chronic indwelling
catheter is associated with excess mor-
bidity from urinary infection [29–30].
4.4 Microbiology
Residents with a chronic indwelling
A wide variety of organisms are isolated catheter, compared with bacteriuric
from both asymptomatic and sympto- residents without catheters, have been
matic urinary tract infection [16, 21]. reported to have three times more epi-
For women, Escherichia coli remains sodes of fever of presumed urinary
the most common organism, although source [29], from three to 39 times the
this species is proportionally lower than frequency of bacteremia from a uri-
observed in noninstitutionalized older nary source [16], and seven times more
populations. For men, Enterococcus frequent histologic evidence of acute
spp and Proteus mirabilis have been pyelonephritis at autopsy [29]. Residents
reported to be the most frequent organ- with an indwelling catheter also have
isms isolated, but the spectrum of infect- increased mortality, but this is attrib-
ing organisms varies among institutions. uted to increased functional and medical
From 10 to 25% of residents with bacte- impairment in these individuals, rather
riuria will have more than one organism than urinary infection [32].
593
5. CLINICAL EVALUATION with voiding managed with an external

condom catheter, a specimen may be col-
5.1 Symptomatic urinary infection lected using a freshly applied clean con-
dom and leg bag (LoE 2a) [4–5].
The diagnosis of lower urinary tract infec-
A urine specimen obtained from an ind-
tion (cystitis) is made when acute local-
welling catheter in place for several days
izing genitourinary findings are present
will sample the biofilm on the interior of
including dysuria, new or increased
the catheter as well as bladder urine [6,
incontinence, urgency, frequency, and
29]. To obtain a more reliable urine speci-
hematuria. For pyelonephritis, costover-
men for microbiology by sampling only
tebral angle pain or tenderness with or
bladder urine, the chronic indwelling cath-
without fever are the usual localizing
eter should be replaced and a specimen
symptoms. Chronic genitourinary symp-
obtained from the new catheter prior to ini-
toms are common in these individuals
tiating antimicrobial therapy (LoE 2a) [6].
including incontinence, nocturia, and fre-
quency. These chronic symptoms are not
improved with treatment of bacteriuria, 5.3 Pyuria
and should not be interpreted as sympto- Pyuria is universally present with symp-
matic infection (LoE 2a) [1]. In addition, tomatic urinary tract infection [33].
a presentation of nonspecific, nonlocaliz- However, it is also present in virtually all
ing symptoms, such as decline in general residents with asymptomatic bacteriuria,
clinical status, is not symptomatic uri- and as many as 30% of residents without
nary infection, even with a positive urine bacteriuria [16, 21]. Thus, the presence of
culture (LoE 2b) [1]. pyuria identified either on urinalysis or
Fever without localizing findings is the with leukocyte esterase screening is not
most common presentation for residents useful to differentiate symptomatic from
with chronic indwelling catheters [29]. asymptomatic infection, and is not an indi-
Costovertebral angle pain or tenderness cation for antimicrobial therapy (LoE 2a).
may be present. Severe systemic infection The absence of pyuria, however, has a high
attributable to urosepsis may present as negative predictive value and is reliable to
an acute confusional state in residents exclude a diagnosis of urinary infection [2].
with or without a catheter, similar to any
other serious infections in this population.
6. TREATMENT
5.2 Microbiologic diagnosis 6.1 Asymptomatic bacteriuria

A urine specimen for culture should be Clinical trials have consistently docu-
obtained prior to initiating antimicrobial mented no benefits with antimicrobial
therapy for any resident with presumed treatment of asymptomatic bacteriuria in
urinary tract infection. A clean catch long term care facility residents (LoE 1a)
voided method is preferred to collect the [1, 3]. Specifically, treatment of asympto-
urine specimen from residents without matic bacteriuria does not improve chronic
chronic indwelling catheters. For women genitourinary symptoms, prevent sub-
with severe incontinence or who are oth- sequent symptomatic episodes, improve
erwise unable to cooperate, it may not be survival, or decrease the overall preva-
possible to obtain a clean catch specimen. lence of bacteriuria. On the other hand
In these cases, where a urine specimen is treatment is associated with increased
necessary for patient management, the adverse effects attributed to the medica-
specimen should be collected by using an tion, increased reinfection with organisms
in and out catheter (LoE 4) [1]. For men of increased resistance, and cost.
594
6.2 Symptomatic infection prior to antimicrobial treatment for

When symptoms are mild or uncertain, symptomatic urinary infection reported a
it is preferable to delay initiation of anti- shorter time to defervescence of fever, and
decreased frequency of recurrent symp-
microbial therapy until the results of a
tomatic urinary infection post-therapy
urine culture are available. This allows
with catheter replacement, in addition
use of optimal, targeted antimicrobial
to obtaining a more reliable urine speci-
therapy and, in some cases, symptoms
men for microbiology [6]. The clinical
may resolve spontaneously so antimicro-
benefits are assumed to reflect removal of
bial therapy is not required.
the biofilm on the catheter where organ-
Ascertainment of symptoms may be
isms may persist despite antimicrobial
difficult because of impaired communica-
therapy.
tion and chronic genitourinary symptoms
[1–2]. A consensus guideline has provided
6.3 Medication/drug therapy
recommendations for criteria to be met
prior to initiating antimicrobial ther- The choice of antimicrobial agent and
apy for presumed symptomatic urinary duration of therapy do not differ for insti-
tract infection [34]. For residents with- tutionalized or non-institutionalized
out indwelling catheters, these criteria older individuals. Antimicrobial selection
are either acute dysuria by itself, or one is determined by severity of presenta-
of fever, acute mental deterioration, or tion, site of infection, known or predicted
chills together with at least one localizing infecting organism, and patient tolerance.
genitourinary symptom (new or worsen- The selection of empiric antimicrobial
ing urgency, frequency, suprapubic pain, therapy should consider the prevalence
gross hematuria, costovertebral angle of resistant organisms in the institution.
tenderness, or urinary incontinence). Few clinical trials directly compare differ-
Thus, genitourinary signs or symptoms ent regimens for management of urinary
must be present. Cloudy or foul smelling tract infection in long term care facility
urine are not, by themselves, sufficient to residents. One study compared a cipro-
diagnose symptomatic infection [17]. For floxacin suspension with trimethoprim/
residents with a chronic indwelling cath- sulfamethoxazole (TMP/SMX) in women
eter, the consensus recommendations for with cystitis and reported improved short
institution of antimicrobial therapy for term cure rates with the ciprofloxacin.
urinary infection include at least one of This was largely attributable to higher
fever, new costovertebral angle tender- baseline TMP/SMX resistance [36].
ness, rigors or new onset delirium with no
alternate source. These consensus guide- 6.4 Duration of therapy
lines have been validated in a prospective A double-blind randomized controlled
randomized trial which document that trial compared 3 to 7 days ciprofloxacin
application of the guidelines is safe and therapy for symptomatic cystitis in
associated with a decreased overall use older women, including some residents
of antimicrobial therapy for urinary tract of long term care facilities. The shorter
infection (LoE 1b) [35]. course of therapy had similar efficacy
For residents with a chronic indwell- and a lower frequency of side-effects
ing catheter, the catheter should be (LoE 1b) [7]. A more prolonged course
replaced and a urine specimen for culture of therapy of 7–10 days should be con-
obtained immediately prior to institut- sidered for pyelonephritis or if there is
ing antimicrobial therapy (LoE 1b) [30]. A an early symptomatic recurrence after
prospective, randomized trial of catheter short course therapy. For men the rec-
replacement or no catheter replacement ommended duration of treatment is 7–14
595
days, but there are no clinical trials catheter is to avoid use of the catheter or
defining optimal duration. If recurrent to limit duration of use, if possible. For
cystitis in men is attributed to chronic men with incontinence, an external con-
bacterial prostatitis, retreatment with dom catheter may be used (LoE 3) [12].
a more prolonged course of 6–12 weeks For some residents, intermittent cath-
is recommended [8], but this more pro- eterization to assist with voiding rather
longed course has not been evaluated in than an indwelling catheter is an option
long term care facility residents (LoE 1b). (LoE 3). A prospective randomized trial
The optimal duration of therapy for indi- reported that clean and sterile technique
viduals with chronic indwelling catheters for intermittent catheterization have sim-
has not been addressed in clinical trials. ilar risks of bacteriuria and symptomatic
If there is a prompt response to antimi- infection but clean technique is less costly
crobial therapy, a duration of only 7 days (LoE 1b) [13]. Thus, use of the clean tech-
is recommended to limit emergence of nique is preferred. When an indwelling
resistant organisms [17]. catheter must be used, symptomatic epi-
sodes can likely be minimized by avoid-
ing catheter trauma to the mucosa, and
7. PREVENTION prompt identification and management
of catheter obstruction. Prophylactic
For residents without indwelling urethral antimicrobial therapy does not prevent
catheters, clinical trials have not identi- symptomatic infection in residents with
fied specific interventions to decrease the chronic indwelling catheters, but is asso-
prevalence of asymptomatic bacteriuria ciated with infection with organisms
in long term care facility residents. Risk of increased resistance (LoE 1b) [37].
factors associated with development of When catheters are changed there is a
symptomatic infection are also not well risk of bacteremia, but limited morbid-
characterized, and no interventions have ity has been reported, so antimicrobial
been documented to be effective in pretherapy with catheter change is not rec-
venting symptomatic infection specifi- ommended (LoE 3) [14–15]. There are no
cally in this population. Trials evaluating studies to suggest routine changing of
estrogen use for women [10] or daily cran- chronic indwelling catheters is beneficial.
berry juice [9] did not report a decrease in Catheters should be changed only if they
symptomatic infection (LoE 1b). Low dose are obstructed, otherwise not function-
prophylactic antimicrobial therapy may ing, or prior to treatment of symptomatic
prevent symptomatic cystitis in older infection. Antimicrobial coated catheters
women, as in younger, but this would not have not been evaluated for patients with
usually be recommended for women resi- chronic catheters, but would not be antic-
dent in long term care facilities because ipated to have a benefit as any impact on
of concerns with increased antimicrobial bacteriuria with these devices appears to
resistance and transmission of organisms be short-term (LoE 4).
among residents. When persons with
asymptomatic bacteriuria undergo trau-
matic genitourinary interventions (e.g. 8. GUIDELINES
transurethral resection of the prostate)
antimicrobial therapy should be initiated Consensus guidelines have been pub-
immediately prior to the intervention to lished to address urinary tract infection
prevent bacteremia or sepsis (LoE 1b) [3]. in long term care facilities. The Society
The most effective means to prevent for Healthcare Epidemiology of America
symptomatic infection or bacteriuria (SHEA) guidelines specifically address
in residents with a chronic indwelling management of urinary infection in
596
long term care [1]. There are also guide- as well as limiting inappropriate use of
lines identifying diagnostic criteria antimicrobials for bacteriuric individuals
for surveillance of urinary infection without an indwelling catheter and with
[38] and when to initiate antimicrobial non localizing symptoms.
therapy for urinary tract infection [34].
The management of asymptomatic bac-
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599
Chapter |11|
Urosepsis
Chair: Bernhard Lobel
CHAPTER OUTLINE
11.2 Pathogenesis of sepsis as related to novel
therapeutic concepts 604
11.3 Urosepsis – from the view of the intensivist 615
11.4 Urosepsis – from the view of the urologist 630
|11.1|
Introduction
Pierre Tattevin, Matthieu Revest, Bernhard Lobel
Université de Rennes 1, Hôpital Pontchaillou, Rennes, France
Corresponding author: Professeur Bernard Lobel, Service d’ Urologie, Hopital Pontchaillou, Rue Henri le Guilloux
F-35033 Rennes Cedex, France
Tel 0033-2-9924.4269, Fax 0033-2-9928.4113, bernard.lobel@chu-rennes.fr
Sepsis is defined as a combination of death. Given this dreadful combination

pathologic infection and physiological of high incidence and potential for severe
changes known collectively as the sys- consequences, urosepsis deserves signifi-
temic inflammatory response syndrome cant consideration from the urology and
[1]. Sepsis is often lethal, killing 20–50% the intensive care communities.
of severely affected patients; epidemio- On this issue, three up-to-date pap-
logic data from the United States showed ers present an overview of urosepsis.
that between 1979 and 2000, there was Firstly, Evangelos Giamarellos-Bourboulis
an annualized increase in the incidence describes what is currently known about
of sepsis of 8.7%, from 164,000 cases sepsis pathogenesis; initially, sepsis may
(82.7 per 1000,000 population) to 660,000 be characterized by increases in inflamma-
cases (240.4 per 1000,000 population) [2]. tory mediators, but as sepsis persists, there
Urinary tract infections (UTI) are among is a shift toward an anti-inflammatory
the most common causes of sepsis, total- state which may adversely affect outcome
ling as much as 20–30% of all sepsis cat- [1]. Indeed, patients with sepsis have fea-
egories in one large multicentric study tures consistent with immunosuppression,
performed in a French ICU [3], the higher including a loss of delayed hypersensitiv-
prevalence of UTI (30%) being encoun- ity, an inability to clear infection, and a
tered among patients presenting with predisposition to nosocomial infections
the most severe forms of sepsis (i.e. sep- [4]. The main mechanisms of immune
tic shock). Thus, urosepsis, now widely suppression demonstrated thus far are:
accepted as the preferred term for any i) a shift to anti-inflammatory cytokines;
degree of systemic inflammatory response ii) anergy; and iii) death of immune cells
related to UTI, is not uncommon and may [1]. Significant progress has been accom-
be associated with severe consequences, plished over the last two decades, the
including long-term disabilities and even most famous finding being the discovery of
toll-like receptors (TLR), and the complex sepsis and septic shock is one of the major
interactions between pathogen-associated prognostic factors for this condition, with
molecular patterns (PAMPs) and pattern- a well-documented impact on morbidity
recognition receptors (PRRs). The manage- as well as mortality. Consequently, every
ment of patients with severe sepsis and physician who may be confronted with
septic shock has been somewhat improved patients with urosepsis, whatever the sit-
through large-scale, double-blind, control- uation (urology department, emergency
led randomized studies, although some of ward, outpatient clinic), must acquire
them brought more confusion than clarity. or preserve standard knowledge about
Issues such as the use of adrenal hormone the key points for the management of
replacement therapy (hydrocortisone), patients with urosepsis.
blood glucose control, and interventions Only with this effort will our patients’
against excess coagulopathy (drotrecogin- prognosis significantly improve, as one
alpha) have probably been pushed too far, hour too late may be too late in rapidly
following a few convincing clinical studies; evolving diseases such as septic shock.
their values are now being re-evaluated Lifen Li et al. carefully present an easy-
throughout selected clinical studies trying to-read, concise, up-to-date review of uro-
to better define the patients who would sepsis management from the view of the
clearly benefit from these interventions. intensivist.
Undoubtedly, the paper by Evangelos Do not forget that any obstruction in
Giamarellos-Bourboulis on this topic will the urinary tract must be treated surgi-
be an invaluable guide for those of us who cally in an emergency with the support
are not aware of the latest developments of intensive care. Mostly in these cases,
in sepsis pathogenesis and novel thera- drainage by itself cures most patients. We
peutic concepts. hope our readers enjoy these papers, and
In the second paper dealing with uro- their patients benefit.
sepsis in this section, Florian Wagenlehner
et al. present the ‘view of the urologist’.
This paper is an executive summary of REFERENCES
the authors’ findings about the manage-
ment of urosepsis, based on a literature 1. Hotchkiss RS and Karl IE, The patho-
review and on the authors’ experience. physiology and treatment of sepsis.
Indeed, given that randomized controlled N Engl J Med, 2003. 348(2): 138–50.
studies have not addressed all of the spe- 2. Martin GS, Mannino DM, Eaton S, and
cific issues relating to this topic, Florian Moss M, The epidemiology of sepsis in the
Wagenlehner’s own expertise in antimi- United States from 1979 through 2000.
crobial treatment of UTI was required to N Engl J Med, 2003. 348(16): 1546–54.
fill the numerous gaps. This up-to-date 3. Alberti C, Brun-Buisson C, Burchardi
H, Martin C, Goodman S, Artigas A,
review provides us with important and
Sicignano A, Palazzo M, Moreno R,
practical ‘take home messages’. Boulme R, Lepage E, and Le Gall R,
Last but not least, Lifen Li et al. per- Epidemiology of sepsis and infection
formed an extensive analysis of the in ICU patients from an international
standard-of-care for patients with urosep- multicentre cohort study. Intensive Care
sis. Although this paper focuses mainly Med, 2002. 28(2): 108–21.
on therapeutics usually administered in 4. Annane D, Bellissant E, and Cavaillon
intensive care units, recent studies have JM, Septic shock. Lancet, 2005.
shown that early management of severe 365(9453): 63–78.
603
|11.2|
Pathogenesis of sepsis as related

to novel therapeutic concepts
Evangelos J. Giamarellos-Bourboulis
4th Department of Internal Medicine, University of Athens, Medical School, Greece
Correspondence: 4th Department of Internal Medicine, ATTIKON University Hospital, 1 Rimin Str., 124 62 Athens, Greece
Tel: 0030 210 58 31 994, Fax: 0030 210 53 26 446, e-mail: giamarel@ath.forthnet.gr
ABSTRACT inflammation or excess coagulation. Meta-

analysis of randomized trials disclosed
The complex pathogenesis of sepsis is ini- survival benefit from the administration
tiated when damage-associated molecular of intravenous immunoglobulins particu-
patterns are recognized by the pattern rec- larly when using preparations enriched
ognition receptors of the cells of the innate in IgM and IgA. Administration of hydro-
immune system of the host. This leads cortisone 50mg intravenously every six
to the generation of pro-inflammatory hours is accompanied by earlier reversal
cytokines which promote intense inflam- of shock. Results of three trials about the
matory phenomena. This reaction is per- benefit of intensive insulin therapy aim-
petuated with transition from the innate ing to achieve capillary blood glucose
to the adaptive immune system. As the levels between 80 and 110 mg/dl are con-
disease progresses, the TH2 anti-inflam- troversial. Considerable reduction of risk
matory response predominate, leading of death from septic shock and multiple
to immunosuppression. In parallel, the organ dysfunctions (MODS) was found
coagulation cascade is triggered by tis- from one randomized trial by the intra-
sue factors expressed on the damaged venous administration of clarithromycin.
vascular bed and on the cell membrane Results of four trials suggest the admin-
of monocytes. Coagulopathy is further istration of recombinant human activated
intensified when protein C levels secreted protein C (rhAPC) in patients with pres-
by the endothelium are decreased. In an entation of signs of MODS within less
attempt to decrease mortality from sep- than 24 hours and an APACHE II score
sis, several trials have been conducted greater than 25. It should not be given in
with compounds aiming to decrease excess children and in patients with a history of
Pathogenesis of sepsis | 11.2 |
recent bleeding or a bleeding predisposi- 30–35% for severe sepsis and 40–50% for
tion. Therapeutic options aiming to inter- septic shock [2]. A registry for sepsis was
vene in the inflammatory cascade of the started in January 2007 in Greece (www.
septic host have been evaluated by the sepsis.gr). Mortality from septic shock is
“Surviving Sepsis Campaign” (SSC) panel almost 50% for patients hospitalized in
of experts, who have also developed a an Intensive Care Unit (ICU) and almost
grading system for recommendations. 65% for those hospitalized on a general
ward. It is estimated that almost 82,000
Key words: sepsis; inflammation; coag-
cases of severe sepsis and septic shock
ulopathy; immunointervention
occur annually in Greece, a country with
10 million inhabitants.
SUMMARY OF RECOMMENDATIONS The great lethality of septic syn-
drome has lead to the creation of world-
recognized efforts attempting to decrease
1. It is suggested that hydrocortisone
overall mortality. This effort is known as
should be administered in patients with
the “Surviving Sepsis Campaign” (SSC)
septic shock at a dose of 50 mg every
which published international guide-
six hours. This leads to earlier reversal
lines in 2004 and 2008 [3–4]. A common
of shock (LoE 1b, GoR A, SSC 2c)
denominator of these guidelines is that
2. It is suggested that capillary glucose patient support should comprise all of the
should be maintained below 150 mg/dl following: a) fluid and oxygen resuscita-
in patients with severe sepsis (LoE 1b, tion; b) administration of vasopressors if
GoR A, SSC 2c) necessary; c) early-directed antimicrobial
3. Recombinant human activated protein therapy; d) eradication of the infection
C (drotrecogin-alpha) is suggested source; e) immunomodulatory therapies;
for patients with severe sepsis and f) conditions of mechanical ventilation;
two or more failing organs or with an and g) transfusion of blood and blood
APACHE II score greater than 25. products.
It is not given in children. Contra- Part of the above therapies is attempt-
indications are signs of active bleeding to modulate the inflammatory
ing, recent hemorrhagic stroke, recent response of the host. This creates the
surgical operation, multiple traumas need to understand the complex patho-
with an increased risk for bleeding genesis of sepsis. The present review
and a predisposition for hemorrhage aims to provide the current schema of
i.e. thrombocytopenia, increased INR pathogenesis of sepsis and to analyze cur-
or prolongation of aPTT. Drotrecogin- rent therapeutic options of intervention
alpha is administered at a dose of in the mechanisms of pathogenesis.
24 µg/kg/h for 94 continuing hours
(LoE 1b, GoR A, SSC 2b)
2. METHODS
1. INTRODUCTION For the presentation of the basic scheme

of pathogenesis of sepsis, 13 review arti-
Severe sepsis and septic shock are recog- cles published in major journals in 2008
nized as the tenth greatest cause of death were included. The articles were retrieved
in the United States [1]. It is estimated by a PubMed search using the following
that almost 1.5 million people develop sep- limits: 2008; English; pathogenesis; sepsis;
tic syndrome annually in North America reviews. Well-cited peer-reviewed research
and another 1.5 million in Northern articles of major interest published the
Europe. The case-fatality ranges among last five years were also applied.
605
Chapter | 11 | Urosepsis
For the treatment recommendations, pneumonia, intrabdominal infections, pri-

20 published major clinical trials were mary bacteremia and ventilator-associated
used. These were retrieved from the pneumonia (VAP). The most common
PubMed database using the following microbial causes are Gram-negative
key-words: clinical trials; anti-endotoxin bacteria and Gram-positive cocci. Their
antibodies; anti-TNF antibodies; drot- frequency differs from country to coun-
recogin-alpha; tifacogin; hydrocortisone; try. Since 1987, Gram-positive cocci pre-
insulin; immunoglobulins; clarithromy- dominate in the Northern countries [7];
cin. The following limits were used in the in other countries like Greece, Gram-
literature search: English; clinical trials. negative bacteria predominate.
The studies were rated according
to the level of evidence (LoE) and the 3.1 Stimulation of the inflammatory
grade of recommendation (GoR) using cascade
ICUD standards (for details see Preface)
Despite the need for an underlying infec-
[5–6]. Since therapeutic options aiming
tious focus, it is considered that the host
to intervene in the inflammatory cascade
creates the disease. Current belief on the
of the septic host have been evaluated by
pathogenesis of sepsis relies on a complex
the “Surviving Sepsis Campaign” (SSC)
interaction between pathogen-associated
panel of experts according to the GRADE
molecular patterns (PAMPs) residing on
system [3–4], grading according to that
the bacterial cell and pattern-recognition
system is also provided in the present
receptors (PRRs) on cell membranes
chapter. This system is given in Table 1.
of the cells of the innate and adaptive
immune system of the host. Several mol-
3. PATHOGENESIS ecules released from cells of the host
following necrosis are able to stimu-
The occurrence of sepsis requires the exist- late PRRs. These are called “alarmins”.
ence of a well-defined source of infection. Both alarmins and PAMPs are known as
The most common sources of infection are damage-associated molecular patterns
acute pyelonephritis, community-acquired (DAMPs) [8].
Table 1 The GRADE system of recommendations adapted by the expert committee of the “Surviving Sepsis Campaign”
guidelines. RCT = Randomised controlled trial.
Grade Benefit/risk Level of evidence Grading
1A Benefit >>> risk RCTs without any methodological problem/ Strongly recommended for all
limitation or high-powered observational studies patients
1B Benefit >>> risk RCTs with several methodological problems/ Recommended for all patients
limitations or strong observational studies
1C Benefit >>> risk Observational studies Recommendation that may change
2A Benefit ≥ risk RCTs without any methodological problem/ Suggested

limitation or high-powered observational studies
2B Benefit ≥ risk RCTs with several methodological problems/ limita- Weak suggestion
tions or strong observational studies
2C Unknown Observational studies Very weak suggestion
606
The best studied PRRs are toll-like tissue cell apoptosis and kidney damage.
receptors (TLRs) that are transmem- IL-6 induces the production of acute phase
brane receptors of blood monocytes reactants from liver. IL-8 is a potent che-
and tissue macrophages. Ten TLRs are moattractant for neutrophils. The latter
described so far of which the most impor- once recruited in the inflammatory site
tant are TLR2, TLR4, TLR5 and TLR9. release reactive oxygen species (ROS)
Endotoxins (LPS) of the outer membrane which further augment tissue injury.
of Gram-negative bacteria and heat- The deterioration of vascular endothe-
shock protein 90 (HSP90) are agonists lium promotes a leak of cytokines in the
of TLR4; lipoteichoic acid (LTA) of the systemic circulation leading to multiple
cell wall of Gram-positive cocci is an ago- organ dysfunction (MODS) [12]. IL-10 is
nist of TLR2; bacterial flaggelin of TLR5; a well known anti-inflammatory cytokine
and CpG DNA of TLR9 [9]. Binding of attempting to eliminate systemic inflam-
LPS to TLR4 triggers the adaptor mol- mation. As the septic response progresses,
ecule myeloid-differentiation factor-88 the innate immune response generat-
(MyD88). Intracellular signaling requires ing the first cytokine storm gives its
bridging of MyD88 with the MyD88- place to an adaptive immune response of
adapter like /TIR-associated protein (Mal/ T-helper cells (TH). Depending on the type
TIRAP). This leads to activation of inter- of released cytokines from TH cells, the
leukin (IL)-1 receptor-associated kinase TH-response is divided into TH1 charac-
(IRAK)-4 which phosphorylates IRAK-1. terized by the release of TNFα, IL-2 and
The latter is activated and recruits TRAF interferon-gamma (IFNγ) and into TH2
(TNF-receptor associated factor)-6 which characterized by the release of IL-4, IL-5,
activates the mitogen activated p38 IL-6 and IL-10. The TH1 response is pro-
(MAP) kinase. The latter phosphorylates inflammatory and the TH2 response is anti-
IkB into nuclear factor-kB (NF-kB). In inflammatory. As time progresses, the TH2
parallel, activator-protein 1 (AP-1) is response predominates which is equivalent
generated. Both NF-kB and AP-1 initiate with immunosuppression of the host [8].
the transcription of genes of pro-inflam- A novel subset of TH cells has been recog-
matory and anti-inflammatory cytokines nized releasing IL-17. They are known as
[10]. Among these pro-inflammatory T17 cells. Released IL-17 is a strong che-
cytokines, IL-1β is generated as a pro- moattractant of neutrophils. The latter
peptide, namely pro-IL-1β. This requires invade tissue and lead to MODS.
cleavage to IL-1β through the cas- A receptor that has been recently recog-
pase-1 IL-1β converting enzyme (ICE). nized is a triggering receptor expressed on
Activation of ICE is regulated though the myeloid cells (TREM-1) embedded on the
NALP-3 inflammasome. Constituents of cell membranes of neutrophils and mono-
the cell wall of Gram-positive cocci like cytes. Its ligand is yet unknown though
muramyl dipeptide are agonists of the Staphylococcus aureus, Pseudomonas
inflammasome [11]. aeruginosa and Aspergillus fumigatus are
There are growing numbers of mol- potential agonists. TREM-1 is stimulated
ecules reported to inhibit the TLR4 sig- in the event of septic shock. Its adaptor
naling pathway. The best known are molecule is DAP12 (DNAX activation pro-
radioprotective 105 (RP105) and a splice tein of 12 KDa). Stimulation leads to the
variant of MyD88 known as sMyD88 [12]. rise of intracellular Ca2+ accompanied by
The best studied pro-inflammatory the release of TNFα and IL-8 [13–14]. A
cytokines are tumour necrosis factor-alpha soluble form of TREM-1 has been recog-
(TNFα), IL-1β, IL-6 and IL-8. TNFα and nized, namely sTREM-1. Though its con-
IL-1β induce fever responses, endothe- centrations are considerably increased
lial leaking, chemotaxis of neuthrophils, in serum in the event of septic shock, it
607
is thought that sTREM-1 behaves as levels of protein S are also decreased

an anti-inflammatory mediator prob- in sepsis [17]. HMGB1 also inhibits the
ably binding to the unknown ligand of APC pathway by interfering with the
TREM-1 [15]. thrombin-thrombomodulin complex [8].
Necrosis of cells due to tissue inflam- As a consequence, a hyper-coagulable and
mation leads to the release of high- hyper-inflammatory state supervenes.
mobility group box-1 (HMGB1). This is Damage of the endothelium in sepsis
a non-histonic protein bound to nuclear leads to release of tissue factor (TF), an
DNA and behaves as a late cytokine pro- effect promoted by HMGB1. TF is also
moting pro-inflammatory phenomena released on the surface of monocytes. TF is
and progression to MODS. HMGB1 also acting as an agonist of cytokine receptors
stimulates TLR4 and leads to a second and it is an initiator of the extrinsic coag-
cytokine storm [8]. ulation pathway. TF-pathway inhibitor
Recent data have shown that early (TFPI) is a serine protease inhibiting acti-
apoptosis of monocytes may be a major vated factor Xa and the TF/VIIa complex.
determinant of the final outcome of the Concentrations of TFPI are decreased in
septic host. Apoptosis of circulating patients with sepsis. The above combina-
monocytes at a level greater than 50% is tion of events promotes further hyper-
connected with favorable outcome in the coagulation and inflammation [18].
event of septic shock; in the contrary a A summary of the above mentioned
level of apoptosis lower than 50% is con- mechanisms of pathogenesis in sepsis is
nected with increased chance for death. shown in Figure 1.
This is probably related to lower biosyn-
thesis of pro-inflammatory cytokines by
the apoptotic monocytes [16]. 4. THERAPEUTIC OPTIONS BASED
ON THE MECHANISMS OF
3.2 Coagulopathy PATHOGENESIS
Sepsis is characterized by excess genera-
The understanding that antimicrobial
tion of thrombin and impaired fibrinolysis.
therapy and source control solely may not
Thrombin on its own is able to stimu-
reduce the high mortality of sepsis led to
late the production of TNFα and IL-6 by
the development of therapeutic strategies
monocytes. It also behaves as a C3 conver-
targeting the mechanisms of pathogen-
tase cleaving C5 compound of the comple-
esis as analyzed above. These strategies
ment into C5a which recruits neutrophils
may be divided into two categories: a)
in the inflammatory site [8]. Protein C
anti-inflammatory therapies; and b) mod-
is secreted by the endothelium; once
ulation of the coagulation cascade.
interacting with the thrombomodulin-
thrombin complex it is activated (APC).
4.1 Anti-inflammatory therapies
Formation of APC is 20-fold enhanced
in the presence of the endothelial pro- These therapies aim to restrain the
tein receptor (EPCR). APC inactivates excess inflammatory state of the host.
coagulation factors Va and VIIIa with They comprise antibodies targeting LPS
protein S as a co-factor. APC has also anti- and TNFα; soluble receptors of TNFα;
inflammatory and anti-apoptotic effects antagonists of TLR4; intravenous immu-
on both monocytes and endothelial cells noglobulins; low dose hydrocortisone;
by inhibiting NF-kB and the subse- intensive insulin therapy; and intrave-
quent production of pro-inflammatory nous clarithromycin.
cytokines. Damage of the endothelium Eleven randomized trials have been pub-
in sepsis reduces production of APC; lished in patients with severe sepsis where
608
Figure 1 A schematic representation of the interplay between monocytes and endothelium in the pathogenesis of sepsis.
Activation of TLR4 by bacterial endotoxins (LPS) or by the late cytokine HMGB1 leads, through the activation of a series of
adaptor proteins, to formation of NF-kB. NF-kB acts as a transcription factor for the genes of pro- and anti-inflammatory
cytokines. The latter disrupt the integrity of vascular endothelium leading to expression of tissue factor (TF) and reduced
production of activated protein C (APC). These result in generation of thrombin and in a hyper-coagulable state. Thrombin
stimulates further production of cytokines.
anti-LPS [19] and anti-TNFα [20–22] anti- neonates) by the application of IVIG. The
bodies and soluble TNFα receptors were greatest benefit arises with the applica-
applied [23–24]. All these trials failed and tion of preparations enriched in IgM and
so these therapeutic strategies were aban- IgA compared with preparations con-
doned. Several TLR4 antagonists have taining only IgG. The proposed dose for
been developed and they are at the stage preparations enriched in IgM and IgA is
of clinical evaluation [25]. 0.03–0.21 g/kg; and for those enriched in
Benefit arising from the application of IgG 0.18–1.33 g/kg [26]. This therapeutic
intravenous immunoglobulins (IVIG) is approach has not however been graded by
connected with improved opsonization the SSC expert panel [3–4].
of the offending pathogens and blockade It is considered that almost 60% of
of LPS. Published trials have given con- patients with septic shock suffer from rel-
flicting results. A recent meta-analysis ative adrenal insufficiency. These patients
comprised 27 randomized trials; 15 in may benefit from the infusion of a low
adults and 12 in pre-term and on-term dose of hydrocortisone. Two randomized
neonates all suffering from severe sep- clinical trials have been published. The
sis or septic shock. Statistical results first enrolled 299 patients who were allo-
revealed a significant reduction of 28-day cated either to placebo or to hormone
mortality (21% in adults and of 44% in replacement. Replacement consisted of
609
50mg intravenous bolus hydrocortisone a mixed ICU population of 537 patients.

every six hours and 50 µg fluodrocorti- The trial was prematurely stopped after
sone orally once daily. Results revealed a the first safety analysis due to the high
significantly lower hazard risk for death frequency of hypoglycemia in the inten-
after 28 days among treated patients with sive-insulin group (12.1% versus 2.1%
relative adrenal insufficiency compared in the conventional therapy group) [32].
with placebo. This was accompanied by The controversial findings of these trials
earlier withdrawal from vasopressors have created a dilemma about the role of
(median time of withdrawal 10 days in intensive insulin therapy in severe sepsis
placebo versus seven days in treated or septic shock [4]. The current sugges-
patients) [27]. The CORTICUS trial pub- tion is to achieve euglycemia after stabili-
lished in 2008 enrolled 499 patients with zation of the patient, aiming to maintain
septic shock allocated either to placebo capillary glucose levels below 150 mg/dl
or to 50mg bolus intravenous hydrocor- (LoE 1b, GoR A, SSC 2c).
tisone every six hours [28]. The total Clarithromycin is a macrolide that
duration of treatment was five days with can inhibit the in vitro formation of
gradual dose tapering. Results failed to NF-kB in monocytes following stimula-
disclose any survival benefit. However, tion by LPS and the subsequent biosyn-
the time for reversal of shock was con- thesis of IL-8 [33]. A randomized clinical
siderably diminished with hydrocorti- trial has been recently published in 200
sone treatment. Results of these trials led patients with sepsis arising in the field
to a recommendation of hydrocortisone of VAP [2]. Patients were allocated to
administration at the dose mentioned either placebo or to clarithromycin.
above only for patients with septic shock The latter was administered once daily
with the goal of earlier reversal of shock at a dose of 1000 mg at one-hour infu-
[29] (LoE 1b, GoR A, SSC 2c). sion time through a central catheter.
Administration of insulin seems to Administration lasted for three consecu-
control hyperglycemia and uncontrolled tive days. Odds ratio for death due to
inflammation. Three randomized clini- septic shock and MODS was 3.78 among
cal trials have been published. A total clarithromycin-treated patients com-
of 1548 patients hospitalized in surgi- pared with 19.00 of the placebo group
cal ICUs were enrolled in the first study. (p: 0.048). Median time to resolution of
They were allocated either to conven- VAP was 15.5 days in the placebo group;
tional insulin therapy aiming to maintain it was reduced to 10.0 days in the clari-
blood glucose below 200 mg/dl or to inten- thromycin group (p: 0.011). Respective
sive insulin therapy aiming to maintain time to withdrawal from mechanical ven-
blood glucose between 80 and 110 mg/dl. tilation was 22.5 and 16.0 days (p: 0.049).
Insulin was infused via a pump. The sur- Median time to progression to MODS
vival benefit of the second strategy was was 3.38 days in the placebo group and
pronounced [30]. A similar study design 5.78 days in the clarithromycin group
was repeated later in 1200 patients hos- (p: 0.006). Administration of clarithro-
pitalized in medical ICUs. No effect of mycin was not accompanied by serious
intensive insulin therapy could be found adverse events. Although results of that
on mortality. A significant benefit was trial point towards a favorable response
however denoted in terms of earlier wean- of clarithromycin treatment in the final
ing from mechanical ventilation, earlier outcome of patients with septic shock
discharge from the ICU and earlier dis- and MODS along with earlier withdrawal
charge from hospital [31]. A third trial from mechanical ventilation, they should
attempted to repeat the same design in be repeated in a second clinical trial.
610
Clarithromycin has not been evaluated Based on the analysis of the above four
as a therapeutic option by the SSC expert trials, rhAPC is licensed in the European
panel. Union for patients with severe sepsis
and two or more failing organs and in
the USA for patients with severe sepsis
4.2 Intervention against excess
and an APACHE II score more than 25.
coagulopathy
It is not given in children. Other contra-
There have been two main attempts; the indications are signs of active bleeding,
development of recombinant human APC recent hemorrhagic stroke, recent surgi-
(rhAPC, drotrecogin-alpha) and the devel- cal operation, multiple traumas with an
opment of recombinant TFPI (tifacogin). increased risk of bleeding and a predispo-
The administration of rhAPC aimed sition towards hemorrhage i.e. thrombo-
to harness its anti-inflammatory, anti- cytopenia, increased INR or prolongation
apoptotic and anti-coagulant properties. of aPTT. rhAPC is administered at a dose
Four randomized clinical trials have been of 24 µg/kg/h for 94 continuing hours
published. In the PROWESS trial, 1690 (LoE 1b, GoR A, SSC 2b).
patients were enrolled and therapy was Tifacogin was administered in a single
started within 24 hours of presentation randomized trial of 1987 patients. In the
with one or more organ failures. The study OPTIMIST trial treated patients were
was prematurely stopped due to the ben- enrolled within <24 hours of presentation
efit from the allocated treatment. A reduc- with signs of two or more failing organs;
tion of the absolute risk of death of 6.1% 1781 patients had INR ≥ 1.2 and 206 had
was identified which was proved by sur- INR <1.2. Tifacogin was administered at
vival analysis for 28 days. This was greater a dose of 0.025 mg/kg/h for 96 consecutive
for patients with an APACHE II score >25. hours. The trial failed to demonstrate
Administration of rhAPC increased the risk any 28-day survival benefit. However,
of serious bleeding (3.5% versus 2% in pla- when considering patients with INR <1.2
cebo) [34]. rhAPC was administered in the mortality was 22.9% among placebo com-
prospective, open-label, non-randomized pared with 12.0% among those treated
ENHANCE trial within <48 hours of pres- with tifacogin (p: 0.051) [38]. Tifacogin
entation with signs of one or more failing has not been evaluated by the SSC panel
organs in 2378 patients. Survival character- of experts.
istics were similar to those of the treatment
arm of the PROWESS trial [35]. No sur-
vival benefit was disclosed by the adminis- 5. CONCLUSIONS
tration of rhAPC in the ADDRESS trial. A
total of 2640 patients were enrolled, all with Despite numerous efforts attempting to
an APACHE II score <25. Treatment was modulate the intense inflammatory reac-
started within <48 hours of presentation tion, it is evident that none of the availa-
with signs of one or more failing organs. ble therapies is sine qua non for the septic
Results revealed a significant risk of serious host. This may be attributed to the complex
bleeding events amongst treated patients pathogenesis of sepsis and to the advent of
[36]. Due to the high risk of bleeding events immunoparalysis with disease progression
by rhAPC the XPRESS trial was conducted at a time when the administration of any
where 1194 patients were enrolled. All immunomodulator may be worthless. In
received rhAPC either with placebo, low any case, interference in the mechanisms
molecular weight heparin or unfractionated of pathogenesis seems to constitute the
heparin. No harmful interaction between only promising pathway for decreasing the
rhAPC and heparin was found [37]. mortality of septic syndrome.
611
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614
|11.3|
Urosepsis – from the view

of the intensivist
Lifen Li 1, Bin Ouyang 1,*, Weide Zhong 2, Xiangdong Guan 1
1
Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
2
Department of Urology, Guangzhou First Municipal People’s Hospital, Guangzhou, China
*Corresponding author: Surgical Intensive Care Unit (SICU), The First Affiliated Hospital of Sun Yat-sen University,
58# Zhongshan Road 2, 510080 Guangzhou, China
Tel: 86 20 8775 5766-8454, Fax: 86 20 8775 5766-8800, e-mail: binouyang@yahoo.com
ABSTRACT tissue and organ perfusion in severe

urosepsis and septic shock. Source con-
Sepsis has drawn much attention because trol and initial broad-spectrum antimi-
of its high morbidity, mortality and enor- crobial therapy is important for early
mous medical cost. Urosepsis is defined and effective control of the infection.
as sepsis caused by urinary tract infection Other adjunctive therapies in urosep-
(UTI). It occurs in approximately 25% of sis include intensive insulin therapy
all sepsis cases. Urosepsis in critically ill for controlling blood glucose <150mg/dl,
adult patients is associated with increased low-dose hydrocortisone for patients with
morbidity, prolonged hospitalization, and septic shock, activated protein C (APC)
greater healthcare expenditure, and a for patients with high risk for death,
high mortality rate of 25–60% in some lung protective ventilation strategy for
critical patients. Early rapid diagnosis patients with mechanical ventilation, and
is crucial in permitting timely treatment prophylactic therapy of deep vein throm-
of urosepsis. The therapeutic strategy of bosis/stress ulcer.
urosepsis consists of hemodynamic resus-
citation, treatment of infection, and spe- Key words: urosepsis; sepsis; severe
cific supportive and adjunctive therapy. sepsis; septic shock; diagnosis; treatment
Early goal-directed therapy is crucial for of urosepsis; antimicrobial therapy;
restoring intravascular volume, correct- EGDT; fluid resuscitation; intensive insu-
ing the septic shock and maintaining lin therapy; rhAPC
SUMMARY OF RECOMMENDATIONS is poorly responsive to dopamine or

norepinephrine (GoR B).
Diagnosis 7. Dobutamine must be used to
increase cardiac output in patients
1. Urine and blood cultures must be
with low cardiac output despite ade-
implemented in the initial routine
quate fluid resuscitation (GoR A).
laboratory tests before antimicrobial
therapy (GoR A). 8. Packed red blood cell transfusion has
to be used to increase oxygen delivery
2. Bedside ultrasound is useful for
when hemoglobin is <70g/L to target a
some critical patients to confirm the
hemoglobin of 70–90g/L in the absence
source of infection (GoR B).
of coronary artery disease, acute hem-
orrhage, or lactic acidosis (GoR A).
Management
Hemodynamic resuscitation Source control
3. Resuscitation has to be started 9. Source control must be implemented

immediately as soon as patients are as soon as possible following success-
recognized as having hypotension or ful initial resuscitation (GoR A).
serum lactate >4mmol/l (GoR A).
Antibiotic therapy
4. The initial six-hour resuscitation must
meet the following goals (GoR A): 10. Intravenous antibiotic therapy must
a. central venous pressure (CVP) be started as soon as possible and
8–12 mmHg, or higher target within the first hour of recognition of
CVP of 12–15 mmHg in patients septic shock (GoR A).
with mechanical ventilation. 11. The initial empirical anti-infective
b. mean arterial pressure therapy in patients with severe sep-
(MAP)≥65mm Hg. sis or septic shock must be broad-
spectrum and include one or more
c. urine output≥0.5mL.kg–1.hr –1. antimicrobials, to cover all likely
d. central venous oxygen pathogens (GoR A).
saturation(ScvO2)≥70%, or 12. De-escalation to an appropriate anti-
mixed venous oxygen saturation microbial can be performed when the
(SvO2)≥65%. causative organism and its antibiotic
5. Fluids for resuscitation must be susceptibilities are defined (GoR C).
either crystalloids or colloids in
patients with normal renal function Corticosteroids
and the cumulative dose of colloids
has to be limited to avoid acute renal 13. Intravenous hydrocortisone should
failure in patients with pre-existing been given only to adult septic shock
kidney disease (GoR A). patients who require vasopressor
therapy despite adequate fluid resus-
6. Either norepinephrine or dopamine
citation (GoR B).
must be the first choice of vaso-
pressor to correct the hypotension 14. The dose of corticosteroids must be
in septic shock (GoR A). Low-dose ≤300 mg hydrocortisone daily or com-
dopamine should not be used for the parable for other steroids (GoR A).
purpose of renal protection (GoR A). 15. Steroid therapy should be weaned
Epinephrine should be the first cho- once vasopressors are no longer
sen alternative agent if septic shock required (GoR B).
616
Urosepsis – from the view of the intensivist | 11.3 |
Intensive glucose control in ICUs associated with the development

of sepsis include: age, diabetes mellitus,
16. IV insulin has to be used to con- immuno-suppression (such as transplant
trol hyperglycemia in patients with recipients), chemotherapy or corticoster-
severe sepsis in the ICU (GoR A). oids treatment, mechanical ventilation,
17. The target glucose level in severe increased duration of urinary catheteri-
sepsis should be adjusted to the zation, length of ICU stay, and preceding
range < 150 mg/dl instead of the systemic antimicrobial therapy [10–12].
range < 110 mg/dl. A safe and vali- On the other hand, some patients with
dated protocol should be applied to underlying severe urological infection,
guarantee the glucose target and who develop severe sepsis or septic shock,
also avoid the occurrence of hypogly- need to be transferred to the ICU for
cemia (GoR B). intensive medical therapy.
Urosepsis in critically ill adult patients
is associated with increased morbidity,
Recombinant human activated
prolonged hospitalization, and greater
protein C (rhAPC)
healthcare expenditures, but not mortal-
18. Activated protein C (APC) should be ity. Patients with a designated urinary
used only in patients with high risk source of sepsis had a significantly lower
for death (typically an APACHE II risk of death than patients with gastroin-
score ≥ 25 or multiple organ failure) testinal, respiratory, or other sources of
(GoR B). sepsis [13]. However, urosepsis still has
a high mortality rate of 25–60% in some
special critical patients [9]. When severe
sepsis or septic shock is present, mortal-
1. INTRODUCTION ity is unbelievably high. Therefore, early
intensive therapy used for urosepsis is
Sepsis has drawn much attention because important and necessary.
of its high morbidity, mortality and enor-
mous medical cost. Sepsis develops in
750,000 people annually in the United 2. METHODS
States, and more than 210,000 die. An
almost 18–29% mortality was reported in To understand the epidemiology, the
sepsis. A higher mortality of 30–52% was diagnosis and the treatment of urosep-
reported in severe sepsis and septic shock sis, we searched the PubMed database
despite advances in critical care. A $16.7 using the following key-words: urosep-
billion annual healthcare cost for sepsis sis, sepsis, sever sepsis, septic shock, uro-
was reported [1–6]. sepsis AND ICU, urinary tract infection,
Urosepsis is defined as sepsis caused urinary tract infection AND ICU, EGDT,
by urinary tract infection (UTI). It occurs fluid resuscitation, corticosteroid AND
in approximately 25% of all sepsis cases septic shock, intensive insulin therapy,
[7]. The incidence of urosepsis was about Drotrecogin alfa OR rhAPC, procalci-
15.8–16 % in different ICUs [8–9]. Most tonin OR PCT AND sepsis, antimicrobial
cases of urosepsis in ICUs developed from therapy AND sepsis. The following limits
nosocomial urinary tract infection (UTI) were added to the searching: published –
and more than 90% of nosocomial UTIs last 10 years; added to Pubmed – last 10
were associated with urinary catheters years; humans; languages – English; type
[10–11]. Critically ill patients are immu- of article – clinical trial; editorial; meta-
no-deficient and easily develop nosoco- analysis; practice guideline; randomized
mial infection and sepsis. The risk factors controlled trial; review; classical article;
617
clinical conference; clinical trial phase • Severe sepsis is defined as sepsis

I to IV; comparative study; consensus associated with organ dysfunction,
development conference; NIH controlled hypoperfusion abnormality, or sepsis-
clinical trial; NIH guideline; NIH multi- induced hypotension. Hypoperfusion
center study; abstract available. A total abnormalities include lactic acidosis,
of 14793 publications (published from oliguria, and acute alteration of mental
1999–2008) were found and screened by status.
title and abstract, and 318 suitable arti- • Sepsis-induced hypotension is defined
cles were selected, analyzed and included by the presence of a systolic blood
in this review. pressure of less than 90 mmHg or its
The studies were rated according to the reduction by 40 mm Hg or more from
level of evidence (LoE) and the grade of baseline in the absence of other causes
recommendation (GoR) using ICUD stand- for hypotension (e.g. cardiogenic shock).
• Septic shock is a subset of severe sep-
sis and is defined as sepsis-induced
hypotension, persisting despite ade-
3. DEFINITION quate fluid resuscitation, along with
the presence of hypoperfusion abnor-
Urosepsis is sepsis caused by urinary malities or organ dysfunction. Patients
tract infection. Sepsis, severe sepsis and receiving inotropic or vasopressor
septic shock are often defined according to agents may no longer be hypotensive
the American College of Chest Physicians/ by the time they manifest hypoper-
Society of Critical Care Medicine (ACCP/ fusion abnormalities or organ dysfunc-
SCCM) Consensus Conference of 1991 as tion, yet they would still be considered
follows [16]. to have septic shock.
• Sepsis is the systemic inflammatory Sepsis and its related syndromes rep-
response to infection. The manifesta- resent a continuum of clinical and patho-
tions of the systemic inflammatory physiologic severity. The degree of severity
response syndrome (SIRS) include, may affect prognosis independently.
but are not limited to, more than one
of the following: (1) a temperature
greater than 38º or less than 36º; (2) 4. DIAGNOSIS OF UROSEPSIS
an elevated heart rate greater than
90 beats per minute; (3) tachypnea, The diagnosis of urosepsis should con-
manifested by a respiratory rate firm the presence of both UTI and sepsis.
greater than 20 breaths per minute Primary urological infection can be identi-
or hyperventilation, as indicated by a fied with exclusive local features such as
PaCO2 of less than 32 mm Hg; and (4) f lank pain, renal colic pain, costoverte-
an alteration in the white blood cell bral angle tenderness, micturition, hae-
count, such as a count greater than maturia, or urinary retention. However,
12,000/cu mm, a count less than 4,000/ special attention needs to be paid to
cu mm; or the presence of more than critically ill patients who have poor con-
10% immature neutrophils. It should sciousness or are under sedation and
be identified whether these manifesta- analgesia since they are incapable of stat-
tions are a part of the direct systemic ing that they are uncomfortable. Besides,
response to the presence of an infec- many ICU-acquired urinary tract infec-
tious process or, in the absence of tions are catheter-related UTI which are
infection, to other known causes for rarely symptomatic [17]. Therefore, the
such abnormalities. definite diagnosis of urosepsis in critical
618
ill patients becomes difficult. Moreover, infection from other inflammatory dis-
patients with long-term indwelling cath- eases. PCT is also an indicator of sever-
eters may have bacteriuria, and thus con- ity and prognosis of sepsis in critically
firmation of the urinary tract as the only ill patients [25–30]. However we should
source of infection remains problematic. still continue to search for rapid diagnos-
Sonography or further radiographic inves- tic methods to identify sepsis precisely.
tigations (such as CT-scan) of the urogeni- A swift diagnosis is crucial in permitting
tal organ should be performed promptly in timely treatment for a life threatening
an attempt to confirm the source of infec- condition and then improving outcomes
tion, if safe to do so [18–19]. Ultrasound of sepsis [31].
should be useful for bedside studies in
some critical patients who are unstable
and difficult to transport outside of the 5. MANAGEMENT OF UROSEPSIS
ICU [20] (LoE 3, GoR B). Urine and blood
cultures must be carried out in initial rou- The management of urosepsis includes
tine laboratory tests before antimicrobial treatment of urinary infection and treat-
therapy, if this is not associated with a sig- ment of sepsis. Once severe sepsis and
nificant delay in antibiotic administration septic shock appear, the treatment strat-
[20] (LoE 3, GoR A). Cultures from other egy is similar with sepsis from other
sites, such as respiratory secretions, celiac sources. It is necessary to follow the
f luid, wounds, or other body fluids that Surviving Sepsis Campaign guidelines
may be the source of infection, should also of 2008, which consist of hemodynamic
be obtained before antibiotic therapy in resuscitation, treatment of infection
order to exclude other causes of infection. (including source control and early anti-
Sepsis is diagnosed according to the microbial therapy), specific supportive
criteria of ACCP/SCCM Consensus and adjunctive therapy [20].
Conference of 1991. However, the symp-
toms and signs of SIRS, which include 5.1 Hemodynamic resuscitation
changes in body temperature, tachycar-
The crucial aspect of the management of
dia, tachypnea, and leukocytosis are nei-
the patient with severe sepsis or septic
ther sensitive nor specific enough for the
shock is optimal hemodynamic resuscita-
diagnosis of sepsis. These parameters
tion, essentially involving administration
can also be misleading because critically
of sufficient fluids and vasoactive agents
ill patients with trauma, or after major
when required.
surgery, often present with systemic
inf lammatory response syndrome but
no infection [21–23]. In the 2001 SCCM/ 5.1.1 Initial resuscitation
ESICM/ACCP/ATS/SIS conference par- General hemodynamic assessment on the
ticipants added several new diagnostic basis of heart rate, blood pressure, central
criteria for sepsis, in particular includ- venous pressure (CVP), and urinary out-
ing the biomarkers procalcitonin (PCT) put is very useful but not enough in guid-
and C-reactive Protein (CRP), despite ing the resuscitation of hypoperfusion
the overall conclusion that it was prema- in shock or occult shock. Hypoperfusion
ture to use biomarkers for sepsis diag- in shock leads to global tissue hypoxia
nosis [24]. Many prospective researches because of the imbalance between sys-
demonstrated that PCT is a reliable and temic oxygen delivery and oxygen
promising marker of sepsis in critically demand. The parameters indicating the
ill patients. It may complement clinical balance of tissue oxygen metabolism
signs and routine laboratory parameters, (such as mixed venous oxygen saturation
suggest severe infection and distinguish (SvO2), arterial lactate concentration, and
619
base deficit) are important hemodynamic Fluid challenge is required firstly for
variables as resuscitation end points restoration of intravascular volume sta-
[31–32]. However, in patients with renal tus to meet the initial target of a CVP
insufficiency, base deficit is not a reliable of 8–12mm Hg (even higher CVP of
parameter for tissue oxygen metabolism. 12–15mmHg if mechanically ventilated).
The invasive procedure of central ven- The types of fluid for resuscitation (col-
ous catheterization or pulmonary artery loids or crystalloids, natural or artificial
catheterization (PAC) for hemodynamic colloids) remain in discussion with regard
monitoring is necessary for critically ill to clinical relevance. The Saline versus
patients with severe sepsis and septic Albumin Fluid Evaluation (SAFE) study
shock although many debates about the indicated 4% albumin administration was
usage of PAC are continuing. Indwelling as safe and equally effective as normal
PAC is the best hemodynamic manipula- saline for fluid resuscitation [38]. This
tion in critically ill patients not only for study demonstrated the safe application
measurement of SvO2 but also for meas- of albumin as well as crystalloids to differ-
urement of cardiac output and pulmo- ent groups of critically ill patients, except
nary arterial wedge pressure [33]. Central patients with brain injury. The disadvan-
venous oxygen saturation (ScvO2) is an tage of crystalloids for fluid resuscitation
attractive alternative to SvO2 because it is is that more fluid is required to achieve
easier and less risky to perform. Recently, the same end points and results in more
studies indicated that SvO2 is 5–7% lower edema, because the volume of distribu-
than central venous oxygen saturation tion is much larger for crystalloids than
(ScvO2) in septic shock [34]. for colloids, while vascular permeability
Many recent studies support the claim is increased. However albumin is expen-
that early goal directed therapy (EGDT) sive and theoretically risks transmission
in patients with severe sepsis and sep- of infectious agents [39], so the study
tic shock provides a good outcome and promoted the more widespread use of
reduces mortality [31, 35–37]. It is recom- semisynthetic colloids for septic patients
mended that resuscitation begin as soon such as Gelatins and hydroxyethyl starch
as patients are recognized with hypo- (HES). For patients with urosepsis, the
tension or an elevated serum lactate risk of renal function impairment is con-
>4mmol/l and this must not be delayed sidered especially. Various crystalloid
pending ICU admission [20] (LoE 3, and colloid solutions are available to cor-
GoR A). During the first six hours of rect hypovolemia but some of them have
resuscitation, the following goals must be been implicated in impairment of renal
achieved: function. Gelatins and HES are preferred
colloids in patients with normal kidney
i. Central venous pressure (CVP) function, although there is some evidence
8–12mm Hg, higher target CVP of that the latter is associated with impaired
12–15 mmHg in the patients with renal function in patients with pre-exist-
mechanical ventilation. ing kidney disease. Moreover any hyper-
ii. Mean arterial pressure oncotic colloid given in large amounts may
(MAP)≥65mm Hg. decrease glomerular filtration and should
therefore be combined with crystalloids
iii. Urine output≥0.5mL.kg–1.hr –1. [40]. Several studies showed the admin-
iv. Central venous (superior vena istration of hydroxyethyl starch for vol-
cava) oxygen saturation (ScvO2) ume resuscitation in patients with septic
≥70% or mixed venous oxygen shock was significantly faster in normal-
saturation (SvO2) ≥65% [20] (LoE 3, izing CVP than Ringer’s lactate ( RL), and
GoR A). had the same effect on 28-day mortality
620
as RL, but the risk of acute renal failure regarding the supremacy of dopamine
increased, associated with the cumula- or norepinephrine [44–45]. There is no
tive dose of hydroxyethyl starch [41–42]. high-quality primary evidence to recom-
However, recently a large multicentre mend one catecholamine over another.
observational European study showed Either norepinephrine or dopamine has
that the administration of normal dose to be recommended as the first choice
HES had no influence on renal function vasopressor agent to correct hypoten-
or the need for renal replacement therapy sion in septic shock [20] (LoE 3, GoR A).
(RRT) in the ICU [43]. Therefore fluids Norepinephrine may be more effective
for resuscitation have to be either crystal- and reliable at reversing hypotension due
loids or colloids in patients with normal to its vasoconstrictive effects in patients
kidney function and the cumulative dose with septic shock. Moreover norepine-
of colloids must be limited to avoid acute phrine was able to increase mean per-
renal failure in patients with pre-exist- fusion pressure without apparent adverse
ing kidney disease [20] (LoE 2, GoR A). effect on peripheral blood flow or on renal
Therefore maybe the safest options for blood f low. Because norepinephrine has a
fluid resuscitation in sepsis for EGDT are greater effect on efferent than on afferent
combination colloids with crystalloids or arteriolar resistance and increases the
crystalloids alone. The rate of fluid chal- filtration fraction in hyperdynamic sep-
lenge in patients with suspected hypo- tic shock, normalization of renal vascular
volemia has to be started with at least resistance could effectively reestablish
1000mL of crystalloids or 300–500mL of urine flow [46]. On the other hand, nore-
colloids over 30 minutes. More rapid and pinephrine has a potential risk of myo-
larger volumes are required in sepsis- cardial ischemia due to the contraction
induced tissue hypoperfusion [20] (LoE 4, of the coronary artery and impairment
GoR A). The degree of intravascular vol- of tissue oxygenation due to excessive
ume depletion in patients with severe vasoconstriction [47]. To avoid such a del-
sepsis varies. With peripheral vasodilata- eterious effect, the rational use of nore-
tion and ongoing capillary leak, most sep- pinephrine should be based not only on
tic patients require further fluid therapy the reversal of hypotension, but also on
during not only the first six hours but the achievement of appropriate physi-
also 24 hours of management. The rate ologic end-points on SvO2 [48]. Dopamine
of fluid administration must be reduced may be particularly useful in patients
substantially if cardiac filling pressures with compromised systolic function, pri-
increase without concurrent hemody- marily due to an increase in stroke vol-
namic improvement [20] (LoE 4, GoR A). ume and heart rate. A placebo-controlled
randomized trial and a meta-analysis
5.1.2 Vasopressors found no difference in either renal protec-
The presence of perfusion abnormalities tion or survival by comparing low-dose
may persist despite adequate fluid resus- dopamine to placebo [49–50]. Low dose
citation in some patients with refractory dopamine should not be used solely for
hypotensions. Therefore vasopressor ther- renal protection [20] (LoE 1, GoR A). In
apy may be required to achieve a minimal some studies, epinephrine showed some
perfusion pressure and maintain ade- disadvantages with potential for causing
quate flow in these patients. The goal of tachycardia, hyperlactemia, and worse
mean arterial pressure (MAP) ≥65 mm Hg circulation, but without showing worse
must be maintained [20] (LoE 3, GoR A). outcomes over dopamine and norepine-
The choice of vasopressors has also phrine [51–53]. Epinephrine should be
been the subject of considerable debate the first chosen alternative agent if septic
with conflicting opinions, in particular shock is poorly responsive to dopamine
621
or norepinephrine [20] (LoE 2, GoR focus [56]. Source control has to be imple-
B). Vasopressin at a dose of 0.01–0.04 mented as soon as possible following
units/min may be a considered alterna- successful initial resuscitation (LoE 3,
tive because of its effectiveness in rais- GoR A) and should be chosen with maxi-
ing blood pressure in patients refractory mum efficacy and minimal physiologic
to other vasopressors [54]. However, we upset [20] (LoE 4, GoR A). In urosepsis,
should be cognizant of the disadvantage when obstruction of the urinary tract is
that higher doses of vasopressin have identified as the source of infection, a low-
been associated with cardiac, digital, and level invasive procedure (e.g. insertion of
splanchnic ischemia. Vasopressin should an indwelling bladder catheter, percu-
not be administered as the initial vaso- taneous nephrostomy or drainage of an
pressor in septic shock [55]. abscess) usually needs to be performed,
and a urological operation should even
5.1.3 Inotropic therapy be considered. In addition, most urosep-
Septic patients with myocardial depres- sis in critically ill patients is caused by
sion present with low cardiac output and catheter-associated urinary tract infec-
elevate cardiac filling pressures, and tions, therefore the first reasonable inter-
have poor tolerance for further fluid chal- vention may be to replace or remove the
lenge. Dobutamine is the first choice for catheter [57].
inotropic therapy. Dobutamine is used to
increase cardiac output and oxygen deliv- 5.2.2 Antibiotic therapy
ery, and thereby elevate ScvO2 or SvO2 in Undoubtedly, antimicrobial therapy is the
order to achieve the resuscitation goal of most essential treatment for critically ill
a ScvO2 ≥70% or SvO2 ≥65% respectively. patients with severe infections. The prin-
If septic patients maintain a low ScvO2 ciple of antibiotic therapy in severe sepsis
or SvO2 during the first six hours of fluid may be summarized in three words: early,
resuscitation and vasopressors or ino- appropriate and adequate.
tropic therapy are used, then a red blood A large retrospective study demon-
cell transfusion to a target hematocrit of strated that initial, prompt antibiotic ther-
30% is recommended to increase oxygen apy within the first hour of sepsis-induced
delivery. It recommend that red blood hypotension improved outcomes in septic
cell transfusion occurs when hemoglobin shock [58]. It showed that 79.9% of septic
decreases to < 7.0 g/dL (< 70 g/L) to target patients survived owing to early antimi-
a hemoglobin of 7.0–9.0 g/dL (70–90 g/L) crobial therapy and survival descended to
in adults in the absence of myocardial 5% with delay of therapy. Therefore intra-
ischemia, severe hypoxemia, acute hem- venous antibiotic therapy must be started
orrhage, cyanotic heart disease, or lactic as early as possible and within the first
acidosis [20] (LoE 2, GoR A). hour of recognition of septic shock (LoE
2, GoR A) or severe sepsis without sep-
5.2 Treatment of infection tic shock [20] (LoE 4, GoR A). Critically
ill patients associated with elderly, bad
5.2.1 Source control underlying disease, severe clinical mani-
Source control is crucial in the manage- festation, and acquired immuno-suppres-
ment of urosepsis. The source of infec- sion have the greatest susceptibility to a
tion should be eliminated by proper wide range of potential pathogens (bacte-
surgical intervention, such as drainage rial and/or fungal). However, there is little
and removal. In principle, source control margin for error in the choices of antimi-
includes identification of the source of crobial therapy for patients with severe
infection and elimination of the infected sepsis or septic shock. The inappropriate
622
use of antimicrobials may cause thera- [64]. Currently, one French multi-center,
peutic failure and accordingly increase randomized, controlled trial (RCT) using
morbidity and mortality [59]. The initial low-dose hydrocortisone therapy in
selection of empirical anti-infective ther- patients with vasopressor-unresponsive
apy in patients with severe sepsis or sep- septic shock and relative adrenal insuffi-
tic shock must be broad-spectrum therapy ciency shows a significantly faster shock
that includes one or more antimicrobials reversal and significant mortality reduc-
to cover all likely pathogens [20] (LoE 2, tion [65]. A recent large, European mul-
GoR A). All patients must receive a full ticenter controlled trial (CORTICUS)
loading dose of each antimicrobial to pen- showed that hydrocortisone did speed up
etrate adequate concentrations into the shock reversal but did not improve sur-
presumed source of sepsis [20] (LoE 2, vival or resolve shock either in patients
GoR A). De-escalation to an appropriate with septic shock or in patients who did
antimicrobial should be performed while not have a response to corticotrophin [66].
the causative organism and its antibiotic It also showed that the use of the ACTH
susceptibilities are defined [20] (LoE 4, test (responders and nonresponders)
GoR B). More importantly, this strategy did not predict the resolution of shock.
can also reduce the development of super- Therefore, intravenous hydrocortisone
infection and antimicrobial resistance [60]. should be given only to adult septic shock
Especially in the antibiotic treatment patients with blood pressure identified
of urosepsis, it is important to achieve to be poorly responsive to fluid resuscita-
optimal exposure to antibacterials both tion and vasopressor therapy [20] (LoE 3,
in plasma and in the urinary tract [61]. GoR B). It is best not to administer corti-
Since bacteriuria is usual in any urinary costeroids for the treatment of sepsis in
tract infection, the role of antibiotics with the absence of shock. Corticosteroid dose
high renal excretion rates is required must be comparable to ≤300 mg hydro-
to achieve high urinary concentrations. cortisone daily (LoE 1, GoR A). Steroid
Furthermore, the bacterial spectrum in therapy should be weaned once vasopres-
urosepsis may also be considered for the sors are no longer required [20] (LoE 4,
selection of antimicrobials. Thus anti- GoR B).
microbials that have a high intrinsic
potency (low MIC) against the common 5.3.2 Intensive glucose control
uropathogens with modest elimination Hyperglycaemia associated with insu-
by renal mechanisms are suitable for the lin resistance is common in critically ill
treatment of urosepsis [62]. patients. We recommend that IV insulin
should be used to control hyperglycemia
5.3 Specific supportive and in patients with severe sepsis in the ICU
adjunctive therapy (LoE 2, GoR A). A well-known prospective,
randomized, controlled study performed
5.3.1 Corticosteroids by van den Berghe in 2001 demonstrated
The prevalence of adrenal insufficiency intensive insulin therapy (maintenance
in septic shock is about 50% [63]. Septic of blood glucose at a level between 80 and
shock may be associated with relative 110 mg/dL) reduced ICU mortality to 4.6%
adrenal insufficiency. However, the use from 8.0% with conventional treatment
of corticosteroid therapy in patients with among critically ill patients in the surgical
sepsis and septic shock has been contro- ICU [67]. In this study, intensive insulin
versial. Initial studies with short courses therapy also showed a reduction of overall
of high dose corticosteroid in sepsis and in-hospital mortality, bloodstream infec-
septic shock showed no benefit in outcome tions, acute renal failure and requirement
623
of mechanical ventilation. Later in 2006, (APC) in Early Severe Sepsis (ADDRESS)

Van den Berghe performed an intensive study involved 2,613 patients with severe
insulin therapy trial in the medical ICU sepsis judged to have a low risk of death
[68]. It was found that intensive insu- (APACHE II score less than 25) at the
lin therapy did not significantly reduce time of enrollment. This study showed no
in-hospital mortality among critically ill benefit in the 28-day mortality with APC
patients in MICU (40.0% in conventional administration (18.5% in the APC group
treatment versus 37.3% in intensive glu- versus 17% in the placebo group) [71]. The
cose control) but carried a high risk of rate of serious bleeding was greater in
hypoglycemia at 17.9%. However, the the APC group (2.4%) than in the placebo
morbidity of newly-acquired kidney injury group (1.2%). Therefore, rhAPC should be
was reduced significantly, length of venti- considered in adult patients with sepsis-
lation decreased, and length of ICU and induced organ dysfunction with clinical
hospital stay decreased significantly. The assessment of high risk of death (typically
multi-center VISEP trial on glucose con- APACHE II ≥25 or multiple organ fail-
trol in Germany was discontinued prema- ure) if there are no contraindications [20]
turely because of a high incidence (12.1%) (LoE 2, GoR B). Because of the absence of
of hypoglycemia but without an identical a beneficial treatment effect coupled with
mortality benefit in the glucose control an increased incidence of serious bleed-
group [69]. Therefore, the target glucose ing complications, adult patients with
levels in severe sepsis should be adjusted severe sepsis and low risk of death (most
to the range < 150 mg/dl instead of the of whom will have an APACHE II score <
range < 110 mg/dl by use of a safe and val- 20 or one organ failure) must not receive
idated protocol for insulin dose [20] (LoE rhAPC [20] (LoE 1, GoR A).
3, GoR B). Further studies are needed to
confirm the safe and effective target glu- 5.3.4 Other supportive therapy
cose levels for intensive insulin therapy. In patients with sepsis-induced acute
lung injury/acute respiratory distress
5.3.3 Recombinant Human Activated syndrome (ALI/ARDS), lung protective
Protein C (rhAPC) strategies coupled with plateau pres-
Drotrecogin alfa (activated protein C), or sures ≤30 cm H2O with limited tidal
recombinant human activated protein C, volume 6 ml/kg predicted body weight
has antithrombotic, antiinflammatory, for mechanical ventilation, has demon-
and profibrinolytic properties. Reduced strated a mortality benefit and has been
levels of protein C are found in the major- widely accepted [72]. In septic patients
ity of patients with sepsis and are associ- with acute renal failure, continuous ven-
ated with an increased risk of death. The ovenous haemodiafiltration (CVHD) is
Recombinant Human Activated Protein C able to offer easier management of fluid
Worldwide Evaluation in Severe Sepsis balance than using intermittent haemo-
(PROWESS) trial, involving 1690 patients dialysis (IHD) when hemodynamics
with severe sepsis from 164 centers in 11 are unstable [73]. For all patients with
countries, showed activated protein C severe sepsis, it is necessary to prevent
(APC) reduced mortality from 30.8% in the deep vein thrombosis (DVT) by using
placebo group to 24.7% in the treatment pharmacologic and/or mechanical therapy
group [70]. The incidence of serious bleed- unless contraindicated [74]. Stress ulcer
ing was insignificantly higher in the acti- prophylaxis is also necessary for patients
vated protein C (APC) group than in the with severe sepsis and septic shock. H2
placebo group (3.5% vs. 2.0%). The recent blocker or proton pump inhibitor may be
Administration of activated protein C used [75].
624
6. FURTHER RESEARCH United States: analysis of incidence, out-

come, and associated costs of care. Crit
Statins, inhibitors of 3-hydroxy-3-meth- Care Med, 2001. 29(7): 1303–10.
ylglutaryl coenzyme A reductase, have 3. Martin GS, Mannino DM, Eaton S, and
anti-inflammatory and immunomodula- Moss M, The epidemiology of sepsis in the
United States from 1979 through 2000. N
tory pleiotropic effects and may provide a
Engl J Med, 2003. 348(16): 1546–54.
new approach for adjuvant therapy in the
4. Angus DC and Wax RS, Epidemiology of
patients with sepsis. Large prospective
sepsis: an update. Crit Care Med, 2001.
and randomize controlled clinical trials 29(7 Suppl): S109–16.
need to be done to test the efficacy and
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safety of statin therapy [76–77]. and practice – results of the German study
on prevalence by the competence network
sepsis (SepNet)]. Anasthesiol Intensivmed
7. CONCLUSIONS Notfallmed Schmerzther, 2006. 41(1):
43–4.
Urosepsis is still associated with high 6. Moerer O, Schmid A, Hofmann M,
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dynamic and evolving process. Early diag- costs of severe sepsis in three German
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as possible in the sepsis process. After resource use. Intensive Care Med, 2002.
obtaining causative samples we should 28(10): 1440–6.
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629
|11.4|
Urosepsis – from the view

of the urologist
Florian M.E. Wagenlehner, Adrian Pilatz, Wolfgang Weidner
Urologic Clinic, Justus-Liebig-University Gießen, Germany
Corresponding author: Florian M.E. Wagenlehner, MD, PhD, Department of Urology, Pediatric Urology and Andrology
University Hospital Giessen, Rudolf-Buchheim-Str. 23, D-35392 Giessen, Germany
Tel: +49-641/ 9944518, Fax: +49-641/ 9944509, Wagenlehner@aol.com
ABSTRACT Adequate initial antibiotic therapy has

to be insured. This goal implies however
Urosepsis accounts for approximately 25% a wide array of measures over time to
of all sepsis cases and may develop from ensure a rational antibiotic policy, includ-
a community or nosocomial acquired uri- ing microbiologists and clinical pharma-
nary tract infection (UTI). The underlying cologists. Dosage of an antibiotic in the
UTI is almost exclusively a complicated septic patient generally has to be high to
one with involvement of parenchymatous ensure adequate pharmacological expo-
urogenital organs (e.g. kidneys, prostate). sure in the individual patient.
In urosepsis, as in other types of sepsis, Key words: Urinary tract infections;
the severity of sepsis depends mostly urosepsis; SIRS; obstructive pyelonephri-
upon the host response. The urological tis; sepsis treatment; antibiotic policy.
management of urosepsis comprises early
diagnosis, early fluid-and oxygen treat-
ment, early antibiotic therapy and early SUMMARY OF RECOMMENDATIONS
control of the complicating factor in the
urinary tract.
Time from admission to therapy is 1. Broad-spectrum beta-lactam antibiot-
critical. The shorter the time to effective ics are the first choice for systemic
treatment, the higher is the success rate. treatment of urosepsis (GoR A).
This aspect has to become incorporated 2. In case of high local rates of entero-
into the organisational process, including bacteria producing extended-spectrum
urologists, radiologists and intensive care beta-lactamases and patients with
specialists amongst others. severe urosepsis, carbapenems should
Urosepsis – from the view of the urologist | 11.4 |
be used for initial systemic treatment ESBL”, urinary tract infection AND ESBL”,
(GoR B). “urinary tract infections AND MRSA”,
3. The patient population warrant- “urinary tract infections AND VRE”, and
ing carbapenem treatment as first using the following limits: published and
line agents must however be defined added to PubMed within the last 10 years;
strictly in order to keep the antibiotic English and German language; and only
pressure of these reserve antibotics as the following types of articles: clinical trial;
low as possible (GoR A). meta-analysis; practice guideline; rand-
omized controlled trial; clinical conference;
4. The most important urological feature clinical trial phase I to IV; comparative
in urosepsis is obstructive pyelone- study; consensus development conference;
phritis. Obstruction in urosepsis NIH controlled clinical trial; NIH guide-
therefore must be diagnosed or ruled line; NIH multicenter study. Papers pub-
out and treated accordingly (GoR A). lished in non-reviewed supplements were
5. Deobstruction in the uroseptic patient not included.
should be performed by the least inva- The search identified a total of 205
sive way (GoR B). articles published from 1999–2008.
The included articles were rated
according levels of evidence following
1. INTRODUCTION ICUD standard [6–7] based on: 1) the
hierarchy of study types and, 2) how well
In 20–30% of all septic patients the infec- the study was designed and carried out.
tious focus is localised in the urogenital The hierarchy of study types was: sys-
tract [1]. The prevalence of urosepsis in tematic reviews and meta-analysis of
urological patients with nosocomial UTI randomized controlled trials, randomized
is high and was in one study on average controlled clinical trials, non-randomized
about 12% [2], whereas in patients with cohort studies, case-control studies, case
nosocomial UTI treated in other speci- series, and expert opinion as the lowest
alities the prevalence for severe sepsis level.
was 2% and for septic shock 0.3% [3]. In Of the 205 identified articles, a total of
recent years, the incidence of sepsis and 45 articles met the criteria for detailed
urosepsis has even increased [4–5], but analysis and rating. These 45 articles
the associated mortality has decreased were reviewed in detail for how well each
suggesting improved management of study was designed and carried out using
patients [4–5]. This review deals with a standard checklist adopted from the
the question about the optimal manage- CONSORT statement (available at http:
ment of urosepsis. This question was //www.consort-statement.org). Of these
divided into several issues, such as choice a total of 35 articles met the criteria for
of antimicrobial drug for empiric therapy; rating (Table 1). According to the hierar-
development of bacterial resistance; most chy of study types these papers included:
important urological feature; and prob- two systemic reviews or meta-analyses,
lems of antibiotic therapy. four randomized clinical trials, three non-
randomized cohort studies, seven case-
control studies, nine case series, three
2. METHODS articles incorporating expert opinion,
no cost-effectiveness studies, and seven
A systematic literature search was per- in vitro, laboratory or animal model stud-
formed the PubMed database with the fol- ies (Table 1).
lowing search terms: “urosepsis”, “sepsis According to the level of evidence,
AND urinary tract infection”, “sepsis AND one study was identified as a Level 1
631
study [8]; nine as Level 2 studies includ- 3. EPIDEMIOLOGY OF UROSEPSIS

ing: one systematic review [9], three ran-
domized clinical trials [10–12] and two Severe sepsis is a critical situation with
non-randomized cohort studies [13–14] a reported mortality rate ranging from
and three case control studies [15–17] 20–42% [5]. Most severe sepsis cases reported
(Table 1); 14 as Level 3 studies includ- in the literature are related to pulmonary
ing: one randomized clinical trial [18], one (50%) or abdominal infections (24%), with
non-randomized cohort study [19], four urinary tract infections (UTIs) accounting for
case-control studies [20–23], eight case approximately 5% [42] to 7% [43]. Sepsis is
series [24–31] (Table 1); and 10 as Level more common in men than in women [5].
4 studies including: three articles based The leading cause for developing uro-
on expert opinion [32–34], and seven in septic shock in urological patients was
vitro, laboratory, or animal model studies urinary obstruction in 78% and uropathies
[35–41] (Table 1). The results of the indi- with significant impact on urodynam-
vidual studies and their level of evidence ics in 22% [44]. 17% of patients develop
are summarized in Table 1. urosepsis after urological interventions.
The studies were rated according to the Obstructive diseases of the urinary tract
level of evidence (LoE) and the grade of leading to obstructive pyelonephritis
recommendation (GoR) using ICUD are caused by ureteral stones in 65%,
standards (for details see Preface) [6–7]. by tumors in 21%, by pregnancy in 5%,
Table 1 Evidence Table: Studies on management of urosepsis that include Original Data, Systematic Review or Meta-analysis,
Expert Opinion, or Other Data (1999–2008).
Study Type First author, Subjects Design Aspects Critical Findings Rating of
year, Evidence
reference
Systematic
reviews and
Meta-analyses
Vidal L et al., 503 Efficacy and safety Aminoglycoside 2, positive

2007 [9] patients with of aminoglycoside monotherapy
end-point monotherapy equally effective as
mortality comparators. Paucity of
patients
with sepsis.
Schwaber MJ 16 studies Mortality and delay in Bacteremia due to 1, positive

et al., 2007 [8] effective therapy asso- enterobacteria
ciated with ESBL pro- producing ESBL
ducing enterobacteria results in increased
bacteremia mortality (RR 1,85) and
delay in effective therapy
(RR 5,56)
Randomized
clinical trials
McKinnon PS 76 Comparative trial of No differences in 2, positive

et al., 2008 cefepime vs ceftazidime outcomes between both
[12] in patients with sepsis antibiotics. Significant
of different origins PK/PD differences in
(cUTI) parameters in both
antibiotics (AUIC ≥
250 and T>MIC = 100%)
632
Byl B et al., 27/ 5 UTI Comparative trial No differences in 2, positive

2001 [10] of imipenem vs endotoxine, IL-6 or
ceftazidime in patients TNF-alpha release
with Gram-negative
infections (7 bacteremia)
Luchi M et al., 33 Comparative trial of No differences in plasma 2, positive

2000 [11] imipenem vs ceftazidime endotoxin, IL-6, TNF-alpha,
in urosepsis with and urine endotoxine,
Gram-negative bacilli IL-6, 8
Kuo BI et al., 50 Comparative trial of No differences in 3, positive

2000 [18] meropenem and clinical or
imipenem in patients microbiological response
with sepsis (pneumonia
and UTI)
Non-
randomized
cohort studies
Bin C et al., 22 Comparative consecuti- Not significantly different 3, positive

2006 [19] ve trial of ceftazidime vs treatment success ratio
imipenem vs cefopera- (ceftazidime 85.7%, imipe-
zone/ sulbactam in nem 87.5%, cefoperazone/
patients with sulbactam 71.4%)
bacteremia due to
ESBL (MIC
ceftazidime ≤ 8 mg/L
Magill SS et al., 182 Association between Patients with 2, positive

2006 [13] anatomic site of candiduria significantly
candida colonization, more frequently
invasive candidiasis and invasive candidiasis (p=0.2).
mortality in critically ill Candiduria at any time in
surgical patients the ICU higher mortality
(OR, 2,86)
Van Dissel JT Chills, bacteremia and Decreased mortality risk at 2, positive

et al., 2005 endotoxemia in patients long-term follow up (OR,
[14] with sepsis and 0,644) for patients with
in-hospital mortality chills at presentation of
and 5–10 years survival sepsis
Case-control
studies
Nguyen LH et Retrospective, Study patients were elderly, 3, positive

al., 2008 [21] comparing 2 time median 3
periods (2001–02 vs comorbidities, median
2005–06), reducing APACHE II score of 13,
empirical 75% had pneumonia or
fluoroquinolone use for urosepsis.
P. aeruginosa Empirical use of
fluoroquinolones was redu-
ced by 30% in 2005–06,
piperacillin/ tazobactam
usse was increased 39%
Venier AG et Clinical and bacterial Being female and having a 3, negative

al., 2007 [23] determinants in E. coli catheter significantly less
UTI bacteremia vs no prevalent among patients
bacteremia with bacteremia. Virulence
factors not different.
(Continued)
633
year, Evidence
reference
Binelli CA et 115 Association between Significant association of 2, positive

al., 2006 [15] candiduria and candiduria and candidemia.
candidemia Isolates from urine and
blood different in 52%
Mariappan P et 115 Comparing 2 time Ciprofloxacin 3, positive

al., 2006 [20] periods. 1st period no pretreatment
treatment, 2nd period significantly reduced upper
1 week ciprofloxacin UTI and SIRS
250 mg/bid p.o. before
PCNL in patients with
stones ≥ 20 mm or dila-
ted pelvicalyceal system
Guidet B et al., 5,675 with 1 Incidence and severity Patients with ≥2 organ 2, positive
2005 [16] organ dys- of organ dysfunction dysfunctions have less UTI
function vs associated with sepsis
12,598 with
≥2 organ
dysfunctions
Ho PL et al., Risk factors and Risk factors for E. coli ESBL 2, positive
2002 [17] outcome of were: severe underlying
bacteremia due to E. diseases (OR 31.2), nosoco-
coli producing ESBL mial origin (OR 16.5),
urinary origin (OR 7.8).
Mortality in ESBL E. coli
patients twice as high as
controls.
Olszyna DP et 33 Production of CXC CXC chemokines are pre- 3, positive

al., 2000 [22] chemokines in urosepsis dominantly produced
within the urinary tract
Case-series
Chou YY et al., 12 Clinical features UTI 8.3%. E. faecium 3, positive

2008 [25] and outcome of higher 60-days
patients with mortality than
vancomycin- E. faecalis (63%)
resistant enterococcal
bacteremia
Lee, CC et al., 890 Outcome of UTI main source for blood- 3, positive
2007 [28] community- stream infections among
acquired bloodstream patients >65 years. Patients
infections >65 years fewer signs and
symptoms of BSI, but wor-
se prognosis
Hsu CY et al., 128 Clinical impact of Bacteremia present in 42% 3, positive

2006 [27] bacteremia in and indicated a more seve-
complicated re disease. Blood cultures
pyelonephritis in cases with complicated
APN
Bjerklund 6033, One day prevalence Urosepsis 12% of 3, positive

Johansen TE et including 727 study on nosocomial UTI nosocomial UTI
al., 2007 [24] with nosoco-
mial UTI
634
Mariappan P et 54 Correlation between Patients with infected 3, positive

al., 2005 [29] different sites of stones significantly higher
microbiological sam- rate of urosepsis
pling and the predictive
value for urosepsis.
Christoph F et 189, 50 Clinical course of in- 7.9% with 3, positive

al., 2005 [26] positive renal fected hydronephrosis
pelvis urine hydronephrosis, developed SIRS/
cultures, 15 predictive parameters sepsis. Initial fever and
patients SIRS/ elevated BMI indicated
sepsis higher risk for SIRS/sepsis
Efstathiou SP 225 Retrospective A score consisting of: 3, positive

et al., 2003 investigation to shock, bedridden status,
[31] predict mortality and age > 65 years, previous
failure of treatment in antibiotic treatment,
acute pyelonephritis in immunosuppression predic-
adults ted mortality in men and
women.
McAleer IM et 34 renal Endotoxin content in Significantly higher levels 3, positive

al., 2003 [30] calculi renal calculi of endotoxin found in renal
calculi of infection stones
compared to non-infection
calculi
Expert opinion
Calandra T et n.a. Definitions of Standardized 4, positive

al., 2005 [32] infections associated definitions for clinical trials
with sepsis
Dhainaut JF et 1,690 Blinded, critical Drotrecogin alfa 4, positive

al., 2003 [33] severe integrated review of beneficial also in urosepsis
sepsis data on PROWESS trial
patients
Naber KG et n.a. Guidelines for Classification, 4, positive

al., 2001 [34] management of diagnosis, treatment,
urinary tract infections follow-up of sepsis
syndrome, urosepsis
Cost-
effectiveness
Studies
none
In vitro,
laboratory, or
animal model
studies
Van Zoelen MA 10 Group box 1 Delayed HMGB1 4, positive

et al., 2007 concentrations in diffe- response in urosepsis.
[41] rent origins of sepsis HMGB1 release at site of
infection.
Moreno E et 150 strains Virulence Similar virulence scores. 4, negative

al., 2005 [38] determinants of Differences in
E. coli in strains phylogenetic groups with
causing UTI regard to
bacteremia vs compromised hosts.
pyelonephritis vs other
sources of bacteremia
(Continued)
635
year, Evidence
reference
Kizirgil A et al., 75 ESBL pro- In vitro activity of In vitro susceptibility of 4, positive

2005 [37] ducing stra- meropenem, cipro- ESBL producing E. coli and
ins of blood floxacin, amikacin K. pneumoniae was 100%
isolates against ESBL-producing for meropenem, 33 and
and non-producing 26% for ciprofloxacin,
strains of E. coli and and 95% and 83% for
K. pneumoniae amikacin
Alhambra A et 482 strains In vitro susceptibility of Ertapenem was the most 4, positive
al., 2004 [35] of UTI ertapenem, active drug tested
ampicillin, cefazolin,
cefuroxime, cefotaxime,
co-amoxiclav,
piperacillin/tazobactam,
imipenem, gentamicin,
amikacin, fosfomycin,
ciprofloxacin,
co-trimoxazole in
uropathogens
Rosenthal EJ, 9,555 Epidemiology of 77.2% enterobacteriaceae 4, positive

2002 [40] isolates septicemia pathogens in urosepsis. Increase in
resistance to beta-
lactams and ciprofloxacin
Jantunen ME, 10 Chromosomal In 8/10 infants 4, positive

et al., 2001 genotypes of E. coli iso- genetically identical
[36] lates from blood, urine E. coli isolates in blood, uri-
and faeces of infants ne and faeces. Reservoir of
with urosepsis pyelonephritogenic
E. coli in infants is colon.
Otto G et al., 81 IL-6 and disease Serum and urine 4, positive

1999 [39] severity in patients with IL-6 higher in
and without bacteremic bacteremic patients vs non-
febrile UTI bacteremic and pyelonep-
hritis vs
non-pyelonephritis
by anomalies of the urinary tract in 5% The patients are affected by microor-

and following operations in 4% [45]. In ganisms capable of inducing inflamma-
another study, from 205 analyzed case tion within the urinary and male genital
histories of urosepsis, 43% resulted from tract.
urolithiasis, 25% from prostatic adenoma, In urosepsis, as in other types of
18% from urologic cancer and 14% suf- sepsis, the severity of sepsis depends
fered other urologic diseases complicated mostly upon the host response. Patients
by urosepsis [46]. who are more likely to develop urosep-
sis include: elderly patients, diabetics,
immunosuppressed patients such as
4. DEFINITION OF UROSEPSIS transplant recipients, patients receiving
cancer chemotherapy or corticosteroids,
Urosepsis is defined as sepsis caused and patients with acquired immunode-
by infection of the urinary tract and/or ficiency syndrome. Sepsis is a systemic
male genital organs (e.g. prostate) [47]. inflammatory response to infection.
636
The signs and symptoms of SIRS (sys- symptoms [50]. Many other clinical or
temic inflammatory response syndrome) biological symptoms must be considered.
which were initially considered to be The classification of the sepsis syndrome
‘mandatory’ for the diagnosis of sepsis follows different levels of criteria:
[48–49], are now considered to be alerting
Criterium I: Proof of bacteremia or clinical suspicion of sepsis.
Criterium II: Systemic Inflammatory Response Syndrome (SIRS)
Body temperature ≥38°C oder ≤36°C

Tachycardia ≥90 beats/min
Tachypnea ≥20 breaths/min
Respiratory alcalosis PaCO2 ≤32 mm Hg
Leucocytes ≥12,000/µl or ≤4,000/µl or band forms >10%
Criterium III: Multiple Organ Dysfunction Syndrome (MODS)
Heart, circulation arterial systolic blood pressure ≤90 mm Hg or mean arterial blood pres-
sure ≤70 mm Hg, ≥1 hour despite adequate fluid- or vasopressure agents
resuscitation.
Kidney Production of urine <0.5 ml/kg body weight/ hour despite adequate fluid
resuscitation.
Lung PaO2 ≤75 mm Hg (breathing room air) or PaO2/FiO2 ≤250 (assissted respira-
tion) ((PaO2, arterial O2-partial pressure; FiO2, inspiratory O2-concentration)).
Platelets Platelets <80,000/µl or decrease ≥50% in 3 days.
Metabolic Acidosis Blood-pH ≤7.30 or base excess ≥5 mmol/l; plasma-lactate ≥1.5fold of
normal.
Encephalopathy Somnolence, agitation, confusion, coma.
Following these criteria the sepsis syn- features and laboratory data, such as
drome is classified into three levels: bacteriuria and leucocyturia.
Sepsis: Criterium I + ≥2 criteria II.
Associated letality: 2 criteria II – 7 %;
3 criteria II – 10 %; 4 criteria II – 17 %. 5. DIAGNOSIS OF UROSEPSIS
Severe sepsis: Criterium I + ≥2 criteria II
A rapid diagnosis is critical to meet
+ ≥1 criterium III.
the requirements of early goal directed
Associated letality: For each affected
therapy [51].
organ: + 15 – 20 %.
The initial patient aspect is often
Septic shock: Criterium I + ≥2 criteria II
directive. The clinical picture of a sep-
+ refractory arterial hypo-
tic patient frequently, but not always,
tension ≤90 mm Hg.
involves warm skin, bounding pulses and
Associated letality: 50 – 80 %.
hyperdynamic circulation. Flank pain,
For therapeutic purposes, the diag- costovertebral tenderness, renal colic,
nostic criteria of sepsis should identify pain at micturition, urinary retention,
patients at an early stage of the syn- prostatic or scrotal pain point to the uro-
drome. The clinical evidence of urosepsis genital tract. A digital rectal examina-
is based upon symptoms, physical exam- tion of the prostate is mandatory to rule
ination, sonographic and radiological out acute prostatitis. Urinary analysis
637
as well as urine and blood cultures must in antimicrobial administration over the
be included into the first routine labora- ensuing six hours was associated with an
tory tests. Sonographic examination of average decrease in survival of 8% [57].
the urogenital organs should be followed, Inappropriate antimicrobial therapy in
including sonographic examination of severe UTI is linked to a higher mortality
the prostate to rule out prostatic abscess. rate [58] as it has been shown with other
Further radiographic investigations (e.g. infections as well [59–60]. Empirical
CT-scan) of the urinary tract are now gen- antibiotic therapy therefore needs to fol-
erally applied to specify the complicating low certain rules [61], which are based
factor. Computer tomography is nowadays upon the expected bacterial spectrum,
almost generally available and offers the the institutional specific resistance rates,
possibility to quickly detect urolithiasis specific pharmacokinetic and pharmaco-
and especially renal abscesses as a source dynamic factors in UTI, and the individ-
of urosepsis with a high sensitivity [52]. ual patient’s requirements.
The presence of hydronephrosis and/or The bacterial spectrum in urosepsis
urinary stones [20, 26, 29] together with predominantly consists of enterobacteria,
systemic signs of infection are suspicious such as E. coli, Proteus spp., Enterobacter
of urosepsis. If a complicating factor war- and Klebsiella spp., non-fermenting
ranting treatment is identified, control organisms such as P. aeruginosa and
and/or removal of the complicating fac- also Gram-positive organisms [40, 62].
tor should follow immediately. This pro- Candida spp. and Pseudomonas spp.
cedure frequently is performed at two occur as causative agents in urosepsis
stages: Low level invasive treatment for mainly if host defence is impaired [63].
control of the complicating factor (e.g. Patients with candiduria also frequently
emergency drainage) and thereafter show invasive candidiasis and candi-
definitive elimination of the complicat- demia [13, 15]. Candiduria at any time
ing factor. Clinically there seems to be no in an intensive care unit is associated
significant difference between ureteral with higher mortality rates (OR, 2,86)
stent and percutaneous nephrostomy for [13]. Viruses are not common causes of
the control of ureteral calculi [53–54]. In urosepsis.
parallel with the urological control of the Although urosepsis is a systemic dis-
septic focus adequate antimicrobial treat- ease the activity of an antibiotic sub-
ment has to be initiated. stance at the site of the infection is
critical. A variety of studies could show
that inflammatory mediators such as
IL-6, CXC chemokines, endotoxin or
6. TREATMENT
HMGB1 are produced and released in the
urinary tract [22, 30, 39, 41]. Therefore
6.1 Antimicrobial therapy
predominantly antimicrobial substances
Immediately after microbiological sam- with a high activity in the urogenital
pling of urine and blood, empirical broad tract are recommended.
spectrum antibiotic therapy should be The increasing antibiotic resistance
started parenterally. An adequate initial rates of pathogens causing urosepsis sig-
(e.g. in the first hour) antibiotic ther- nificantly diminish the choice of antibiotic
apy ensures improved outcome in septic substances available for adequate empiri-
shock [55–56]. Administration of an effec- cal initial treatment in urosepsis. The
tive antimicrobial within the first hour of increasing rates of enterobacteriaceae pro-
documented hypotension was associated ducing extended spectrum β-lactamases
with a survival rate of 80% in a retrospec- (ESBL) especially pose clinically relevant
tive cohort study [57]. Each hour of delay problems [8, 17, 37] (LE 1, positive). Other
638
developments comprise the increased initial treatment with a carbapenem

rates of fluoroquinolone resistant entero- might be advisory [10–11, 18–19, 35]
bacteria and vancomycin resistant ente- (LoE 2; GoR B). Aminoglycosides as mon-
rococci [21, 25]. Dosing of the antibiotic otherapy might be an alternative, how-
generally has to be high. There are ever the data supporting monotherapy in
no specific pharmacokinetic/pharmacody- uroseptic patients are not sufficient [9]
namic parameters yet available for the (LoE 2, GoR B). In case of candiduria and
treatment of uroseptic patients. signs of sepsis antifungal treatment is
Correct dosing in urosepsis has to recommended [13, 15] (LoE 3, GoR B).
consider the altered systemic and espe- Biofilm infection plays a considerable
cially renal pathophysiology in patients role in urosepsis, in association with uri-
with urosepsis. Sepsis and the treatment nary catheters, scar tissue, stones, pros-
thereof result in higher clearances of anti- tatitis and in any obstructed urinary
bacterial drugs [64]. The increased vol- tract [66–69]. The MICs in biofilm are
ume of distribution as a result of edema increased several 10 to 100-folds, there-
in sepsis will lead to underexposure espe- fore generally high dosages of antimicro-
cially of hydrophilic antimicrobials such bials need to be applied in conjunction
as β-lactams and aminoglycosides, which with the attempt to eliminate the biofilm
exhibit a volume of distribution mainly and the biofilm causing complicating fac-
restricted to the extracellular space [65]. tor [70].
Sepsis may also cause increased clear-
ance of antibacterial drugs and increased 6.2 Other issues related to clinical
dosing is therefore necessary. Only in the assessment
case of multiple organ dysfunctions, such
as hepatic or renal dysfunction, result- Further intensive medical treatment
ing in decreased clearance of antibacte- encompassing adjunctive sepsis therapy
rial drugs, is a dose reduction necessary. such as cardiovascular support, mechani-
As β-lactams are time-dependent anti- cal ventilation, organ substitution, or man-
bacterials, the best administration is agement of endocrine insufficiency should
via continuous infusion. In one study an be instigated if warranted [71–72]. In con-
area under the antibiotic concentration trast to earlier reports Drotrecogin alpha
time curve (AUIC) ≥ 250 and time over (activated protein C) seems also to be ben-
the minimal inhibitory concentration eficial in urosepsis [33] (LoE 4, GoR C).
(T>MIC) = 100% has been associated with
treatment success [12]. Fluoroquinolones
on the other hand display largely concen- 7. FURTHER RESEARCH
tration dependent activity. The volume of
distribution of fluoroquinolones in sepsis The widespread current management of
is not much influenced by fluid shifts and urosepsis by urologists is rather good and
therefore no alterations of standard doses successful, although organizational proc-
are necessary, unless renal dysfunction esses always can be improved. Urosepsis
occurs [64]. nowadays has a much more benign clini-
Depending on the local susceptibil- cal course than any other sepsis entity.
ity patterns a third generation cepha- Therefore urosepsis should serve as a
losporin, piperacillin in combination gold-standard control group to which
with a β-lactamase inhibitor (BLI) or other sepsis entities should be compared.
carbapenem may be appropriate for In this way important mechanisms might
empiric treatment [10–12, 18–19] (LoE 2, perhaps be discovered which regulate the
GoR B). In areas with a high (> 10%) rate complex sepsis pathways for the worse or
of enterobacteriaceae producing ESBL for the better.
639
Adequate initial antibiotic treatment etiology and antimicrobial susceptibil-

is still one of the most important aspects ity (ESGNI-003 study). European Study
in sepsis management. Pharmacokinetics Group on Nosocomial Infections. Clin
in septic patients, however are not ade- Microbiol Infect, 2001. 7(10): 523–31.
quately investigated, which frequently 4. Brun-Buisson C, Meshaka P, Pinton P,
leads to underdosing and perhaps treat- and Vallet B, EPISEPSIS: a reappraisal
of the epidemiology and outcome of severe
ment failure. Therefore studies in
sepsis in French intensive care units.
this specific patient group should be Intensive Care Med, 2004. 30(4): 580–8.
undertaken.
5. Martin GS, Mannino DM, Eaton S, and
The prevention of sepsis is especially Moss M, The epidemiology of sepsis in the
important in urosepsis, because a signifi- United States from 1979 through 2000. N
cant portion of urosepsis is caused by uro- Engl J Med, 2003. 348(16): 1546–54.
logical procedures. Therefore risk factors 6. US Department of Health and Human
for urosepsis should be evaluated in more Services, Public Health Service, Agency
detail in the future. for Health Care Policy and Research.
1992: 115–127.
8. CONCLUSIONS Evidence – based medicine overview of the
Urosepsis is one of the most frequent sep- guideline recommendations. Prog Urol,
sis entities. The lethality rate is however 2007. 17(3): 681–4.
much lower, which might be attributable 8. Schwaber MJ and Carmeli Y, Mortality
to a good current management of uro- and delay in effective therapy associated
sepsis patients. The increasing antibiotic with extended-spectrum beta-lactamase
production in Enterobacteriaceae bacter-
resistance, however, and especially the
aemia: a systematic review and meta-
increasing rates of extended-spectrum
analysis. J Antimicrob Chemother, 2007.
β-lactamase producing enterobacteria, 60(5): 913–20.
pose a significant threat for a favourable 9. Vidal L, Gafter-Gvili A, Borok S, Fraser
outcome in those patients. Currently car- A, Leibovici L, and Paul M, Efficacy
bapenems can still fill the gap. However and safety of aminoglycoside mono-
increased use of carbapenems will inevi- therapy: systematic review and meta-
tably lead to an increase in carbapenem analysis of randomized controlled trials.
resistant strains. Therefore a prudent J Antimicrob Chemother, 2007. 60(2):
antibiotic policy is nowadays more impor- 247–57.
tant than ever. 10. Byl B, Clevenbergh P, Kentos A, Jacobs
F, Marchant A, Vincent JL, and Thys JP,
Ceftazidime- and imipenem-induced endo-
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644
Chapter |12|
Prevention of infections
associated with urological
surgery
Chair: Magnus Grabe
CHAPTER OUTLINE
12.2 Hygiene and education 649
12.3 Sterilisation and disinfection of urological instruments
for endoscopy and for prostate biopsy 660
12.4 Preoperative assessment of the patient,
risk factors identification and tentative
classification of surgical field contamination
in urologic surgery 667
12.5 Antibiotic prophylaxis in urological surgery,
a European viewpoint 686
12.6 Antibiotic prophylaxis in urological surgery:
a USA viewpoint of best practice 699
|12.1|
Introduction
Magnus Grabe
Department of Urology, Malmö University Hospital, University of Lund, Malmö, Sweden
Corresponding Author: Magnus Grabe, MD, Associate Professor, Department of Urology, Malmö University Hospital
University of Lund, S-20502 Malmö, Sweden
Tel 0046-40-33 18 25, Fax 0046-40-33 70 49, magnus.grabe@skane.se
“There are rather a large number of cases in Table 1 shows the different types of infec-
which the gravest accidents, and even death tious complications encountered in urolog-
itself, have supervened upon catheterism
without our being able to find upon exami-
ical wards and associated with surgery.
nation after death anything but some simple Infections associated with the care of
affection of the urethra”. the patients were formerly often called
Velpeau, 1841 Nosocomial infections from the old Greek
words nosos (disease) and komiál (care):
Healthcare associated infections (HAI) nosokomeíon or disease acquired in the
are a global phenomenon and have been care of the patient in a hospital and
a hot topic for decades. Their prevalence transferred from one patient to another.
appears to be about 8% in high-income More recently, the terms healthcare
countries, with national values ranging acquired or healthcare associated infec-
from 6–12% (1). Urinary tract infections tions (HAI) have been introduced to bet-
represent some 30–40% of those, mainly ter cover modern aspects of health care.
related to indwelling catheter treatment The exact frame of healthcare associated
[1]. HAI are also common in urological infections is still under debate. Surgical
care. In a series of prevalence studies car- Site Infections (SSI) are traditionally
ried out in a large number of urological used as a parameter of infection rates
centres worldwide, as many as 10–12% and infection control. The criteria for SSI
of the hospitalized patients presented are defined as either incisional/wound
with a healthcare associated infection. Of related or confined to an organ or space
these, approximately one in ten had clini- [3]. By extension, the urinary tract can
cal signs of septicaemia [2]. Prevention be regarded as an organ and/or space.
of infection is, consequently, of primary A HAI in urological care can be related
important for the security of the patients. to a transmission within the patient’s
Table 1 Different types of infectious complications associated with urological interventions.
Site of infection Minor events Major events
Surgical wound or incisional Superficial wound infection Deep wound infection

infection (SSI) Wound abscess
Deep wound rupture
Organ/Space SSI Asymptomatic Bacteriuria Pyelonephritis

Urinary tract (UTI) Colonization Febrile UTI
Symptomatic lower UTI Renal scaring
Other urogenital site Epididymitis Acute bacterial Prostatitis (NIH

type I)
Blood stream Bacteriemia Septicaemia/sepsis
Other site/organs Pneumonia

Septic emboli
group (nosocomial) or being introduced transmission of pathogens and 3) that

into the patient during the care or dur- careful cleaning, washing, drying and
ing a diagnostic or therapeutic procedure sterilisation of instruments by appropri-
(iatrogenic ) or even, in a wider sense, be ate means is necessary. The basic meth-
caused by an undetected infection har- ods of choice are described.
boured by the patient. The shares of these The role of the host and the procedure
infection routes are not known. are discussed in the third sections, focus-
Infectious complications can be related ing on the identification and preoperative
to the host, the environment and the control of the patients’ risk factors and
procedure. The present chapter explores the relative risk associated with different
the current knowledge in the field. The types of interventions. A comprehensive
chapter is divided into four sections and assessment of each patient is as impor-
six reports. The two first approaches tant as good hygiene and sterilization.
the key questions of a secure and clean The bacterial burden has to be estimated
environment both in the ward and in in each individual case. All similar proce-
the operation theatre. It is of para- dures and all patients are not the same.
mount importance that the introduction Figure 1 in the chapter on assessment of
of virulent, more or less resistant bacte- the patient (see chapter 10.4) illustrates
rial strains in the patient in conjunction the complexity and interactions between
with health care and any procedure is the host and the different procedures,
avoided. These two first topics are cov- passing through a similar environment.
ered by Bong-Suk Shim who reviews the This detailed assessment in each individ-
importance of hygiene and education ual case will determine the level of meas-
and Shingo Yamamoto who describes the ures to be taken to keep the infectious
basic principles of sterilization and dis- complication rates as low as possible.
infection of standard instruments used Antibiotic prophylaxis is one of several
on a daily basis in urological praxis. measures to keep the rates of infectious
The conclusions are that 1) the environ- complication as low as possible. Antibiotic
ment must be clean, 2) that hand wash- prophylaxis has been controversial for
ing and disinfection between all patients decades. In a recent systematic review
contact and appropriate hospital clothing on the topic, Bootsma and co-workers [4]
are of paramount importance to limit the came to the conclusion that “Except for
647
Chapter | 12 | Prevention of infections associated with urological surgery
the TURP and prostate biopsy, there is eliminate the preventable infections
a lack of well performed studies investi- that might follow in the track of a lack
gating the need for antibiotic prophylaxis of preparation of the patient, an unclean
in urologic interventions”. Consequently, environment, inappropriate antibiotic
assumption and extrapolation from com- prophylaxis and poor clinical praxis.
plication rates in surgery in general and The present chapter aims at assisting the
surveillance programmes in particular is urologist to act in that direction.
necessary. As opinions are diverging, the
policy has to be based on data from the
literature in association with a consen- REFERENCES
sus of expert opinions and local routines.
Dissimilarity in guidelines is explained 1. Marcel, J.P., et al., Healthcare-associated
by difference in the interpretation of the infections: think globally, act locally. Clin
results of studies and the weight given Microbiol Infect, 2008. 14(10): p. 895–907.
to risk factors. This appears in the dif- 2. Bjerklund Johansen, T.E., et al.,
ference presented between the European Prevalence of hospital-acquired urinary
and American viewpoints in for instance tract infections in urology departments.
antibiotic prophylaxis. Eur Urol, 2007. 51(4): p. 1100–11; discus-
sion 1112.
Another reason for a global strategy
3. Mangram, A.J., et al., Guideline for pre-
and a behavioural change is that anti-
vention of surgical site infection, 1999.
biotic prophylaxis is contributing to the Hospital Infection Control Practices
total antibiotic load and, thus, to the Advisory Committee. Infect Control Hosp
development of antibiotic resistance, a Epidemiol, 1999. 20(4): p. 250–78; quiz
worldwide on-going threat [5]. Surgeons 279–80.
thus face the paradox of having to both 4. Bootsma, A.M., et al., Antibiotic prophy-
secure a low infectious rate and to limit laxis in urologic procedures: a systematic
the use of antibiotics, in other words to be review. Eur Urol, 2008. 54(6): p. 1270–86.
rational. 5. Cars, O., et al., Meeting the challenge of
Not all infections can be avoided. antibiotic resistance. BMJ, 2008. 337: p.
The ambition must nonetheless be to a1438.
648
|12.2|
Hygiene and education

Bong-Suk Shim
Bong-Suk Shim, M.D., Ph.D., Professor, Department of Urology, School of Medicine,
Ewha Womans University Hospital, 911-1, Mok-6-Dong, Yangchoen-ku, Seoul, 158-710, Korea
Tel: +82-2-2650-2863, Fax: +82-2-2654-3682, e-mail: bonstone@ewha.ac.kr
ABSTRACT Key words: Hospital environment, Per-

sonal hygiene, Hand washing, Education,
The safety of the patient depends upon a Infection control
clean environment in the wards and oper-
ating theatre. Good hospital hygiene is
an integral and important component of a SUMMARY OF RECOMMENDATIONS
strategy for preventing hospital acquired
infections. The hospital environment Note that most recommendations are of
must be visibly clean, free from dust and grade (GoR) B or C based on available lit-
spoilage, acceptable to the patients, their erature. Nonetheless, they merit a strong
family and visitors and to the staff. Each recommendation grade A, because no
hospital should have rules and recom- weaknesses in the maintenance of clean-
mendations for maintaining a clean envi- ness and hygiene are acceptable for a safe
ronment with scheduled routines. All staff environment.
must maintain good personal hygiene.
Appropriate hospital clothing is recom- Hospital environment hygiene
mended in conjunction with all patient
contact in the wards, the out-patient 1. The hospital environment must be
departments and operating area. Careful visibly clean, free from dust and
hand washing and disinfection and appro- spoilage, and acceptable to patients,
priate clothing are key measures to limit their visitors and staff (GoR C)
cross-contamination and each hospital
must have written policies and proce- Operating room hygiene
dures for these matters. Regular teaching
and training of staff in infection control • Cleaning
is required to reach the aims of reducing 2. All surfaces kept clean, free from
health acquired infections. dust and spoilage (GoR B).
3. Regular schedule for cleaning and disin- 12. Wear a cap or hood to fully cover
fection of the operating theatre (GoR B): hair on the head and face when
• Every morning before any inter- entering the operating room (GoR B).
vention: cleaning of all horizontal 13. Wear a surgical mask that fully cov-
surfaces ers the mouth and nose when enter-
• Between procedures: cleaning and ing the operating room if an operation
disinfection of horizontal surfaces is about to begin or is already under
and all surgical items (e.g. tables, way, or if sterile instruments are
buckets) exposed. Wear the mask throughout
the operation (GoR B).
• At the end of the working day:
complete cleaning of the operating 14. Full body, fluid repellent gowns
theatre using a recommended dis- should be worn where there is a risk
infectant cleaner of extensive splashing of blood, body
fluids, secretions and excretions,
• Once a week: complete cleaning of
with the exception of sweat, onto
the operating room area, includ-
the skin of health care practitioners
ing all annexes such as dressing
(GoR B).
rooms, technical rooms, cupboards.
15. Do not wear shoe covers for the
4. Perform routine cleaning of these sur-
prevention of SSI (GoR B).
faces to re-establish a clean environ-
ment after each operation (GoR B). 16. Gloves must be worn for invasive
procedures, contact with sterile
5. Wet vacuum the operating room
sites, and non-intact skin, mucous
floor after the last operation of the
membranes, and all activities that
day or night with an Environmental
have been assessed as carrying a
Protection Agency-approved hospital
risk of exposure to blood, body fluids,
disinfectant (GoR B).
secretions and excretions; and when
• Ventilation handling sharp or contaminated
6. Maintain positive-pressure ventilation instruments. (GoR B).
in the operating room with respect to 17. Gloves should be worn as single use
the corridors and adjacent areas (GoR B). items. Put gloves on immediately
7. Maintain a minimum of 15 air before an episode of patient contact
changes per hour, of which at least 3 or treatment and remove them as
should be fresh air (GoR B). soon as the activity is completed.
8. Filter all air, re-circulated and fresh, Change gloves between caring for
through the appropriate filters per different patients, or between differ-
the American Institute of Architects’ ent care/treatment activities for the
recommendations (GoR B). same patient (GoR B).
9. Introduce all air at the ceiling, and 18. Powdered and polythene gloves
exhaust near the floor (GoR B). should not be used in health care
activities (GoR B)
10. Limit the number of personnel enter-
ing the operating room to necessary • Sampling
personnel (GoR C).
19. Do not perform routine environmen-
• Surgical attire tal sampling of the operating room.
11. All persons entering the surgical Perform microbiologic sampling
theatre must wear surgical attire of operating room environmental
restricted to being worn only within surfaces or air only as part of an
the surgical area (GoR C). epidemiologic investigation (GoR B).
650
Hygiene and education | 12.2 |
Personal Hygiene Disposal of sharps
20. All staff must maintain good personal 26. Sharps must not be passed directly
hygiene. Nails must be clean and kept from hand to hand and handling
short. False nails should not be worn. should be kept to a minimum (GoR C).
Hair must be worn short or pinned up. 27. Used sharps must be discarded into
Beard and moustaches must be kept a sharps container at the point of
trimmed short and clean (GoR C). use. These must not be filled above
the mark indicating that they are
Hand hygiene full. Containers in public areas must
not be placed on the floor and should
21. Hands must be decontaminated be located in a safe position (GoR C).
immediately before each and every
episode of direct patient contact and Education
care and after any activity or contact
that potentially results in hands 28. All staff involved in hospital hygiene
becoming contaminated (GoR B) activities must be included in educa-
tion and training related to the pre-
22. Hands that are visibly soiled or poten-
vention of hospital-acquired infection
tially grossly contaminated with dirt
(GoR C).
or organic material must be washed
with liquid soap and water (GoR B).
1. INTRODUCTION
23. Apply an alcohol-based hand rub
or wash hands with liquid soap
and water to decontaminate hands The aim of prophylaxis in urological
between caring for different patients, intervention is to prevent infectious com-
or between different caring activities plications resulting from diagnostic and
for the same patient (GoR B). therapeutic procedures, as defined in
the introduction to the chapter. A clean,
24. Remove all wrist and ideally hand hygienic environment is one of the essen-
jewellery at the beginning of each tial pillars of surgical practice. A clean
clinical shift before regular hand environment aims at reducing bacterial
decontamination begins. Cuts and burden and risk of contamination in the
abrasions must be covered with clinical and surgical environment. For
waterproof dressings (GoR C). urological intervention, the same rules
25. Effective hand washing technique are applied as in hygiene for preven-
involves three stages: preparation, tion of nosocomial infections. Risk factors
washing and rinsing, and drying. for perioperative infections are related,
Preparation requires wetting hands among others, to the patient, the health-
under tepid running water before care workers and the environment in the
applying liquid soap or an antimicro- wards and operating rooms [1–4]. Patient
bial preparation. The hand wash solu- related risk factors such as advanced age,
tion must come into contact with all malnutrition, diabetes, smoking, obesity,
the surfaces of the hand. The hands infections at sites other than the surgi-
must be rubbed together vigorously cal sites, deficiency of the immune status
for a minimum of 10–15 seconds, pay- and a long preoperative hospital stay, are
ing particular attention to the tips of reviewed in this chapter in the section on
the fingers, the thumbs and the areas “preparation of the patient”. Healthcare
between the fingers. Hands should be worker factors are contaminated hands
rinsed thoroughly prior to drying with and poor hygiene of personal protective
good quality paper towels (GoR C). equipment such as working clothes, shoes,
651
caps, masks and gloves. Environmental activities that are generally considered to
risk factors are inappropriate skin prepa- be central to the prevention of hospital-
ration, preoperative hair removal, pro- acquired infection (LoE 3) [8–9]. Routine
longed operation time, inappropriate cleaning is necessary to ensure a hospital
antimicrobial prophylaxis, poor controlled environment which is visibly clean, and
operating room ventilation system, inade- free from dust and soil. 90% of microor-
quate sterilization of surgical instruments, ganisms are present within visible dirt,
foreign body use in operation, inappropri- and the purpose of routine cleaning is
ate drain use, and inappropriate surgical to eliminate this dirt. Neither soap nor
techniques. Good hospital hygiene is thus detergents have antimicrobial activity,
an integral and important component of a and the cleaning process depends essen-
strategy for preventing hospital-acquired tially on mechanical action. There must
infections. The environment should be be a hospital policy and recommenda-
maintained in accordance with the hospi- tions specifying the frequency of cleaning
tal hygiene team’s recommendations. and cleaning agents used for walls, floors,
windows, beds, curtains, screens, fixtures,
furniture, baths and toilets, and all reused
2. METHODS medical devices. Bacteriological testing
of the environment is not recommended
A standard search of the literature includ- except in selected circumstances such as
ing available guidelines and expert opin- 1) epidemic investigation where there is a
ions was performed with the following suspected environmental source, 2) dialy-
key words: infection, hygiene, hospital, sis water monitoring for bacterial counts,
environment, and education one by one, as required by standards, 3) quality con-
using only English language papers with trol when changing cleaning practices
the abstract available. A total number of (LoE 1b) [9].
600 publications were found, which were
screened and reviewed by title and abstract
and finally 60 publications were included
4. OPERATION ROOM HYGIENE
into this review. No randomised control-
led trials were found which are usually
4.1 Operating room environment
not appropriate for the present topic. The
present review is based on available litera- In the operating room environment, air-
ture, established praxis and recommenda- borne bacteria must be minimized, and
tions by manufacturers. Case reports or surfaces kept clean (LoE 1b). A recom-
oral presentations are not included. The mended schedule for cleaning and disin-
studies were rated according to the level fection of the operating theatre is [9]:
of evidence (LoE) and the grade of recom- • every morning before any intervention:
mendation (GoR) using ICUD standards cleaning of all horizontal surfaces
(for details see Preface) [5–6].
• between procedures: cleaning and dis-
infection of horizontal surfaces and all
3. HOSPITAL HYGIENE surgical items (e.g. tables, buckets)
• at the end of the working day: complete
3.1 Hospital environmental hygiene cleaning of the operating theatre using
Good hospital hygiene is an integral and a recommended disinfectant cleaner
important component of a strategy for • once a week: complete cleaning of the
preventing hospital-acquired infections operating room area, including all
[7]. Hospital environmental hygiene annexes such as dressing rooms, tech-
encompasses a wide range of routine nical rooms, cupboards.
652
4.2 Ventilation ensure that medical equipment left in

Operating rooms should be maintained at the operating room be covered so that
positive pressure with respect to corridors solutions used during cleaning and dis-
and adjacent areas [10]. Positive pressure infecting do not contact sterile devices or
prevents airflow from less clean areas into equipment [17].
cleaner ones. All ventilation or air condi-
tioning systems in hospitals, including 4.4 Microbiologic sampling
those in operating rooms, should have two Because there are no standardized
filter beds in series, with the efficiency of parameters by which to compare micro-
the first filter bed being >30% and that bial levels obtained from cultures of
of the second filter bed being >90% [11]. ambient air or environmental surfaces
Operating room ventilation systems proin the operating room, routine microbio-
duce a minimum of about 15 air changes logic sampling cannot be justified. Such
of filtered air per hour, three (20%) of environmental sampling should only be
which must be fresh air. Air should be performed as part of an epidemiologic
introduced at the ceiling and exhausted investigation LoE 2b) [1].
near the floor [12–13]. Laminar airflow
has been suggested as additional meas- 4.5 Operating room activities
ures to reduce surgical site infections
(SSI) risk for certain operations. Laminar Operating room air may contain microbial-
airflow is designed to move particle-free laden dust, lint, skin squamae, or res-
air (called ultraclean air) over the asep- piratory droplets. The microbial level in
tic operating field at a uniform velocity operating room air is directly proportional
(0.3 to 0.5 µm/sec), sweeping away parti- to the number of people moving about
cles in its path. Laminar airflow can be in the room [18]. Therefore the number
directed vertically or horizontally, and re- of persons entering the theatre during
circulated air is usually passed through a an operation should be minimized. And
high efficiency particulate air (HEPA) fil- unnecessary movement or conversation
ter [14–15]. HEPA filters remove particles should be avoided (LoE 3).
>0.3µm in diameter with an efficiency of
99.97% (LoE 1b) [12, 14, 16].
5. PERSONAL HYGIENE
4.3 Environmental surfaces
Staff can normally wear a personal uniform
Environmental surfaces in operating or street clothes covered by a white coat in
rooms such as tables, floors, walls, ceil- hospital. However, in view of the increas-
ings, lights, are rarely implicated as an ing number of resistant bacterial strains,
important source of pathogens in the most hospitals nowadays recommend
development of SSIs. Nevertheless, it is wearing only short sleeved working clothes
important to perform routine cleaning of and disposable aprons in all contact with
the surfaces to restore a clean environ- the patients. The working outfit must be
ment after each operation [12, 14]. There made of a material which is easy to wash
are no data to support routine disinfecting and decontaminate. If possible, a clean out-
of environmental surfaces or equipment fit should be worn each day. An outfit must
between operations in the absence of con- be changed after exposure to blood or if it
tamination or visible soiling (LoE 3–4). becomes wet through excessive sweating or
Wet-vacuuming of the floor with a hos- other fluid exposure (LoE 3) [9].
pital disinfectant should be performed All staff must maintain strict personal
routinely after the last operation of the hygiene. Nails must be clean and kept
day or night. Care should be taken to short. False nails should not be worn.
653
Hair must be worn short or pinned up. Patients are put at potential risk of
Beards and moustaches must be kept developing a hospital-acquired infection
trimmed short and clean (LoE 4). when a health care practitioner caring
for them has contaminated hands. Hands
must be decontaminated before every epi-
6. HAND HYGIENE sode of care that involves direct contact
with patients’ skin, their food, invasive
There must be written policies and pro- devices or dressings. Hands need to be
cedures for hand washing. There are sev- decontaminated after completing an epi-
eral levels of hand cleaning according to sode of patient care to minimize cross con-
the needs. In summary (LoE 2b): tamination of the environment [21–23].
• Routine care and contact: Hand wash- The preparations for the decontami-
ing with non-antiseptic soap or hygi- nation of hands include washing with
enic hand disinfection with alcoholic plain soap and water, antimicrobial hand
based solution; wash, and alcohol hand rub. In general,
effective hand washing with a liquid soap
• Antiseptic hand cleaning in the care of
will remove transient microorganisms
infected patients: hygienic hand wash-
and render the hands socially clean. This
ing with antiseptic soap following the
level of decontamination is sufficient for
manufacturer’s instructions or, as a
general social contact and most clinical
minimum, hand disinfection as above;
care activities. The use of an antimicro-
• Surgical hand and forearm bial liquid soap preparation will reduce
preparation: transient microorganisms and resident
❍ Surgical hand and forearm washing flora, and result in hand antisepsis [21–
with antiseptic soap for sufficient 22, 24]. The effective use of alcohol-based
time and duration of contact, usu- hand rubs on contaminated hands will
ally 3–5 minutes (manufacturer’s also result in substantial reductions of
instruction) transient microorganisms, although alco-
hol is not effective at removing dirt and
❍ Surgical hand and forearm washing
organic material [24]. However, alcohol
with standard soap for same period
hand rubs offer a practical and accept-
of time, followed by drying and two
able alternative to hand washing when
applications of a hand disinfectant
the hands are not grossly soiled and are
until dryness or according to the
increasingly being recommended for rou-
product’s recommendations
tine use [22, 24].
The duration of hand decontamination,
6.1 Patient contact
the exposure of all aspects of the hands
Hand hygiene is considered the primary and wrists to the preparation being used,
measure to reduce the transmission of the use of vigorous rubbing to create fric-
nosocomial pathogens (LoE 2b) [19–20]. tion, thorough rinsing in the case of hand
The importance of hands in the transmis- washing, and ensuring that hands are
sion of hospital infections has been well completely dry are key factors in effec-
demonstrated, and can be minimized with tive hand hygiene and the maintenance
appropriate hand hygiene. The consist- of skin integrity [21–22].
ent practice of adequate hand hygiene,
either by washing the hands with soap
6.2 Hand washing before surgery
and water or disinfecting them with an
antiseptic solution [21], is considered to The preparation of hand asepsis before sur-
be the single most important intervention gery is well established and each hospital
to prevent nosocomial infections [20]. has to have clear rules. It includes washing
654
of the hands and wrists and forearms for efficacy and cost-benefit of surgical masks
a defined period of time, clean short cut in reducing SSI risk are inconclusive.
nails, rubbing with soap or antiseptic soap, Nevertheless, wearing a mask can be ben-
thorough rinsing, drying and application eficial since it protects the wearer’s nose
of a disinfectant solution. Procedures will and mouth from inadvertent exposures
vary with the patient risk assessment [9]. (i.e. splashes) to blood and other body
fluids. There should be full coverage of
6.3 Jewells the mouth and nose area with a surgical
mask for everyone entering the operating
Jewellery must be removed before washing. suite [31].
Masks of cotton wool, gauze, or paper
are ineffective. Paper masks with syn-
7. SURGICAL ATTIRE
thetic material for filtration are an effec-
tive barrier against microorganisms [8].
The term surgical attire refers to scrub
suits, caps/hoods, shoe covers, masks, • Masks are used in various situations;
gloves, and gowns. All persons entering mask requirements differ for different
the surgical theatre must wear surgical purposes.
attire restricted to being worn only within • Patient protection: staff must wear
the surgical area. The design and compo- masks to work in the operating room,
sition of surgical attire should minimize to care for immuno-compromised
bacterial shedding into the environment. patients, and to puncture body cavi-
The use of surgical attires seems prudent ties. A surgical mask is sufficient.
to minimize a patient’s exposure to the • Staff protection: staff must wear
skin, mucous membranes, or hair of sur- masks when caring for patients with
gical team members, as well as to protect airborne infections, or when per-
surgical team members from exposure to forming bronchoscopies or similar
blood and blood borne pathogens [25–27]. examination. A high-efficiency mask is
All personnel entering in the operating recommended. Masks with additional
suite must remove any jewellery; nail transparent face and eyes shields are
polish or artificial nails must not be worn. used in case of patients with blood
borne infectious diseases.
7.1 Surgical caps or hoods • Patients with infections which may
Surgical caps/hoods reduce contamination be transmitted by the airborne route
of the surgical field by organisms shed from must use surgical masks when outside
the hair and scalp. SSI outbreaks have their isolation room.
occasionally been traced to organisms iso-
lated from the hair or scalp (S.aureus and 7.3 Grown and apron
group A Streptococcus), even when caps
were worn by personnel during the opera- Protective clothing should be worn by
tion and in the operating suites [28–29]. All all health care practitioners when blood,
head and facial hair, including sideburns, body fluids, secretions, and excretions
and neckline, must be covered [9]. (with the exception of sweat), or close
contact with the patient, materials or
equipment may lead to contamination of
7.2 Masks the clothing with microorganisms [24].
The wearing of surgical masks during Plastic aprons are recommended for
operations to prevent potential micro- general use [15]. Full body gowns need
bial contamination of incisions is a long- only be used where there is the possibil-
standing surgical tradition [30]. The ity of extensive splashing of blood, body
655
fluids, secretions or excretions, and these sharps injuries are predominantly caused
should be fluid repellent [32]. by needle devices and associated with
blood vessel puncture, administration of
7.4 Shoe cover medication via intravascular lines and
The use of shoe covers has never been recapping of needles during the disassem-
shown to decrease SSI risk or to decrease bly of equipment [40–42].
bacteria counts on the operating room
floor [33–34]. Shoe covers may, however,
protect surgical team members from 9. EDUCATION
exposure to blood and other body fluids
during an operation. Infection prevention and control personnel
must be specifically trained in methods of
7.5 Surgical gloves SSI surveillance. They must have knowl-
edge of and the ability to prospectively
Operating staff must wear sterile gloves. apply the Centre for Disease Control and
The use of gloves protect hands from Prevention definitions of SSI. Also, they
contamination with organic matter and should possess basic computer and math-
microorganisms and reduce the risks of ematical skills, and be adept at providing
transmission of microorganisms to both feedback and education to healthcare per-
patients and staff [30]. The reported occur- sonnel when appropriate [1].
rence of glove punctures ranges from 11.5% It is essential to regularly provide
to 53% of procedures [35], and double glov- education to the surgeons and operat-
ing is recommended when operating on ing room staff through continuing educa-
patients known to be infected with blood tional activities focusing on minimizing
borne pathogens such as the human immu- the SSI risk through implementation of
nodeficiency virus (HIV), hepatitis B, or recommended process measures. Several
hepatitis C [36]. Gloves should be changed educational components can be com-
immediately after any accidental puncture. bined into concise, efficient, and effec-
Gloves must be discarded after each tive recommendations that are easily
care activity for which they were worn understood and remembered [43]. This
in order to prevent the transmission of also includes feedback on the outcome of
microorganisms to other sites in that implemented preventive measures from
individual or to other patients [35, 37]. patients [14] families, surgeons, and
Cornstarch powder, used to assist in associated staff.
the donning of gloves, is harmful and is
associated with adhesions, latex allergy,
and increasing risks of infection associ- 10. FURTHER RESEARCH
ated with invasive devices contaminated
with cornstarch powder [38]. As a conse- The evidence concerning the control of
quence, powdered gloves should not be perioperative infections in the urologi-
used in healthcare [39]. cal field are limited. Hygiene refers to
practices associated with ensuring good
8. DISPOSAL OF SHARP ITEMS health and cleanliness. Existing study
designs for hygiene are inherently weak.
The safe handling and disposal of nee- Unfortunately, appropriate prospective
dles and other sharp instruments should randomised studies are missing for most
form part of an overall strategy of clinical urological procedures. At present, most
waste disposal to protect staff, patients studies are poorly designed. Further stud-
and visitors from exposure to blood borne ies for additional evidence, particularly
pathogens. In general clinical settings, specific to urological intervention, are
656
necessary to make these guidelines more 6. Abrams P, Khoury S, and Grant A,

appropriate. Alternative precautions for Evidence – based medicine overview of the
high risk procedures are also required. main steps for developing and grading
Education is one of the cornerstones for guideline recommendations. Prog Urol,
improvement within hygiene practices. 2007. 17(3): 681–4.
Hygiene education must be promoted at 7. Dancer SJ, Mopping up hospital infection.
J Hosp Infect, 1999. 43(2): 85–100.
all levels of experience to maintain good
8. Pratt RJ, Pellowe C, Loveday HP,
hygiene and aseptic techniques.
Robinson N, Smith GW, Barrett
S, Davey P, Harper P, Loveday C,
McDougall C, Mulhall A, Privett S,
11. CONCLUSIONS
Smales C, Taylor L, Weller B, and
Wilcox M, The epic project: developing
Good hospital hygiene is an integral national evidence-based guidelines for
and important component of a strategy for preventing healthcare associated infec-
preventing hospital-acquired infections, tions. Phase I: Guidelines for preventing
therefore hygiene for both environment hospital-acquired infections. Department
and personnel should be carried out. This of Health (England). J Hosp Infect,
includes hospital environment hygiene, 2001. 47 Suppl: S3–82.
hand hygiene and the use of personal 9. Ducel G, Fabry J, Nicolle LE, and World
protective equipment. Education should Health Organization, Prevention of hospi-
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2nd ed. 2002, Geneva: World Health
perioperative personnel through continu-
Organization. vi, 64 p.
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10. Lidwell OM, Clean air at operation and
subsequent sepsis in the joint. Clin Orthop
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659
|12.3|
Sterilisation and disinfection

of urological instruments for
endoscopy and for prostate biopsy
Shingo Yamamoto, Ryoichi Hamasuna
Corresponding author: Shingo Yamamoto, M.D., Ph.D., Professor and Chairman, The Department of Urology,
Hyogo College of Medicine, 1-1 Mukogawacho, Nisinomiya, Hyogo, 663-8501, Japan
Tel: +81-798-45-6366, Fax: +81-798-45-6368, E-mail: shingoy@hyo-med.ac.jp
ABSTRACT sterilants used most commonly as high-

level disinfectants. However, OPA is now
The Spaulding Classification System contraindicated for the disinfection of
determines the level of sterilisation urologic endoscopes because of its ana-
required. Endoscopic equipment entering phylactic toxicity. Peroxyacetic acid may
sterile body cavities, such as the urinary cause corrosion of metallic materials.
tract, must be sterilised. Several modes Transrectal ultrasound (TRUS) guided
predominate for cleansing of urologic prostate biopsy is a potential cause of cross
instruments: pressurized steam sterili- infection, unless strict disinfection and
zation, ethylene oxide gas, liquid chemi- sterilization protocols are followed between
cal germicides, and hydrogen peroxide patients. Outbreaks of cross-contamination
gas plasma sterilization, and each mode have been reported after core prostate
has its advantages and drawbacks. Some biopsy and endoscopy. A significant rate
rigid and semi–rigid endoscopes may of perforation of condoms following TRUS
be sterilized using a pressurized steam guided prostate biopsies has also been dem-
autoclave. Ethylene oxide gas is the most onstrated. The probe and the needle guide
common effective method of sterilization have to be separately disinfected in a high-
for medical instruments that cannot be level disinfectant.
autoclaved, although the entire process
can take up to 14 hours. Glutaraldehyde, Key words: Sterilisation, disinfection,
orthophthalaldehyde solution (OPA), and urological endoscopes, transrectal ultra-
peroxyacetic acid are the liquid chemical sound guided prostate biopsy
Sterilisation and disinfection of urological instruments | 12.3 |
SUMMARY OF RECOMMENDATIONS Ethylene oxide gas is the most com-

mon effective method for sterilisation
Note that most recommendations are of medical instruments that cannot
of grade B or C based on available lit- be autoclaved (GoR B).
erature according to level of evidence. 10. Hydrogen peroxide gas plasma steri-
Nonetheless, they merit rather a strong lisation is safe for the environment
recommendation (GoR A), because no and staff (GoR B).
weaknesses in the maintenance of clean-
11. High-level disinfection is achieved
ness and hygiene are acceptable for a safe
with liquid chemicals such as glu-
environment.
taraldehyde and peroxyacetic acid.
Cleaning of urological instruments Disinfectants must be used only in
for endoscopy well-ventilated areas, and be com-
1. Avoid drying (GoR C). pletely rinsed by sterilised distilled
2. Disassemble all instruments and water before clinical use (GoR B).
detachable parts before pre-cleaning 12. It is recommended to use automatic
(GoR B). endoscope washer-disinfectors when-
3. Clean immediately after use to ever possible (GoR C).
remove debris which may cause 13. Store appropriately to ensure
insufficient sterilisation (GoR B). that the instruments are not
4. Brush clean the exterior of the re-contaminated (GoR B).
device and all channels and internal 14. It is essential to inspect the instru-
ports with an enzymatic detergent. ments for damage at all stages of
Channels that are too small to brush handling (GoR C).
manually, should be flushed with an 15. Users should be familiar with the
enzymatic solution (GoR C). manufacturer’s recommendations
5. Rinse with tap water and flush all (GoR C).
channels with clean water (GoR C). 16. Formaldehyde and orthophthalalde-
6. Dry with a disposable cloth and hyde (OPA) are contraindicated for
purge channels with air. Dry disinfection of urologic instruments
condition both outside and inside the (GoR B)
endoscopes is required to achieve 17. Pressurised steam sterilisation is
effective sterilisation using ethylene deleterious for heat-labile instru-
oxide gas or hydrogen peroxide gas ments such as flexible endoscopes
plasma (GoR B). (GoR B)
7. Visual inspection to ensure that the Transrectal ultrasound guided
devices are clean and dry (GoR C). core biopsy of the prostate
Sterilisation and high-level 18. After TRUS-guided prostate biopsy,
disinfection the rectal probe as well as the nee-
8. Steam sterilise all heat-stable dle guide must be cleaned and dis-
reusable components (Many infected to prevent cross infection
manufactures may recommend between patients (GoR B).
low-temperature sterilisation of 19. The process requires disassembling
autoclavable instruments to prolong the device and immersing the probe
the life if the devices/optics) (GoR C). and the needle guide separately in
9. Sterilisation with ethylene oxide a high-level disinfectant such as
or hydrogen peroxide gas plasma. glutaraldehyde (GoR B).
661
1. INTRODUCTION 3. STERILISATION PROCESS OF

UROLOGIC INSTRUMENTS
It is important to sterilise and disinfect
instruments after urological instrumen- 3.1 Urologic endoscopes
tation to avoid infectious complicati-
In 1968, Earle H. Spaulding developed a
ons. Studies have reported outbreaks of
classification system categorizing medical
P. aeruginosa via biopsy-needle guides,
instruments by their use and the risk of
endoscopes and contaminated cystoscopy
infection associated with their use [8]. In
rooms, which indicates that inadequate
the Spaulding Classification System, med-
sterilization of instruments for endos-
ical instruments are classified into three
copy and biopsy can be environmental risk
categories as critical, semi–critical or non–
factors for infections after urologic inter-
critical, and the cleaning levels required to
ventions [1–3] (LoE 3). Guidelines for gas-
prevent infection have been determined.
trointestinal endoscopy have been published
According to this classification, laparo-
and have achieved widespread adoption
scopes, arthroscopes and some endoscopic
[4–5]. Guidelines for the care and steriliza-
accessories, such as biopsy forceps, are
tion of urologic endoscopes and ultrasound
categorized as critical equipment, and all
probes are much less widespread.
microbes, including bacterial endospores,
The aim of the present report is to
must be inactivated during the steriliza-
present the methods for decontamination
tion/disinfection process (LoE 4). Thus
of instruments and risk factors for infec-
sterilization or high-level disinfection is
tions after endoscopy and TRUS prostate
required for processing endoscopic equip-
biopsy, which are the two most common
ment in urologic departments and oper-
urologic procedures.
ating rooms, since these are used under
sterile conditions, i.e., in the urinary sys-
2. METHODS tem (LoE 4). New thinner and flexible uro-
logic endoscopes have been designed for
A standard search of the literature in smoother use in the urinary tract. These
PubMed and of available guidelines and instruments are more delicate and frag-
expert opinions was performed using the ile than those for other procedures, and
following key words: sterilization, disin- the slightest damage can leave the instru-
fection, infection, endoscope, and prostate ment useless. Poor care should therefore
biopsy. Approximately 200 of 1,600 articles be avoided to avoid breakage and ruin the
were identified to be appropriate for the fine instruments during the sterilization
present topic, and were screened by title process [9] (LoE 4).
and abstract. In regard to sterilisation of Previously, steam–formaldehyde was
urologic instruments, randomised con- used widely for disinfection of endoscopic
trolled trials were not found. Therefore, instruments. However, this chemical can
the present review is mainly based on remain in the disinfected material, and
available guidelines, literatures and case should be avoided because of its toxicity,
reports, established practice and recom- including carcinogenicity, to humans [10]
mendation by manufactures. The level and unreliability for disinfection [11–12]
of evidence (LoE) is consequently mostly (LoE3, GoR B). Today, several modes
Level 3 and 4 and the grade of recommen- predominate for cleansing of urologic
dation (GoR) B and C and only suggestive. endoscopes: pressurized steam steriliza-
The studies were rated according to the tion, ethylene oxide gas, liquid chemical
level of evidence (LoE) and the grade of germicides, and hydrogen peroxide gas
recommendation (GoR) using ICUD stand- plasma sterilization, and each mode has
ards (for details see Preface) [6–7]. its advantages and drawbacks.
662
Pre-cleaning before sterilization is be autoclaved, since the gas penetrates

an important step to remove the debris, medical packaging and plastics, and it
which causes insufficient sterilization is compatible with most medical materi-
(GoR B). All instruments and detach- als that must be stored in a sterile con-
able parts must be disconnected (GoR B). dition and be ready for use (LoE3, GoR
After soaking in a detergent enzymatic B). Although the operating and monitor-
solution, the exterior of the endoscopes, ing processes are easy, the time required
as well as all channels and internal ports, to process through an entire sterilization
should be cleaned with appropriately cycle can be up to 14 hours. For this rea-
sized brushes. Channels that are too son, instruments that must be sterilized
small to be manually brushed should be using the ethylene oxide method can
flushed with an enzymatic solution. Next, only be used once in a 24-hour period.
the entire endoscope should be immersed This is impractical when doing more
in clean rinse water, and all channels than a single procedure per day; e.g.,
should be flushed with clean water and cystoscopy in an outpatient clinic. The
then purged with air to remove water potential hazard to patients and staff
from the channels. Completely dry condi- must also be noted, since ethylene oxide
tions outside and inside the endoscopes is gas is a severe local irritant and has
required to achieve effective sterilization been implicated as a carcinogen, and its
using ethylene oxide gas or hydrogen peruse requires satisfactory aeration [9, 12]
oxide gas plasma (GoR B). For this pur- (LoE 3, GoR B).
pose, flushing with alcohol followed by air
purging may be recommended (GoR C). 3.4 Liquid chemical germicides
3.2 Pressurized steam sterilization Glutaraldehyde, orthophthalaldehyde

(OPA) and peroxyacetic acid are the
Pressurized steam autoclaving is non- most commonly used sterilants for high-
toxic, inexpensive, and easy to control and level disinfectants of endoscopes, since
monitor (LoE3, GoR B). Its rapid cycle the process of sterilization using these
time and microbicidal effect are also rea- liquid chemicals is easy and requires a
sons for it being the most popular mode of shorter time than other methods (LoE 3).
sterilization of medical equipment in hos- However, the safety of patients and staff
pitals. Furthermore, pressurized steam is not always ensured because the chemi-
sterilization can penetrate medical packing cals are irritating to the skin, therefore,
and device lumens, and is little affected the instruments need to be completely
by organic/inorganic soils. However, this rinsed by sterilized distilled water before
mode is deleterious for heat-labile instru- clinical use (LoE 3, GoR B). Furthermore,
ments such as flexible endoscopes. Some since the vapour may cause irritation of
rigid and semi–rigid endoscopes may be the eyes and nasal mucosa, the chemi-
sterilized using pressurized steam steri- cals must be used only in well-ventilated
lization, while many manufacturers rec- areas, and if possible, use of automatic
ommend low-temperature sterilization endoscope washer–disinfectors is recom-
whenever possible to prolong the life of the mended (GoR C). Some cases of anaphy-
lens even if the instruments can be auto- lactic reactions after using cystoscopes
claved (LoE4, GoR C). disinfected with OPA have even been
reported [13–14] (LoE 3) and OPA is
3.3 Ethylene oxide gas now contraindicated for the disinfec-
Ethylene oxide gas is the most com- tion of urologic endoscopes [15] (GoR B).
mon effective method of sterilization Peroxyacetic acid may cause corrosion of
for medical instruments that cannot metallic materials (LoE 4).
663
3.5 Hydrogen peroxide gas plasma patients were hospitalized, and three were
Hydrogen peroxide gas plasma steriliza- admitted with a diagnosis of septicemia.
tion is a new technology for sterilization A likely origin for these infections was tap
of medical devices. This method is safe water contamination of the probe and nee-
for the environment and staff, because dle guide during inadequate rinsing and
it leaves no toxic residues and requires drying; i.e., by means of an alcohol rinse
no ventilation (LoE 3, GoR B). The cycle following the tap water rinse and forced-
time of the procedure is as short as air drying [2] (LoE 3). Another report has
60 minutes, and the process temperature demonstrated a significant rate of condom
is up to 45°C. The method is compatible perforation (9%; 10/107) following TRUS-
with most heat-labile medical devices and guided prostate biopsies [22] (LoE 3).
convenient for instruments used several Probe swab samples after condom perfo-
times per day. Since some endoscopes are ration have also been shown to be positive
not effectively sterilized because of their for bacterial growth in patients undergoing
lumen internal diameters and lengths, transvaginal sonography [23] (LoE 3).
their manufacturer’s recommendation An in vitro study of P. aeruginosa has
should be consulted before use. The cost demonstrated that disinfection can be
of the hydrogen peroxide gas plasma ster- achieved if the needle guide is removed
ilizing machine is still expensive. from the probe when the equipment
is immersed in 2% glutaraldehyde for
20 minutes. However, disinfection is not
achieved when the needle guide is left in
4. TRANSRECTAL ULTRASOUND- the probe channel during immersion in
GUIDED CORE PROSTATE BIOPSY glutaraldehyde, which indicates that the
process requires disassembling the device
Transrectal ultrasound (TRUS) guided and immersing the probe and the needle
biopsy of the prostate is a standard uro- guide separately in a high-level disinfect-
logic procedure for detecting prostate ant [24] (LoE 2b).
cancer. Although infections following
this procedure are generally believed to
be infrequent when prophylactic oral or 5. FURTHER RESEARCH
intravenous antibiotics are administered
[16–19] (LoE 1b), in some cases, infec- Although sterilization or high-level dis-
tive complications are potentially fatal infection is required for processing endo-
[20–21] (LoE 3). Furthermore, TRUS scopic equipment, most urologic flexible
guided prostate biopsy potentially causes endoscopes are too delicate and fragile.
cross infection, particularly with blood- Disinfection using liquid chemical steri-
borne communicable diseases such as lants is convenient and inexpensive,
hepatitis and HIV infection, unless strict but these germicides are more or less
disinfection and sterilization protocols toxic for patients and staff. To overcome
are followed between patients (LoE 4). these drawbacks and establish a safe
In TRUS guided prostate biopsy, to pro- and economical procedure of sterilization
tect patients from cross infection, the rectal or high-level disinfection, more effort on
probe as well as the needle guide must be industrial development will be needed.
cleaned and disinfected between patients
(GoR B). One study has reported an out-
break including four cases of P. aeruginosa 6. CONCLUSIONS
infection after TRUS guided prostate biop-
sies, in which contamination of the TRUS According to the Spaulding Classification
equipment was the likely source. All four System, endoscopic equipment entering
664
sterile body cavities, such as the urinary 6. Abrams P, Khoury S, and Grant A,
tract, must be sterilised by pressurized Evidence – based medicine overview of the
steam sterilization, ethylene oxide gas, main steps for developing and grading
liquid chemical germicides, or hydro- guideline recommendations. Prog Urol,
gen peroxide gas plasma sterilization. 2007. 17(3): 681–4.
Steam–formaldehyde as well as orthoph- 7. U.S. Department of Health and Human
thalaldehyde solution (OPA) is now
contraindicated for the disinfection of
115–127.
urologic endoscopes because of their tox-
8. Spaulding EH, Chemical disinfection
icity. The probe and the needle guide for of medical and surgical materials, in
TRUS guided prostate biopsies have to Disinfection, sterilization, and preserva-
be separately disinfected in a high-level tion, Lawrence CA and Block SS, Editors.
disinfectant. 1968, Lea & Febiger: Philadelphia,.
p. viii, 808 p.
9. Gregory E, Simmons D, and Weinberg
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666
|12.4|
Preoperative assessment of the

patient, risk factors identification
and tentative classification of
surgical field contamination in
urologic surgery
Magnus Grabe1, Henry Botto2, Mete Cek3, Peter Tenke4, Florian M.E. Wagenlehner5,
Kurt G. Naber6, Truls E. Bjerklund Johansen7
1
Department of Urology, Skåne University Hospital, Malmö, University of Lund, Sweden
2
Department of Urology, Hôpital Foch, Suresnes Cedex, France
3
Department of Urology, Taksim Teaching Hospital Istanbul, Istambul, Turkey
4
5
Department of Urology, University if Giessen, Giessen, Germany
6
7
Department of Urology, Århus University Hospital, Skejby, Århus University, Århus, Denmark
Corresponding author: Magnus Grabe, MD, PhD, Associate Professor, Department of Urology,
Skåne University Hospital, University of Lund, S-20502 Malmö, Sweden
Tel 0046-40-33 18 25, Fax 0046-40-33 70 49, magnus.grabe@skane.se
ABSTRACT patient and type of surgery is suggested

considering: 1) the ASA score, 2) the gen-
Identifying and controlling risk factors eral risk factors, 3) the individual endog-
for infectious complications minimises the enous and exogenous risk factors, 4) the
patient’s risk of being subjected to such class of surgery and the potential bac-
a complication. Risk factors are bound terial contamination burden and 5) the
to the patient and to the procedure itself level of severity of the surgical interven-
and are associated with the environ- tion. A cumulative approach will identify
ment where the healthcare is provided. the level of risk for the individual patient
Assuming a clean environment, a five and define the preventive measures such
level assessment ladder related to the as the type of antibiotic prophylaxis or
therapeutic measures before surgery. 1. INTRODUCTION

There are data suggesting that the higher
the ASA score, the higher the risk of Preparing the patient for urologic instru-
infectious complication. Dysfunction of the mentation or surgery involves the assess-
immune system, hypoalbuminemia/malnu- ment of the patient’s vulnerability for a
trition or extreme weight, and uncontrolled complication in general and an infectious
blood glucose are independent general risk complication in particular and aims at
factors whilst bacteriuria, indwelling cath- identifying risk factors for such compli-
eter treatment, urinary tract stone disease, cations. The control of risk factors aims
urinary tract obstruction and a history of at minimising the complications. This
genitourinary infection are urological spe- section describes the factors shown or
cific risk factors. There is inconclusive evi- assumed to put a patient at a particular
dence for most other reported risk factors. risk of infectious complication in conjunc-
The level of contamination of the surgical tion with an urological intervention, with-
field is of the utmost importance and has out, though, pretending to be complete as
to be reflected by the subsequent antibiotic the independent contribution of the dif-
prophylaxis strategy. ferent risk factors has not been assessed
Key words: Urologic surgery, endourol- after the control of confounding factors
ogy, risk factors, infectious complications, and only a few risk factors have been well
urinary tract infection, surgical classes, defined.
surgical field contamination.
2. METHODS
SUMMARY OF RECOMMENDATIONS A review of the topic risk factors for infec-

tious complications was undertaken
for the International Consultations on
1. It is recommended to assess all
Nosocomial and Health Care Associated
patients before surgery for: (GoR B)
Infections in Urology in Paris 2000 [1].
a. the ASA score P1–P5 An updated search on Medline from the
b. the presence of general risk factors year 2000 related to risk factors in uro-
for complications logic surgery by procedure was under-
taken using the following keywords:
c. the presence of particular endog-
endourological surgery, endourology, gen-
enous and exogenous risk factors
itourinary surgery, risk factors, infectious
d. the class of surgery and potential complications, urinary tract infection.
bacterial contamination or burden A variety of unspecific articles on urology
e. the expected level of surgical inva- were displayed in large numbers but only
siveness and degree of difficulty very few of them appeared at screening to
2. Special concern is given to general address the issues of patient preparation
risk factors and specific risk factors as and risk factor evaluation. All presump-
stated in Tables 1–7 (GoR B). tive or generally accepted risk factors
could not be reviewed, i.e. diabetes mel-
3. Infectious complications should be reg- litus, smoking, overweight, individually
istered. Infection control is a valuable or cumulatively, as each merits an inde-
method for monitoring a department’s pendent systematic review. The list of
quality output and for feedback to sur- references thus includes, whenever possi-
geons (GoR B). ble, review articles. Furthermore, all arti-
4. Quality registries and risk factor reg- cles reviewed for the section on antibiotic
istration should be developed (GoR C). prophylaxis were specifically scrutinised
668
Preoperative assessment of the patient | 12.4 |
by the first author for reported risk fac- between a variable and an event or dis-
tors. As there are no international stand- ease. In the context of surgical site infec-
ards for scoring risk factors, each of them tion (SSI) for instance, a risk factor strictly
were weighted and reported as evidence refers to a variable that has a significant
for if there was consistency in the findings independent association with the develop-
or inconclusive evidence for if there were ment of SSI after a specific operation. The
conflicting data on their role (Table 7). same is true for urinary tract infections
A tentative classification of the urologi- (UTI).
cal procedures in relation to the present Risk factors are identified by multivar-
accepted surgical classes is suggested. iate analysis. However, commonly, uni-
The studies were rated according to variate analysis is also used. Thus, both
the level of evidence (LoE) and the analytical methods have to be considered
grade of recommendation (GoR) using in accepting predictors for increased risk
ICUD standards (for details see Preface) for infection in conjunction with health-
[2–3]. The data presented in this section care [4–5].
and references lists are a linked to the Risk factors are related to the patient,
ones presented in the two sections on the environment and to the procedure
antibiotic prophylaxis (European and itself.
US view).
3.2 Risk factors related to the host
3. RISK FACTORS FOR INFECTIOUS Risk factors related to the patient can
COMPLICATIONS be built in a stepwise level. A key ques-
tion is whether the source of bacteria in
urological infections is exogenous, that
3.1 Defining a risk factor
is brought into the patient in conjunc-
There is a baseline risk of infection asso- tion with instrumentation, or whether
ciated with each type of intervention. This the infection is endogenous, that is har-
level is not always known and can only be boured, undetected by standard cultures,
assumed studying the natural history – in the patient and exacerbated during the
the expected natural development of a procedure.
process after intervention – using cohorts Figure 1 gives a synoptic image of the
or placebo controlled studies. A risk fac- different groups of risk factors to be con-
tor is a factor that further increases the sidered in the preparation of the patient.
risk of an infection, beyond the baseline
level of a given procedure. To measure the
relative role of a risk factor or its interac- 3.2.1 General physical status
tive cumulative impact in modifying the The first step in the assessment of a
course of the natural history requires patient’s risk is to determine the general
very large sized studies. health state of the patient as defined by
Identifying the risk factor is defining associations of anaesthesiology such as
the relative risk. Measuring the relative the American Society of Anaesthesiology.
risk is assessing the independent value of The risk groups are given by the classes
different variables for the occurrence of a P1–P5 related to the general health of the
certain event. The term risk factor has a patient (Table 1) [6].
particular meaning in epidemiology and Opinions diverge on the relationship
expresses the probability that an event between the classes P1–P5 and SSI. There
occurs in an exposed group as compared are, however, studies that identify an
with an unexposed group. It is a ratio increased risk of infectious complications
that assesses the strength of association in patients with reduced general health
669
Figure 1 Stepwise assessment of the patient’s risk factors and procedure, given a fully controlled
surgical environment (modified from 1).
Table 1 General physical status defined by the American Society of Anaesthesiology [6].
Category Clinical evaluation
P1 A normal healthy patient
P2 A patient with a mild systemic disease
P3 A patient with a severe systemic disease
P4 A patient with a severe systemic disease that is a constant threat of life
P5 A moribund patient who is not expected to survive with or without the operation
status [7], especially P3 and above. Those mean an increased risk for infectious
patients are usually older with more complication.
advanced disease and co-morbidity [8].
3.2.3 Diabetes mellitus
3.2.2 General risk factors The independent role of diabetes for SSI is
The second step is to identify risk fac- still controversial [4]. In a recent prospec-
tors for complications. These factors have tive study from Japan, poor postoperative
principally been identified for the risk of blood glucose control was directly cor-
a SSI [4]. Several of these remain contro- related to an increased rate of SSI [9]. A
versial because the independent contribu- stable and correct blood sugar level is con-
tion has usually not been assessed after sidered important before, during and after
controls for confounding factors [4]. Very surgery [10–11]. It is also recognised that
little work has been done so far as uro- bacteriuria is more often present in indi-
logical surgery is concerned. Most stud- viduals with diabetes, is more severe and
ies are related to cardiac and orthopaedic lasts longer [12–13]. As bacteriuria is a well
surgery. It is, however, assumed that defined risk factor for post-operative infec-
the characteristics presented in Table 2 tious complications, patients with diabetes
670
Table 2 General patient related risk factors that may deleterious and increased the risk of SSI.
influence the risk for SSI [4]. Only hypoalbuminaemia and previous
surgery were associated with deep wound
General Risk factors infections. It is, however, worth under-
High age
lining that the benefits of preoperative
nutritional repletion in reducing the SSI
Deficient nutritional status risk are unproven [4] (LoE 2a).
Diabetes mellitus
Smoking 3.3 Particular risk factors

Extreme weight The third step is the identification of par-
Coexisting infection at a remote site
ticular risk factors. These can be divided
into two major sub-groups, endogenous
Colonization with micro-organisms
and exogenous risk factors (Table 3).
Altered immune response
Long preoperative hospital stay 3.3.1 Endogenous risk factors

Lack of elimination or control of risk factors The endogenous risk factors are those
prevailing in the individual patient. They
are secondary to an anatomical abnor-
must be considered at risk and their treat-
mality, an organic dysfunction or one or
ment optimised. As diabetes mellitus is
several concomitant disease(s). The most
increasing in most societies, we can assume
frequently reported risk factors are listed
that there will be an increased number of
in Table 3a. In urological prevalence stud-
patients at risk of infectious complications.
ies, catheterisation, previous hospitali-
Obviously, more studies are necessary to
sation, antibiotic treatment and urinary
better understand the role of diabetes in the
tract stones were found to be the key risk
healing process and as a risk factor of infec-
factors for nosocomial UTI [16]. The fact
tious complications (LoE 2a).
that previous antibiotic treatment and
hospitalisation go with increased risk
3.2.4 Other characteristics
may be interpreted to the fact that those
Nicotine use delays primary healing and patients have a known focus, have a more
may increase the risk of SSI [14] (LoE 3). severe disease or have a weaker status.
The same is valid for steroid use and
malnutrition. Malnutrition, measured 3.3.1.1 Bacterial colonization
by the nutritional risk index, was found The periurethral zone and the distal
to be an independent factor associated urethra are naturally colonized by both
with nosocomial infections [15]. Low Gram-negative and Gram-positive bacte-
level of albumin is one marker of mal- ria [17] that can enter the bladder either
nutrition. In a review of 10,253 general by own migration, via an indwelling cath-
(non urological) surgical procedures, eter or during instrumentation (LoE 3).
Haridas and Malangoni [8] found that Bacterial presence naturally increases
316 (3.1%) developed SSI, mainly super- with age, especially in women [18] (LoE 3).
ficial wound infections (84%) (LoE 2a). Also in men subjected to TURP and hav-
In a matched control study using mul- ing no indwelling catheter, preoperative
tivariate analysis, they found that pre- bacteriuria is observed in more than 10%
vious operation, hypoalbuminaemia [19]. Bacteriuria at the time of TURP
and or low haemoglobin levels, and a increases the risk of a febrile infection
history of chronic obstructive lung dis- by 5–10 times [20] (LoE 2b). Regrettably,
ease were independent risk factors for baseline data do not exist for most uro-
SSI. Also excessive use of alcohol was logical interventions but there are no
671
Table 3 List of the most important endogenous and exogenous risk factors (modified from [1]).
Endogenous risk factors (3a) Exogenous risk factors (3b)
High age Introduction of micro-organisms
Colonization Increased burden
Faecal – intestinal flora Increased virulence factors
Periurethral Susceptibility to antibiotics
Increased microbial burden Instrumentation
Immunity (native or altered) Endoscopic diagnosis
Age related Surgical intervention
Compromised host defence mechanisms Catheterization
HIV/AIDS Indwelling catheter
Haematological Nephrostomy tubes
Related to a concomitant disease Stents (double J-stent)
Associated with burns Metallic stents
Genetic determinants Central vein catheters
Gender Perfusion
Familial
Genitourinary (GU) anatomical factors Implantation of prosthetic devices
Prepuce
Vesico-ureteral reflux
Bladder dysfunction
Residual urine
Augmentation related
Poor vascularisation
Poor emptying of the GU system
Hydronephrosis
Urinary tract stones
Inflammatory disease of the prostate
Particular physiological status
Pregnancy Sexual activity
Postmenopausal hormonal deficiency
Concomitant diseases
Diabetes mellitus
Renal insufficiency
Cardiovascular diseases with poor circulation
Obstructive pulmonary diseases
Anatomic area subjected to radiotherapy
672
reasons to believe the situation would 3.3.2.1 Indwelling catheter

be different than for TURP. Bacteria can The urinary tract is the commonest source
be “hidden” in the ducts of the prostatic of HAI, particularly when the bladder is
gland [21], in the bladder, in dilated cal- catheterised, representing some 40% of
ices or diverticulae or other sites and health care associated infections, origi-
adhere to biofilms of urinary tract stones nating from either urological manipu-
or implanted devices [22] that would not lation (10–20%) or permanent urethral
always be detected by standard cultures catheterisation (approx 80%) [28] (LoE 3).
and might produce a clinical infection at Most UTIs are derived from the patient’s
the time of surgery and lesion of the pro- own colonic flora. All type of catheters,
tective mucosa layer. i.e. bladder catheter, nephrostomy tube
or double-J stents, predispose to UTI.
3.3.1.2 Renal stones
Duration of catheterisation is the most
Urease-producing bacteria such as important risk factor. Most episodes of
Proteus spp are well known in infectious short-term catheter-associated bacteriu-
calculi and staghorn stones. However, it ria are asymptomatic and caused by a sin-
has also been clearly shown by consecu- gle organism. When the catheterisation is
tive stone culture that pathogens adhere long-lasting, there is a tendency for multi-
to stones in 30–70 % of the stones [23]. ple strain colonisation (LoE 2a). Biofilms
Although a urine culture is recommended and encrustations are formed on the
before an intervention, it is not necessar- catheter creating a secondary limitation
ily a good predictor of a microbial pres- of the inner tube and finally obstruction.
ence [24]. Thus, all stone situations with Stone formation in the bladder is seen in
a major kidney stones or stones of the conjunction with long-term catheterisa-
proximal ureter, especially in the pres- tion. While a catheter is in place, routine
ence of an obstruction of the system, have urine culture and antibiotic treatment is
a potentially increased microbial burden not recommended in asymptomatic cases.
even in the absence of growth on a stand- However, a urine culture is mandatory
ard urine culture [24–25] (LoE 2b). prior to surgery in order to direct the
treatment and sterilise the urine before
3.3.1.3 Inflammatory disease of the the intervention [28] (LoE 2b).
prostate
Little is known about the role of asymp- 3.4 Surgical field classification
tomatic prostatitis and the risk of infec- in urology
tious complications at endoscopic surgery. 3.4.1 Surgical class
However, a history of urogenital infection
The fourth step in the planning of sur-
or prostatitis is shown to be a risk factor
gery is defining the category of surgery or
for infectious complication after core pros-
surgical class, in other words the level of
tate biopsy [26], TURP [20, 27] and prob-
contamination of the procedure. The cur-
ably other surgery [16] which confirms
rent classes of surgery/surgical field con-
the clinical empirical experience (LoE 3).
tamination were developed during World
War II and adapted to war surgery. They
3.3.2 Exogenous risk factors were subsequently updated for open sur-
The exogenous risk factors are those gery and determining the relative risk of
introduced for one or another reason into surgical wound infection [29]. Urological
the patient and that contribute directly interventions have not been classified
to increase the risk of infection. The most and the current definitions do not include
frequently reported risk factors are given endoscopic surgery, ESWL or core pros-
in Table 3b. tate biopsy. It is, however, understood
673
that opening the urinary tract, even in divided into two sub-groups. Table 4a
the presence of a negative urine culture, shows a tentative classification of open
should automatically classify the inter- and laparoscopic procedures. In an exten-
vention as a clean-contaminated infection sion, this classification could theoretically
[4, 29] (LoE 3). It is also suggested here be widened to also cover endoscopic uro-
that the opening of the gastro-intestinal logical procedures, the surgical site being
tract would theoretically implies a heav- the urinary tract and the SSI being UTI.
ier bacterial load, clean-contaminated or This suggestion is also presented in Table
contaminated class. Therefore, for prac- 4a and the extended criteria of classifica-
tical reasons in urology, clean-contam- tion for common urological procedures are
inated operations are in this proposal given in Table 4b.
Table 4a Surgical Wound Classes (based on [4, 29]) and risk of wound infection [29] and suggested ESIU classification of
urological instrumentation and procedures in the different classes. The risk of wound infection is that of classical wound
infection and not bacteriuria or UTI in urological surgery.
Category of Open or laparoscopic Endoscopic urological

intervention (risk of urological surgery instrumentation and
wound infection) Description (Examples) surgery (examples)
Clean (1–4%) Urogenital tract not entered Simple nephrectomy Cystoscopy

No evidence of inflammation Planned scrotal Urodynamic study
surgery
No break in technique TURB (minor, fulguration)*
Vasectomy
Blunt trauma ESWL*
Varicocele surgery
Clean-contaminated Urogenital tract entered with Pelvio-ureteric junction TURB (major, necrotic)*
(4–10%) no or little (controlled) spillage repair
TURP*
No major break in technique Nephron-sparing tumour
Diagnostic URS*
resection
Uncomplicated URS* and
Total/radical prostatectomy
PCNL stone management
Bladder surgery and partial
ESWL*
cystectomy
Incl. Vaginal surgery
Gastrointestinal tract Urine diversion (orthotopic

entered with no or little bladder replacement; ileal
(controlled) spillage conduit)
No break in technique
Contaminated (10–15%) Spillage of Gastrointestinal Urine deviation (colon) and Core prostate biopsy*
content small intestine/spillage
TURP*
Inflammatory tissue Trauma surgery
Impacted proximal stone
Major break in technique Concomitant gastrointestinal management
disease
Open, fresh accidental wounds Complicated PCNL
Dirty (15–40%) Pre-existing infection Drainage of abscess Infectious stone surgery

Perforated viscera at surgery Large dirty trauma surgery
Old traumatic wound
*Detailed description in table 4b.
674
Table 4b Tentative list of essential criteria for assessment of surgical class/surgical field contamination level of common
urological procedures: The estimated risk of infectious complication is related to the surgical class or category.
Operation/ Endoscopy Prostate

Category TURB TURP Stone ESWL biopsy
Clean Small tumours - Distal ureteral stone Standard ureteral -

or kidney stone
No history UTI Not impacted
No history UTI
Sterile urine Sterile urine
(similar Sterile urine
No or minor obstruction
cystoscopy)
No or mild
No other RF
obstruction
Clean- Large tumours No history All ureteral stone Standard ureteral Transperineal
contaminated UTI/UGI or kidney stone
History UTI History UTI Sterile urine
Sterile urine History UTI
Sterile urine Sterile urine No history UTI/UGI
No catheter Sterile urine
Minor/moderate
obstruction Moderate
obstruction
No stent
Other RF
Other RF
Contamin- Large tumours History UTI/UGI Proximal impacted Complex stone Transperineal
ated stone
Necrosis Catheter prior History UTI Sterile urine
to surgery History UTI
Bacteriuria Obstruction History UTI/UGI
controlled Bacteriuria Sterile urine or
Bacteriuria Transrectal
controlled controlled bacteriuria
controlled
No- or history UTI/
Moderate obstruction
Stent or UGI
Stent/catheter nephrostomy
Sterile urine
tube
Dirty Clinical infected Clinical infected Clinical infected Clinical infected Transrectal
Emergency Emergency Drainage only Drainage only Presence of
catheter or
bacteriuria
*UTI = urinary tract infection. UGI = urogenital infection (i.e. prostatitis). RF = risk factor.
The criteria for assessment of contami- Criteria for assessment of contamina-

nation categories in open surgery are the tion in endoscopic urological surgery and
same as for other types of open surgery: ESWL are mainly:
• Type of incision (primary, secondary, • History of UTI or other urogenital
tertiary) infection
• Opening of a tract • History of infection in relation to stone
• Spillage from tract (renal obstructed disease
cavity, small bowel, colon) • Knowledge of contamination level
• Evidence of infection or inflammation • Result of the urine examination before
in the surgical field surgery
675
• Catheter in place at the start of one initially sterile needle is used for sev-
surgery eral core biopsies in the same patient,
• Site of entry of surgery (urethra, passing the rectal contaminated field and
nephrostomy channel, pouch, vagina) not renewed or disinfected between each
the biopsies.
• Perforation of the urinary tract
• Evidence of infected urine found dur-
ing surgery (obstructed area, cavity) 3.5 Risk of infectious complication
associated with urological
In essence, these characteristics deal
surgery
with the contamination due to the proce-
dure per se, and the contamination of the Table 5 gives baseline data without
surgical field, whenever present before antibiotics on the range of infectious
surgery. Thus, an operation within the complications as reported in the litera-
urinary tract in the presence of a positive ture for a limited number of urological
culture is either contaminated or in some procedures. Most data are older but are
situations dirty. usually the only ones that present a
For transrectal core biopsy of the pros- natural history perspective to the differ-
tate the circumstances are particular as ent procedures.
Table 5 Approximate rates of infectious complications after a selected number of urological instrumentations, in patients
assumed free from infection within the genitourinary tract at time of the procedure and receiving no antibiotic prophylaxis.
Febrile or
Procedure Bacteriuria symptomatic UTI Sepsis References
Cystoscopy 1–9% 1–5% No data [37–45]
Urodynamic studies 13% (average; 2–3% No data [46–48]

range 4–30%)
Transrectal core prostate 5–26% 3–10% <5% [49–53]

biopsy
TURB 4–6% No data No data [42, 54–55]
TURP 6–70% 5–10% 0–4% [19, 56–59]
ESWL 0–28% 5,7% (median 1% but limited [60–68]

probability) data
Ureteroscopy (standard) Up to 13% No data No data [25, 69–71]
Percutaneous stone extraction Up to 35% 4–25% 15% [24–25,

and difficult ureterorenoscopy 72–73]
Open/Lap Nephrectomy Skin SSI < 5% No data [31, 34, 74]

Catheter Higher reported
associated
Open/Lap/robotic Total Dito SSI <5% No data, [75–78]

prostatectomy no RCT
Cystectomy and bladder Dito SSI 10–15% Limited data [79–81]

substitution
Scrotal surgery Skin SSI 3–9% No data [82–83]
Implantation of prosthetic Skin 1–16,7% No data [84–85]

devices
676
Table 6 General operative and environmental risk factors associated with an increased risk of infectious complications [1, 4].
Preoperative and operative characteristics Surgical environment (related to theatre, staff,

(patient and procedure related) microbial environment)
Preoperative preparation of the patient
Long preoperative hospitalisation Staff related
Insufficient cleaning of surgical site Hygiene and aseptic environment
Inappropriate antibiotic prophylaxis Elimination of transmission between staff and patients
Operation characteristics Operation theatre
Length of operation Clean environment
Surgical technique Ventilation
Tissue damage Number of staff
Bleeding Order of surgery
Experience of the surgeon Sterilisation of instruments
Implantation of prosthetic devices Microorganisms
Drainage Burden
Perioperative oxygen tension Virulence
Sensitivity to antibiotics
Special strains
Specific pathogens
Viruses (HIV, Hepatitis, Herpes)
3.5.1 Risk factors associated with studies but must eventually be reported
the surgical environment in a standardised way (LoE 4).
and managemant Has the introduction of laparoscopic
The fifth step is to estimate the complex- and robotic surgery changed the risk of
ity of the procedure in terms of severity, infectious complications? No RCT cov-
difficulty and size of the intervention ers the subject in urology. Montgomery
(i.e. size of prostate, bladder tumour, showed a lower rate of wound infections
stone localisation), time of operation, in hand-assisted laparoscopic urologic
risk of bleeding and tissue trauma, sur- surgery compared with open surgery, but
geon’s experience; all factors that have more often than with standard laparos-
been linked to complications [4] Table 6. copy [31]. We have to refer to informa-
Obviously, these parameters may change tion from other abdominal surgery. In one
during the procedure. For instance, a meta-analysis about laparoscopic versus
large prostate resection in an older man open surgery for peptic ulcer, there was
cannot be compared with a smaller resec- a significant lower frequency of surgical
tion in a healthy man; a large impacted, site wound infections in the laparoscopic
ESWL resistant proximal stone is dif- group, 2.5% versus 6.9% [32]. Similar
ferent from a distal 6–8 millimetre dis- results have been shown for other laparo-
tal stone in an otherwise normal ureter scopic digestive surgery [33]. The NNIS
[30]. Such factors are rarely considered in database supports this trend [34] (LoE 3).
677
3.5.1.1 Prolonged preoperative hospital stay mentioned as risk factors for SSI. Con-
A long preoperative hospitalisation is versely, meticulous surgery performed as
often claimed as a risk factor for increased quickly as is safe, with as little blood loss
SSI risk. Indeed, the risk of colonisa- as possible followed by scrupulous post-
tion by resistant strains is increased. operative care are obviously key factors
However, a long hospital stay may also that may keep the infection rate as low
be the indicator for the severity of illness as possible. This may also be extended to
and co-morbidity, influencing both the endoscopic surgery [4] (LoE 2a). Also the
preoperative diagnostic and therapeutic perioperative administration of supple-
procedures [4, 8] (LoE 2b). mentary oxygen reduces the rates of sur-
gical wound infection [35].
3.5.1.2 Prolonged operation time
As for preoperative hospital stay, this fac-
tor may be related to more advanced dis-
3.5.2 Evidence of risk factors for
ease and more complicated surgery [8, 34] different type of procedures
(LoE 2b).
Table 7 shows the risk factors by level of
3.5.1.3 Surgical technique evidence for a certain number of proce-
Tissue traumas, poor haemostasis, fail- dures. Bacteriuria and any type of cathe-
ure to obliterate dead spaces, and the ter (urethral catheter, nephrostomy tubes,
experience of the surgeon have all been JJ-stents) and a recent history of UTI or
Table 7 Risk factors and level of evidence for infectious complications in some urological procedures.
Type of intervention Evidence for Inconclusive evidence for
Aspiration biopsy/cytology Connective tissue disease Prostatitis

of the prostate
Transrectal Core biopsy Bacteriuria Diabetes mellitus

of the prostate
Indwelling catheter Steroids
History of UTI or Prostatitis Pre-biopsy enema
Absence of antibiotic prophylaxis
Cystoscopy (diagnostic) Bacteriuria Bladder dysfunction

Indwelling catheter Impaired immune status
History of associated UTI Foreign body
Transurethral resection Preoperative indwelling catheter High age

of the prostate (TURP)
Renal failure Bladder dysfunction
Rupture of closed drainage Surgeons experience
Bleeding
Duration of surgery
Other endoscopic surgery Bacteriuria High age

Urethral stent Renal failure
Nephrostomy tubes Duration of surgery
Diabetes mellitus
678
Type of intervention Evidence for Inconclusive evidence for
ESWL Bacteriuria High age

Urethral stent Renal failure
Nephrostomy tubes Diabetes
Staghorn stones
Open adenoma enucleation Bacteriuria High age

of the prostate
Indwelling catheter Renal failure
Rupture of closed drainage Duration of surgery
Diabetes mellitus
Nephrectomy Increasing number of risk factors
Total prostatectomy
Other operations with open Bacteriuria Absence of antibiotic prophylaxis

urinary tract
Indwelling catheter
Surgery and urinary diversion Absence of antibiotic prophylaxis Length of surgery

with open bowel
Implantation of prosthetic Concomitant procedures Diabetes mellitus

devices
Remote site infection Transplanted and immune system
deficiency
Previous radiotherapy
Repeated implantation
Spinal cord injury
prostatitis are reckoned to be risk factors the factors that might influence the devel-
with a high level of evidence, whilst other opment of infectious complications in con-
risk factors are reported inconclusively junction with urological surgery. There
in the literature. Diabetes mellitus for are no international standards for a com-
instance was shown in prostate biopsy to prehensive assessment of patients before
be a risk factor in one study on core pros- surgery. The ASA score is related to the
tate biopsy [36], but most other studies risk of anesthesia but reflect also the
have not been broken down into subgroups, health state of the patient. The general
making a conclusion impossible. For most risk factors are based on large registry of
urological studies, there are no prospective infectious complications in mainly general
or case controlled studies looking specifi- and digestive surgery, cardiovascular and
cally at risk factors, leaving many ques- orthopedic intervention, rarely on uro-
tions to be answered in the forthcoming logical procedures. Data are not always
years. The only approach to identify risk consistent and most studies reporting on
factors is probably very large prospective infectious complications have not spe-
quality control studies including key risk cifically addressed the role of specific risk
factor parameters in the reporting [26]. factors. For this reason, we advocate that
contamination classes should be assessed
according to the basic surgical principles
4. DISCUSSION and criteria, especially when new proce-
dures or approaches are being introduced.
The present review shows the relative Frequently, what was expected to be a
lack of systematic knowledge regarding clean or a clean-contaminated operation
679
has to be upgraded during the procedure categorization of patients undergoing

due to intraoperative findings or infec- urological surgery. However, as all new
tious foci. score systems, it has to be tested in large
We know of a few key risk factors such scale through quality registries. It is the
as the presence of bacteriuria, with or ambition of the ESIU to develop the well
without an attachment to an indwelling established Global Prevalence Study on
catheter, kidney stones, a history of former Infections in Urology [16] into an impor-
genitourinary infection. However, the tant instrument in this direction.
knowledge of the underlying mechanism, The mechanism of infectious complica-
the exact source of the germs, the relative tions, molecular basis and bacterial viru-
role of the host, the parasite and the envi- lence are areas for further research. There
ronment are still poorly understood. is also a need to develop better diagnostic
A key question is whether the patient tools to detect “hidden” infections.
harbours a virulent pathogen that is
not detected by standard pre-operative
means, as for instance in stone surgery 6. CONCLUSIONS
[24] and prostate biopsy. There is a lack
of tools to identify “hidden” infections. A It is essential to carefully asses a patient
urine culture is important if showing bac- before undergoing urological surgery to
terial growth, but in a substantial number reduce postoperative morbidity and mor-
of cases it would turn out negative, even tality. A stepwise assessment ladder is
in the presence of bacterial growth in proposed including a risk factor analy-
some location of the urinary tract. Thus, sis. We know of a few general key risk
new methods have to be developed. factors such as high age, nutritional and
In the abscence of large databases on immunological deficiencies, high body
infective complications after urological pro- mass index and prolonged preoperative
cedures, we are confined to assume criteria hospital stay. It can be stated that the
and categorise procedures on a reasonable presence of bacteriuria, with or without
ground in order to asses the patient’s risk an attachment to an indwelling catheter,
for complications and to give recommenda- kidney stones, a history of former uro-
tions on antimicrobial prophylaxis. genital infection are specific risk factors.
However, there is a lack of evidence for a
large number of factors that eventually
5. FURTHER RESEARCH have to be assessed. For this, large cohort
studies and quality registries includ-
Registration of infectious complications ing infectious complication controls have
and relating them to risk factors would to be set up. We suggest a new frame of
eventually improve our knowledge on how categorization of urological patients to
to minimize postoperative complications undergo surgery into the classical surgi-
in general and infectious complications cal field contamination classes.
in particular. This can preferably be done
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|12.5|
Antibiotic prophylaxis in urological
surgery, a European viewpoint
Magnus Grabe
Associate Professor, Department of Urology, Skåne University Hospital, University of Lund, S-20502 Malmö, Sweden
Tel 0046-40-33.37.55/4, Fax 0046-40-33.70.49, magnus.grabe@skane.se
ABSTRACT SUMMARY OF RECOMMENDATIONS
Surgical site infections (SSI) including The reader will find a paradox in the level
urinary tract infections (UTI) cause a of evidence and the policy recommended.
significant morbidity in urological sur- The reasons are therefore explained for
gery. Antibiotic prophylaxis is one of sev- each procedure in its respective section.
eral factors impacting on infection rates.
Antibiotic prophylaxis is relevant only for
clean and clean-contaminated operations 1. INTRODUCTION
and in the absence of bacterial growth in
the urine. Strict classification is lacking, The use of antibiotics in urologic sur-
but a proposal is presented in the previ- gery has been controversial for decades
ous section. Only TURP and transrectal [1–2]. Over the same period of time, sur-
core prostate biopsy are well documented. gical procedures and interventions have
The present review confirms that there is evolved remarkably from high-invasive
a lack of hard data, insufficient consist- open to low-invasive surgery due to a fas-
ency in classification and definitions, and cinating improvement of technologies and
that new well-powered RCT and large instruments. Also, medical treatment has
multicentre quality cohort studies includ- replaced surgery in a substantial number
ing risk factor analysis are necessary to of situations and in this way modified the
improve recommendations for antibiotic profile of patients undergoing surgery.
prophylaxis in urologic surgery. The basic principle of antibiotic proph-
Key words: Surgical site infection, ylaxis is to protect the patient undergoing
wound infection, urinary tract infection, surgery against undesirable infectious
antibiotic prophylaxis complications by lowering the bacterial
Antibiotic prophylaxis in urological surgery, a European viewpoint | 12.5 |
Table 1 Summary of recommendation for antibiotic prophylaxis (ABP) per type of procedure.
Type of procedure Level of recommendation Remarks
Diagnostic procedures
Cystoscopy No systematic ABP (GoR A) Low frequency of infections

Contradictory findings
Urodynamic study No systematic ABP (GoR A) Low frequency of infections

Core prostate biopsy To all patients (GoR A) Single dose to all low risk patients (GoR A)
Prolonged in high risk patients (GoR C)
URS diagnostic No systematic ABP (GoR C) No available studies
Therapeutic procedures
TURB As for cystoscopy in standard small No concern of tumour burden in studies

TURB (GoR C)
Consider in large tumours (GoR C)
TURP All patients (GoR A) Well documented
Show-wave lithotripsy (ESWL) No systematic ABP (GoR A) Low frequency of infections

Ureteroscopic stone To all patients (GoR B) Simple mid and distal stones
management
Complex, proximal stones as for PCNL
Percutaneous stone To all patients (GoR B) Single dose to simple stones (GoR C)
management
Consider prolongation in complex stones
(GoR C)
Open/Lap nephrectomy No systematic ABP (GoR C) Catheter related BU/UTI
Open/lap nephroureterectomy To all patients (GoR C) No available studies

Defined as clean-contaminated – single dose
PUJ repair To all patients (GoR C) Defined as clean-contaminated – single dose
Open/lap bladder resection, To all patients (GoR C) Defined as clean-contaminated – single dose
ureteral repair
Open/lap prostatectomy To all patients (GoR B) Defined as clean-contaminated – single dose
Cystectomy with urine To all patients (GoR B) Defined as clean-contaminated – single dose
deviation
Prolongation of ABP on individual basis
Surgery for hydrocele and No systematic ABP (GoR B) Review studies contradictory
spermatocoele
Prosthetic procedures To all patients (GoR B) Regimen not defined
burden. Antibiotic prophylaxis is appli- of detectable bacterial growth in urine

cable for clean and clean-contaminated (<104 cfu/ml). In clean operations, the
operations. For the urinary tract, anti- urinary tract is not opened. In clean-
biotic prophylaxis implies the absence contaminated operations, the urinary
687
tract is opened and, in case of urinary the topic. Of the remaining 95 reports,
diversion, the intestinal tract, implying a majority was related to transurethral
an increased bacterial burden. In the case resection of the prostate (TURP). As this
of bacterial growth and surgery associated procedure has been reviewed by other
with opening of the bowel with spillage – authors by means of systematic review
contaminated operations – an individual [5] and covered more recently by two
treatment strategy is prescribed [3]. meta-analyses [6–7], the outcome was
Two types of infections dominate uro- built on these works. Also urodynamic
logic surgery: 1) urinary tract infection studies were critically reviewed [8] and
(UTI), a space or organ infection, associ- the conclusions reported. For all other
ated with both endoscopic, endoluminal procedures, the articles were system-
interventions and open or laparoscopic atically reviewed and the conclusions
surgery, mostly coinciding with catheter compared to those drawn by one other
and stent placement or undetected har- recent systematic review by a group
boured bacterial load and 2) wound infec- from the Netherlands [9] and the conclu-
tion after open and laparoscopic surgery. sions presented by a working group in
Furthermore, a third form of infection is the USA [10].The quality of the studies
observed in terms of infection of the male were found to vary largely, essentially in
genital system (prostatitis, epididymitis terms of design, description of randomi-
and orchitis). A fourth form of infection, sation, sample size, level of dropout,
blood stream born sepsis, resulting from power, and strength of the conclusion.
urologic instrumentation, is feared by The procedures were divided between
patients and urologists, and is far from diagnostic procedures (cystoscopy, uro-
negligible accounting for 12% of health- dynamic studies and transrectal core
care associated infections (HAI) in uro- biopsy of the prostate) and therapeutic
logic wards [4]. endoscopic procedures (transurethral
resection of bladder tumours and of
the prostate, endourological interven-
2. AIM tions including shock wave lithotripsy),
open and laparoscopic interventions
The present report focuses on the most (nephrectomy, pelvic junction surgery,
frequent diagnostic and therapeutic uro- total prostatectomy, cystectomy with uri-
logic interventions (Table 1) and results nary diversion) and elective surgery for
from a systematic review. It is out of benign scrotal surgery.
range to be comprehensive and cover all As far as possible, the expected natu-
specific or special procedures as several of ral history of infectious rates is presented
these have never been studied. Also pae- followed by the results of randomised
diatric urologic surgery is not covered. placebo/no antibiotic controlled studies
(RCT). Thereafter, RCTs of different anti-
biotic regimens are presented to detect
3. METHODS the most rational one (shortest, low cost
and effective course) when applicable.
A systematic search was performed in The studies were rated according
Medline, Cochrane Library and EMBASE to the level of evidence (LoE) and the
and using the keywords antibiotic proph- grade of recommendation (GoR) using
ylaxis, prophylaxis, antibiotics, urologi- ICUD standards (for details see Preface)
cal surgery, urogenital surgery and the [11–12]. The LoE and GoR are given at
procedures one by one. Approximately the end of each surgical procedure and
200 abstracts were identified of which the recommendation reported to the sum-
over 100 were not directly related to mary table.
688
4. RESULTS PER TYPE OF PROCEDURE analysis of 995 patients including eight

RCT, bacteriuria (>105 cfu/ml) was
4.1 Cystoscopy reduced by 40% by antibiotic prophylaxis
[8]. The authors concluded that it was
The natural history of the events fol-
necessary to treat 13 individuals in order
lowing cystoscopy is important. In one
to avoid one episode of bacteriuria. In one
study from 1990, Clarks and Higgs [13]
other study combining cystoscopy and
showed the appearance of bacteriuria
urodynamic study in women, there was
three days after instrumentation in
found to be no difference between one day
12/161 (7.5%). In two recent studies, a
of antibiotic prophylaxis and no antibiot-
spontaneous acquired bacteriuria was
ics [24]. In one Swedish study of 123 con-
observed in 2.7% and 4.5% [14–15]. The
secutive men undergoing a flow-pressure
fate of this bacterial contamination is
investigation, 4.1% acquired bacteriuria
not known and the spontaneous cure is
and 2.5% fever [25]. The overall inter-
probably high. In a large British study
pretation is, as for cystoscopy, that the
with flexible cystoscopy [16], a single
frequency of infectious events is low, that
dose of trimethoprim or ciprofloxacin
the outcome and role of bacteriuria after
reduced by more than half, 2% and
urodynamic investigation is unknown
3.2% respectively, the post-cystoscopy
and that there is a lack of support in the
frequency of bacteriuria as compared
literature for the systematic use of anti-
to placebo (6.8%). These results were in
biotic prophylaxis in patients without
accordance with an older study observ-
risk factors. For investigations of patients
ing a significant reduction of post-cys-
with other underlying urological diseases
toscopy bacteriuria and clinical UTI
such as neurological bladder dysfunction,
[17]. Other studies were contradictory
refer to the chapter on “UTI in patients
in their results, some advocating antibi-
with underlying urological diseases” (LoE
otic prophylaxis [18–19], others finding
1a, GoR A).
it no use [20–23]. The overall conclu-
sions are that the frequency of bacteriu-
ria is low and that of clinical infections 4.3 Transrectal core prostate biopsy
even lower, and that the frequencies There are only very few studies on the
of these events are, globally, margin- natural history of infectious complica-
ally reduced by antibiotic prophylaxis. tions after transrectal prostate biopsy. In
Thus, the recommendation of giving a few cohort series, infectious complica-
systematically antibiotic prophylaxis to tions such as febrile UTI, acute prostati-
all patients undergoing cystoscopy can- tis and sepsis are reported in frequencies
not be advocated in view of the lack of between 2.9–10% [26–28]. In RCT, fre-
knowledge of the risk associated with quencies of 5–26% bacteriuria and up to
the bacterial contamination and its 10% febrile UTI are given in the control
fate, the low frequency of clinical infec- groups [29–31]. In older studies, fre-
tion, the recommendation and praxis quencies up to 48% have been reported
in most European countries, the enor- [32–33]. There is a consistent significant
mous amount of such instrumentation reduction of the frequencies of both bac-
and overtreatment, and the subsequent teriuria and febrile urogenital infections
amount of antibiotics that would be by antibiotic prophylaxis, below 5% in
used (LoE 1b-2b, GoR A). low risk patients [29–34]. Recent stud-
ies have shown that one day [35–36]
4.2 Urodynamic studies and even one single dose [31, 37–38] is
Most studies are carried out on women appropriate to keep the infectious rate
investigated for incontinence. In a meta- at 1% or below, including less than 0.5%
689
of sepsis. These low frequencies are con- 4.5 Transurethral resection of the
firmed by a few consecutive cohort series prostate (TURP)
with antibiotic prophylaxis [39–40]. The TURP is the most well studied of all uro-
antibiotic dose can be given in direct logical studies. More than 50 studies have
conjunction with instrumentation and been conducted, some of them of medium to
there is now evidence for giving the high quality. Postoperative bacteriuria has
medication one to two hours before the been reported in up to 70% of the patients.
procedure [37]. Fluoroquinolones achieve In a systematic review of subsequent stud-
the highest concentrations in the pros- ies from the 1980s, it was shown that anti-
tate [41] and are best documented for biotic prophylaxis reduced the frequency
prophylaxis. However, new studies have of bacteriuria in men with pre-operative
to be done to avoid the overuse of fluo- sterile urine from an average of 34% to
roquinolones wherever possible due to 10% [5]. In recent years, two high quality
the worldwide development of resistant meta-analysis have been done including
strains in both community and hospital 32 and 28 participant controlled studies,
settings. It is unknown how long proph- (respectively [6–7]). The conclusions are
ylaxis should be given to risk patients similar: a short course of antimicrobial
(risk factors are presented in the preced- agents reduces the risk of bacteriuria from
ing chapter). It is also unknown whether an average of 26% to 9%. Berry and Barrat
spontaneous acquired bacteriuria after also analysed the impact on sepsis: the
core prostate biopsy can spontaneously impact was even more important, reduc-
cure (LoE 1b; GoR A). ing the risk from 4.4% to less than 1%.
Both reviews show that a prolonged course
4.4 Transurethral resection of (< 72 hours) is more effective than a single
bladder tumour (TURB) dose, but less effective than one week [6].
Although TURB is one of the most fre- Any antibiotic except nitrofurantoin would
quent urological procedures, there are do. In a recent high quality multicentre
no base-line data. Only three older, study conducted in Germany, Wagenlehner
rather weak, small size studies cover- [44] confirmed these results, although the
ing antibiotic prophylaxis were dis- difference was less marked. Interestingly,
closed [18, 42–43]. The data from the they also showed that the total amount of
studies do not give any evidence in antibiotics used in the study was lower in
favour of antibiotic prophylaxis in the antibiotic prophylaxis group, confirm-
TURB. However, the studies focus only ing data from one older similar analysis
on smaller tumours or fulguration, an [45]. This observation is interesting in the
intervention very similar to standard argument for antibiotic prophylaxis, as
cystoscopy, and do not mirror the large nowadays there is a high level of concern
spectrum of resection of bladder cancer about the total amount of antibiotics used
from the single minor non-muscle inva- in the community. Long operation time,
sive bladder tumours (Ta, G1–2) to large postoperative disconnection of drainage
muscle-invasive ≥ T2, G3), sometimes system and longer catheterisation period
necrotic, tumours that are part of daily were associated with increased frequency
practice. Future studies covering all of bacteriuria despite antibiotic prophy-
TURB procedures and breaking them laxis [46] (LoE 1a. GoR A).
down according to the intervention’s Consequently, there is a scientifi-
level of severity and difficulty, duration cally high level of evidence for the use of
and other risk factors has to be under- short regimens of antibiotic prophylaxis
taken (LoE 2b, GoR C). in TURP to reduce the postoperative
690
frequencies of both bacteriuria and, espe- bacteriuria but not of symptomatic UTI.
cially, severe febrile infections and sep- One study comparing ESWL and URS
sis. The conclusions are not applicable to for mid and distal ureteral stones dem-
other prostate interventions such as ade- onstrated a higher frequency of complica-
noma enucleation, micro-wave thermo- tions including infectious complications
therapy or laser ablation, as there are no in the URS treated group as compared
quality RCT studies on the matters. to the ESWL group [58]. The studies do
not differentiate the degree of invasive-
4.6 Extracorporeal shock-wave ness in terms of stone burden and locali-
lithotripsy (ESWL) sation (impacted proximal stone versus
A remarkably poor number of studies small mid and lower stones), surgical dif-
have been conducted for such an enor- ficulty and complexity of the treatment,
mous worldwide procedure. In a few duration of operation, experience of the
follow-up studies, the frequency of post- surgeon; a weakness, as it is known that
ESWL bacteriuria has been shown to be the risk of infectious complications varies
≤ 5% in patients without known risk fac- [59]. In conclusion, there is only a weak
tors [47–49]. In only one [50] of five ran- level of evidence for antibiotic prophy-
domised placebo/non antibiotic controlled laxis in URS, although it is probably of
studies was a significant reduction dem- value, especially in complex stone situa-
onstrated [50–54]. In most studies, the tions (Diagnostic: LoE 2b, GoR C. Stone
sample size or the frequencies of infec- management: LoE 2b, GoR B).
tions were low and no clear-cut conclu-
sions could be drawn. In a systematic 4.8 Percutaneous stone extraction
review and meta-analysis Pearle ana- (PCNL)
lysed eight prospective controlled studies Bacteriuria is reported in up to 35% and
[55]. The frequencies of bacteriuria and/ febrile UTI in around 10% of patients
or symptomatic UTI were reported to be receiving no antibiotics [60–61]. Only one
0–28 % in the non-antibiotic control group controlled study comparing antibiotic
and 0–7% in the intervention group. They prophylaxis with no antibiotics was identi-
estimated the risk of acquiring a UTI to fied [56] and one comparing two different
be 5.7% and 2.1%, respectively. antibiotic regimens [62]. As for compli-
The overall conclusion is that in cated URS, the danger of PCNL in terms
patients with sterile urine, uncompli- of severe, febrile UTI and sepsis has been
cated kidney or ureteral stones and no underlined [59, 63]. Antibiotic prophy-
known risk factors, the risk of post-ESWL laxis appears to reduce the frequencies of
bacteriuria/UTI is low, that the reduction infectious complications and there seems
by antibiotic prophylaxis is marginal and to be no difference between antibiotics.
that, subsequently, there is no evidence As mid-stream urine culture is not a good
for antibiotic prophylaxis in this category predictor for the endogenous presence
of low risk patients, which represents the of pathogens [63], the urologist faces an
majority of patients undergoing ESWL incertitude as to the real risk of infectious
(LoE 1a-2b, GoR A). complications. Moreover, following the
remarkable improvement of equipment,
4.7 Ureteroscopy (URS)
older studies are not necessarily repre-
No studies on ureteroscopy as a diagnos- sentative of the present profile of renal
tic tool were found. Two studies concerned stone management. Consequently, as for
with stone management were identi- URS, there is a substantial lack of data on
fied [56–57]. Both show a reduction of the use of antibiotics in PCNL and only a
691
very limited evidence for antibiotic proph- a risk factor for SSI, antibiotic prophy-
ylaxis. Nonetheless, the infectious rates laxis had no impact in low risk patients
being high and the potential complications whereas it reduced the frequency in
severe, there are reasons to believe that patients with at least one risk factor [67].
antibiotic prophylaxis is of value. Large Scrotal surgery for elective benign con-
multicentre controlled studies focusing on ditions, mainly hydrocele and sperma-
antibiotic regimens and risk factor analy- tocele, is a reasonably clean procedure. No
sis are required (LoE 2b; GoR B). RCT was identified. In a few recent stud-
ies [68–69], including a Medline search
4.9 Open and laparoscopic review, infectious complications were
urologic surgery reported in up to 9%. In most reports, no
antibiotic prophylaxis had been used. A
An extensive search on open and laparo- lower frequency of infections (3.6%) was
scopic surgery, nephrectomy, nephron observed in patients receiving antibiotic
sparing surgery, pelvic junction recon- prophylaxis [70]. Multicentre RCT have
struction bladder resection, cystectomy, yet to be undertaken to confirm this find-
total/radical prostatectomy and scrotal ing (LoE 3, GoR C).
surgery has revealed the lack of RCT
and the weaknesses of available data
[9–10]. Expected data have to be extrap- 4.9.2 Clean-contaminated operations
olated from bottom-line data on type Nephroureterectomy, kidney resection
of surgery [3] and from colorectal and and pelvic junction surgery have, to the
abdominal gynaecologic surgery. There best of our knowledge, never been studied
are indications that infectious complica- in RCT. The searches have revealed no
tions are fewer after laparoscopic and RCT on antibiotic prophylaxis versus pla-
robotic surgery in abdominal surgery cebo/no antibiotic in total prostatectomy.
[64]. The issue has however not been Thus, there is a lack of baseline data on
studied in RCT as far as urologic surgery the infectious profile of this nowadays so
is concerned. A few examples of common frequent operation. There are a few ret-
surgery by type of intervention follow. rospective and prospective cohort studies
looking at SSI and catheter associated
4.9.1 Clean operations bacteriuria following different antibiotic
Trans-abdominal open or laparoscopic regimens. The conclusion of this series
nephrectomy is classed as a clean opera- of publications is that the frequency of
tion. Only one RCT was identified [65]. wound infections is low and that a single
Infectious complications in terms of oral antibiotic dose is sufficient [70–73].
wound infection were 20.4% when no The importance of the post-operative
antibiotics were given versus 0% for catheter associated bacteriuria, observed
patients receiving one single preopera- in the majority of the patients at catheter
tive dose. The results indicate a marked removal, is unknown as is whether it has
impact of antibiotic prophylaxis but no to be treated or not (LoE 3, GoR B).
other study confirms the data. In one There are no RCT on antibiotic proph-
report on SSI in which antibiotic prophy- ylaxis in urologic surgery including urine
laxis was not in the protocol, Montgomery deviation and the use of bowel. Post-
reports wound infections in 6.8% (range operative wound infection is reported in
5.0–7.9%) in clean and clean contami- up to one third of cases, usually 10–15%,
nated hand assisted kidney surgery, with even when using antibiotic prophy-
no difference whether the urinary tract laxis [74–76]. Also UTI, pyelonephritis
was opened or not [66]. In one study of and sepsis are added to the burden of
clean surgery in patients with or without infections.
692
4.9.3 Penile prosthesis after a defined intervention and therefore

Implantation of penile prosthetic devices have also been used to some extent.
is a special case. Infection of the pros- It is remarkable that there are so few
thetic device remains the most trouble- studies on very frequent interventions
some complication. Infection may lead such as transurethral resection of blad-
to more surgery, loss of penile tissue and der tumours and endoscopic stone man-
even the inability to replace penile pros- agement including ESWL. It is thus not
thesis. Antibiotic prophylaxis in addition astonishing that Bootsma et al stated
to standard sterility and good surgical that “except for TURP and prostate
technique reduces the risk of infection biopsy, there is a lack of well performed
[77–78]. studies investigating the need for anti-
biotic prophylaxis in urologic interven-
tions” [9]. On the other hand, urologists
5. DISCUSSION need a working hypothesis for antibiotic
prophylaxis.
The present review requires a certain One approach is to stick to the clas-
number of remarks on the validity and sification of surgical interventions in
relevance of the references revealed by an clean, clean-contaminated and contami-
in-depth search of the literature. Firstly, nated classes and follow the experience of
the remarkable technical development other surgical practices such as general,
and medical achievements in urology orthopaedic and gynaecologic surgery.
during the past 25–30 years means that Theoretically, there should be no need
older studies from the 1970s and 1980s for antibiotic prophylaxis in clean opera-
have partly lost their relevance. Secondly, tions, while a single dose should be advo-
the quality of older studies in the present cated for clean-contaminated procedures.
view of good clinical practice is usually In case of contaminated procedures (i.e.
poor in terms of sample size, consistency urine deviation with bowel, presence of
in definitions, statistical estimates and asymptomatic bacteriuria in urine), the
power. Thirdly, risk factors for infectious antibiotic regiment’s start and length is
complications are rarely debated and, less obvious and documentation is insuffi-
as shown in the preceding section about cient. In standard colorectal surgery, usu-
preparation of the patient for surgery, our ally a single dose or very short regiment
knowledge of the relative importance of is advocated. Bacteriuria is a known risk
individual risk factors and their cumula- factor and, in conjunction with urological
tive impact is limited. Fourthly, numerous procedures should therefore, reasonably,
reports have given results on a mixture of be treated. Thus, individual adjustment
procedures and the breakdown has shown has to be suggested depending on patient
so low a sample size per procedure that it susceptibility, bacterial load and the
is difficult to draw a conclusion. Fifthly, development of the procedure in terms
the lack of consistency in definitions of of spillage and duration. However this
infectious complications, especially UTI, approach is not totally satisfactory; it is
the level of bacterial growth and the rela- only indicative and usually no strong rec-
tion between clinical symptoms and bac- ommendations can be given in guidelines,
terial growth weakens the possibility of such as those of the European Association
comparison. Clear definitions are often of Urology, except in a few situations [79].
lacking. The results are therefore more Therefore, there is an inevitable discre-
indicative, than proof. Against this back- pancy between the level of evidence and
ground, large cohort studies and histori- the grade of recommendation in Table 1.
cal controls gain indicative importance by The role of antibiotics is to reduce the
giving a “natural history” of the events bacterial burden, not necessarily to cover
693
all potential strains. Also, antibiotics for 1999. Hospital Infection Control Practices
prophylaxis should ideally be limited to a Advisory Committee. Infect Control Hosp
few and usually different from those used Epidemiol, 1999. 20(4): 250–78; quiz
for therapeutics to avoid an overload of 279–80.
drug doses and local environmental pres- 4. Bjerklund Johansen TE, Cek M, Naber K,
sure. Recommendations should be set in Stratchounski L, Svendsen MV, and
Tenke P, Prevalence of hospital-acquired
cooperation with specialists in infectious
urinary tract infections in urology depart-
diseases and hospital environmental ments. Eur Urol, 2007. 51(4): 1100–11;
hygiene. discussion 1112.
5. Grabe M, Antimicrobial agents in
transurethral prostatic resection. J Urol,
6. FURTHER RESEARCH 1987. 138(2): 245–52.
6. Berry A and Barratt A, Prophylactic anti-
This review underlines the absolute need biotic use in transurethral prostatic resec-
for serious, well-conducted studies and tion: a meta-analysis. J Urol, 2002. 167
large, multicentre quality registries per (2 Pt 1): 571–7.
type of procedure including breakdowns 7. Qiang W, Jianchen W, MacDonald R,
in the level of severity of surgery and the Monga M, and Wilt TJ, Antibiotic prophy-
reporting of potential risk factors. laxis for transurethral prostatic resection
in men with preoperative urine contain-
ing less than 100,000 bacteria per ml: a
7. CONCLUSIONS systematic review. J Urol, 2005. 173(4):
1175–81.
An extensive search of the literature and 8. Latthe PM, Foon R, and Toozs-Hobson P,
Prophylactic antibiotics in urodynamics:
systemic reviews has revealed a lack of
a systematic review of effectiveness and
well-built data for antibiotic prophylaxis
safety. Neurourol Urodyn, 2008. 27(3):
in urological surgery. Strong recommen- 167–73.
dations can only be given for transrectal 9. Bootsma AM, Laguna Pes MP, Geerlings
core biopsy of the prostate and transure- SE, and Goossens A, Antibiotic prophy-
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has markedly changed over the decades review. Eur Urol, 2008. 54(6): 1270–86.
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in quality, it is mandatory to initiate new RR, Hollenbeck BK, Pearle MS, and
large industry-independent, prospective, Schaeffer AJ, Best practice policy state-
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Services, Public Health Service,. 1992,
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698
|12.6|
Antibiotic prophylaxis in
urological surgery: a USA
viewpoint of best practice
Anthony J. Schaeffer, J. Stuart Wolf Jr, Carol J. Bennett, Roger R. Dmochowski,
Brent K. Hollenbeck, Margaret S. Pearle
Corresponding author: Anthony J. Schaeffer, MD, Professor of Urology, Chairman, Department of Urology, Feinberg
School of Medicine, Northwestern University, 303 E. Chicago Ave., Tarry Bldg. 16-703, Chicago, Illinois 60611-3008
Tel 001 (312) 908-8145, Fax 001 (312) 908-7275, ajschaeffer@northwestern.edu
Because SSIs and UTIs cause major post- The recommendations given later in the
operative morbidity, antimicrobial proph- text are themselves a summary of the
ylaxis should be employed in conjunction recommendations reported in the origi-
with other techniques to reduce postoper- nal article (1). Therefore, the reader is
ative infections. The decision to use anti- directed to the main text “Best Practice
microbial prophylaxis in surgery and the Policy Statement on Urologic Surgery
selection of the agent and dosing can be Antimicrobial Prophylaxis”.
based in part by the guidelines suggested
herein. However, it is up to the individ-
ual care giver to make decisions requir- 1. INTRODUCTION
ing prophylaxis in individual patients
because of the wide variation in patients This chapter is abstracted from the “Best
and environmental circumstances in the Practice Policy Statement on Urologic
perioperative setting. Surgery Antimicrobial Prophylaxis” which
was chaired by J. Stuart Wolf, Jr. Other Association (AUA) Practice Guidelines
members of the Best Practice Policy Committee and Board of Directors for
panel included Carol J. Bennett, Roger R. approval. Funding of the panel was pro-
Dmochowski, Brent K. Hollenbeck, vided by the AUA. The members received
Margaret S. Pearle and Anthony J. no compensation for their work and each
Schaeffer [1]. This panel was convened panel member provided a conflict of inter-
because surgical site infections and post- est disclosure to the AUA.
operative urinary tract infections are
common problems affecting patients’
safety, cost of hospitalization, and 3. RESULTS OF REVIEW AND BEST
readmission rates [2–4]. In addition, the PRACTICE, THE U.S.A VIEWPOINT
panel was convened because of the wide
variation in periprocedural antimicro- 3.1 Principles of surgical
bial prophylaxis, procedure utilization, antimicrobial prophylaxis
timing of antimicrobials and duration of Five principles were delineated:
prophylaxis [5]. Portions of this text were
taken directly from the “Best Practice 1. Antimicrobial prophylaxis is only
Policy Statement on Urologic Surgery one of many factors associated with
Antimicrobial Prophylaxis” by Wolf et al., the reduction in surgical site infec-
originally appearing in The Journal of tions (SSI). Surgical antimicrobial
Urology [1]. These sections, denoted with prophylaxis is defined as the peripro-
a *, are referenced accordingly and repre- cedural systemic administration of
sent best practice policy. an antimicrobial agent in order to
reduce the risk of post-procedural
local and systemic infections. Other
2. METHODS commonly employed techniques
include bowel preparation, preopera-
Because initial assessment of the litera- tive hair removal, antiseptic bathing,
ture revealed there was insufficient infor- hand washing, double gloving, and
mation available to draw up a guidelines sterile preparation of the operative
statement for antimicrobial prophylaxis field. These practices have varying
during urologic surgery based solely on degrees of scientific support in the
literature meta-analysis, the panel was surgical literature. For example, the
charged with developing a Best Practice value of mechanical bowel prepara-
Policy Statement using published data tion and removal of hair in prepara-
and expert opinions, but without employ- tion for surgery have recently been
ing formal meta-analysis of the literature. called into question. Surgical hand
The panel formulated recommendations scrubbing or hand rubbing appeared
based on a review of all material revealed to have similar benefits in reducing
in a Medline search and the panel mem- SSIs [8]. Many substances are effec-
bers’ expert opinions. The studies were tive for sterile preparation of the
rated according to the level of evidence operative site such as the formula-
(LoE) and the grade of recommendation of povidone-iodine and alcohol
tion (GoR) using ICUD standards (for which delivers effective antimicrobial
details see Preface) [6–7]. The document activity with only a 30-second appli-
was submitted for peer review and com- cation [9].
ments from all 20 responding physicians 2. The potential benefit of surgical anti-
and researchers were considered in mak- microbial prophylaxis is determined
ing revisions. The final document was by three factors: A) patient-related
submitted to the American Urological factors, i.e. the ability of the host to
700
Antibiotic prophylaxis in urological surgery | 12.6 |
respond to bacterial invasion; B) pro- benefit of prophylaxis is directly

cedural factors, i.e. likelihood of bac- related to the severity of the patient’s
terial invasion at the operative site; underlying condition. For exam-
and C) the potential morbidity of the ple, a minor infection of the bladder
infection. Patient-related factors affect can cause severe complications in a
the host response and are listed in patient who is severely debilitated.
Table 1 [10]. (N.B. For more detailed 3. Surgical antimicrobial prophylaxis
discussion see also section 11.4. of this should be utilized only when the
chapter.) potential benefit exceeds the risks and
The likelihood of bacterial invasion anticipated costs. Though it is evident
is affected by the amount of bacteria that prevention of SSIs by appropriate
at the site of the surgical procedure antimicrobial prophylaxis will reduce
as classified in Table 2 [11]. (See also length of stay and hospital costs, inap-
section 11.4, Table 4 in this chapter.) propriate antimicrobial prophylaxis
Note that all procedures entering the will increase costs without benefit and
urinary tract are considered “clean- can lead to other complications such
contaminated”. Lastly, the potential as allergic reactions and development
of resistant bacteria. Hence, guide-
lines should stipulate the indication,
timing, duration and selection of anti-
Table 1 Patient-related factors affecting host response to
surgical infections.*† microbial therapies that are critical
for achieving optimal results.
Advanced age
4. The antimicrobial agent used for
Anatomic anomalies of the urinary tract prophylaxis should be effective against
Poor nutritional status the putative disease-relevant bacterial
Smoking flora at the operative site. Cost, ease
Chronic corticosteroid use
of administration and safety are also
important considerations. In order for
Immunodeficiency
effective antimicrobial prophylaxis,
Externalized catheters the appropriate agent must be present
Colonized endogenous/exogenous material in the serum and tissue levels at the
Distant coexistent infection surgical site in advance of the opera-
Prolonged hospitalization
tive procedure. Ideal agents will have
long enough half-lives to be present
*Modified from reference 8.
for the entire procedure. If necessary,
†
Reprinted from The Journal of Urology, 179, Wolf JS, Bennett CJ,
Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, Best re-dosing for long procedures may
Practice Policy Statement on Urologic Surgery Antimicrobial be necessary. A variety of classes of
Prophylaxis, 1379–1390, ©2008, with permission from Elsevier.
agents including some beta lactams
Table 2 Surgical wound classification.*†
*modified from reference [11].

†
Reprinted from The Journal of Urology, 179, Wolf JS, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ, Best Practice Policy
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier.
701
and fluoroquinolones have been effec- be resistant to the prophylactic agent.

tive, but it is important to realize that Therefore, in most patients with indwell-
changing resistance patterns will have ing catheters, antimicrobial prophylaxis
dramatic impact on antimicrobial should not extend beyond 24 hours.
prophylaxis efficacy.
5. The surgical antimicrobial prophylaxis
3.2 Recommended antimicrobial
should precede the procedure and
prophylaxis for urologic
extend throughout the period in which
procedures*
bacterial invasion is facilitated and/
or is likely to establish an infection. The Panels’ recommendations are pro-
Infusion of the first dose should begin vided in Tables 3 and 4 [12] of this
within 60 minutes of the surgical pro- section, and levels of evidence with jus-
cedure (with the exception of 120 min- tifications are provided in the text below.
utes for intravenous fluoroquinolones Recommended Antimicrobial Prophylaxis
and vancomycin) [1]. The dose should for Urologic Procedures, Table 3a, lists
be adjusted to the patient’s body weight those procedures for which antimicrobial
or body mass index. Additional doses prophylaxis is recommended, as well as
are required intraoperatively if the pro- the agent(s) of choice, alternative agents,
cedure extends beyond two half-lives and duration of therapy. Important con-
of the initial dose [2]. In most cases, siderations are the limitation of prophy-
antimicrobial prophylaxis should be laxis to patients with risk factors in
a single dose or at least discontinued some cases and the recommendation that
within 24 hours of the end of the proce- prophylaxis should not exceed 24 hours.
dure. Exceptions to these guidelines in In cases where an external urinary cath-
which a longer duration of antimicrobi- eter is present prior to or is placed at the
als are considered include placement of time of the procedure, additional anti-
a prosthetic material, the presence of microbial treatment (≤24 hours) is rec-
an existing infection, and the manipu- ommended in patients with risk factors.
lation of an indwelling tube. Alternatively, a full course of culture-
directed antimicrobial can be admin-
There is little guidance in the duration istered for documented bacteriuria, or
of antimicrobial prophylaxis after pros- treatment can be omitted if the urine
thesis, such as a penile implant, but data culture shows no growth. Antimicrobials
from joint replacement literature indicate and Dosages, Table 3b, lists the recom-
that prophylaxis should be discontinued mended doses and dosing intervals for
within 24 hours of the procedure [2]. If the agents listed in Table 3a. For some
an existing infection is present, a thera- procedures, dosing may need to be more
peutic dose of antimicrobials should be frequent than the intervals listed in
administered prior to the procedure. If Table 3b. Table 4 provides recommenda-
emergency procedures prevent steriliza- tions for Antimicrobial Prophylaxis for
tion of the surgical site prior to operation, Patients with Orthopedic Considerations
it would be reasonable to use therapeu- [12]. In all cases, the absence of an
tic rather than prophylactic dosing for agent in the Tables does not preclude its
a period extending beyond the routine appropriate use, depending on specific
24 hours after the procedure. The use of situations – including medication intoler-
antimicrobials in patients with indwell- ance, agent compatibility, prior infection
ing catheters does temporarily prevent history of the patient and community
bacterial growth, but inevitably bac- resistance patterns. The Panel’s recom-
teriuria develops and the bacteria will mendations are generally similar, but
702
Table 3a Recommended antimicrobial prophylaxis for urologic procedures.†
†
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier [1].
differ in varying specific situations, to 4. BEST PRACTICE

guidelines from other groups and recog-
nized references [1, 13–18]. 4.1 Removal of external urinary
catheter (prophylaxis indicated
3.3 Prevention of infectious if risk factors)
endocarditis
The Panel concluded that the benefit of
It is important to note that the American antimicrobial prophylaxis at removal of an
Heart Association (AHA) no longer rec- external urinary catheter most likely is lim-
ommends antimicrobials in association ited to patients with risk factors (Table 1).
with genital urinary procedures solely to Alternatively, a full course of culture-
prevent infectious endocarditis [19]. directed antimicrobial therapy can be
703
Table 3b Antimicrobial agents and doses for periprocedure use.†
†
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier [1].
Table 4 Antimicrobial prophylaxis for patients with orthopedic conditions.*†
*Modified from reference [12].

†
Statement on Urologic Surgery Antimicrobial Prophylaxis, 1379–1390, ©2008, with permission from Elsevier.
704
administered for documented bacteriuria, 0.7%). Clinical efficacy was proven for a
or treatment can be omitted if the urine number of antimicrobial classes, includ-
culture shows no growth (LoE 1b, 3, 4). ing fluoroquinolones, cephalosporins,
aminoglycosides, and trimethoprim-sul-
famethoxazole. A subsequent meta-analy-
4.2 Cystography, urodynamic study, sis using updated methodology came to the
or simple cystourethroscopy same conclusion [27]. Similar results have
(prophylaxis indicated if risk been shown with prophylaxis in patients
factors) undergoing transurethral resection of
Antimicrobial prophylaxis is probably not bladder tumor [28]. Although RCTs have
necessary if the urine culture shows no not been performed for other cystoscopic
growth. However, culture documentation procedures involving transurethral manip-
is often lacking and a negative urinalysis, ulation, the Panel felt that data regarding
although reassuring, does not eliminate transurethral resection of the prostate and
the possibility of post-procedure urinary bladder tumor can be reasonably extrapo-
tract infection (UTI). A decision-analysis lated to other cystoscopic procedures with
model based upon estimates from the manipulation including bladder biopsy,
literature and consensus suggested that urethral catheterization, laser prostatec-
prophylactic antimicrobials after urody- tomy, etc (LoE 1a, 1b, 4).
namic studies are beneficial once the rate
of UTI without antimicrobials exceeds 4.4 Prostate brachytherapy or
10% [20]. In addition, a randomized con- cryotherapy
trolled trial (RCT) involving a single oral
There are no RCTs regarding the use of
dose of ciprofloxacin versus placebo in
antimicrobial prophylaxis for these proce-
patients who had negative urine cultures
dures. However, the destructive nature of
before urodynamic studies found that
the treatments, coupled with entry near
post-procedure UTIs decreased signifi-
a clean-contaminated space, makes the
cantly, from 14% to 1%, with prophylaxis
use of antimicrobial prophylaxis by many
[21]. However, other RCTs demonstrated
practitioners a reasonable consideration.
no reduction by prophylaxis of infection
rates associated with urodynamic study
4.5 Transrectal prostate biopsy
[22–23] as well as cystography [24] or
cystourethroscopy [25] (LoE 1b, 3, 4). A number of large RCTs have concluded
that a single dose of an antimicrobial,
4.3 Cystourethroscopy with such as a fluoroquinolone, is as effective
manipulation (prophylaxis as 3-day therapy in reducing the incidence
indicated in all patients) of all types of complications, specifically
UTI. However, recent development of anti-
The most convincing evidence support-
microbial resistance has led to significant
ing the use of antimicrobial prophylaxis
infectious sequelae in patients taking a
for this category of procedures is in asso-
fluoroquinolone and antimicrobial prophy-
ciation with transurethral resection of the
laxis; therefore, the urologic community
prostate. Berry and Barratt [26] performed
needs to be vigilant for post-infectious com-
a meta-analysis of 32 RCTs comprising
plications after transrectal prostate biopsy.
4,260 patients, and confirmed that anti-
microbial prophylaxis prior to transure-
4.6 Shock-wave lithotripsy*
thral resection of the prostate significantly
reduced the incidence of both bacteriuria A meta-analysis of eight RCTs assessing
(26% to 9.1%) and clinical sepsis (4.4% to the efficacy of antimicrobial prophylaxis
705
for shock-wave lithotripsy demonstrated 24 hours was as effective as a long course

a benefit of therapy in significantly in preventing post-operative infections [34].
reducing the incidence of postopera-
tive bacteriuria from a median of 5.7% 4.10 Open or laparoscopic surgery
to 2.1%, even with preoperative urine without entering the urinary
showing no growth. Subgroup analysis tract
to assess the effectiveness of a particular
In a prospective but non-randomized com-
regimen could not be performed due to
parison of hand-assisted laparoscopic
the wide variability in practice patterns
nephrectomies with and without antimi-
[1, 29].
crobial prophylaxis (cephalosporin), wound
infections occurred significantly more
4.7 Percutaneous renal surgery
often in patients without prophylaxis (13%
There are no RCTs that confirm the need versus 5.4%) [35]. However, meta-analysis
for antimicrobial prophylaxis for percu- evaluating antimicrobial prophylaxis for
taneous renal surgery. However, non- non-urologic “clean” abdominal surgery
controlled studies suggest efficacy of provided mixed support for antimicrobial
antimicrobial prophylaxis [30–31]. prophylaxis in this setting [36–39].
Single dose prophylaxis appears to be
as effective as multiple doses. 4.11 Open or laparoscopic surgery
involving entry into urinary
4.8 Ureteroscopy* tract
In a RCT involving 113 patients undergo- Limited data suggest that antimicrobial
ing ureteroscopy for stone removal rand- prophylaxis would reduce significantly
omized to a single oral dose of levofloxacin the rate of febrile urinary tract infection.
versus no antimicrobials, the treatment Regarding duration of prophylaxis, one
arm had a significantly lower incidence RCT confirmed that one day of intrave-
of postoperative bacteriuria (13% versus nous cephalosporin was equivalent to
2%) [32]. Another author suggests that four days of the same agent after radical
the expected rate of bacteriuria after ure- prostatectomy [40].
teroscopy without prophylaxis might be
in excess of 30%, with an expected rate
of febrile urinary tract infection of 4% to 4.12 Open or laparoscopic surgery
25% [1, 16]. involving intestine†
Although RCTs involving urologic sur-
4.9 Vaginal surgery gery involving bowel (primarily urinary
diversion, with or without cystectomy)
Randomized controlled trials involving have not been reported, meta-analyses
antimicrobial prophylaxis for vaginal of percutaneous endoscopic gastrostomy
urologic surgery have not been reported, [41], appendectomy [42], and colorectal
but considerable evidence exists regard- surgery [43] confirm benefit to antimicro-
ing vaginal hysterectomy, which can be bial prophylaxis in the setting of surgery
considered similar to vaginal urologic involving intestinal components [1].
surgery in terms of infection risk† [1].
But considerable evidence exists regard-
4.13 Open or laparoscopic
ing vaginal hysterectomy wherein stud-
surgery involving implanted
ies demonstrated dramatic decrease in
prosthesis*
the incidence of pelvic infections when
antimicrobial prophylaxis was used [33]. The implantation of foreign material
A course of antimicrobials less than raises the specter of disastrous infectious
706
complications. Although there are no 7. Abrams P, Khoury S, and Grant A,

RCTs regarding antimicrobial prophy- Evidence--based medicine overview of the
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Y, von Theobald P, Bensadoun H, Bouvet
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A, Lemarchand F, and Le Coutour X,
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Hand-rubbing with an aqueous alcoholic
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709
Chapter |13|
Epididymitis, orchitis,
prostatitis (male adnexitis)
Chair: Wolfgang Weidner
CHAPTER OUTLINE
13.2 Acute bacterial prostatitis 714
13.3 Treatment of chronic bacterial prostatitis 728
13.4 Epididymitis and orchitis 744
13.5 Chronic urogenital infections: alterations of
sperm quality and potential impact on male fertility 752
|13.1|
Introduction
Wolfgang Weidner
Corresponding Author: Wolfgang Weidner, MD, PhD, Professor of Urology and Head of Department of Urology, Pediatric
Urology and Andrology, Justus Liebig-University Giessen, Rudolf-Buchheim-Strasse 7, D-35392 Giessen, Germany
Tel. +49-641-99 44 501, Fax +49-641-99 44 509, Email: Wolfgang.Weidner@chiru.med.uni-giessen.de
Urogenital infections and inflammations Prostatic abscess always has to be ruled

are common. Prevalence rates up to 15% out. The news for everybody is that ele-
have been reported among men with andro- vated serum PSA levels may be used as
logical problems [1]. In a urological setting, simple tools for the diagnosis and therapy
UTIs and urogenital infections account for control. Furthermore, it is very important
8–10% of all inpatients. Unfortunately, the that long-term outcomes do not seem to be
majority of investigations focus on “male clear, despite effective antibiotic therapy:
accessory gland infection/inflammation”, a persistent bouts of symptoms and even
suggestion by the WHO not differentiating development of chronic bacterial prostati-
between prostatitis, epididymitis, orchitis, tis may result from the entity. Concerning
and inflammatory alterations of the ure- chronic bacterial prostatitis, we have to
thral compartment [2]. This may be due accept that at least 8–10% of all men with
to the focus of many experts on the inter- symptomatic “prostatitis/pelvic pain” have
action with male infertility not related to a bacterial infection of the prostate. These
a specific location, but also due to rather patients have to meet the criteria of the
unspecific criteria to establish the diag- two- or four-glass test. The regulations
nosis, the common inability to dissociate for therapy are well defined. Nevertheless
affected compartments and last, but not for common E. coli infections the bacterial
least, the occurrence of non-infectious, but cure rate is only up to 60–80% – meaning
inflammatory alterations. no symptomatic relief or disappearance
In 2010, clear definitions of the above of inflammatory signs in prostatic secre-
mentioned diseases were published [2–6]. tions in a concordant way. This is an
Acute bacterial prostatitis, although rep- aspect which needs to be addressed dur-
resenting only a very small number of ing proper counselling of these men.
patients in daily work, is well defined in Finally, epididymitis, orchitis and the
origin, diagnostic schedule and therapy. interaction with male infertility have to
be addressed. Whereas the etiology and 3. Schaeffer AJ, Anderson RU, Krieger JN,
therapy of acute epididymitis and orchi- Lobel B, Naber K, Nakagawa M, Nickel
tis seem to be clear, the pathogenesis of JC, Nyberg L, and Weidner W, The assess-
chronic epididymitis and orchitis remains ment and management of male pelvic
pain syndrome including prostatitis, in
debatable until today. Recent experimental
Male Lower Urinary Tract Dysfunction.
data provide evidence that the hallmark
Evaluation and Management. 6th
of chronic inflammatory reactions in the International Consultation in Prostate
human testis after ascending hematogenic Cancer and Prostate Diseases, McConnel
infection is a disturbance of the local J, Abrams P, Denis L, Khoury S, and
immunoregulation: infiltrating inflamma- Roehrborn C, Editors. 2006, Health
tory cells obviously overcome the immu- Publications: Paris. p. 343–385.
nosuppressive influence in the testis [7]. 4. Schneede P, Tenke P, and Hofstetter AG,
These new aspects have to be proven in the Sexually transmitted diseases (STDs) – a
future in all our patients who become sub- synoptic overview for urologists. Eur Urol,
fertile in the follow-up of these diseases. 2003. 44(1): 1–7.
5. Horner PJ, European guideline for the
management of epididymo-orchitis and
REFERENCES syndromic management of acute scro-
tal swelling. Int J STD AIDS, 2001. 12
1. Dohle GR, Colpi GM, Hargreave TB, Suppl 3: 88–93.
Papp GK, Jungwirth A, and Weidner W, 6. Workowski KA and Berman SM, Sexually
EAU guidelines on male infertility. Eur transmitted diseases treatment guide-
Urol, 2005. 48(5): 703–11. lines, 2006. MMWR Recomm Rep, 2006.
2. Weidner W, Wagenlehner FM, Marconi M, 55(RR-11): 1–94.
Pilatz A, Pantke KH, and Diemer T, Acute 7. Bhushan S, Schuppe HC, Fijak M,
bacterial prostatitis and chronic prostati- and Meinhardt A, Testicular infection:
tis/chronic pelvic pain syndrome: andro- microorganisms, clinical implications
logical implications. Andrologia, 2008. and host-pathogen interaction. J Reprod
40(2): 105–12. Immunol, 2009. 83(1–2): 164–7.
713
|13.2|
Acute bacterial prostatitis

U-Syn Ha, Yong-Hyun Cho
Department of Urology, Catholic University of Korea, Medical College, Seoul, South Korea
Corresponding author: Yong-Hyun Cho, Department of Urology, Catholic University of Korea, Medical College, Seoul,
South Korea
Tel: 82-2-3779-1024, FAX: 82-2-761-1626, cyh0831@catholic.ac.kr
ABSTRACT management of ABP includes rapid initi-

ation of broad-spectrum parenteral anti-
Bacterial prostatitis represents a small biotics and symptomatic support.
portion of the prostatitis spectrum, Key words: prostatitis; acute bacterial
and acute bacterial prostatitis (ABP) is prostatitis; infection; inflammation
uncommon. But ABP is a urologic emer-
gency. Even if there is a wide consensus
for the diagnosis and treatment of ABP,
many physicians need detailed guide-
For evaluation, the following should
lines with clear evidence. We suggest the
be considered:
diagnosis and treatment criteria of ABP
with extensive review of the current lit- 1. Patients with acute bacterial prosta-
eratures. The initial diagnosis of ABP is titis present with typical signs and
based on signs and symptoms like fever symptoms of an acute urinary tract
or voiding problem. Patients with symp- infection including irritative and/or
toms should undergo urine analysis and obstructive voiding complaints, and
culture of the urine. An imaging study of have additional symptoms of systemic
the prostate including transrectal ultra- infections like malaise, nausea, vomit-
sound (TRUS) is suggested to exclude ing, chills and fever, and sometimes
prostatic abscess (LoE 4). Elevated lev- present with signs of symptoms of uro-
els of prostate-specific antigen (PSA) are sepsis. They also complain of perineal
helpful to distinguish ABP from other and suprapubic pain due to a painful
febrile UTI. The predominant causa- swollen prostate and may have associ-
tive organisms are Gram-negative bacte- ated pain or discomfort of the external
ria, mainly Escherichia coli. Appropriate genitalia (GoR B).
Acute bacterial prostatitis | 13.2 |
2. Digito-rectal examination reveals a 11. There is a significantly higher rate

hot, boggy, and exquisitely tender of mixed infection in prostatitis from
prostate gland (GoR B). prior manipulation as compared with
3. Prostatic massage for the expres- spontaneous acute prostatitis (GoR B).
sion of prostatic fluid is not indicated
and perhaps even harmful because Treatment
it could precipitate bacteremia or
12. Rapid initiation of broad-spectrum
sepsis (GoR B).
parenteral antibiotics and sympto-
4. A midstream urine specimen is suffi- matic support are mandatory for the
cient and will show prominent leuko- patients with acute bacterial prosta-
cyturia and bacteriuria with typical titis (GoR B).
uropathogens (GoR B).
13. Supportive measures include i.v.
Functional findings hydration and catheter drainage if
the patient cannot void (GoR B).
5. The sonographic determination
14. Insertion of a suprapubic cystotomy
of residual volume is an impor-
tube is the optimal therapy for relief
tant diagnostic procedure, because
from urinary obstruction (GoR B).
infravesical obstruction may play an
important pathogenic role in acute 15. In-and-out catheterization to relieve
bacterial prostatitis (GoR B). the initial obstruction or short-term
(<12 hours) indwelling catheteriza-
Imaging studies tion with a small-caliber Foley cath-
eter is appropriate (GoR B).
6. Transrectal ultrasound (TRUS) does
not need to be performed on every 16. The selection and course of antibi-
patient with suspected acute bacte- otics should be adjusted according
rial prostatitis (GoR B), but can aid to the pathogens isolated and the
in the diagnosis or exclusion of a pro- results of bacterial susceptibility
static abscess (GoR B). testing (GoR B).
7. Computer tomography (CT) and mag-
Prostatic abscess
netic resonance imaging (MRI) offer
no advantage over TRUS, unless the 17. Suspicion of a developing abscess
abscess has penetrated the confines is raised if there is no response to
of the prostate gland or there are fur- appropriate antibiotic therapy, and
ther abscess foci suspected (GoR B). can be confirmed by TRUS (GoR B).
Serum prostate-specific antigen (PSA) 18. If prostatic abscess is discovered,
initiation of broad-spectrum antibiot-
8. PSA is moderately to markedly ics and prompt surgical drainage is
elevated in a patient with acute bac- crucial (GoR B).
terial prostatitis, but is not a diag-
nostic requirement (GoR C).
9. In patients with elevated PSA serial 1. INTRODUCTION
measurement is recommended as a
useful tool for follow-up (GoR B). Acute bacterial prostatitis constitutes
Microbiology a urologic emergency. It is uncommon
and usually occurs in concert with a
10. Escherichia coli is the most common UTI but can have a dramatic presenta-
pathogen encountered in acute pros- tion. Usually, many clinicians diagnose
tatitis (GoR B). and treat the acute bacterial prostatitis
715
Chapter | 13 | Epididymitis, orchitis, prostatitis
empirically. A correct diagnosis has thera- The prostatitis syndrome is a common

peutic implications since acute prostatitis healthcare issue affecting 10–14% of men
may require a longer course of treatment of all ages and ethnicities. Acute bacte-
than other forms of urinary tract infec- rial prostatitis is associated with severe,
tion and because the choice of antibiotic mainly Gram-negative infection [4]. In
to complete treatment after fever sub- the 1999, NIH consensus statement on
sides should be based on its ability to prostatitis, prostatitis and prostatitis-like
penetrate into prostatic tissue. Thus, it is symptoms were classified into four broad
of great necessity to define detailed and categories [5]. Type I prostatitis refers to
consensual diagnosis and treatment cri- acute bacterial prostatitis.
teria for acute bacterial prostatitis. Acute bacterial prostatitis is the rarest
category among the NIH classification.
It is diagnosed in less than 0.02% of all
2. METHODS patients seen for prostatitis [6]. However,
the potential morbidity and mortality of
We surveyed the extensive literature acute prostatitis constitutes a true uro-
regarding acute bacterial prostatitis logic emergency [7]. It is characterized by
available in Medline via Pubmed and also an acute onset of pain combined with irri-
considered other relevant publications tative and obstructive voiding symptoms
up to October 2008. We used terms pros- in a patient with manifestations of a sys-
tatitis, bacterial prostatitis, acute bacte- temic febrile illness. The hospital admis-
rial prostatitis, combined with the terms: sion rate for acute bacterial prostatitis in
diagnosis, evaluation, management or the USA in 1994 was 12.7 in 100,000 as
treatment, for the search strategy. For the the first, second or third principal diagno-
purpose of this review a total of 74 pos- sis for hospital admission [8] (LoE 4).
sibly eligible publications were included
into the analysis, which were screened
by title and abstracts. The limitations for 4. EVALUATION OF ACUTE BACTERIAL
this literature search were English lan- PROSTATITIS
guage (two eligible publications were not
fully reviewed because just only abstracts The diagnosis of acute bacterial prostati-
were written in English). The studies tis does not generally present much dif-
were rated according to the level of evi- ficulty for the urologist [9] (LoE 4) and
dence (LoE) and the grade of recommen- it is usually based on typical signs and
dation (GoR) using ICUD standards (for symptoms [10]. Patients with symptoms
details see Preface) [1–2]. of acute bacterial prostatitis have to
undergo urine analysis and culture of the
urine. An initial imaging of the prostate
3. DISEASE OVERVIEW is suggested to exclude prostatic abscess
[11] (LoE 4).
Acute bacterial prostatitis represents an
acute infection of the prostate gland. It is
4.1 Symptoms and signs
a male urinary tract infection (UTI) that
has some features in common with lower There are no common key symptoms
UTI in females, including the etiologi- of acute bacterial prostatitis. The NIH
cal organisms involved and some of their revised classification of prostatitis deals
urovirulence factors. The host response, more with pathophysiology and labora-
however, is very different from simple tory diagnosis and describes the clinical
cystitis and the treatment course is more features of acute bacterial prostatitis only
complicated [3]. briefly as “signs of acute UTI” [5] (LoE 4).
716
Irritative and/or obstructive voiding com- massage is not recommended during the
plaints including dysuria, urinary fre- early phase of acute bacterial prostatitis
quency and urgency are typical [5] (LoE (see above) [16]. Moreover, expressed pro-
4). Obstructive voiding complaints includ- static secretion (EPS) or voided bladder
ing hesitancy, poor interrupted stream, 3 urine (VB3) are not necessary because
and even acute urinary retention are com- the diagnosis can be made from sympto-
mon. The patients complain of perineal matic presentation and midstream urine
and suprapubic pain and may have asso- culture [7] (LoE 4, GoR C).
ciated pain or discomfort of the external
genitalia. The patients have a swollen 4.3 Functional findings
prostate which is extremely painful when
The sonographic determination of resid-
investigated. Patients with acute bacterial
ual volume is an essential diagnostic pro-
prostatitis are often acutely ill and dis-
cedure, because infravesical obstruction
tressed. Symptoms of systemic infection
may play an important pathogenic role in
like malaise, nausea, vomiting, chills and
acute bacterial prostatitis [3, 17] (LoE 3).
fever may vary. These patients may even
And the difference in voiding problems
be systemically toxic, i.e. flushed, febrile,
may reflect age differences and the pros-
tachycardic, tachypnoic, hypotensive, and
tate volume. In addition, the frequency
present even with all signs and symptoms
of voiding problems, particularly urinary
of an urosepsis [5–6, 12–14] (LoE 4).
retention, was remarkably higher in the
Digito-rectal examination reveals a
group that underwent prior manipulation
hot, boggy, exquisitely tender and tense
[18] (LoE 3).
prostate gland. Fluctuation during pal-
Some investigators suggested that
pation is suspicious for prostatic abscess.
bladder outlet obstruction may not be
Defecation may cause pain [10]. Perineal
the main cause of acute bacterial prosta-
pain and anal sphincter spasm may com-
titis [19] (LoE 3). For this reason, more
plicate the digital rectal examination [14]
evidence is necessary to clarify the rela-
(LoE 4). Although a gentle rectal exami-
tionship between obstructive bladder dys-
nation can be performed in patients who
function and acute bacterial prostatitis.
have suspected acute bacterial prosta-
titis, prostatic massage for the expres-
sion of prostatic fluid is not indicated 4.4 Imaging studies
and perhaps even harmful because it is
painful for the patient and it could pre- No routine clinical, biological or imaging
cipitate bacteremia or sepsis [4, 13–14] test can currently provide evidence that
(LoE 4). adequately rules out prostatic involve-
ment in male UTI [20]. The French
guideline and one American guideline
4.2 Urine analysis and culture
just consider that “any UTI in male has
In patients presenting with acute bacte- the potential for a prostatic involvement”
rial prostatitis, a midstream urine speci- [21–24] (LoE 4).
men will show prominent leukocyturia There are only a few studies which
and bacteriuria [10]. Midstream urine describe ultrasonographic findings in
culture is considered the only labora- non-abscessed acute prostatitis [25–28].
tory evaluation of the lower urinary tract Recently, in a prospective study of 45
and usually shows typical uropathogens patients with a clinical diagnosis of
[11, 15] (LoE 4). acute bacterial prostatitis, transrec-
The NIH revised classification of pros- tal ultrasound (TRUS) was performed
tatitis does not include the “four-glass- upon admission as well as one month
test” for diagnosis [5], because prostatic after antibiotic therapy and the findings
717
correlated with the clinical presenta- infected tissue and whether uptake
tion of disease [24]. The authors con- responded to treatment [34]. Scintigraphs
clude that TRUS does not need to be prior to antibiotic treatment showed
performed on every patient with sus- uptake in prostates of all patients with
pected acute bacterial prostatitis (as only acute bacterial prostatitis; after treat-
47% had sonographically demonstrable ment no uptake was noted in nine out of
lesions on admission and 61% had lesions 10 patients, and one out of 10 had mark-
improved or disappeared post treatment), edly decreased uptake. In the patients
but TRUS would be indicated to exclude with UTI, if there was no involvement in
the presence of prostatic abscess (LoE the prostate, no uptake occurred in pros-
2a, GoR B). In conclusion, carefully per- tates. ILLs could be useful for detecting
formed TRUS can aid in the diagnosis acute bacterial prostatitis in the future
or exclusion of a prostatic abscess with- [11].
out increasing the risk for urosepsis [24] The latter showed the prostate is con-
(LoE 2a, GoR B). currently involved in men with febrile
Current reports indicate that the more UTI with a transient increase in prostate
cost-intensive computer tomography (CT) volume and serum PSA during the acute
and magnetic resonance imaging (MRI) stage of disease [25, 33] (LoE 3). With
offer no advantage over TRUS, unless these two concepts, the presence of an
the abscess has penetrated the confines inflammatory reaction within the pros-
of the prostate gland or there are further tate can inform us of acute prostatitis
abscess foci suspected [3, 17] (LoE 3). when the diagnosis is not clear [20].
In some papers, the investigators
stated that intraprostatic color flow
4.5 Serum prostate-specific
in patients with acute prostatitis was
antigen (PSA)
greater than in the normal prostate, or
those with chronic inflammation or carci- Although prostate-specific antigen (PSA)
noma [29] (LoE 3). According to the study, levels are not a mainstay of diagnosis,
in most of the patients, the vascularity of they are generally moderately to mark-
the prostate was increased in the acute edly elevated in the setting of acute bac-
phase of inflammation (15-spot scale). terial prostatitis [35–37] (LoE 3). The
With recovery from infection color flow role of serum PSA in the differential
in the prostate decreased to ≤ 15 spots, diagnosis and evaluation of acute bacte-
the pattern in healthy men [30] (LoE 3). rial prostatitis is not clear. But elevated
Hypoechoic areas in the peripheral zone levels of prostate-specific antigen (PSA)
of the prostate can persist for a long time have been described in 70% of men with
in patients with acute prostatitis. Color acute bacterial prostatitis [38] (LoE 3)
doppler ultrasonography of these areas as a consequence of increased vascular
can helps to differentiate them from those permeability and disrupted epithelium
with carcinoma [31]. of the gland. In a prospective study of 39
There are also two interesting imaging men with pyrexia (>38.3 °C), serum PSA
studies – one performed with prostatic levels were used to categorise patients
Indium-labeled leukocyte scintigraphy according to an initial diagnosis of acute
and one performed with a combination of bacterial prostatitis, pyelonephritis, uro-
PSA levels and TRUS-provided evidence genital infection or fever of unknown ori-
supporting a frequent involvement of the gin. All of the 20 cases with pyrexia and
prostate in male UTI [32–33] (LoE 2a). elevated PSA were diagnosed and treated
The former was carried out to deter- as acute bacterial prostatitis [35]. Game´
mine whether indium-111 (111In)-labelled et al. [39] demonstrated a decreased
leukocytes (ILLs) accumulated in the free-to-total (f/t) PSA ratio up to 30 days
718
following adequate antimicrobial therapy, to treat first for Neisseiria gonorrhea and
indicating the significance of increased Chlamydiae trachomatis in young adults
bound PSA in acute prostatitis [39] (LoE [20, 46–47].
3). The decrease of f/t PSA ratio has been
correlated to systemic inflammation as
measured by serum C reactive protein 6. TREATMENT
(CRP) levels. In a prospective study of
70 men with febrile UTI with prostatic Patients with acute bacterial prostati-
involvement as measured by tPSA, this tis are easily diagnosed and successfully
marker has been proven useful to assess treated with appropriate antibiotic ther-
prostatic infection. Effective treatment apy and possible urinary drainage, as
with antibiotics resulted in significantly long as the clinician keeps a high index of
reduced serum PSA. A decline of tPSA suspicion for prostatic abscess in patients
levels in patients after appropriate anti- who fail to respond quickly [14] (LoE 4).
microbial treatment has been suggested
to indicate a healing process [25] (LoE
6.1 Use of antibiotics
3). So the authors recommend PSA as a
concise, accurate, rapid and cost-effective Appropriate management of acute bacte-
tool for identifying acute bacterial prosta- rial prostatitis includes rapid initiation
titis and for follow-up [11] (GoR B). of broad-spectrum parenteral antibiotics
and symptomatic support [31]. Treatment
of acute bacterial prostatitis is well
5. AETIOLOGY standardised. Current guidelines for the
treatment of acute bacterial prostatitis
Acute bacterial prostatitis is the result of have only been worked out by the EAU
severe infection of mainly Gram-negative [21] (LoE 4).
bacteria, which can be easily isolated Pharmacologic penetration of antibiot-
from the urine. Escherichia coli is the ics in the acutely inflamed prostatic tis-
most common pathogen encountered in sue is considered to be sufficient in the
acute prostatitis, accounting for 87% of case of susceptible bacteria. In severe
cases [40–43]. However, other pathogens cases, parenteral administration of high
include Pseudomonas, Proteus, Klebsiella, doses of bactericidal antibiotics, such as
Streptococcus, Enterobacter, and a broad-spectrum penicillin derivative,
Staphylococcus. Mixed flora infections a third-generation cephalosporin with
can occur in 2.5% of cases [40]. Some or without aminoglycosides, or a fluo-
investigators reported causative microor- roquinolone, is required until fever and
ganisms as below. Escherichia coli (64%), other parameters of acute infection are
Enterococcus (7%), Pseudomonas (6%) normalized. It can be performed alone
and other Gram-negative rods (12%) [42] or in combination with supportive meas-
(LoE 3). The spectrum of microbial etiolo- ures including i.v. hydration and cath-
gies reported is similar to those found in eter drainage if the patient cannot void
complicated female UTI, both in the case [18, 48] (LoE 4).
of community-acquired infections (two In less severe cases, an oral fluoroqui-
third of Enterobacteriacae sp, 5–10% of nolone for 10 days may be sufficient [3]
Enterococcus sp and P. aeruginosa) as well (LoE 4). The selection and course of anti-
as for nosocomial infections (large propor- biotics can be adjusted according to the
tion of resistant bacteria) [44–45] (LoE pathogens isolated and the results of bac-
3). The prevalence of venereal agents are terial susceptibility testing [9].
low, reported as 2%. These results do not In most cases the fever resolves in
support the recommendations suggesting 36–48 h [31, 49] (LoE 2a-4). After successful
719
initial therapy, switching to an oral regi- As in the previous report, ciprofloxacin

men such as a fluoroquinolone is appro- alone may be an inadequate choice, espe-
priate. The oral antibiotic therapy should cially in patients with prior manipula-
be continued at least for a total of two to tion of the renal tract. Considering the
four weeks [21] (LoE 4) although currently very low susceptibility to cephalosporins
there is no consensus on the optimal treat- (<60%) in pathogens other than E. coli,
ment duration. and the relative high isolation rates
The duration of therapy for acute pros- (>40%) of pathogens other than E. coli,
tatitis has not been well studied. If the cephalosporins as single therapeu-
patient is responding clinically and the tic agents may have limited use in this
pathogen is sensitive to treatment, most community. Most commonly, antibiotic
experts recommend that antibiotic therapy combination therapy for acute bacte-
be continued for three to four weeks to pre- rial prostatitis includes a cephalosporin
vent relapse, although a longer course is and an aminoglycoside. The second- and
sometimes necessary [49] (LoE 4, GoR C). third-generation cephalosporins have
A patient with acute bacterial prostatitis been prescribed relatively frequently
must be over-treated rather than under- for this purpose. Administration of an
treated [50] (LoE 4, GoR C). Kravchick et aminoglycoside must be confined to the
al. reported that three months after the group of patients without prior manipu-
end of a six-week therapy, EPS cultures lation owing to their susceptibility. In
were still positive in a third of the men. the group of patients with prior manipu-
Prolonged therapy (at least six weeks) and lation in which pathogens other than E.
subsequent follow-up with Stamey’s test coli constitute a substantial number of
at the three-monthly visits are required to isolates, a combination of a cephalosporin
prevent early recurrence [31] (GoR B). and amikacin should be recommended for
empirical therapy [18] (GoR B).
6.2 Antibiotic resistance
6.3 Relief from obstruction
In a recent guideline for antibiotic treat-
ment of acute bacterial prostatitis, the In acute bacterial prostatitis, urinary
administration of cephalosporins or a qui- obstruction is a very common symptom.
nolone alone or in combination with an Because patients can have significant
aminoglycoside has been recommended obstruction from an acutely inflamed
[21] (LoE 4). prostate, bladder scanning for postvoid
The susceptibility to ciprofloxacin of residual urine is recommended. If the
E. coli was shown to be relatively low residual urine is less than 100 mL, the
(76.2%) in some local areas [18] (LoE 3). patient should be initiated on alpha
A result as such probably reflects the blocker therapy; if the residual is large,
increase in resistant bacteria owing to consideration should be given to place-
the recent excessive use of ciprofloxacin ment of a small urethral catheter if short-
at that local area. The guidelines for the term drainage is required or a suprapubic
treatment of urinary tract infection of catheter if longer-term drainage is
the Infectious Disease Society of America required [6–7] (GoR B).
(IDSA) published in 1999 do not recom- Traditionally, it has been suggested
mend a specific antibiotic for empirical that the insertion of a suprapubic cystot-
treatment when the local level of resist- omy tube is the optimal therapy because
ance among E. coli strains exceeds 20%. an indwelling Foley catheter may further
The IDSA also emphasizes that physi- obstruct urethral ducts, resulting in the
cians should obtain information about potential to develop prostate abscesses
local resistance rates [18, 51] (GoR C). [52–54] (LoE 4). In most patients, however,
720
an in-and-out catheterization to relieve study found a bacterial persistence rate

the initial obstruction or short-term (<12 at three months of 33% [31] (LoE 2a).
hours) indwelling catheterization with a Therefore, prolonged therapy of fluoro-
small-caliber Foley catheter is appropriate quinolones for six weeks and reevaluation
[14] (GoR C). after that has been recommended [31]
(GoR B). In this manner, patients with
6.4 Additional points to be acute prostatitis tend to have persistent
considered infection. Acute prostatitis tends to per-
sist and bacterial localization cultures
Another supportive treatment options like
should be taken at subsequent follow-up
alpha blockers, antipyretics or anti-inflam-
visits for at least three months [31]. Along
matory agents may be beneficial, although
with this, PSA levels could be high even
current data are lacking.3 Stool softeners
up to three months after an acute episode
are also recommended [13] (GoR C).
[31] (GoR B).
Some investigators reported that
Morote et al. [55] showed that acute
empirical antibiotic treatments lead to
inflammation contributed to PSA
inadequate antibiotic treatment in 42% of
increases but did not influence the per-
the cases and a higher rate of bacteriolog-
centage of free PSA in patients with can-
ical failure. Moreover, the clinical failure
cer-free biopsies (LoE 3). Moreover, some
rate being much higher than the bacte-
patients with carcinoma could be missed
riological failure rate suggests that anti-
during the acute phase of inflammation.
biotic treatment frequently induces an
Therefore, PSA and TRUS monitoring are
incomplete resolution of the symptoms,
strongly recommended (GoR B).
even without any early infection relapse,
possibly because of a persistent underly-
ing urological disorder [20] (GoR B).
In the previous study of acute prosta- 8. SPECIAL CONSIDERATIONS
titis, the abnormalities requiring surgi-
cal correction were detected in 24% of the 8.1 Prostate abscess
patients after a check-up including digital Prostatic abscesses are uncommon but
rectal examination, prostatic ultrasound, potentially serious manifestations of acute
post-void residual urine measurement infection of the prostate and demand
and uroflow measurement [33] (GoR B). prompt treatment. It represents a severe
complication of acute bacterial prostatits
with an estimated incidence of 2–18% [19]
7. PROGRESS AND FOLLOW-UP (LoE 3) and a mortality rate of 3–30%.
Antibiotic treatment of acute bacterial
Although the role of serum prostate- prostatitis is simple but abscess forma-
specific antigen (PSA) in the differential tion is well described and may have dev-
diagnostic evaluation of acute bacterial astating sequelae. Its clinical diagnosis
prostatitis is not finally proven, elevated is somewhat difficult and suspicion of a
PSA is common. Effective treatment with developing abscess is raised if there is no
antibiotics results in significantly reduced response to appropriate antibiotic therapy,
serum PSA. Therefore some authors and can be confirmed by TRUS [49] (LoE 4).
recommend PSA as a concise, accurate, TRUS should not be postponed for > 48 h
rapid and cost-effective tool for identify- in patients who do not respond to appro-
ing acute bacterial prostatitis and for the priate antibiotic therapy [31] (GoR B).
follow-up [11, 15] (LoE 4). This is particularly important for the
After antibiotic treatment, the long- patients with immunocompromised dis-
term response is unclear. A prospective ease or diabetes [11, 24] (GoR C). Patients
721
who are immunocompromised, especially or resection, suprapubic adenectomy, peri-

patients who have HIV/AIDS, seem to neal incision and transrectal or transperi-
be more susceptible to the development neal prostatic puncture and drainage
of acute bacterial prostatitis and to the under sonographic guidance have been
occurrence of a potentially life-threatening applied according to location and exten-
prostatic abscess. The incidence rate rises sion of the abscess [3, 17] (GoR C & B).
to roughly 14% in those who have devel- Transperineal incision and drainage
oped AIDS [56] (LoE 3). If a prostatic [64] must be considered when the abscess
abscess is discovered, initiation of broad- has penetrated beyond the prostatic cap-
spectrum antibiotics and prompt surgical sule or penetrated through the levator ani
drainage is crucial [7, 57] (GoR C). muscle [14] (GoR C). Although transure-
thral unroofing and perineal drain-
8.1.1 Diagnostics of prostatic abscess age were once the mainstays of surgical
As previously mentioned, the most impor- drainage, transrectal ultrasound-guided
tant urological investigation to exclude aspiration of prostatic abscesses has been
the formation of prostatic abscesses increasingly used as an effective means
is transrectal ultrasound (TRUS) [15] of drainage that may avoid the potential
Although CT and MRI are effective morbidity associated with transurethral
modalities for the diagnosis of prostatic drainage [58–59] (GoR B). Some authors
abscess, TRUS has been increasingly also support urinary diversion with a
recommended due to its high sensitivity, suprapubic catheter [17, 60].
greater cost-effectiveness, and ability to In small abscesses, patients may be
provide diagnosis and directed treatment treated conservatively by the administra-
in a single procedure, with CT being used tion of antibiotic agents together with the
primarily in cases where the transrec- placement of a suprapubic catheter. The
tal ultrasound is non-diagnostic or sug- follow-up requires regular TRUS controls
gestive of more extensive involvement [3, 17] (GoR C & B).
[58–59] (LoE 3, GoR B).
8.2 Seminal vesiculitis
8.1.2 Microbiology of prostatic abscess Seminal vesiculitis can occur as a conse-
Escherichia coli and Staphylococcus spe- quence of local bacterial infection in acute
cies are the most commonly isolated and chronic bacterial prostatitis, and
pathogens in prostatic abscess, although patients can present with seminal vesicle
other pathogens, such as Mycobacterium abscesses [65–66] (LoE 4 & 3). Seminal
tuberculosis, Actinomyces, Citrobacter, vesicle abscesses, diagnosed clinically by
Bacteroides fragilis, Aeromonas aerophyla, a positive ejaculate culture and imaged
and Klebsiella pneumonia have been traditionally by seminal vesiculography
reported [17, 59–63] (LoE 3). Burkholderia [67–68] (LoE 3), but now with CT [69],
pseudomallei overwhelmingly predomi- transrectal ultrasonography [70], or MRI
nates in the Thai population [62]. [71] can be managed with antibiotic ther-
apy, transrectal aspiration, and, if neces-
8.1.3 How to treat the prostatic sary, an operation to remove the seminal
abscess vesicles [14] (LoE 4).
Recommended treatment of prostatic
8.3 Secondary to previous
abscess consists of broadspectrum anti-
manipulation
biotic coverage and, in most cases, drain-
age of the abscess. Several surgical One of the most serious complications of
procedures have been described to relieve transrectal biopsy of the prostate is the
abscess formation. Transurethral incision development of postbiopsy prostatitis
722
and septicemia. A recent report found 18–19] (GoR B). In addition, some papers
bacteremia in 44% patients undergoing suggested that patients older than 49
transrectal biopsy without preprocedural had both higher rates of clinical failure
antibiotics [72] (LoE 3). Besides, place- and higher rates of underlying urological
ment of a urethral catheter can contrib- disorders, and thus might be the target
ute to the acute prostatitis also [73]. population for prostate-centered investi-
Although these complications are rare, gations [20] (LoE 3).
the severity of symptoms often necessi- Proper antibiotic prophylaxis, generally
tates an inpatient admission for admin- with a single dose of a fluoroquinolone,
istration of broad-spectrum intravenous prevents infectious complications effec-
antibiotics [7] (GoR C). tively (bacteremia develop in only 1% to
In a retrospective study, Millán- 2%). But the timing of antibiotic prophy-
Rodríguez et al.[19] pointed out that two laxis may not be critical [72] (GoR B).
different forms of acute prostatitis should The role of prebiopsy enema is a matter
be differentiated according to their clini- of debate. Some evidences suggest that a
cal course. Patients with acute bacterial prebiopsy enema is not beneficial when
prostatitis secondary to manipulation patients are given preprocedural antibiot-
have been found older and have larger ics [73–74] (LoE 1b & 3).
prostate volume [19] (LoE 3). In another
report, the difference in voiding problems
may reflect age differences and the pros- 9. FURTHER RESEARCH
tate volume. The frequency of voiding
problems, particularly urinary retention, The diagnosis of acute bacterial pros-
was significantly higher in the group tatitis is usually based on signs and
that underwent prior manipulation. symptoms and sometimes it is not dis-
Consequently, the frequency of suprapu- tinguished from other febrile UTI ini-
bic or urethral catheterization was rela- tially. If there were some specialized
tively high [18] (LoE 3). method to diagnose ABP, many physi-
Since infection from prior manipula- cians would gain benefit from it. As
tion is iatrogenic, there is a significantly mentioned above, ILLs could be useful
higher rate of mixed infection in pros- for detecting acute bacterial prostatitis
tatitis from prior manipulation as com- in the future.
pared with spontaneous acute prostatitis, In the field of treatment, antibiotic
and a higher rate of infections by patho- resistant microorganisms are increasing
gens other than Escherichia coli., like in ratio with the lapse of time. The effort
Pseudomonas spp. Furthermore, there is to find a new range of antibiotics or the
a higher percentage of patients with fever best combination of antibiotics to sup-
or complications such as prostatic abscess press resistance should be continued. A
in case of secondary to manipulation com- system to improve penetration of drugs to
pared with spontaneous one [3, 19] (LoE prostatic tissue is as needed as ever.
4 & 3). Immunocompromised patients, espe-
Finally, acute bacterial prostatitis cially those who have HIV/AIDS, are
with prior manipulation showed distinct considered to be more susceptible to
characteristics with regard to clinical infectious disease including acute bac-
and microbiological features. As a con- terial prostatitis or prostatic abscess.
sequence, these patients may require However, the reports regarding the
modified treatment options. Local micro- incidence rate in immunocompromised
biological sensitivity patterns and the patients are quite old and not large
history of prior manipulation of the lower enough in number. More attentive
urinary tract should be regarded [3, research is requested.
723
10. CONCLUSIONS Data Tape Documentation 1994. 1996,

Hyattsville, MD: Centers for Disease
Accurate diagnosis of acute bacterial pros- Control and Prevention.
tatitis is fundamental. With symptomatic 9. Wagenlehner FM and Naber KG,
management, initial empiric broad-spec- [Therapy of prostatitis syndrome].
Urologe A, 2001. 40(1): 24–8.
trum parenteral antibiotic therapy should
10. Neal DE, Acute bacterial prostatitis, in
be considered carefully. In patients with
Textbook of prostatitis, Nickel JC, Editor.
persistent infection, an evaluation for
1999, Isis Medical Media: Oxford.
prostate abscess including an antibiotics p. 115–122.
sensitivity test is essential. Measurement 11. Weidner W and Anderson RU, Evaluation
of serum PSA is useful for differential of acute and chronic bacterial prostatitis
diagnosis and follow-up. Throughout this and diagnostic management of chronic
entire process, the evidence-based guide- prostatitis/chronic pelvic pain syndrome
lines can help many physicians to make with special reference to infection/
a decision for patients. Further research inflammation. Int J Antimicrob Agents,
on prostatitis should be carried out and 2008. 31 Suppl 1: S91–5.
the contents of this guideline need regular 12. Meares EM, Jr., Prostatitis. Med Clin
update. North Am, 1991. 75(2): 405–24.
13. Roberts RO, Lieber MM, Bostwick DG,
and Jacobsen SJ, A review of clinical
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|13.3|
Treatment of chronic bacterial

prostatitis
Florian M.E. Wagenlehner1, John N. Krieger2
1
Urologic Clinic, Justus-Liebig-University Gießen, Gießen, Germany
2
Department of Urology, University of Washington, Seattle, United States of America
Corresponding author: Florian M.E. Wagenlehner, MD, PhD, Department of Urology, Pediatric Urology and Andrology,
University of Giessen, Germany
Tel: +49-641/9944518, Fax: +49-641/9944509, Wagenlehner@aol.com
ABSTRACT of E. coli against fluoroquinolones in

many countries is of great concern in
Bacterial infection of the prostate can be that respect. In patients with pathogens
demonstrated by the Meares & Stamey resistant to fluoroquinolones, but suscep-
4-glass or the pre and post prostate tible to trimethoprim-sulfamethoxazole,
massage (PPM) 2-glass test in only about a three month course of treatment with
10% of men with symptoms of chronic trimethoprim-sulfamethoxazole can be
prostatitis/chronic pelvic pain syndrome. administered. In patients with patho-
Chronic bacterial prostatitis is mainly gens resistant to fluoroquinolones and
caused by Gram-negative uropathogens. trimethoprim-sulfamethoxazole, currently
The role of Gram-positives, such as sta- no recommendation can be given. Clinical
phylococci and enterococci, and atypicals, trials with other antibiotics are urgently
such as chlamydia, ureaplasmas, myco- needed in this patient population.
plasmas, are still debateable. For treat- Key words: Chronic bacterial prostatitis;
ment, fluoroquinolones are considered the refractory chronic bacterial prostatitis; anti-
drugs of choice because of their favoura- biotic treatment; antimicrobial resistance.
ble pharmacokinetic properties and their
antimicrobial spectrum, with the best
evidence supporting ciprofloxacin and
levofloxacin. The optimal treatment dura- SUMMARY OF RECOMMENDATIONS
tion is 28 days. Relapse and reinfection
due to antimicrobial resistant pathogens 1. The fluoroquinolone drug class is the
are major problems in chronic bacterial first choice systemic treatment for
prostatitis. The increasing resistance chronic bacterial prostatitis, with the
Treatment of chronic bacterial prostatitis | 13.3 |
best evidence supporting use of cip- originate from infection of the prostate
rofloxacin and levofloxacin (GoR A). using the Meares and Stamey four-glass
2. Other drugs with evidence of efficacy or the pre- and post-prostate massage
include: gatifloxacin (discontinued in two-glass test. These patients meet the
the US), lomefloxacin, moxifloxacin criteria for chronic bacterial prostati-
(no clinical data), prulifloxacin (not tis (NIH category II) and represent the
available in the US), and trimetho- focus of this consultation. Most cases of
prim-sulfamethoxazole (GoR B). chronic bacterial prostatitis are caused
by Gram-negative uropathogens. The
3. The optimal duration of therapy is role of Gram-positive and atypical bac-
at least 28 days, with some studies teria is still debateable. The purpose of
supporting treatment for up to eight this guideline is to evaluate the evidence
weeks (GoR B). supporting current treatment options for
4. The optimal length of clinical fol- patients with chronic bacterial prostati-
low-up is at least six months (GoR A). tis, including treatment-refractory cases.
5. The main unresolved issue is the
increasing rate of antimicrobial 1.1 Prostatitis syndromes
resistance and lack of promising oral Prostatitis syndrome is one of the most
alternatives to the fluoroquinolones. common problems encountered in uro-
In patients with pathogens resistant logic practice. Classification of the pros-
to fluoroquinolones and trimetho- tatitis syndrome is based on the clinical
prim-sulfamethoxazole, currently presentation of the patient, the presence
no recommendation can be given. or absence of white blood cells in the
Clinical trials with other antibiotics expressed prostatic secretions (EPS),
are urgently needed in this patient and the presence or absence of bacteria
population (GoR A). in the EPS [1]. Prostatitis is described as
6. In refractory chronic bacterial pros- chronic when symptoms are present for
tatitis repeated treatment or antimi- at least three months.
crobial prophylaxis is recommended
using antimicrobials to which the
pathogen is susceptible. More studies 1.2 Classification
of this important issue are however The internationally-accepted classifica-
warranted (GoR C). tion of the prostatitis syndrome follows
7. Interventions are only recommended the National Institute of Diabetes and
in patients with chronic bacterial Digestive and Kidney Diseases (NIDDK)/
prostatitis who have proven bladder National Institutes of Health (NIH) rec-
outflow obstruction (GoR C). ommendations (Table 1) [2]. There are
four categories of prostatitis.
8. There are insufficient data on alter- Acute bacterial prostatitis (NIH cat-
native and complementary medicine egory I) is defined as an acute bacterial
approaches for patients with chronic infection of the prostate, associated with
bacterial prostatitis (GoR D). severe prostatitis symptoms, signs and
symptoms of systemic infection and acute
bacterial urinary tract infection [3].
1. INTRODUCTION Chronic bacterial prostatitis (NIH
category II) is defined as a chronic (≥ 3
Approximately 10% of men with symp- months) bacterial infection of the pros-
toms of chronic prostatitis/chronic pel- tate, proven by adequate microbiologi-
vic pain syndrome have bacteriuria cal tests, with documented bacteriuria
with pathogens that can be proven to caused by the same bacterial strain. Only
729
Table 1 National Institutes of Health Prostatitis Syndrome 3. What is the desired length of
Classification [2]. follow-up?
I Acute Bacterial Prostatitis

4. What is the major outstanding issue
for treatment?
II Chronic Bacterial Prostatitis
III Chronic Prostatitis/Chronic Pelvic Pain Syndrome

2.1 Review of the literature
a) Inflammatory
We searched the major databases covering
b) Non-inflammatory
the last 10 years (e.g., Medline, Embase,
IV Asymptomatic Inflammatory Prostatitis Cochrane Library, Biosis, Science Citation
Index) using the search term bacterial
prostatitis in binary combinations with
about 10% of men with chronic prostatitis
the terms: chronic, treatment, outcome,
symptoms have chronic bacterial infec-
complications, antibiotic and antimicro-
tion of the prostate that can be demon-
bial. Similar searches were also conducted
strated by the four-glass test [4].
using the search term chronic bacte-
Other categories of prostatitis are not
rial prostatitis in binary combinations
associated with prostatic infection proven
with the terms: trimethoprim, refrac-
by standard microbiological methods in
tory, antibiotic resistance, surgery, TURP
patients with chronic symptoms, termed
and prostatectomy. To identify papers
chronic prostatitis/chronic pelvic pain syn-
not yet indexed in the major databases,
drome (NIH category III), or in patients
we reviewed the tables of contents of the
who have no symptoms but have proven
major journals of urology and other rel-
prostatic inflammation, termed asympto-
evant journals, for the last three months.
matic prostatitis (NIH category IV).
Papers published in non-reviewed sup-
plements were not included. There is
1.3 Epidemiology also a microbiological rationale support-
The incidence of bacterial prostatitis may ing restriction of the literature search to
be higher than previously reported [5]. the last 10 years, because in most areas
A recent study evaluated new physician- a minimal inhibitory concentration (MIC)
diagnosed prostatitis cases in a managed shift has taken place in the pathogens
care population over a two-year interval causing chronic bacterial prostatitis.
[6]. The incidence of acute or chronic bac- The studies were rated accord-
terial prostatitis was 1.26 cases per 1,000 ing to the level of evidence (LoE) and
men per year. the grade of recommendation (GoR)
using ICUD standards (for details see
Preface) [7–8].
2. METHODS
2.1.1 Results
We defined one major question, “What
is the optimal antimicrobial therapy for These searches identified a total of 1,656
patients with chronic bacterial prostati- articles, including 1,014 articles pub-
tis?” This question was then divided into lished from 1999–2008. Review of the
four issues: titles and abstracts of the 1,014 identi-
fied articles, identified a total of 72 arti-
1. What is the first choice antimicrobial cles that met the criteria for detailed
drug category and which drugs have analysis and rating. These 72 articles
the best evidence for clinical efficacy? were reviewed in detail for how well each
2. What is the optimal duration of study was designed and carried out using
therapy? a standard checklist adopted from the
730
CONSORT statement (available at http: 3. CLINICAL PRESENTATION AND

//www.consort-statement.org). RECOMMENDED EVALUATION OF
PATIENTS WITH CHRONIC
2.2 Rating of the literature BACTERIAL PROSTATITIS
Of the 72 articles reviewed in detail, in
Chronic bacterial prostatitis is charac-
total 57 papers met the criteria for rat-
teristically associated with recurrent uri-
ing (Table 2). According to the hierar-
nary tract infections caused by the same
chy of study types these papers included:
bacterial strain. Chronic bacterial prosta-
no systematic reviews or meta-analy-
titis represents the most frequent cause
ses, three randomized clinical trials,
of recurrent urinary tract infections in
three non-randomized cohort studies,
young and middle aged men. Chronic
two case-control studies, six case series,
bacterial prostatitis can be a devastating
27 articles incorporating expert opin-
disease, characterized by relapsing febrile
ion, two cost-effectiveness studies, and
episodes, if not treated adequately from
14 in vitro, laboratory or animal model
the beginning. Potential complications
studies (Table 2).
include: urosepsis, prostatic abscess and
acute urinary retention.
2.2.1 Results
Accurate diagnosis of chronic bacterial
Results are shown in table 2. prostatitis (NIH category II) depends on
Three Level 1 studies (LoE 1b) were quantitative segmental bacteriological
identified: three randomized clinical tri- localization cultures and EPS micros-
als [9–11]. These studies included a total copy. The classical four-glass procedure,
of 655 participants (Table 2). first described by Meares and Stamey,
The committee identified four Level remains the gold standard [67]. Nickel
2 studies (two studies with LoE 2a, two et al validated a simpler test to assess
studies with LoE 2b): two non-randomized inflammation/infection as a screening
cohort studies [12–13] and two case series test in primary care patient populations.
[14–16]. These studies included a total o The two-glass test is a reasonable alter-
359 participants (Table 2). native when EPS cannot be obtained or
The committee identified 25 level when microbiological assistance is not
three studies including: one non-ran- available, because EPS should be exam-
domized cohort study [17], two case- ined expeditously. Interpretation of local-
control studies [18–19], four case series ization test results can follow various
[20–23], 16 expert opinion reviews definitions that have been evaluated, but
[24–39] and one cost-effectiveness study the NIH definition is the most accepted.
[40]. These studies included a total of
652 participants with chronic prostatitis
3.1 Microbiology
(Table 2).
The committee identified 25 Level 4 A bacterial strain is considered a patho-
studies including: 11 articles based on gen if the colony forming unit (CFU)
expert opinion [41–51], one cost-effective- concentration in EPS or post-prostate
ness study [52], and 14 in vitro, labora- massage voided urine is at least 10 times
tory, or animal model studies [53–66]. higher than in mid-stream or first-void
These studies included no participants urine. The bacterial spectrum of chronic
with chronic bacterial prostatitis (Table bacterial prostatitis has been carefully
2). Although the Delphi process can be investigated in patients from tertiary care
used to give ‘expert opinion’ greater institutions [4, 68]. Similar to the experi-
authority, we identified no article that ence with acute prostatitis, these series
used this approach. report that facultative Gram-negative
731
Table 2 Evidence Table: Studies of Chronic Bacterial Prostatitis Treatment that Include Original Data, Systematic Reviews or Meta-analysis, Expert Opinion, or Other Data (1999–2008).
732
Lead author, Rating of
Chapter
Study Type year, reference Subjects Design Aspects Critical Findings Evidence
Systematic
| 13 |
reviews and
Meta-analyses
None
Randomized
clinical trials
Naber, 2002[9] 182 Multicenter, lomefloxacin 400 mg At 5–9 days, 4–6 weeks, 3 and 6 months after therapy 1b, Positive
once daily vs. ciprofloxacin 500 mg eradication rates were 80, 72, 74, and 63% in the lom- (non-
twice daily for 4 weeks. efloxacin group and 84, 81, 82, and 72% in the cipro- inferiority)
floxacin group.
Bundrick, 2003[10] 377 Multi-center, levofloxacin 500 mg Microbiologic eradication rates 75% for levofloxacin and 1b, Positive
once daily or ciprofloxacin 500 mg 76.8% for ciprofloxacin; 6-month relapse rates were (non-
twice daily for 28 days similar. inferiority)
Giannarini, 2007[11] 96 randomized to receive a 4-week oral 6 months after therapy, microbiological cure rate was 1b, Positive
course of either prulifloxacin 600 mg 72.73% for prulifloxacin and 71.11% for levofloxacin (non-
Epididymitis, orchitis, prostatitis
or levofloxacin 500 mg once daily. (p=0.86) inferiority)
Non-randomized
cohort studies
Naber, 2000[12] 65 Multi-center study of ciprofloxacin Eradication rates were 32/39 (82.1%) after 3 months, 26/34 2a, Positive
500 mg bd for 28 days (76. 4%) after 6 months and 13/22 (59.1%) after 9 months.
Kunishima, 2008[17] 10 Multi-center, 200 mg gatifloxacin 58.1% symptomatic response rate 4 weeks after 3, Positive
twice daily for 4–8 weeks treatment
Naber, 2008[13] 117 Multi-center open-label study of Microbiological eradication rate was 82/98 (83.7%) at 2a, Positive
levofloxacin 500 mg once daily (p.o.) 1 month and the continued eradication rate was 52/57
for 28 days. Patients were followed (91.2%) at 6 months post treatment.
for 6 months.
Case-control
studies
Nickel, 2008[19] 146 (average symptom Multi-center study comparing levo- Bacteria eradication rate was 74.0% not different from 3, Positive
duration was 8.4 weeks, floxacin or ciprofloxacin for 4 weeks men with no localization of pathogenic bacteria.
median 3.5). with 6 months of follow-up
Hu, 2002[18] 50 Amikacin 400 mg daily for 10 days “Cure rate” 33.3% for anal submucosal injection vs. 5% 3, Positive
via submucosal anal (30 cases) or for IM injection (P<0.05)
intramuscular injection (20 cases).
Case-series
Weidner, 1999[14] 40 E. coli chronic bacterial prostatitis Microbiological eradication was 92% at 3 months and 2b, Positive
treated with 4 weeks of ciprofloxacin 70–80% 12–24 months after treatment.
500 mg bid with 12–24 months
follow-up.
Nickel, 2001[23] 14 Various regimens 57% “moderate to marked improvement,” similar to 3, Positive
response in patients with category III.
Gutierrez, 2004[22] 105 Various regimens Symptoms either disappeared or diminished, irrespective 3, Positive
of whether positive cultures remained.
Guercini, 2005[21] 320 with symptoms of Antibiotic cocktails (based on cul- 68% of patients were “cured clinically.” 3, Positive
chronic prostatitis tures) with betamethasone by pros-
tate infiltration, weekly for 3 doses.
Chen, 2006[20] 7 Combination of ciprofloxacin, doxa- Bacterial eradication rate was 71% after ciprofloxacin 3, Positive
zosin, allopurinol and biofeedback treatment during a follow-up of 6 months.
perineal massage.
Magri, 2007[15–16] 137 Combination therapy with ciproflo- 64.2% microbiological response at the end of Rx. Of 49 2b, Positive
xacin, azithromycin, alfuzosin and a patients showing persistence or reinfection at the end of
S. repens extract for 6 weeks. treatment, 36 completed a second combination therapy
cycle: 27 patients (75%) showed eradication. The cumu-
lative eradication rate was 83.9%.
Expert opinion
Naber, 1999 Review of guidelines For chronic bacterial prostatitis, a category of its own is 4, Positive
proposed rather than using the general category of com-
plicated UTI.
Lipsky, 1999[45] Review Trimethoprim-sulfamethoxazole or, preferably, a 4, Positive

fluoroquinolone for 6 to 12 weeks.
Stevermer, 2000[50] Review Antibiotics are continued for at least 3 to 4 weeks, altho- 4, Positive
Treatment of chronic bacterial prostatitis
ugh some men require treatment for several months.
Shoskes, 2001[48] Review Ciprofloxacin has been shown to be effective. Newer 4, Positive
quinolones may be more effective against gram-
733
| 13.3 |
positive pathogens and anaerobes.
continued
Table 2 Evidence Table: Studies of Chronic Bacterial Prostatitis Treatment that Include Original Data, Systematic Reviews or Meta-analysis, Expert Opinion, or Other Data (1999–2008) – (Cont’d)
734
Chapter
Naber, 2001[26] Review 3, Positive
| 13 |
Iakovlev, 2002[44] Review 4, Positive
Fowler, 2002[43] Review (minimal data) Fluoroquinolone antibiotics given for 2 to 4 weeks will 4, Positive
cure about 70%.
Wagenlehner, 2003, Reviews of pharmacokinetics and Fluoroquinolones are the first choice. 3, Positive
2004, 2005, 2006, pharmacodynamics
2007[32–38]
Croom, 2003[25] Review 28 days of oral levofloxacin 500mg daily achieved similar 3, Positive
clinical and bacteriological response rates to oral ciproflo-
xacin 500mg twice daily.
Fish, 2003[42] Review Important role of levofloxacin. 4, Positive
Naber, 2003[28] Review of antimicrobial penetration Fluoroquinolone concentrations at the site of infec- 3, Positive
into prostate tissue and seminal fluid tion should be sufficient for treatment of susceptible
pathogens.
Charalabopoulos, Review of antimicrobial penetration Of agents, beta-lactam drugs penetrate poorly. Good to 3, Positive
2003[24] into prostate tissue and secretions excellent penetration into prostatic fluid and tissue has
been demonstrated with many antimicrobial agents, in-
cluding tobramycin, netilmicin, tetracyclines, macrolides,
quinolones, sulfonamides and nitrofurantoin.
Pharmacokinetic studies of antimicrobials use heterogeno-
us methodology. Antibiotic concentrations in prostatic fluid
suitable for treatment of infections are only found with flu-
oroquinolones, macrolides, lincosamides and trimethoprim.
Skerk, 2004[49] Croatian guidelines Ciprofloxacin is the drug of choice. 4, Positive
Nickel, 2005[77] Review 3, Positive
Zvara,2002[51] Review Minimally invasive therapies (intraprostatic injections) in 4, negative

the treatment of chronic prostatitis are not a standard of
care.
Liu, 2005[46] Review Recommend fluoroquinolones, especially levofloxacin 4, Positive

and gatifloxacin.
David, 2005 [41] Review Only trimethoprim and the fluoroquinolones possess 4, Positive
both the appropriate bactericidal activity and the ability
to diffuse into the prostate. Levofloxacin shows particu-
larly good penetration.
Wagenlehner, Review Follow up of at least 6 months is necessary. Most fluoro- 3, Positive

2008[29] quinolones with this indication should be sufficient for
susceptible pathogens.
Naber, 2008[27] Review The fluoroquinolones (2–4 weeks) are the first choice, in 3, Positive
particular levofloxacin is as effective as ciprofloxacin but
shows a better prostatic
penetration and is given once daily.
Cost-
effectiveness
Studies
Kurzer, 2002[40] hypothetical cohort of Model comparing 90 days of Ciprofloxacin 500 mg twice daily for 28 days appears to 3, Positive
100 men trimethoprim-sulfamethoxazole and be the most cost effective treatment.
14, 28 and 60 days of ciprofloxacin.
Sanchez-Navarro, 50 Analysis of pharmacy and chart 4, Positive

2002[52] records
In vitro, labora-
tory, or animal
model studies
Drusano, 2000[66] Population pharmacoki- Monte Carlo simulation of Mean prostate tissue/ plasma concentration ratio was 3, Positive
netic analysis of prostate Levofloxacin concentrations in 4.14. 70% of the population had a penetration ratio in
penetration by levofloxa- plasma and prostate tissue after excess of 1.0
cin 33 subjects repeated administration of 500 mg
levofloxacin orally
Wagenlehner, 2006, 12 healthy volunteers Concentrations of moxifloxacin in Moxifloxacin might be a good alternative for the prosta- 3, Positive
2008[30–31] and 39 TURP patients plasma, urine, prostatic fluid, prostatitis treatment.
te tissue.
Rippere-Lampe, Rat model Cytotoxic necrotizing factor type 1-positive uropathoge- 4, Positive
2001[60] nic E. coli caused more inflammation-mediated and hi-
Treatment of chronic bacterial prostatitis
stological damage than isogenic CNF1-negative mutants

despite similar bacterial counts.
continued
735
| 13.3 |
Table 2 Evidence Table: Studies of Chronic Bacterial Prostatitis Treatment that Include Original Data, Systematic Reviews or Meta-analysis, Expert Opinion, or Other Data (1999–2008) – (Cont’d)
736
Chapter

Velasco, 2001[63] 83 patients with FQ resi- Comparison of quinolone resistant Quinolone resistance of invasive cases was 8% versus 4, Positive
| 13 |
stant E. coli isolates E. coli isolates of invasive urinary 20% in cystitis cases. Quinolone resistant E. coli is less
tract infection and prostatitis cases likely to produce invasive disease than susceptible E. coli.
versus cystitis cases
Naber, 2001[59] 10 normal volunteers Gatifloxacin concentrations in plas- Good penetration into prostatic and seminal fluid sug- 4, Positive
ma, urine, ejaculate, prostatic and gest that gatifloxacin may be a good alternative.
seminal fluid, and sperm cells.
Giannopoulos, 50 Pefloxacin concentrations in serum Tissue levels of pefloxacin were well above MICs of 4, Positive
2001[54] and prostate tissue after 800 mg common bacteria causing bacterial prostatitis. Pefloxacin
intravenuous pefloxacin were deter- could be a satisfactory alternative for surgical prophylaxis
mined in BPH tissue using a micro- and treatment of bacterial prostatitis
biological plate assay
Scelzi, 2001[61] 12 TURP patients Lomefloxacin concentrations in Tissue/ serum ratio was > 2 in prostatic capsule and > 1.6 4, Positive
serum and prostate tissue after 400 in adenomatous tissue. Lomefloxacin could be an efficacio-
mg oral application us therapeutic option for treatment of chronic prostatitis
Horcajada, 2002[56] 23 E. coli isolates Emergence of quinolone-resistance in 11 of 23 patients, developed quinolone-resistant strains, 4, Positive
faeces of patients with prostatitis tre- during and just after therapy. 2 months after treatment, the-
ated with ciprofloxacin for 1 month. se were completely displaced by quinolone-susceptible E. coli.
Lee, 2005[58] Rat model Catechin, an extract of green tea. Combination treatment of catechin and ciprofloxacin had 4, Positive
synergistic effect.
Johnson, 2005[57] 17 E. coli prostatitis Molecular analysis Prostatitis isolates exhibited more virulence factors than 4, Positive
isolates cystitis isolates (n = 23).
Cattoir, 2006[53] 1 Quinolone resistance mechanisms in 4, Positive

an E. coli clinical isolate (Ar2).
Wang, 2006, 2008 Rat model Vancomycin and amikacin evaluated Higher antibiotic concentration in the prostate tissues 4, Positive
[64–65] than in sera.
Soto, 2007[62] 32 E. coli prostatitis Strains causing prostatitis produced biofilm in vitro more 4, Positive
isolates frequently than those causing other urinary tract infec-
tions and had a higher frequency of hemolysin
(p = 0.03 and 0.0002, respectively).
Han, 2008[55] Rat model Lycopene may have a synergistic effect with ciprofloxacin 4, Positive
in prostatitis treatment.
bacilli (especially E. coli) were responsi- In another study 19 patients with

ble for the great majority of cases. Recent chronic bacterial prostatitis were com-
reports from clinical series of patients pared to controls and patients with chronic
have reported a preponderance of Gram- pelvic pain syndrome [72]. Hot uptake was
positive cocci [10, 39]. In these latter found in 68% of chronic bacterial pros-
series, the median duration of patients’ tatitis patients and 70% of patients with
symptoms was 3.5 weeks. One recent chronic pelvic pain syndrome. Therefore,
report however describes that cultures the data suggest that imaging procedures
suggesting localization of Gram-positive are of limited or no benefit in diagnosing
bacteria are not consistent in more than chronic bacterial prostatitis or in predict-
90% of patients [69]. Nevertheless, most ing response to treatment.
reports suggest that the bacterial spec-
trum resembles that of complicated 3.2.3 National Institutes of Health
urinary tract infections, with a prepon- Chronic Prostatitis Symptom Index
derance of enterobacteria. P. aeruginosa (NIH-CPSI)
and Enterococci are found less frequently,
The NIH-CPSI provides a standardized
but are more difficult to treat.
assessment of prostatitis symptoms [73].
The NIH-CPSI was designed as a tool
3.2 Other issues related to clinical for monitoring response in clinical trials
assessment of chronic prostatitis/chronic pelvic pain
syndrome rather than as a diagnostic tool.
3.2.1 Semen culture Only limited data are available to validate
A comprehensive study of 40 men with use of this instrument in assessing the
E. coli chronic bacterial prostatitis evalu- clinical response to therapy in patients
ated the role of semen analysis and cul- with chronic bacterial prostatitis.
tures. Bacteriospermia (>103 CFU/ml)
was documented in 21 (53%) of the 40
men prior to treatment.[14]. Therefore, 4. PRINCIPLES OF THERAPY
semen culture is not sufficient to diagnose
chronic bacterial prostatitis [14]. 4.1 Antimicrobial treatment
Appropriate antimicrobial therapy rep-
3.2.2 Imaging studies and urodynamics resents the cornerstone of successful
The role of transrectal prostate ultrasound treatment for patients with bacterial pros-
and urodynamic investigations was evalu- tatitis. For effective antimicrobial therapy
ated in a prospective study of 164 men. the pathogens at the site of infection must
This study found that these investigations be exposed to a drug concentration suf-
had no role in discriminating chronic bac- ficient to inhibit bacterial growth or even
terial prostatitis from chronic prostatitis/ eradicate the pathogens from that site.
chronic pelvic pain syndrome [70]. Although it remains unproven in humans,
In one study magnetic resonance evidence suggests that bacteria in prostatic
imaging of four acute bacterial prostati- tissue may survive in a milieu protected
tis and five chronic bacterial prostatitis by biofilms [62, 74]. Although the efficacy
cases were compared to prostate cancer, of antimicrobial therapy is markedly less
benign prostatic hyperplasia and chronic against biofilm-associated bacteria, fluoro-
prostatitis/chronic pelvic pain cases [71]. quinolones and macrolides are more active
Bacterial prostatitis showed some fea- in biofilm than other antimicrobials, e.g.
tures similar to carcinoma suggesting beta-lactams or aminoglycosides [75].
that magnetic resonance imaging may A rather extensive review on pharma-
provide little diagnostic specificity. cokinetic studies of antimicrobial agents
737
and their penetration into the prostate has in the levofloxacin group and 77% in the
been performed by Charalabopoulos et al. ciprofloxacin group.The specific eradica-
[24]. If only studies with a suitable meth- tion rate of E. faecalis was 72% with levo-
odology are used, e.g. assessment of antibi- floxacin and 76% with ciprofloxacin. The
otic concentrations in prostatic fluid, than eradication rate of P. aeruginosa was not
antibiotic concentrations in prostatic fluid indicated in this study. The other recent
sufficiently high to treat chronic infections study by Naber et al. [13] was a non-
in the prostate are only found with fluoro- randomized patient cohort study inves-
quinolones, macrolides, lincosamides and tigating levofloxacin 500mg once daily,
trimethoprim. Encompassing pharmacoki- patients were not required to have docu-
netic and pharmacodynamic aspects, the mented bacteriuria with the localizing
fluoroquinolones are considered the drugs bacterial “pathogens.” The study also used
of choice for antimicrobial treatment of different classification schemes for the
chronic bacterial prostatitis. All clinical diagnosis of chronic bacterial prostatitis.
studies within the last 10 years have been The corresponding [10] total eradica-
performed with fluoroquinolones. tion rate at four weeks was 79%, and at
Because clinical experience suggests six months 92%.
that relapse and reinfection are common The specific eradication rate of E. faeca-
observed in patients with chronic bacte- lis in the comparable classification scheme
rial prostatitis, only the results of clini- to the Bundrick study [10] was 56%
cal studies with a follow-up of at least (10/18) and of P. aeruginosa 100% (3/3).
six months is recommended [76]. Overall,
it appears that 60–80% of patients with
4.2 Duration of antibiotic treatment
E. coli and other Enterobacteriaceae can
and clinical follow-up
be cured with a four-week course of fluoro-
quinolone therapy (Table 2). However, clin- We identified no clinical studies compar-
ical experience suggests that prostatitis ing different durations of antibiotic treat-
due to P. aeruginosa or enterococci seem ment. Almost all studies used a four week
to cause more failures. Therefore fluo- treatment regimen [9–13, 19]. In one
roquinolones with a broad anti-bacterial study treatment with gatifloxacin was
spectrum, like levofloxacin, gatifloxacin, four to eight weeks [17], but this was not
or moxifloxacin with improved activity a comparative study. A cost effectiveness
against Gram-positive pathogens might study comparing different antibiotics and
be a better option in case of enterococci, duration concluded that ciprofloxacin 500
although comparative RCT data suggest mg twice daily for 28 days was the most
that these agents are equivalent to results cost-effective treatment [40]. Based upon
of ciprofloxacin treatment. Levofloxacin these results in chronic bacterial prosta-
was investigated in two recent clini- titis, an oral fluoroquinolone should be
cal studies. The study by Bundrick et al. given for at least four weeks after the ini-
[10] was a randomized double-blind mul- tial diagnosis (LoE 2, GoR B).
ticenter study comparing levofloxacin Follow up in most clinical studies was
500mg once daily to ciprofloxacin 500mg at least 6 months [9–14, 19–20], which
twice daily and found levofloxacin was therefore should also be performed in
equivalent to ciprofloxacin. Microbiological clinical routine (LoE 2 GoR B).
eradication was however only followed
up to four weeks and patients were not
required to have documented bacteriuria 4.3 Procedures
with the localizing bacterial “pathogens.” One study investigated amikacin 400 mg
In this study, the microbiological eradiac- daily administered for 10 days via submu-
tion rate by patient at four weeks was 75% cosal anal or intramuscular injection [18].
738
This study reported inferior results. Non- prostatitis [16]. Of these 36 patients, 27
systemic application of antibiotics is there- (75%) were cured by a second cycle of
fore not recommended (LoE 3, GoR C). combination pharmacological therapy
No published study from the last 10 with antibacterial agents (ciprofloxacin/
years evaluated interventions in chronic azithromycin), alpha-blockers (alfu-
bacterial prostatitis. Expert opinions only zosin) and the phytotherapeutic, Serenoa
recommend interventions in patients repens. No other study evaluated patients
with chronic bacterial prostatitis who with recurrent disease. More studies of
have proven bladder outflow obstruction this important issue are therefore war-
although this has not been validated in ranted, therefore currently no recom-
studies (LoE 4, GoR C). mendation can be given for refractory
patients.
4.4 Alternative and complementary
medicine approaches 5. DISCUSSION AND CONCLUSIONS
One animal study investigated cat-
echin, a green tea extract, in combina- Antimicrobial resistance to fluoroquinolo-
tion with ciprofloxacin in the treatment nes is increasing world-wide. The impact
of chronic bacterial prostatitis (58). The of fluoroquinolone resistance on the treat-
authors reported a statistically signifi- ment of chronic bacterial prostatitis
cant decrease in bacterial growth and has not been evaluated systematically.
improvements in prostatic inflamma- However, from a pharmacological view-
tion compared with the ciprofloxacin only point, treatment failure with increasing
group [58]. Further studies are necessary pathogen MICs has been observed anec-
to validate these observations. dotally in our patients with chronic bac-
One retrospective clinical study evalu- terial prostatitis, as we have seen with
ated results of a 6-week course of com- urinary tract infections and other uro-
bination therapy with ciprofloxacin, genital infections, such as gonorrhea (for
azithromycin, alfuzosin and a Serenoa which fluoroquinolones are no longer
repens extract in patients with chronic recommended in the USA). In patients
bacterial prostatitis [15]. Microbiological with pathogens susceptible to trimetho-
eradication rates were between 75.5% and prim-sulfamethoxazole and resistant to
82.3%, and clinical success rates between fluoroquinolones, expert opinion recom-
78.8% and 85.7%, depending on the path- mends a three-month course of treatment
ogens isolated and were thus not higher with trimethoprim-sulfamethoxazole LoE
than in those studies with antibiotics 4, GoR C). In patients with pathogens
alone [10, 13]. Thus, there are insufficient resistant to fluoroquinolones and trimeth-
data on alternative and complementary oprim-sulfamethoxazole, currently no rec-
medicine approaches for patients with ommendation can be given.
chronic bacterial prostatitis (LoE 4, GoR D, Clinical trials with other antibiotics are
no recommendation possible.) therefore urgently needed in this patient
population (LoE 4, GoR A).
4.5 Refractory patients 6. FUTURE RESEARCH

There are limited data available on
treatment outcomes for patients who The microbiological success of treatment
fail initial therapy for chronic bacterial of chronic bacterial prostatitis mainly
prostatitis. One study investigated 36 depends upon the antimicrobial´s phar-
patients with relapsing chronic bacterial macological properties in the prostate
739
and the susceptibility of the pathogens. 9. Naber KG, Lomefloxacin versus cipro-
Future research should therefore espe- floxacin in the treatment of chronic bacte-
cially be directed to the activity of other rial prostatitis. Int J Antimicrob Agents,
antibiotics, not tested up to now, and 2002. 20(1): 18–27.
substances active in biofilm, to evaluate 10. Bundrick W, Heron SP, Ray P, Schiff WM,
possible synergism, in the treatment of Tennenberg AM, Wiesinger BA, Wright
PA, Wu SC, Zadeikis N, and Kahn JB,
chronic bacterial prostatitis.
Levofloxacin versus ciprofloxacin in the
treatment of chronic bacterial prostatitis:
a randomized double-blind multicenter
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743
|13.4|
Epididymitis and orchitis

Thorsten Diemer, Florian M.E. Wagenlehner, Wolfgang Weidner
Department of Urology, Pediatric Urology and Andrology, University of Giessen, Giessen, Germany
Department for Urology, Pediatric Urology and Andrology, UKGM GmbH, Campus Giessen, Justus-Liebig-University
Giessen, Germany
Corresponding author: Thorsten Diemer, MD, PhD, Department of Urology, Pediatric Urology and Andrology, University
Hospital Giessen and Marburg GmbH – Campus Giessen, Justus Liebig-University Giessen, Rudolf-Buchheim-Str. 7,
D-35392 Giessen, Germany
Tel. +49 641 99 44 505, Fax +49 641 99 44 519, Email: Thorsten.Diemer@chiru.med.uni-giessen.de
ABSTRACT Bacterial persistence after acute

epididymo-orchitis has been proposed as
Acute epididymitis/epididymo-orchitis can pathophysiological mechanism suggest-
be considered a bacterial infection due to ing an infectious etiology.
sexually transmitted bacteria, namely Isolated orchitis that does not affcet
Neisseria gonorrhoeae and Chlamydia tra- the epididymis is a rare condition usually
chomatis, or pathogens that cause urinary due to a viral infection (e.g. Mumps orchi-
tract infections (Enterobacteria). Acute tis). Severe forms that result in complete
infections require urgent therapeutical distruction of the testicular tissue occur.
intervention based on anti-microbial ther- Post-infectious infertility due to azoosper-
apy. Oral fluoroquinolones represent the mia respresents a classical cause of male
medication of the first choice, severe infec- infertility. Therapy with interferon-alpha
tions require inpatient conditions and i.v. 2b is still discussed as protective mean
application of fluoroquinolones or use of for testicular tissue and spermatogenesis.
third-generation cephalosporins, however, Key words: orchitis, epididymitis,
the choice of anti-bacterial therapy should epididymo-orchitis, testicular abszess,
be selected according to the underlying eti- acute scrotum, scrotal swelling, Mumps
ology. Supportive physical means of ther-
apy such as ice packs are recommended.
Chronic epididymitis is typified by SUMMARY OF RECOMMENDATIONS
induration, pain, and discomfort of the
epididymis, however, etiology and thera- 1. In acute epididymitis/epididymo-
peutical strategies are not evidence-based. orchitis diagnostic work-up should
Epididymitis and orchitis | 13.4 |
at least include general (testicular) 7. In epididymitis/epididymo-orchitis

examination, scrotal ultrasound, resulting from subvesical obstruction
colour duplex ultrasound and urine and urinary infection suprapubic
culture (LoE 2, GoR B). urinary diversion may be helpful in
2. Color-duplex ultrasound may be cases of urinary retention. Urinary
helpful to distinguish epididymo- diversion in general without residual
orchitis from testicular torsion. post-voiding urine is debatable
However, when in doubt, surgi- (LoE 2, GoR B).
cal scrotal exploration is strongly 8. Acute epididymitis/epididymo-
recommended (LoE 1, GoR A). orchitis can result in epididymal
3. Bacterial epididymitis/epididymo- obstruction, however obstructive
orchitis is caused by STD bacteria azoospermia after epididymitis is
or bacteria causing UTI. The choice not frequent. Surgical exploration
of medication should reflect the etio- followed by microsurgical reconstruc-
pathology in a respective patient. tion (e.g. tubulovasostomy) together
Immediate treatment should there- with sperm retrieval is recommended
fore be commenced by use of fluoro- in infertile patients (LoE 1, GoR A).
quinolones (e.g. levofloxacine) if an 9. Rare forms of epididymitis due to
UTI etiology is suspected or third causes other than conventional bacte-
generation cephalosporins (cefo- ria (STD, UTI) are difficult to diagnose.
taxime or ceftriaxone) plus doxy- Therapy is frequently based on reports
cycline, if the acute epididymitis is of case series and cannot be considered
most likely caused by gonococcal or standardized (LoE 4, GoR D).
chlamydial infection (LoE 1, GoR A). 10. Surgical intervention is recom-
4. The sexual partner(s) should be mended in cases of large abscess for-
involved in the diagnostic protocol mation and testicular necrosis due to
and treatment respectively in case perfusion damage of infectious origin
of pathogenesis due to STD-bacteria. (LoE 3, GoR C).
This might also apply in cases
where pathogens cannot be
1. INTRODUCTION
retrieved/identified in the diagnostic
work-up (LoE 2, GoR B).
Acute epididymitis is an acute painful swell-
5. Supportive therapy (anti-phlogistic ing in the scrotum that usually occurs uni-
medication, cool packs) may be help- laterally [1–2]. The testes may be involved
ful to ease symptoms. There is no in the inflammatory process in most cases
evidence that these factors have an as ‘epididymo-orchitis’. Acute epididymitis/
impact on the duration and severity epididymo-orchitis is considered a bacterial
of the disease (LoE 3, GoR C). infection that requires urgent therapeutical
6. Isolated orchitis is always suspicious to intervention [2] (Table 1).
be of viral origin, e.g. Mumps orchitis. Chronic epididymitis appers to be a
Treatment is based on symptomatic narrowly defined clinical entity typified
and anti-inflammatory treatment, by induration and/or swelling of the epidi-
diagnosis is certified by serological dymis with localized pain and discomfort.
means. Treatment of Mumps orchitis The etiology of the disease is uncertain,
mit interferon-alpha 2b can exert an however, bacterial persistence in the
protective effect on testicular tissue epididymis following acute epididymitis
and later testicular function (sperma- has been described and may occur in up
togenesis) (LoE 2, GoR B). to 15% of all epididymitis patients [3].
745
Table 1 Classification of epididymitis and orchitis.
Acute epididymitis or Granulomatous epididymitis or orchitis Viral

epididymo-orchitis (specific orchitis) orchitis
Neisseria gonorrhoeae (STD) Mycobacterium tuberculosis Mumps
Chlamydia trachomatis (STD) Treponema pallidum Enteroviruses
Escherichia coli Brucella spp. Lassa
Streptococcus pneumoniae, Enterococcus spp. Sarcoid Ebola
Klebsiella spp. Fungal Other viruses
Salmonella spp. Parasitic
Other urinary tract pathogens
Specific epididymitis/orchitis is defined 3. METHODS

as a chronic form of epididymitis caused
by specific bacteria (e.g. M. tubercu- We searched the Pubmed database for
losis, Treponema pallidum and Brucella original papers covering the last eight
spp.) and is typified by chracteristic years (English) using the search terms:
histo-pathological features (Table 1) orchitis, epididymitis, epididymo-orchitis,
[4–5]. Therapeutical approaches follow acute scrotum, scrotal pain, MAGI, ejac-
the guidelines for treatment of the under- ulate infection, and MESH terms with
lying disease. Epididymectomy under diagnosis and therapy. Furthermore,
anti-microbial therapy might be helpful all reviewed supplements (2000–2008),
to particularly ease symptoms (such as in covering the topic orchitis, epididymitis
tuberculosis) [6–7]. and urogenital infections of Andrologia,
Inflammatory processes that primarily Human Reproduction, European Urology
involve the testicular tissue such as viral and Fertility & Sterility have scanned for
orchitis usually do not involve the epidi- issues addressing epididymitis, orchitis or
dymes [8]. Viral orchitis can be isolated infectious impact on testicular function.
meaning that viral infection specifically The studies were rated according to the
locates to the testis or is observed for cer- level of evidence (LoE) and the grade of
tain viruses that primarily cause a sys- recommendation (GoR) using ICUD
temic inflammatory reaction such as in standards (for details see Preface) [9–10].
hemorrhagic fevers. For example, orchitis Published Meta-analyses have not
has been described in systemic infections been available on the topic epididymitis/
with Lassa and Ebola virus in humans. orchitis. Review articles have been cited
in the text independently from the sys-
tematic search, reviews of older date of
2. OBJECTIVES publication than year 2000 have also
been considered, and so have “classical
The objective of this paper is to identify papers”.
accepted criteria for classification, diag-
nosis, and therapy of epididymitis, epidi-
dymo-orchitis and orchitis based on the 4. EPIDEMIOLOGY
literature search. Special and rare forms
of the diseases are considered, recom- Orchitis and epididymitis are classified
mendations for diagnosis and therapy are as acute or chronic processes according
provided where available. to their cause and clinical features [2]
746
(Table 1). Chronic inflammation with more than two to three months has been
induration develops in about 15% of diagnosed in about 80% of these men [3].
patients following an episode of acute Mumps orchitis has been common
epididymitis. Viral and bacterial before widespread vaccination in child-
inflammation of the testes can lead to tes- hood. Mumps orchitis can be considered a
ticular atrophy and destruction of sper- major complication of a general infection
matogenesis, however, the natural course with Mumps, a paramyxovirus. It has
of the disease cannot be predicted from become rare in the 1990s. Due to decreas-
severity and clinical symptoms [11–12]. ing vaccination coverage in western popu-
In general, acute epididymitis/epididymo- lations, mumps notifications and orchitis
orchitis is considered as a consequence cases have been rapidly increasing within
of STD-transmitted bacteria (namely the last years. Mumps orchitis is said to
Neisseria gonorrhoeae and Chlamydia tra- occur in 20–30% of postpubertal men who
chomatis) in younger patients less than have Mumps. Typically, Mumps orchitis
35 years of age, and is considered a com- develops within athree to 10 day delay
plication of voiding disorders and UTI to primary parotitis and occurs bilater-
in patients older than 35 years [13–15]. ally in about 30% of all cases. However,
Epididymitis is particularly common Mumps orchitis can also be found in
among individuals who have high-risk patients without recent parotitis [17].
sexual behavior (frequent change of sexual Other viral infections can also cause
partners) and is one of the leading causes orchitis, particularly enteroviruses. The
of acute admission to hospitals among testes can also be involved as a continu-
military personnel. It occurs in 1–2% of ation of epididymitis, particularly when
patients who have gonococcal and chlamy- suppurative UTI pathogens are involved.
dial urethritis, with an equal risk from each Granulomatous orchitis is a rare con-
pathogen. It is usually unilateral and is due dition of uncertain etiology [18]. With
to an extension of the urethral infection via regard to chronic inflammatory condi-
the vas deferens to the epididymis (ascend- tions, a so-called ‘low-grade autoimmune
ing) [2, 16]. orchitis’ [19] has been described.
In middle-aged and older men Epididymo-orchitis can lead to abscess
(<35–40years), epididymitis is usu- formation, testicular infarction, testicu-
ally due to the same organisms as those lar atrophy, chronic epididymitis, infertil-
that cause UTI and is presumably a ity, and hypogonadism in some icidents
direct extension from the urinary tract. [4, 19]. In men who have azoospermia,
Epididymitis is more common in patients postinflammatory epididymal obstruction
with subvesical obstruction and particu- can sometimes be cured by reconstructive
larly in those who have indwelling cath- surgery [20]
eters. Bladder outlet obstruction and
LUTS of any origin and urogenital abnor-
malities are also risk factors for acute and 5. CLINICAL FEATURES AND
chronic epididymitis/epididymo-orchitis. DIAGNOSIS
Prevalence studies of chronic epidi-
dymitis do not exist, and not much is Inflammation, pain, scrotal swelling and
known about chronification of symptoms tenderness of the epididymis character-
after acute epididymitis. In a 14-day ize acute epididymitis [4]. Frequently
representative prevalence study among the tail of the epididymis is involved pre-
Canadian urologists about 1% of outpa- dominantly. In less than 10% of cases
tient visits accounted for office visits due both sides appear to be involved. The
to epididymitis. Chronic epididymitis spermatic cord is usually tender and
defined as symptoms with a duration of enlarged. The testes may be spared or
747
may be involved to produce a contiguous epididymitis, as epididymo-orchitis (see

large painful mass. Studies indicate that Table 1). Testicular swelling, frequently
the testis is involved in up to 60% of cases accompanied by fever, is typical. Antibody
based on clinical evaluation [13]. Acute and other specific serum investigations
epididymitis/epididymo-orchitis always should be carried out to identify mumps,
requires immediate evaluation by sonog- enteroviruses and other potential viral
raphy and Colour duplex scanning to dif- pathogens. In chronic infections, ejacu-
ferentiate between acute epididymitis late analysis may demonstrate structural
and acute torsion of the spermatic cord sperm defects providing reduced sperm
[21–23]. CRP determination in serum can motility and number [19]. Testicular
also be helpful to distinguish between biopsy in these cases may demonstrate
epididymitis and testicular torsion in focal inflammation, mixed atrophy and
cases of acute scrotum [24–26]. complete Sertoli-cell-only syndrome in
Testicular torsion requires urgent sur- the follow-up [17, 19].
gical intervention to prevent testicular The most frequent form of isolated orchi-
infarction and irreversible tissue necro- tis is Mumps orchitis. Mumps orchitis typ-
sis [27–28]. An inflammatory hydrocele is ically develops after Mumps parotitis with
frequently seen in the acute event but it a delay of three to 10 days in post-pubertal
does not distinguish between epididymi- men. In some incidences Mumps orchitis
tis and testicular torsion. may develop without preceeding paroti-
The microbiologic diagnosis of acute tis or with longer delay. The clinical hall-
epididymitis must be made as specifically marks are swelling of the testis (bilaterally
as possible. A urethral Gram stain, urine in about 30%), testicular pain, and fever
culture and other studies, such as ampli- while the epididymis appears clinically
fication techniques, for identification of unaffected. The clinical picture together
Neisseria gonorrhoeae and Chlamydia with evidence of IgM antibodies in serum
trachomatis should be obtained for all provide the diagnosis in clinical suspicion
patients when available [29]. Blood cul- of Mumps orchitis. Testicular atrophy due
tures are valuable if the patient is febrile to Mumps orchitis is expected two to three
or has systemic signs of toxicity. Ejaculate months after the acute event [17].
analysis according to World Health
Organization (WHO) criteria, includ-
ing leukocyte analysis, may be of value, 6. TREATMENT
however, this is usually not possible and
required in the acute and painful state In acute epididymitis (epididymo-orchitis),
of the disease. A transiently decreased antimicrobial agents should be chosen
sperm count or azoospermia is common. for initial empiric treatment based on
Infertility due to obstructive azoosper- the probability of the etiologic agent [24,
mia is a rare complication unless there is 34–36]. In sexually active men who are
bilateral involvement [30–32]. at risk of infection with C. trachomatis
Chronic epididymitis is character- or N. gonorrhoeae, a therapeutic regimen
ized by thickening and induration of the that covers both these pathogens is man-
epididymis. Especially in patients who datory [37–38]. Antibiotic resistance in N.
are infertile, ejaculate analysis concern- gonorrhoeae increased dramatically over
ing semen quality is a necessary inves- the last years. The WHO surveillance of
tigation to exclude azoospermia [19] and antibiotic resistance in Neisseria gonor-
changes of sperm maturation [33]. rhoeae in the Western Pacific Region,
Orchitis, an isolated inflammation carried out in 2005, revealed resistance
of the testis, is a rare event. Most fre- rates of penicillins and quinolones up to
quently it occurs in association with 100%, and of tetracyclines up to 80% in
748
some countries [39]. Penicillin and fluoro- administration of interferon-alpha 2b in

quinolone resistant strains have allready Mumps orchitis have provided conflict-
reached the western countries. The CDC ing results. Further studies performing
therefore adapted to this resistance trend testicular biopsies after treatment have
and now recommend ceftriaxone as the shown, that systematic treatment with
first line agent for the treatment of acute interferon-alpha 2b is not completely
epididymitis caused by N. gonorrhoeae in effective in preventing testicular atrophy
a rather low single dose of 250 mg applied after mumps orchitis [42]. Therapy with
intramuscularly [15]. Additional treatment nonsteroidal anti-inflammatory agents
of non-gonococcal agents is also recom- has also been recommended [43] as has
mended, which can be a tetracycline agent treatment with long-acting gonado-
(Doxycycline 100 mg /2x/day/10 days) [15]. trophin-releasing hormone agonists [43].
Additional therapy includes physi-
cal means such as scrotal support, up-
positioning of the testes and bed rest. 7. FURTHER RESEARCH
Abscesses may require surgical drain-
age, however, microabszesses within the One of the future scientific goals will
epididymis can resolve spontaneously. be the development of rapid diagnostic
If urinary tract pathogens are consid- tools that can easily distinguish between
ered to be the probable etiologic agent, infections due to STD-bacteria and
fluoroquinolones (ofloxacin 300 mg 2x/ enterobacteria. These tools will enable
day/10 days or levofloxacin 500 mg 1x/ physicians to specifically prescribe effec-
day/10 days) are recommended as first tive and targeted treatment with a low
line agents [15]. The rational behind this rate of treatment failures. It is likely
recommendation is represented by the that these tools will use molecular biol-
fact that ofloxacin/levofloxacin – imnstead ogy techniques (available in more sophis-
of ciprofloxacin – is considered to be effec- ticated appications and protocols) in a
tice versus urinary tract pathogens as technical application that will allow rapid
well as atypical bacteria and STD patho- diagnostic performance.
gens. Experimental [40] and clinical stud-
ies [36] suggest that the fluoro-quinolones
are very effective if the pathogens are 8. CONCLUSION
tested susceptible. However the dra-
matic increase of quinolone resistance Correct diagnostic and therapeutic man-
in uropathogens (particularly resistance agement of epididymo-orchitis is pri-
E. coli resistance versus fluorochinolones) marily directed to deliver optimum
and will cause significant clinical prob- healthcare to the patients involved.
lems in the empiric antibiotic treatment. However, particularly in case of involve-
Antiphlogistic therapy with methyl-pred- ment of bacteria responsible for STD,
nisolone (40 mg a day) followed by dose this management has great implications
reduction over time may be considered, for actual and potential sexual partners
although data from prospective ran- underlining the significance of these
domised studies are not available. problems for public healthcare in gen-
In acute mumps orchitis, interferon- eral. From an economical point of view it
alpha 2b has been prescribed as sup- also appears important that therapeuti-
portive therapy (3×106 IU daily/7 days) cal intervention due to current standards
intended to reduce the testicular dam- might prevent cases of male and female
age due to testicular inflammation and to infertility as a consequence of epididymo-
exert a protective effect on spermatogene- orchitis and subsequently costs for infer-
sis [4, 19, 41]. However, clinical data after tility treatment.
749
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751
|13.5|
Chronic urogenital infections:

alterations of sperm quality and
potential impact on male fertility
Wolfgang Weidner, Thorsten Diemer
Department of Urology, Pediatric Urology and Andrology, University of Giessen, Giessen, Germany, Department of
Urology, Pediatric Urology and Andrology, Justus-Liebig-University of Giessen, Germany
Corresponding author: Wolfgang Weidner, MD, PhD, Professor of Urology and Head of Department of Urology, Pediatric
Urology and Andrology, Justus Liebig-University Giessen, Rudolf-Buchheim-Str. 7, D-35392 Giessen, Germany
Tel. +49 641 99 44 501, Fax +49 641 99 44 509, Email: Wolfgang.Weidner@chiru.med.uni-giessen.de
ABSTRACT Key words: urogenital infections, bacte-

riospermia, leukozytospermia, male infer-
Urogenital infections and inflamma- tility, chronic bacterial prostatitis, CP/
tion are proven causes of male infertil- CPPS
ity. Underlying entities, e.g. the poorly
defined “Male Accessory Gland Infection”,
are often related to infections and inflam- SUMMARY OF RECOMMENDATIONS
mation of the prostate gland, which con-
tributes about 70–90% to the ejaculate. 1. OAT-syndrom appears not to be rel-
Bacteriospermia and leukocytospermia evant in CBP and CP/CPPS (LoE 2,
are typical “markers” for chronic uro- GoR B).
genital infections; the relevance for both
findings is debatable depending upon 2. Increased morphological abnor-
cutpoints and status of infection and malites of spermatozoa are detectable
inflammation. Alterations of sperm count, in CP/CPPS (LoE 3, GoR C).
motility and sperm morphology do occur 3. Bacteriospermia is common in CBP.
in this context, the biological significance The definition of biological significance
remains debatable. This is the same with is different for the pathogens (e.g.
alterations of seminal plasma. E. coli, St. faecalis, U. urealyticum,
Chronic urogenital infections | 13.5 |
C. trachomatis) in urogenital infec- infection-associated therapeutic altera-

tions (LoE 2, GoR B). tions will be addressed.
4. Leukozytospermia is debatable in cut-
points and relevance for bacteriosper-
2. OBJECTIVES
mia. Addition of other inflammatory
parameters, e.g. elastase or IL-8, is
under debate for a better diagnosis of A short classification of chronic urethritis,
inflammation in the seminal pathways CBP, CP/CPPS and MAGI from an andro-
(LoE 4, GoR C). logical point of view will be provided.
Then we defined questions concerning
5. Cytokine-evaluation may support altered ejaculate parameters are defined
“inflammation” as diagnostic marker. that influence male fertility in a nega-
Negative effects on sperm motility are tive way in men suffering from the above
debatable (LoE 3 GoR B). Oxidative mentioned entitities:
Stress (ROS↑) is correlated with rising
number of leukocytes and impaired 1. What is the relevance of OAT (oligo-
fertility (LoE 3, GoR C). ASA do not astheno-teratozoospermia) syndrome?
demonstrate an association to urogeni- 2. Are there infectious/inflammatory
tal infections (LoE 2, GoR A). related alterations of sperm
6. Seminal plasma alterations occur morphology?
in CP/CPPS. The significance remains 3. Is there an accepted definition of bac-
unclear. teriospermia and a defined interaction
to spermatozoa?
4. What is the importance of leukocyt-
1. INTRODUCTION ospermia in this context?
5. What is the importance of cytokines,
Urogenital infections and inflammation
ROS and sperm antibodies in the
are accepted causes of male infertility.
inflammatory/infectious situation?
The percentage of men in andrological
populations with infectious and inflam- 6. Do seminal plasma alterations play a
matory entities is between 6.9% [1] and role in urogenital infections?
8% [2]. Underlying diseases, diagnosed in Finally, a short statement to infection-
this context are chronic urethritis, chronic related therapy is given.
bacterial prostatitis (CBP) and inflam-
matory chronic prostatitis/chronic pelvic
pain syndrome (CP/CPPS) [3]. Orchitits 3. METHODS
and epididymitis, also significant for
male infertility [4], are covered in a sepa- We searched the Pubmed database cover-
rate chapter of this book. Male accessory ing the last eight years (English-German)
gland infection (MAGI), as defined by the using the search terms: male infertil-
WHO [5], is also addressed separately. ity, ejaculate parameters, chronic ure-
The purpose of this text is to define the thritis, chronic bacterial prostatitis, CP/
evidence of current data demonstrating CPPS, MAGI, ejaculate infection, ejacu-
negative influence of the described enti- late inflammation, sperm morphology,
ties on standard ejaculate parameters sperm motility, seminal plasma altera-
including sperm count and morphology, tions, ROS, bacteriospermia, leukocyt-
motility disorders due to bacteriospermia, ospermia, seminal plasma cytokines,
induction of sperm antibodies and inflam- ASA. Furthermore, all reviewed sup-
mation – related changes of the ejaculate plements (2000–2008), covering the
and seminal plasma alterations. Finally, topic urogenital infections of Andrologia,
753
Human Reproduction, European Urology Consultation on New Developments in

and Fertility & Sterility have been looked Prostate Cancer and Prostate Diseases
through for issues addressing male [10] has been discussed recently [3]. This
infertility in its relation to infections/ paper thoroughly evaluates the consensus
inflammations of the urogenital tract. summary statement of the Paris expert
These searches identified a total of 127 group with particular focus on the feasi-
articles, which were screened by title and bility of suggested diagnostic procedures
abstracts. 45 publications met the inclusion and therapeutic trials in the andrologi-
criteria. Unfortunately there were not any cal context [3]. Although not worldwide
systematic reviews, metaanalyses, or ran- accepted in Andrology, all statements
domized clinical trial. They only included and suggestions [3, 10] are based on the
non-randomized trials, case reports, case National Institutes of Health (NIH) classi-
report series and expert opinions. fication of prostatitis syndromes (Table 1)
The studies were rated according to the (LoE 4, GoR C).
recommendation (GoR) using ICUD 4.4 MAGI
standards (for details see Preface) [6–7].
The WHO [5] suggests that two of the fol-
lowing criteria are required to diagnose
4. CLASSIFICATION OF INFECTIOUS/ MAGI in men with oligo-, astheno- or
INFLAMMATORY DISEASES teratozoospermia: (i) history or physical
signs of UTI, epididymitis, or abnormal
rectal examination; (ii) abnormal urine
4.1 Chronic urethritis
after prostatic massage (describing the
The definition of chronic urethritis is not four-glass test); or (iii) elevated num-
really clear. Patients, without urethral bers of peroxidase positive white blood
discharge, suffer from burning and ure- cells (WBCs), high numbers of bacteria
thral itching during voiding. Chlamydial in semen, C. trachomatis findings, and/
and gonococcal infections are typical etio- or abnormal biochemistry or elevated
logical causes [8]. Normally, the diagnosis inflammatory markers in the seminal
is based on the evidence of leukocytes in fluid. Analysis of prostatic fluid is not rec-
the first voided urine and PCR findings of ommended. This suggested classification
the mentioned microorganisms. Taking does not clearly differentiate between
together, sexually transmitted infec- prostatitis, epididymitis, and inflamma-
tions represent the predominant causes tory alterations of the urethral compart-
for chronic urethritis, but non-infectious ment [3] (LoE 4, GoR C).
causes (physical, postendos-copy) also have
to be considered [9] (LoE 4, GoR C).
Table 1 Prostatitis NIH Classification.
4.2 Chronic bacterial prostatitis
I Acute Bacterial (ABP)
Chronic Bacterial Prostatitis (CBP) is
an accepted cause for bacteriospermia in II Chronic Bacterial (CBP)
men [3, 10] 8). This entitity is covered in III Chronic Prostatitis/Chronic Pelvic Pain Syndrome
a special chapter of this book by Krieger (CP/CPPS)
& Wagenlehner. a) inflammatory
b) non-inflammatory
4.3 CP/CPPS
IV Asymptomatic, Inflammatory
The andrological relevance of the con-
NIH (National Institutes of Health)
sensus findings of the 6th International
754
4.5 Evidence of OAT-syndrome 5. MORPHOLOGY

In men with evidence of DNA from sexu-
ally transmitted infectious pathogens 5.1 Morphology according to “strict
in semen a decrease of sperm concen- criteria“
tration and motility has been observed In cases with chronic epididymitis
[11]. Urethritis “per se” seems not to be increased numbers of macrophages and
a major problem. After chronic urethri- disturbed epididymal maturation seem
tis, the development of obstruction either to be predominant, as indicated by blue
as normal stricture or at the level of the immotilized flagella in SHORR stain
veromontanum has been discussed as a (overview in [17]). The clinical impact
cause of decreased ejaculate volume [4]. of these findings remains in association
HIV infections have a negative impact to DBP and CP/CPPS remains unclear.
on testicular function with progression Our data, using strict criteria, provide
of immunodeficiency, but the percent- evidence that a negative effect is evalu-
age of OAT-syndrome is not described in able in inflammatory chronic prostatitis/
detail [12]. chronic pelvic pain syndrome [18] (LoE 3,
In this context, especially data for GoR B).
CBP and CP/CPPS are of high impor-
tance. Available data on prostatitis do
5.2 Morphological findings affecting
not demonstrate reduced ejaculatory
the acrosome
volumina in men with non-inflamma-
tory CP/CPPS [13]; this is similar to It is evident that microorganisms adhere
other data demonstrating no reduced to spermatozoal membranes resulting in
ejaculate volume in men with inflam- ultrastructural alterations and damage
matory signs in the ejaculate [14]. of the plasma membrane also involving
These examinations reconfirm earlier the head of the spermatozoa including
findings that sperm count, motility and the acrosome [19]. Leukozytospermia
morphology are unlikely to be affected has been discussed as cause for abnor-
[14] (LoE 2, GoR B). Table 2 summa- mal morphology and midpiece abnormali-
rizes abailable data demonstrating no ties not depending upon the underlying
significant effect on sperm count, motil- entity [20]. Unfortunately clear study
ity and morphology in infectious and results are not available, in inflammatory
inflammatory prostatitis (NIH II and CP/CPPS associated with leukocytosper-
NIH IIIa). mia significant morphological alterations
Table 2 OAT-syndrome in men with CBP (NIH II) and CP/CPPS (NIH III).
Significant changes to controls
Cohort n Reference NIH Groups Sperm count Motility Morphology
276 [15] II, IIIa, IIIb NS NS NS
44 [16] IIIa, IIIb NS NS NS
112 [14] IIIa, IIIb NS NS NS
30 [13] IIIb NS p.001* NS
*p.001 = s. better motility than controls; NS = not significant
755
are not detectable [16], other data in in patients with bacterial prostatitis
inflammatory and non inflammatory CP/ [3, 10] (LoE 2, GoR B).
CPPS demonstrate poorer sperm mor-
phology compared to controls and a sig-
nificantly reduced acrosomal inducibility 6.1 Direct interactions between
[21] (LoE 3, GoR C). spermatozoa and bacteria
Some pathogenic microorganisms have
the ability to directly interact with sper-
6. BACTERIOSPERMIA matozoa. Attachments between bacte-
ria and spermatozoa are followed by
After exclusion of urethritis and blad- agglutination phenomena and morpho-
der infection, the presence of ≥1,000,000 logical alterations of spermatozoa [19].
peroxidase-positive WBC/ml ejaculate The majority of observations of these
indicates an inflammatory process [3, 5]. phenomena are derived from experi-
In these cases a culture for common uri- mental in vitro studies and their sig-
nary tract pathogens, especially gram- nificance for in vivo infections has been
negative bacteria, should be performed. questioned. Among bacterial species
It must be kept in mind that ejaculate that interact with spermatozoa are well-
analysis does not allow a definitive locali- established causative pathogens of geni-
zation of the infectious process, because tourinary infections such as Escherichia
ejaculate represents a mixture of dif- (E.) coli, Ureaplasma (U.) urealyticum,
ferent genital secretions and is usually Mycoplasma (M.) hominis and Chlamydia
contaminated by flora of the anterior (C.) trachomatis [27]. E. coli likely rep-
urethra. The most common bacteria resents the most frequently isolated
are Escherichia coli, Enterococcus fae- microorganism in cases of genitourinary
calis and Ureaplasma urealyticum [22]. infections. E. coli rapidly adheres to
Unfortunately, conventional counting of human spermatozoa in vitro, resulting
WBCs has only a poor sensitivity/specifity in agglutination of spermatozoa. A pro-
for the detection of bacteria due to found decline in sperm motility is evident
unclear cutpoints, different identification over time caused by severe alterations in
techniques and spontaneous resolution sperm morphology [28]. Morphological
due to phagocytal activity and apoptosis alterations involve both defects of the
[23] (LoE 3, GoR B). Furthermore com- plasma membrane and degeneration of
parative data are available comparing acrosomes. U. urealyticum also attaches
bacterial counts from first void urine, to plasma membranes of spermatozoa
midstream urine, semen, WBCs in semen and affects motility, but seems not to
and pregnancy rates giving no correla- have a clinical effect on sperm quality
tion [24]. A concentration ≥1000 cfu/ml of [29]. Specific defects localized to heads
urinary tract pathogens in the ejaculate of spermatozoa including acrosomal
is regarded as significant bacteriosper- structures have been observed for C. tra-
mia [3–4] (LoE 4, GoR C). Cleaning of chomatis [30]. Bacterial concentrations
the foreskin and the glans penis reduces utilized in vitro experiments undoubtedly
the bacterial content [25]. Nevertheless, are much higher than ever recoverable
we know that about 70% of randomized from ejaculate specimens. This condition
semen samples are contaminated with might contribute considerably to the out-
non-pathogenic bacteria, so bacteriosper- come of the studies. Similar discrepancies
mia does not inevitably mean infection have bee observed in tests for the induc-
[26]. On the other hand, bacteriospermia ibility of the acrosome reaction in artifi-
is significantly represented (about 50%) cially infected semen samples. None of
756
these phenomena evident in vitro clearly Table 3 Cutpoints for expressed prostatic secretions
has been documented in semen speci- EPS, urine after P.M. (VB3) and ejaculate/seminal plasma
mens of patients with MAGI. As bacte- parameters indicative for inflammation (according to [36]).
rial concentrations required for affecting
sperm motility, morphology, and function Parameter Cutpoint
are considerably high, the clinical impact EPS Leukocytes ≥10–20/1000 x
remains unclear also concerning interac-
VB3 Leukocytes ≥10/mm³
tion to inflammation [27, 31].
Semen PPL ≥0.113 x 106/ml
6.2 C. trachomatis in semen Seminal plasma Elastase ≥280 ng/ml
The diagnostic difficulty with C. trachom- Seminal plasma IL-8 >10600 pg/ml
atis infections has provoked researchers to
develop new molecular methods to detect
this microorganism in semen. However, classification the presence of ≥1 × 1000
until now an “ideal“ diagnostic test for 000 WBC/ml is defined as leukocytosper-
C. trachomatis in semen has not been mia [3, 5, 10] (LoE 4, GoR C). The great
established [30]. In contrast to serological majority of leukocytes are polymorphnu-
findings in women, serological tests for clear granulocytes, (PMN) as suggested
C. trachomatis in seminal plasma are not by the specific staining of the peroxi-
indicative if no type-specific methods are dase reaction. Although most authors
used. Unfortunately, the high frequency consider leukocytospermia to be a sign
of serum antibodies and seminal plasma of bacterial induced inflammation, this
activity in both infertile and healthy men condition is not necessarily associated
hampers a clear differentiation [30]. This with bacterial or viral infections. This
problem is also the cause for the debate is in accordance with earlier findings
on the association of chlamydial antibod- that elevated leukocyte numbers are not
ies with leukocytospermia. Questionable, a natural cause of male infertility [34].
the interaction between IL-8 and anti- Only a few studies have analyzed altera-
chlamydial mucosal Ig-A in the ejaculate tions of WBC in the ejaculate of patients
provides a new chance for a better, clear with proven prostatitis (overview in
diagnosis [31]. Numerous publications [27]) demonstrating a higher number of
cover the problem of C. trachomatis infec- leukocytes in men with proven bacterial
tions and changes of semen quality, but infections. There is also an obvious reso-
unfortunately the data are confusing and lution of leukocytospermia after antibi-
provide no clear evidence for significant otic therapy [35]. Despite these data, the
alterations [32]. influence of leukocytospermia on sperm
function is complex and not really clari-
fied in much detail. It is the suggestion
7. LEUKOCYTOSPERMIA of the authors to re-establish the result
of inflammation in all men with leu-
The clinical significance of an increased kocytospermia using elastase and/or
concentration of WBCs in the ejaculate IL-8 determination. In case of a proven
is highly controversial [33]. It is gener- inflammatory situation, exclusion of a
ally accepted that only an increased bacterial infection including CBP and
number of leukocytes (particularly poly- Epididymitis appears seems to be man-
morphonuclear granulocytes) and their datory. Table 3 summarizes our current
products secreted into the seminal fluid inflammatory cut-points in prostatic
(e.g. leukocyte elastase) are an indica- secretions (EPS) and ejaculate for the
tor of inflammation. According to WHO routinely use [36] (LoE 4, GoR C).
757
8. CYTOKINES, ROS AND SPERM 8.3 Anti-sperm Antibodies (ASA)

ANTIBODIES (ASA)
The relevance of seminal plasma
antibodies in genitourinary infections
8.1 Cytokines is still debatable. Some authors suggest
Cytokines are inflammatory mediators an association between increased levels
secreted by activated leukocytes or other of sperm antibodies and prostatitis [42],
immunocompetent cells in semen. The also associations between chlamydial
role of these cytokines (IL-6, 8) is decisive infections and sperm antibodies have
for the course of the inflammatory reac- been described [43]. The prevalence of
tion [37]. The deleterious effects of these MAGI in patients with a positive mixed
proinflammatory cytokines on the motil- antiglobulin (MAR) test seems to be in
ity and the function of spermatozoa have the range of 20%, whereby it is generally
been observed in experimental and clini- accepted that only antibodies bound to
cal studies (overview in [38]) (LoE 3, GoR surface antigen of vital spermatozoa are
B). The proinflammatory cytokines also clinically significant [44]. Own data in
affect Leydig cells that, which produce chronic urethritis, epididymitis and CP/
the gonadal steroids; this effect has been CPPS do not demonstrate an association
verified after the induction of bacterial between proven inflammatory/infectious
Lipopolysaccharide (LPS) in mice, causing diseases of the male reproductive tract
immediate degradation of steroidogenesis and the presence of ASA [45] (LoE 2,
[39]. Since recent studies demonstrate GoR A).
a high correlation between IL-8 levels
and elastase in seminal plasma [40], the
measurement of one of these both inflam-
matory parameters seems mandatory to 9. SEMINAL PLASMA ALTERATIONS
us mandatory in the suspected inflam-
matory situation of the urogenital tract The first demonstration that infection of
(LoE 3, GoR B). the sex glands could impair their excre-
tory function was made in the late 1960s.
Decreased quantities of citric acid, phos-
8.2 Reactive oxygen species (ROS)
phatase, fructose concentration, zinc and
The ROS-source in semen are the poly- alpha-glutamyltransferase (α-γ-GT) activ-
morphonuclear granulocytes (PMN) and ity have been evaluated as disturbed pro-
the seminal macrophages in response to static secretory parameters and reduced
cytokine-stimulating factors, enhanced in fructose concentration as indicator of
the presence of cytokines and LPS. In a disturbed vesicular function (overview in
normal situation, the antioxidant mech- [4]) (LoE 4, GoR C). Epididymitis reduces
anisms of seminal plasma are likely to the quantity of the epididymal marker
quench these ROS and protect against alpha-glucosidase [46]. Fructose has been
any spermatozoal damage. However, dur- found reduced in asymptomatic men with
ing infection/inflammation these antioxi- leukocytospermia and in severe prostato-
dant mechanisms may create a situation vesiculitis (overview in [4]). Own data in
called ‘oxidative stress’ due to the ele- inflammatory CP/CPPS provide evidence
vated levels of ROS beyond the available that in cases with elevated numbers of
total antioxidant capacity in the semen granulocytes in EPS, secretory damage of
[41]. At present “oxidative stress” is cor- the prostate gland is detectable [14] (LoE
related with rising WBCs and impaired 3, GoR B). Neverless, the biological role
fertility [41] (LoE 3, GoR C). remains unclear.
758
10. INFECTION-RELATED THERAPY on sperm quality in cases with prostati-

AND INTERACTIONS TO SPERM tis, if this infection is a major factor for
QUALITY this disorder? It has been hypothesized
that only men with a chronic active infec-
Therapy in infectious diseases of the tion, “where the pathological organism
urogenital tract is normally targeted to is still present and where the degree of
relieve symptoms [3, 10]. Andrologically, damage is still limited”, may benefit from
targets of therapy regarding altered semen a suitable therapy. However, when focus-
composition in male adnexitis include: ing on prostatitis, only CBP is a type of
infection which may correctly fit into this
• Eradication or reduction of microor-
category. This is a type of infection, which
ganisms in prostatic secretions and in is evaluable in only 5–10% of Prostatitis/
semen. chronic pelvic pain patients [10]. Modern
• If possible, normalization of inflam- fluoroquinolones are ideal therapeutic
matory parameters such as leuko- substances and show bacteriologic cure
cytes and inflammatory secretory rates between 60 to 86% (see the separate
parameters. chapter in this book). On the other hand,
• If possible, improvement of sperm we do not consider that common antibi-
parameters to counteract impaired otic substances in normal ‘in-vivo’ dosage
fertility (3) (LoE 4, GoR C). really affect spermatogenesis and sperm
function. Therefore, it seems to us abso-
Modalities of therapy include surgi- lutely necessary to re-analyze the influ-
cal procedures, antibiotics, antiphlogistic ence of antibacterial treatment on sperm
drugs, normalization of urine flow, physi- quality, sperm function and secretory
cal therapy, and changes in general and disorders following the new classification
sexual behavior [10]. Transurethral sur- proposal of prostatitis-syndrome [3]. If
gery in chronic bacterial prostatitis means this work is done, then new studies have
radical transurethral resection of the pros- to be scheduled to analyse the outcome
tate (TUR-P) [10]. It is generally accepted for the infertile couple with pregnancy as
that only patients with a stubborn resist- the goal of therapeutic effect.
ance to long-term medical treatment,
remaining symptomatic with a concomi-
tant obstruction can be considered for rad-
ical resection, e.g., including the removal 11. FURTHER RESEARCH
of prostatic calculi which act as perma-
nent foci of infection. This therapy results Targets of research include the investi-
in permanent retrograde ejaculation. gation of molecular tools which interact
Unfortunately, until now only the between microorganisms “triggering”
antibiotic therapy of CBP has proved to infection, development of inflammation
be really efficacious in providing symp- and disturbances of spermatogenesis.
tomatic relief, eradication of microor- Today, the testicular compartment seems
ganisms and a decrease in cellular and to be the “key” for understanding dis-
humoral inflammatory parameters in uro- turbed semen quality and chronic inflam-
genital secretions [3, 10]. Although antibi- mation as sequaela of urogenital infection
otic therapy provides an improvement in in (sub-)fertile men with poor sperm qual-
male sperm quality in some studies (over- ity. Clinically, infection-related therapy
view in [3]), therapy does not enhance the has to be evaluated in prospective studies
probability of conception. Why is it so dif- for improvement of sperm quality and the
ficult to demonstrate an antibiotic effect possible impact on male infertility.
759
12. CONCLUSIONS 8. Schiefer HG, Microbiology of male ure-

throadnexitis: diagnostic procedures
The data provide evidence that in men and criteria for aetiologic classification.
with alterations of the ejaculate, chronic Andrologia, 1998. 30 Suppl 1: 7–13.
urogenital infections have to be con- 9. Schneede P, Tenke P, and Hofstetter AG,
Sexually transmitted diseases (STDs) – a
sidered. Clear diagnostic criteria are
synoptic overview for urologists. Eur Urol,
necessary to define underlying entities
2003. 44(1): 1–7.
especially chronic bacterial prostatitis
10. Schaeffer AJ, Anderson RU, Krieger JN,
and inflammatory CP/CPPS. Infection- Lobel B, Naber K, Nakagawa M, Nickel
related therapy does not improve the fer- JC, Nyberg L, and Weidner W, The assess-
tility status in most of these men with ment and management of male pelvic
chronic diseases. pain syndrome including prostatitis, in
Male Lower Urinary Tract Dysfunction.
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762
Chapter |14|
Sexually transmitted
infectious diseases
Chair: John N. Krieger
CHAPTER OUTLINE
14.2 Sexually transmitted infectious diseases (STDs) – updated
synopsis for practicing urologists 765
14.3 Urethritis 777
14.4 Pelvic infections in women 804
14.5 HIV infection in urological practice 830
14.6 Male circumcision and HIV infection risk 847
|14.1|
Introduction
John N. Krieger
John N. Krieger, M.D., Department of Urology, University of Washington, School of Medicine, Seattle, WA USA 98195
Tel: 206-543-3640, Fax: 206-764-2239, Email: jkrieger@u.washington.edu
Since antiquity, urologists have had the of what the urologist needs to know.
responsibility to diagnose and manage Drs. Peter Schneede and Boris Schlenker
sexually transmitted infections and their from Klinikum Memmingen (Germany)
sequelae. Much has changed since I was a summarize current recommendations for
medical student. In those olden days, we diagnosis and management of the com-
were taught that there were five venereal mon STI syndromes based on extensive
diseases: syphilis, gonorrhoea, donovano- review of available guidelines. Dr. Ryoichi
sis, lymphogranuloma venereum and chan- Hamasuna from the University of
croid. In the US, gonorrhoea and syphilis Miyazaki (Japan) summarizes diagno-
were far more important than the others. sis and treatment of urethritis in males
Imagine my frustration when I arrived emphasizing the role of Mycoplasma geni-
in urology clinic to find that most patients talium. Dr. Gilbert Donders from Leuven
with urethral symptoms and inflamma- University (Belgium) describes the man-
tion did not respond to treatment for gon- agement and consequences of ascending
orrhoea! We saw patients with genital STIs in women. The final chapters cover
ulcers, but very few had syphilis. Now, we what the urologist should know about
have much more sophisticated insights HIV infection. Dr. Seung-Ju Lee from
into the range of clinical STI presenta- Catholic University College of Medicine
tions and the etiological agents. We have (Korea) provides a concise summary of
greatly improved tools for diagnosis, HIV infection in urological practice. The
treatment, and, often, prevention. section concludes with a review of the
The chapters in this section present a evidence on male circumcision and HIV
concise summary of critical clinical infor- infection risk (John N. Krieger, University
mation. Remarkably, this information is of Washington, USA). Together, this sum-
presented from a practical clinical stand- mary emphasizes what is new, differ-
point by active consultants. These author- ent and important for everyday clinical
ities present a world-wide consensus practice.
|14.2|
Sexually transmitted infectious

diseases (STDs): updated synopsis
for practicing urologists
Peter Schneede1, Boris Schlenker2
1
Department of Urology, Klinikum Memmingen, Germany
2
Department of Urology, University of Munich-Großhadern, Germany
Corresponding author: Peter Schneede, MD, PhD, Head of Department of Urology, Klinikum Memmingen,
Bismarckstr. 23, 87700 Memmingen, Germany
Tel. 0049 8331 702373, Fax: 0049 8331 702374, E-mail: Schneede.peter@klinikum-memmingen.de
ABSTRACT 1. INTRODUCTION
This chapter updates the practicing urol- The classical bacteria that cause venereal
ogist on current recommendations for diseases, e.g. gonorrhoea, syphilis, chan-
sexually transmitted infectious disease croid and granuloma inguinale account
(STD) diagnosis and clinical management for a small proportion known STDs today.
based on updated recommendations from Other bacteria and viruses, as well as
the EAU Urinary Tract Infection (UTI) yeasts, protozoa and epizoa must also be
Working Group STD review, 2003 [1]]. regarded as causative organisms of STD.
The EAU review incorporated many of More than 30 relevant bacteria and viruses
the recent US Centers for Disease Control are now recognized as causes of STDs.
and Prevention (CDC) recommendations However, not all pathogens that can be sex-
[2]. Because this information is topical ually transmitted cause genital diseases.
and important for urological practice we Furthermore, not all infections of the geni-
were charged with providing a clinically- tals are exclusively sexually transmitted.
focused synopsis, rather than a lengthy Concise information and tables summa-
evidence-based review.We also incorpo- rising the diagnosis and management of
rated new antimicrobial recommenda- important urological STDs are presented
tions and the recently approved human based on recent international guidelines
papilloma virus (HPV) vaccines. [2–5]. In addition, we provide a resource
Chapter | 14 | Sexually transmitted infectious diseases
for information on other clinical syndromes 3. Chancroid

and infections that may be encountered 4. Donovaniosis/granuloma inguinale
by the urologist (e.g., HIV infection, preg-
nancy, infants, allergy). Consequently, this 5. Lymphogranuloma venereum
overview does not offer a list of references, 6. Chlamydial, mycoplasmal and urea-
levels of evidence or grades of recommen- plasmal urethritis
dation. These are included in the more
detailed chapters which follow or can be Viral STDs
found in the recent international guide- 1. HPV lesions
lines this overview is based on [2–11].
2. Molluscum contagiosum
3. Genital herpes virus infections
2. DEFINITIONS AND CLASSIFICATION
STDs caused by protozoa and epizoa
STDs can be categorized as curable or
1. Trichomoniasis
incurable by currently available thera-
pies. The common curable STDs are gon- 2. Phthirus pubis (“crab”) infestation
orrhoea, chlamydial, mycoplasmal and 3. Sacroptes scabiei infestation
ureaplasmal infections, syphilis, tricho-
moniasis, chancroid, lymphogranuloma Images of the STDs:
venereum and donovanosis. In addition,
Informations and images of the STDs are
STDs caused by yeasts, protozoa and
provided by the Dermatology Online Atlas
epizoa can be cured. The STDs that are
(www.dermis.net/index_d.htm) or the CDC
preventable but not curable are the viral
(www.cdc.gov/std/training/clinicalslides)
STDs, including: human immunodefi-
websites.
ciency viruses (HIV), human papillomavi-
ruses (HPV), hepatitis B/C viruses (HBV,
HCV), cytomegalovirus (CMV) and herpes
simplex viruses (HSV). 3. BACTERIAL STDs (TABLE 1); [1-11]
Only those genital infections that are
indeed transmitted exclusively sexually 3.1 Syphilis
will be dealt with below. Other pathogens Syphilis represents one of the first recog-
that lead to organ manifestations consid- nized and most infectious systemic STDs,
ered primarily by other specialities will be particularly in its primary and second-
mentioned briefly in terms of their sexual ary stages. Unless treated, the infection
transmissibility and co-morbidity. With will progress through a series of stages,
regard to further details on these patho- during which its symptoms often mimic
gens, the reader should refer to guide- those of other diseases and make diagno-
lines from appropriate specialist societies sis difficult. There is a close bidirectional
and internet links [2–4, 6–11]. Clinical epidemiological interrelationship between
pictures such as urethritis, genital ulcers, syphilis and HIV infection, resulting
prostatitis, and epididymitis characteris- in high prevalence rates for both infec-
tic of by various STD pathogens in men tions among commercial sex workers
are not included in this overview. and injecting drug users, particularly in
This synopsis considers the following developing countries. Recommendations
STDs that are important in urology: should be made to test all patients who
Bacterial STDs have syphilis for HIV infection and
retesting should be recommended for HIV
1. Syphilis infection after three months if the first
2. Gonorrhoea HIV test result was negative.
766
Table 1 Bacterial STDs [1–11].
STDs Causes Symptoms Diagnosis Treatment
Syphilis Treponema pallidum Primary stage (lues I): Microscopic and direct fluorescent anti- The dosage and the length of treatment
(spirochete bacterium), Chancre (not painful) at the body (DFA) tests of the tissue taken from depend on the stage and clinical
90% transmission location where the bacterium a chancre or sore may identify the spiro- manifestations of the disease.
by sexual contact, entered the body, usually with chete for diagnosing early syphilis.
Primary/secondary stages:
transmission by non- regional lymphadenopathy.
Serologic blood tests:
sexual contact is rare. Benzathine penicillin 1 × 2,4 Mio IU i.m.;
Secondary stage (lues II):
Syphilis is classified as Screening by combination of the or Clemizolpenicillin G
2–12 weeks later the Treponemas spread
acquired or congenital. Venereal Disease Research Laboratories
throughout the body, causing a rash, 1 Mio IU i.m. for 14 days
The incubation period Test (VDRL) or Rapid Plasma Reagin
small open sores, flu-like fever, swelling of
ranges between 10 an (RPR) and Treponema Pallidum No comperative trials have been adequately
lymph nodes, condylomata lata
90 days. Hemagglutionation Test (TPHA); conducted to guide the selection of the
Latent and tertiary stages (lues III): optimal penicillin regimen (i.e. the dose,
Confirmation by IgG Fluorescence
Symptoms and infectiousness duration and preparation).
Treponema Antibody Absorption Test
disappear; one third of untreated
(IgG-FTA-Abs) or 19-S-IgM-FTA-Abs. Persons allergic to penicillin:
persons will progress to the tertiary stage
where the bacteria attacking the patients Follow-up testing by VDRL-test or Doxycycline 2 × 100 mg p.o. for 14 days
heart, eyes, brain, nervous system, bones 19-S-IgM-FTA-Abs-test 3, 6, 12 months
and joints. Gummatous syphilis and annually for another 4 years after Erythromycin 4 × 500 mg for 14 days
treatment. Late or unknown stages:
Final Stage (lues IV):
Heart diseases, blindness, insanity, paralysis Some HIV infected patients can have Benzathine penicillin
and death atypical serologic test results.
2,4 Mio IU i.m. on day 1, 8, 15.
or Clemizolpenicillin G
1 Mio IU i.m. for 21 days
Persons allergic to penicillin:
Doxycycline 2 × 100 mg p.o. for 28 days
Erythromycin 4 × 500 mg p.o. for 28 days
Management of sex partners: Persons who
were exposed within the 90 day preceding
the diagnosis of primary, secondary, or early
Sexually transmitted infectious diseases (STDs)
latent syphilis in a sex partner should be

treated presumptively.
continued
767
| 14.2 |
Table 1 Bacterial STDs [1–11] – (Cont’d)
768
Chapter
Gonorrhoea Caused by a Initial symptoms within two weeks: Fever, Microscopic examination of Gram-/ World-wide, different strains of gonorrhoea
bacterium (Neisseria chills, painful swelling of the genitals and methylene blue- stained and specially have become resistant to penicillin and
| 14 |
gonorrhoeae), which prostate in men. Men cultured pus samples will readily confirm quinolones. Due to the resistances found in
enters the body by report burning during urination, the clinical diagnosis by visualization different countries and co-infections with
mucous membranes urethral pus and painful bowel of diplococci in leucocytes. Amplified other STDs antibiotics such as Ceftriaxone
of the urethra, cervix, movements in rectal infections. In women, antigen detection tests or nucleic acid (1 × 125 mg i.m.), Spectinomycin (1 × 2 g
rectum, mouth, throat infections of the uterus and fallopian tubes amplification tests (NAAT) offer high i.m.) Cefixime (1 × 400 mg p.o.) should be
and eyes. are common, resulting in sterility, ectopic sensitivity and provide confirmation of preferred.
pregnancy, and pelvic inflammatoy disease the diagnosis in asymptomatic patients.
Gonorrhoea is nearly In general, if chlamydial infection is not
(PID). Newborns’ eyes might be affected. NAATs are FDA-cleared for use with
always transmitted by ruled out it is recommended that patients
After the bacteria enter the bloodstream, endocervical swabs, vaginal swabs, and
direct sexual contact. treated for gonococcal infection also
the disease can affect the joints, heart and female and male urine.
Transluminal spread of should be treated routinely with a regimen
brain. Asymptomatic infection of the ure-
infection may Follow-up: Patients who have that is effective against uncomplicated
thra is rare (<10%).
occur to involve the uncomplicated gonor-rhea and who are genital Chlamydia. trachomatis infection
epididymis and treated with any of the recommen-ded (Azithromycin 1 g p.o. single dose or
prostate. regimens do not need follow-up testing. Doxycyclin 2 × 100 mg for 7 days).
Patients who have symptoms that persist
Haematogenous Routine cotreatment might also hinder the
after treatment should be evaluated by
dissemination is development of antimicrobial-resistant N.
culture for antimicrobial susceptibility.
uncommon. gonorrhoeae. Azithromycin 1g p.o. might be
effective against uncomplicated gonococcal
All patients tested for
infection, but concerns over emerging
gonorrhoea should be
Sexually transmitted infectious diseases
antimicrobial resistance to macrolides

tested for other STDs,
should absolutely restrict its use to limited
including Chlamydia,
circumstances (e.g. allergy).
syphilis, and HIV.
Management of sex partners: All sex part-
ners of patients who have N. gonorrhoeae
infection should be evaluated and treated
for N. gonorrhoeae and C. trachomatis
infections if their last sexual contact was
within 60 days before symptoms or diagnosis
of infection in the patient. Patients should be
instructed to avoid sexual intercourse until
therapy completed.
Chancroid Bacterial disease 3–14 days after contact, a tender bump Usually diagnosed by microscopic Chancroid has become resistant to penicillin,
caused by develops where the bacteria entered the examination ofa smear sample Tetracycline and Erythromycin in some
Haemophilus ducreyi, body. The bump transforms into one or (Gram-stained). This should be cases. Preferred treatments now involve
that is transmitted by more shallow sores, which will break confirmed by a culture. The presence Azithromycin (1 × 1 g p.o.), Ceftriaxone
direct sexual contact. open and become the typical painful soft of other STDs has to be ruled out. PCR (1 × 0.25 g i.m.) or Ciprofloxacin (2 × 500
Uncircumcised men chancre. The lymph nodes in the groin are testing is possible. mg p.o. for 3 days) or Erythromycin
are more likely to pus-filled (bubos), and often burst through 3 × 500 mg for 7 days. Bubos may need
Test for HSV performed on the ulcer
contract the disease the skin. to be drained.
exudates usually is negative.
than circumcised men.
Coinfections with T.
pallidum or HSV occur
in 10% of persons
who have chancroid.
Donovanosis/ A chronic, mildly con- Red, vulnerable, easily bleeding sores on Generally diagnosed by visual Azithromycin (1 × 1g per week, for 3 weeks)
Granuloma tagious STD caused and around the genitals and anus are typi- observation of the external symptoms. or
inguinale by an intracellular cally noticed one week to several months Gram-stained samples will show the
Erythromycin (4x 500 mg p.o. for 3 weeks)
gram-negative bac- after initial exposure to the bacteria. In bacteria, which can be cultured under
or
terium, Klebsiella men the lesions appear first on the head special conditions only. Donovan bodies
(Calymmatobacterium) or shaft of the penis. The sores are not are found in macrophages on tissue Doxycycline (2 × 100 mg for 3 weeks) or
granulomatis very painful, but can spread throughout crush preparation or biopsy. Coinfections Trimethoprim-Sulfamethoxazole
the groin and cause abscesses. In extreme with other STDs are known. (2 × 1 (800/160mg) die for 3 weeks) or
cases, their dissemi-nation can give rise to Ciprofloxacin 2 × 750 mg for 3 weeks or
cancer. until all lesions have completely healed.
Lymphadenopathy is unusual. Sometimes wound resection is necessary.
Scars left by the sores are regarded
as precancerous. Therefore, annual
examinations are recommended.
Lympho- Caused by Chlamydia First symptoms may be a sore resembling The chlamydia have to be cultu- Doxycycline (2 × 100 mg for 3 weeks) and
granuloma trachomatis (serotypes a pimple, blister or soft bump at the point red in special cell cultures (Mc Coy Erythromycin (4 × 500 mg for 3 weeks)
venereum L1-L3), that is spre- of infection 3–30 days after exposure. 1–2 cells) and can be diagnosed by direct
Azithromycin (1 × 1g p.o. per week for
ad by direct sexual weeks later, the lymph nodes swell mostly immunofluorescens or nucleic acid
3 weeks) is probably effective.
contact, particularly unilateral, creating a painful, pus-filled detection. Complement fixation titers ≥
in homosexuals who bulge. The disease progresses slowly 1:64 are consistent with the diagnosis of Buboes may require drainage.
engage in anal sex. causing fever, throbbing pain and breaking lymphogramuloma venereum.
Proctocolitis and of the skin, leaving masses of scartissue.
perianal or perirectal
fistulas and strictures
may result.
continued
769
| 14.2 |
Table 1 Bacterial STDs [1–11] – (Cont’d)
770
Chapter
Chlamydial, Non-gonococcal 7–21 days after contact signs and The diagnosis of urethritis should Single dose Azithromycin (1 g) or Doxycycline
mycoplasmal uretritis (NGU) is symptoms are mainly due to urethritis and by confirmed by demonstrating (2 × 100 mg for 7 days);
| 14 |
and caused by Chlamydia complications like anorectal discomfort, polymor-phonuclear leucocytes in

Erythromycin (4 × 500 mg for 7 days);
ureaplasmal trachomatis (serotypes reactive arthritis and conjunctivitis Gram-stained urethral smears or first pass
D-K) in 30–50% (Reiter`s syndrome), prostatitis and urine specimens. Diagnostic tests include Ofloxacin (2 × 200 mg for 7 days);
urethritis
and Ureaplasma epididymo-orchitis. cell cultures (sensitivity range 40–85%),
urealyticum and direct antibody assays (sensitivity range Levofloxacin 1 × 500mg for 7 days
Important sequelae can result from C.
Mycoplasma hominis/ 50–90%), Enzyme- immunoassays Roxithromycin (2 × 150 mg for 7 days);
trachomatis infection in women (e.g. PID,
genitalium in 10–20%, (sensitivity range 20–85%) and PCR/ LCR
infertility, and ectopic pregnancy). Clarithromycin (2 × 250 mg for 7 days.
respectively. techniques (sensitivity range 70–95%).
First pass urine specimens can be used
All patients who Abstinence from sexual intercourse for 7 days
for PCR/LCR , and urethral swabs will be
have urethritis is recommended. Sex partners (within 60
needed for the othertests. Cooled (4–8°C)
should be evaluated days) should be evaluated, tested and treated.
special transport vehicles and cell cultures
for the presence
are mandatory.
of gonococcal and
non-gonococcal
infection. Some
cases of presistent or
recurrent urethritis are
due to Trichomonas
vaginalis, HSV, and
adenovirus. Enteric
bacteria have been

identified as an
uncommon cause of
NGU and might be
associated with
insertive anal sex.
Sexually transmitted infectious diseases (STDs) | 14.2 |
3.2 Gonorrhoea and developing areas (India, Papua-New

An annual incidence of approximately Guinea, central Australia and Southern
62 million new cases of gonorrhoea is Africa). Though only moderately conta-
estimated world-wide, with the greatest gious it is transmitted most often when
number in South and South-East Asia, the disease is in its early stages.
followed by sub-Saharan Africa. A signifi-
cant proportion of infected people (up to 3.5 Lymphogranuloma venereum
80% among women, 10% among men) are (LGV)
asymptomatic. Co-infections with chlamy- This disease, also known as Durand-
dia and other STDs are very common and Nicolas-Favre disease, is relatively rare
specific diagnostic testing and appropri- in developed countries. Most cases occur
ate treatment should be recommended. in men having sex with men (MSM).
The prevalence of gonococal infection Lymphogranoloma venereum is most
varies widely among communities and prevalent in South East Asia, Africa,
patient populations. Central and South America and the
Caribbean. Infection is characterized by
3.3 Chancroid a painful swelling of the inguinal lymph
nodes and elephantiasis of the geni-
Limited understanding of the epidemi-
tals. The infection is invasive, systemic
ology and natural history of the disease
and might lead to chronic fistulas and
and the absence of routine clinical tests
strictures.
make it difficult to reliably estimate
prevalence and duration of infection.
Definitive diagnosis of chancroid requires 3.6 Nongonococcal urethritis
isolation of the causative bacterial path- (chlamydial, mycoplasmal
ogen, Haemophilus ducreyi, on special and ureaplasmal urethritis)
media that are not available commer- The major pathogens causing nongono-
cially. Probable diagnosis may be made coccal urethritis are Chlamydia tracho-
in a patient with the combination of geni- matis, and Ureaplasma urealyticum.
tal ulcer(s) and inguinal adenapathy who Mycoplasma hominis and Mycoplasma
has a negative darkfield examination and genitalium represent other probable
serology for syphilis plus negative test causes of non-gonococcal urethritis. These
results for HSV infection. It is estimated organisms are estimated to account for
that there are approximately 7 million 30–50% and 10–20% of cases, respec-
new cases of chancroid annually. The inci- tively. 20–30% of men with non-gonococcal
dence of chancroid varies greatly between urethritis have no organism detected.
countries and regions. In the US, for Asymptomatic infection is common in
example, there are endemic areas and women, while approximately 70% of men
also outbreaks of infection. In contrast, in have symptoms like urethral discharge,
Africa and parts of Asia chancroid may be dysuria, penile irritation and signs of
a common cause of genital ulcers. epididymo-orchitis or prostatitis.Women
may suffer from C. trachomatis associ-
3.4 Donovanosis/Granuloma ated pelvic inflammatory disease, ectopic
inguinale pregnancy, or infertility.
Donovanosis is a very rare genital
ulcerative STD in most areas. Infection 3.7 Other bacterial and yeast STDs
occurs primarily occurs in people who Gardnerella vaginalis is characteristically
engage in anal sex or oral-anal contact. associated with a diffuse disturbance of
Donovanosis is endemic in certain tropical the normal vaginal flora associated with
771
bacterial vaginosis. Men may carry the equally susceptible to infection, women
bacterium, but do not seem to be adversely suffer a much higher risk of developing
affected. Additionally, bacterial vaginosis the HPV-associated malignancies.
is not a STD per se, and the change in the With the recently developed prophy-
balance of bacterial organisms that exists lactic bivalent (HPV 16, 18) and quadri-
in the vagina is not clearly understood. valent (HPV 6, 11, 16, 18) vaccines, it is
Other infections most frequently associ- now possible to prevent (a) HPV infection
ated with vaginal discharge are tricho- of the cervical epithelium and other squa-
moniasis and candidiasis. Vulvovaginal mous epithelia, (b) the development of
candidiasis is not usually acquired premalignant lesions, and in the case of
through sexual intercourse. Treatment of the quadrivalent vaccine, (c) the develop-
male sex partners is only recommended ment of condylomata acuminata [4].
in rare cases of balanitis or in women who
have recurrent infection. In contrast, tri- 4.2 Molluscum contagiosum
chomoniasis is a common sexually trans-
mitted infection that merits diagnosis and Molluscum contagiosum is characterized
treatment (see below). by self-limiting viral infection of the skin
which is spread by sexual contact as well
as manual and casual contact. Children
4. VIRAL STDs (TABLE 2); [1-11] are often infected. High prevalence (13%)
of molluscum is noticed in HIV-positive
This section summarized viral STDs that adults, justifying molluscum as an STD.
cause typical genital tract lesions includ- Individual blisters may disappear on
ing: HPV, MCV and HSV infections. their own after several months or may
Information on other viral STDs, i.e. HIV, require local therapy.
hepatitis, cytomegalic inclusion body dis-
ease and Epstein-Barr virus-associated 4.3 Genital herpes
disease are considered in the guidelines
Genital herpes is a chronic, lifelong viral
of other specialities.
infection that afflicts up to 80% of adults.
The human herpes viruses include: herpes
4.1 HPV-associated lesions
virus type 1 (HSV-1), herpes virus type 2
(genital warts)
(HSV-2), cytomegalovirus, varicella-zoster
Condylomata acuminata caused by HPV virus (VZV), Epstein-Barr virus (EBV),
infection represent the most common human herpes virus type 6 (HHV-6),
viral STD world-wide. More than 30 mil- human herpes virus type 7 (HHV-7), and
lion people develop genital warts every Kaposi’s sarcoma-associated herpes virus
year. HPV belongs to the same group of (also knows as HHV-8). Of these, HSV,
viruses that produce common skin warts. CMV, EBV and HHV-8 can be transmitted
However, HPV can also be closely associ- sexually. Although they are all spread by
ated with intraepithelial neoplasia and direct skin-to-skin contact, urologists are
anogenital cancers in both genders. Most primarily concerned with management of
HPV infections are subclinical or latent – patients infected with HSV-1 and HSV-2.
that means that they are not directly vis- HSV1 has been found historically on the
ible or that they can only be diagnosed mouth, and can increasingly be isolated in
by laboratory testing. Visible signs of the genital infections. This probably reflects
disease include condylomata, Bowen’s changes in sexual practices. Herpes is
disease, bowenoid papulosis, Buschke incurable today. The associated symptoms
Löwenstein tumors and anogenital can- may never become manifest clinically or
cers. Although men and women are symptoms may come and go periodically
772
Table 2 Viral STDs [1–11].
Genital HPV low-risk Typically growing without symptoms External warts are usually diagnosed An update of the guidelines in
warts genotypes (i.e. untreated genital warts can spread and visually. Application of acetic acid dermatology, venereology, gynecologyand
90% HPV 6 or HPV multiply into large clusters. Giant warts solution (5%) causes the warts and subc- urology [3] unanimously recommends
11) transmitted (Buschke Löwenstein tumours) are rare. linical flat HPV lesions to whiten, making treatment options for medically prescri-
by intimate sexual Genital warts may cause a variety of health identification much easier. A magnifying bed self-treatment and for exclusively
contact. Warts develop complications depending on where they instrument should be used to diagnose physician-managed treatment. Topically
within 3 weeks to 8 are located. Symptoms may range from subclinical lesions. For demarcation of applied drugs such as Podophyllotoxin (0,5%
months. discomfort and pain, to bleeding and urethral HPV lesions, fluorescence ureth- solution or gel)or Imiquimod 5% cream
difficulty in urination. roscopyhad been used by analogy with are suitable for therapy at home. Medically
Immunodeficiency
the acetic acid test of the outer genitals applied treatment involves trichloracetic acid
leads to rapid and
[11]. Both the acetic acid test and flu- (TCA), cryotherapy, electro-surgery, laser
extensive growth of
orescence urethros copy are limited in treatment and surgical excisions of the HPV
HPV lesions, even
specificity. A tissue biopsy or Pap smear lesions. Irrespective of the therapy used,
affecting untypical
may be taken to determine whether the HPV may persist in the adjacent tissues,
epithelial tissue (e.g.
HPV lesions are cancerous. Generally, resulting in recurrences and the need for
urinary bladder), and is
both sexual partners should be tested for further courses of treatment. Substantial
associated with higher
warts. Routine HPV type analyses have breakthroughs in the prevention of HPV
rates of cancer.
not been recommended in genital warts. infection have been made in recent years.
Precancerous changes HPV nucleic acid testing may be useful in The FDA-approved quadrivalent HPV vaccine
in the cervix, vulva, Cervical Cancer Screening Programs. (HPV 6, 11, 16, 18) can effectively prevent
anus, or penis are due 90% of genital warts an 70% of cervical
to HPV high-risk-types cancers through preexposure vaccination.
(e.g. HPV 16, 18). Very
rarely, HPV infection
results in anal or
genital cancers.
Molluscum Caused by Molluscum Typical blisters can be flesh-colored, white, The blisters are distinctive, providing Blisters will regress spontaneously under
contagiosum contagiosum virus. 2–3 pink, yellow or clear. Itching is common, typical criteria for visual diagnosis. The the control of the immune system. If not,
months after infection, but pain is rare. Clusters of lesions may diagnosis can be confirmed by light surgical removal by laser, cryotherapy,
a waxy and rounded develop. In adults HIV coinfection has to be microscopy or electron microscopy of electro-surgery or chemical treatment is
blister with a dimple ruled out. biopsies taken from a blister. recommended.
on the top develops.
Scratching, picking or
breaking spreads the

virus.
continued
773
| 14.2 |
Table 2 Viral STDs [1–11] – (Cont’d)
774
Chapter
Genital Herpes simplex viruses Symptoms can vary. Initially flu-like Sometimes the diagnosis can be Herpes is incurable. Systemic antiviral drugs
herpes (HSV 1(30%) and symptoms, swelling of lymph nodes, made by physical examination (Acyclovir 3 × 400mg or 5 × 200mg per os,
| 14 |
HSV 2 (70%)) can chills, fever may be noticed. Fluid-filled alone. Cell culturing (HSV is a labile Famciclovir 3 × 250mg per os, Valacyclovir
cause genital lesions blisters are then followed by eruption and virus and successful virus culture- 2 × 1g per os) may be used to reduce the
2–20 days after ulceration of the skin; both are painful. depends on main-taining the cool discomfort from the sores. Healing might be
infection. Most cases Clusters on the genitals, buttocks and (4C0), rapidly transporting speci- increased, and pain as well as viral shedding
of recurrent genital adjacent areas are typical.Other symptoms mens to the laboratory and avoiding can be reduced.
herpes are caused by may include tenderness, aching pain, freeze-thaw cycles) and type analysis by
Treatment of first clinical episode (for 7–10
HSV-2. Herpes virus itching, burning or tingling. Painful immunofluorescence tests are standard
days) or recurrent episodes of genital herpes
invades the body via urination and a sensation of abdominal options for diagnosis. Fluorescence tests
(for 3–5 days) requires initiation of therapy
breaks in the skin or pressure are known. can be done without viral amplification
within the first day of lesion onset. Patients
moist membranes in the cell culture, but sensitivity is only
Although HSV 1 and HSV 2 persist in who have frequent recurrences (i.e., ≥ 6
of the penis, vagina, fair. PCR and LCR amplification of HSV
the body of infected persons indefinitely, recurrences per year) may be treated by
urethra, anus, vulva show much better sensitivity, but the
symptoms tend to lessen with time. suppressive therapy ( i.e. Valacyclovir (1 × 1g
or cervix. All practices techniques are too expensive for
p.o./ die), Acyclovir (2x400mg) or Famciclovir
of intercourse may routine use.
(2 × 250mg), for 16 weeks up to years).
transmit HSV. HSV
may be passed on to Supressive therapy reduces the frequency of
the baby during birth genital herpes recurrences by 70–80%. Do
as well. not use topical creme.
The sex partners of patient who have genital
herpes likely benefit from evaluation and
counselling.
Sexually transmitted infectious diseases (STDs) | 14.2 |
throughout a person’s lifetime. There are two weeks are also recommended. The
even more people who have no symptoms scalp is treated with lindane shampoo.
who can still transmit infection to their Patients with pediculosis pubis should be
sexual partners. A number of drugs have evaluated for other STDs.
proven effective for clinical management.
5.3 Sacoptes scabiei infestation
5. STDs CAUSED BY PROTOZOA Sarcoptes scabiei is a whitish-brown,
AND EPIZOA [2–3, 5] eight-legged mite that burrows into its
host to lay its eggs. This burrowing causes
5.1 Trichomoniasis a skin irritation or rash. The mites, their
feces and eggs cause a progressive sensi-
Trichomoniasis is caused by the parasitic
tivity in the host after about two weeks,
protozoon, Trichomonas vaginalis, and
producing the characteristic itch. Finding
is often diagnosed in patients that are
a mite or identifying its bumps and bur-
infected with other STDs. Trichomonas
rows will corroborate the diagnosis. There
can be transmitted by direct sexual con-
are a variety of topical medications that
tact or by infected body fluids. Symptoms
will clear scabies infestations. Effective
in men are uncommon, and typically
treatments include: lindane, petroleum
include discharge from the urethra and
jelly and 5% sulfar mixture. Permethrin
painful or difficult urination. The proto-
cream (5%) or Ivermecin 200 ug/kg p.o.
zoon can be found by dark-field micro-
repeated in 2 weeks are also effective in
scopy of specimens from the vagina,
scabies treatment.
urethral secretions or in the sediment of
urine. Culturing these samples before the
microscopic examination will improve sen-
sitivity substantially. Generally, treatment REFERENCES
should involve both sexual partners. A sin-
gle dose of Metronidazole (1 × 2 g p.o.) or 1. Schneede P, Tenke P, and Hofstetter AG,
Tinidazole (1 × 2g p.o.) is usually effective. Sexually transmitted diseases (STDs)–a
An alternative regimen is Metronidazole synoptic overview for urologists. Eur Urol,
2 × 500 mg for 7 days. 2003. 44(1): 1–7.
2. Smellie JM, Ransley PG, Normand IC,
Prescod N, and Edwards D, Development
5.2 Phthirus pubis (“crab”) of new renal scars: a collaborative study.
infestation Br Med J (Clin Res Ed), 1985. 290(6486):
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They use crab-like claws to grasp the A, Jr., URINARY TRACT INFECTION
host’s hair and can crawl several centime- IN SCHOOL CHILDREN: AN
tres per day. Female lice lay two to three EPIDEMIOLOGIC, CLINICAL AND
LABORATORY STUDY. Medicine
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in male infants: how important is the
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involves application of 1% gamma ben- Ikoma F, New development and progres-
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776
|14.3|
Urethritis
Ryoichi Hamasuna1,2, Hiromasa Tsukino2
1
Department of Urology, University of Occupational and Environmental Health, Kitakyushu, Japan
2
Division of Urology, Department of Surgery, Faculty of Medicine, University of Miyazaki, Japan
Corresponding author: Ryoichi Hamasuna, Department of Urology,
University of Occupational and Environmental Health,1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu,
Fukuoka, 807-8555, Japan
Tel:+81 93 691 7446, fax:+81 93 603 8724, E-mail:hamaryo@med.uoeh-u.ac.jp
Gonococcal urethritis (GU) remains a fre- 1. It should be considered that preva-

quent disease in the US, Eastern Europe, lence rates of gonococcal urethritis
Asian and African countries. Because remain high worldwide (GoR C).
fluoroquinolon-resistant Neisseria gonor-
rhoeae strains have become widespread 2. Fluoroquinolone-regimens for gonococ-
worldwide, fluoroquinolone regimens cal urethritis cannot be recommended
can no longer be recommended for GU. (GoR B).
Chlamydia trachomatis is the major caus- 3. In some regions, cefixime-resistant
ative bacteria for non-gonococcal urethri- N. gonorrhoeae has increased sub-
tis (NGU) and azithromycin (AZM)- or stantially therefore cephalosporin
doxycycline-regimens are recommended to regimens should only be recommended
treat chlamydial urethritis. Mycoplasma with caution (GoR C).
genitalium also appears to represent a fre- 4. For the tratment of chlamydial ure-
quent cause of male urethritis, for which thritis, azithromycin or doxycycline-
AZM is the treatment of choice. Therefore regimens are recommended (GoR A).
AZM should be considered the first line
5. It is important to consider that M.
treatment of NGU, but not tetracyclines.
genitalium is an important causative
Key words: Urethritis, STI, ICUD, bacterium of male urethritis (GoR B).
gonococcal urethritis, non-gonococcal ure- 6. For M. genitalium urethritis, azithro-
thritis, N. gonorrhoeae, C. trachomatis, mycin is the the first line regimen
M. genitalium (GoR C).
1. INTRODUCTION the following key words: Neisseria gon-

orrhoeae, Chlamydia trachomatis or
The most common sexually transmitted Mycoplasma genitalium combined with
infection (STI) that urologists see is male urethritis, prevalence, susceptibility, sus-
urethritis. The management of urethritis ceptibilities, treatment, clinical trials or
is proposed in the following guidelines: other related terms. Regarding the preva-
i) CDC guidelines lence of pathogens for male urethritis, we
searched for peer-reviewed papers pub-
• Sexually transmitted diseases treat- lished within the last five years, because
ment guidelines, 2006 [1] we were only interested in the most recent
• Update to CDC’s sexually transmit- data of prevalence. Papers not includ-
ted diseases treatment guidelines, ing the numbers of patients or objective
2006: fluoroquinolones no longer population were excluded. Regarding the
recommended for treatment of pathogenicity of M. genitalium, papers
gonococcal infections [2] on non-gonococcal urethritis (NGU) were
ii) Guidelines of the British Association included. We searched for peer-reviewed
for Sexual Health and HIV papers published after the analysis by
• National Guideline on the Jensen’s review [7]. Regarding the sus-
Diagnosis and Treatment of ceptibilities of causative bacteria to anti-
Gonorrhoea in Adults 2005 [3] biotics, only papers that contained the
numbers of strains and the year of test-
• 2006 UK National Guideline for
ing were accepted. The methodology for
the Management of Genital Tract antimicrobial susceptibility testing was
Infection with Chlamydia tracho- not evaluated because of a poor concord-
matis [4] ance among laboratories on the definition
• 2008 National Guideline on the of resistant N. gonorrhoeae [8–9]. Papers
Management of Nongonococcal from developing countries were accepted
Urethritis [5] as much as possible, because antimicro-
iii) Guideline on the management of uri- bial susceptibility data in African, Asian
nary and genital tract infections by the or South American countries are rare. We
European Association of Urology [6] searched for peer-reviewed papers pub-
Urologists should know and understand lished in the last five years because only
the major evidence-based guidelines on recent susceptibilities data are important
STI diagnosis and management. However, for clinicians. Regarding clinical studies
these guidelines are not adapted to world- of antimicrobial treatment for urethri-
wide medical practice because the avail- tis, we searched for peer-reviewed papers
ability of diagnostic tests, prevalence of published within the last 10 years.
pathogens causing urethritis or the anti- The papers about susceptibilities of
microbial susceptibilities of causative N. gonorrhoeae to antibiotics also inclu-
pathogens differ subsantially. This review ded case series. The paper about suscepti-
evaluates the scientific evidence of the bilities of M. genitalium to antibiotics also
prevalence for urethritis and of antimi- included experimental results, because
crobial susceptibilities that determine the laboratories which can measure the anti-
appropriate treatment for male urethritis. microbial susceptibility of M. genitalium
are limited in the world.
The studies were rated according
2. METHODS to the level of evidence (LoE) and the
grade of recommendation (GoR) using
We searched for peer-reviewed papers ICUD standards (for details see Preface)
in Medline. The search strategy used [10–11].
778
Urethritis | 14.3 |
3. AETIOLOGY The parevalence of pathogens for male

urethritis were analysed by one meta-
Microorganisms usually considered as analysis, three randomized cohorting
causative pathogens of male urethritis studies, 11 case-controlled studies, 12 case-
are listed in Table 1. N. gonorrhoeae and series and 12 non-randomized cohorting
C. trachomatis have been recognized as studies. The rates of N. gonorrhoeae from
the most important bacterial pathogens the males with urethritis in European
causing urethritis. There is an assump- countries, Asian countries, USA, or South
tion that gonococcal urethritis (GU) has Africa were 2–21%, 9–45%, 12–35% and
decreased in the developed countries, but 22–52%, respectively (Table 3). Prevalence
the prevalence rates of GU remain high rates of gonococcal urethritis remain high
in the developing countries. To confirm worldwide (GoR C). In these papers, seven
this assumption, the prevalence data of papers were written about the screenig
many countries were compared. data of the pahogens for urethritis among
the sexually active general population
3.1 Prevalence or men who have sex with men (MSM).
C. trachomatis or N. gonorrhoeae were
We searched for epidemiological data which detected from 1–10% or 1–11%, respectively.
included the prevalence of both N. gonor- There were no differences in the prevalence
rhoea and C. trachomatis. In addition, the rates among the tested countries. In NGU,
pathogenicity of M. genitalium in male the tested pathogens could not be compared
urethrits has been strongly supported by directly. The prevalence of C. trachomatis
a well-done recent meta-analysis. Jensen was almost one to three times higher than
performed a meta-analysis of epidemiologi- the prevalence of M. genitalium. Thus, urol-
cal studies of M. genitalium PCR positivity ogists should consider both C. trachomatis
and male urethritis from 1993–2003 [7]. and M. genitalium as important pathogens
We added new epidemiological data from in NGU.
recently published articles to Jensen’s
analysis.
The prevalence of the major bacterial 3.2 The pathogenicity of
pathogens in males with urethritis found M. genitalium in NGU
in 35 papers is summarized in Table 2. In the last five years, 13 papers were
identified including one meta-analysis
[7], seven case-controlled studies and five
Tabel 1 Microorganisms for considering the causative case-series (Table 4). In patients with
pathogens for male urethritis. NGU or non-chlamydial NGU, the prev-
alence of M. genitalium was 15.0% and
• Gonococcal urethritis 14.9%, respectively. The odds ratio in all
Neisseria gonorrhoeae
epidemiological studies of M. genitalium
• Non-gonococcal urethritis (NGU) PCR-positivity in patients with NGU was
Chlamydia trachomatis 3.61 (95%CI: 3.00–4.34). These findings
Mycoplasma genitalium strongly suggest that that M. genitalium
Ureaplasma urealyticum (biovar 2) is a causative agent for male urethritis
Neisseria meningitides
(GoR B).
Haemophilus species
Gardnerella vaginalis
Candida species
Trichomonas vaginalis 4. ANTIMICROBIAL SUSCEPTIBILITY
Herpes simplex virus 1
Herpes simplex virus 2
To determine the appropriate treatment
adenovirus
for male urethritis, it was necessary to
779
Table 2 Evidence table for recent studies of the prevalence of pathogens for male urethritis that include original data,
systematic reviews or meta-analysis, expert opinion, or other data (2003–2008).
Lead author
Year Level of
Study type Reference Study area Design evidence
Systematic review,
Meta-analysis
(NGU) Jensen [7], 2006 Meta-analysis data, 2,261 men 1

with NGU and 2,107 men
without urethritis
Randomized
cohorting study
(urethritis) Geisler [55], 2005 North America, USA 2,266 men with urethritis 2
Newman [56], 2006 North America, USA 38,095 men attended to STD 2
clinic in USA
Massari [57], 2006 Western Europe, FRA 859 cases of urethritis 2
Case controlled
study
(urethritis) Dupin [53], 2003 Western Europe, FRA 83 men with urethritis, 3
60 men with urethral
symptoms but no urethritis,
and 50 asymptomatic men
Salari [58], 2003 Asia, IRI 125 men with NGU and 125 3
control
Schlicht [59], 2004 North America, USA 26 symptomatic men and 3

67 healthy men
Kohl [60], 2004 North America, USA 20,451 men with urethritis and 3
23,188 asymptomatic menf
Sturm [61], 2004 Africa, RSA 335 men with symptoms and 3
100 men without symptoms
Deguchi [62], 2004 Asia, JPN 572 men with urethritis and 3
141 men without urethritis
Iser [63], 2005 Oceania, AUS heterosexual men with 3

symptoms (80) and without
symptoms (79)
Gaydos [64], 2006 North America, USA 862 symptomatic men and 3
16,850 asymptomatic men
Bradshaw [65], 2006 Oceania, AUS 329 NGU and 307 control 3
Vesic [66], 2007 Eastern Europe, 630 men with urethral 3

Serbia symptoms
Lewis [67], 2008 Africa, RSA 27 symptomatic, 274 3

asymptomatic men
Yu [68], 2008 Asia, HKG 98 men with urethritis and 236 3

men without urethritis
780
Urethritis | 14.3 |
Lead author
Year Level of
Non-randomized
cohorting study
(urethritis) Varela [69], 2003 Western Europe, ESP 1116 men with urethritis 3
Jensen [70], 2004 Western Europe, DEN In 1,852 specimens, 6.8% was 3
positive for MG-PCR
Talor-Robinson [71], Western Europe, UK 52 men with recurrent or 3

2004 persistant NGU
Maeda [72], 2004 Asia, JPN 153 men with NGU 3
Anagrius [73], 2005 Western Europe, DEN Cross-section study. 501 male 3
STD clinic attendees
Dolapci [74], 2005 Asia, TUR 63 mne with urethral 3

symptoms
Leung [75], 2006 Western Europe, UK 680 men attending to 3

genitourinary medicine
Gubelin [76], 2006 South America, CHI 23 NGU and 14 NG 3
Stamm [38], 2007 North America, USA 170 men with urethritis 3
Lee [77], 2007 Asia, KOR 70 urine from men with 3

urethritis
Yokoi [78], 2007 Asia, JPN 309 men with NGU 3
Davies [79], 2007 Asia, INA 273 men with urethritis 3
(screening in the Kahn [80], 2005 North America, USA 98,296 males 3
general population)
Leutscher [81], 2005 Africa, MAD 240 men in MAD 3
Lee [82], 2005 Asia, KOR 202 male students 3
Amirkhanian [83], Eastern Europe, RUS 125 MSM 3

2006
Chen [84], 2006 Asia, CHN 530 track-drivers 3
Benn [85], 2007 Western Europe, UK 613 MSM 3
Gunn [86], 2008 North America, USA 7,333 MSM 3
Abbreviations:
CT: Chlamydia trachomatis, NG: Neisseria gonorrhoeae, MG: Mycoplasma genitalium, GU: gonococcal urethritis, NGU: non-gonococcal urethritis,
MSM: men who have sex with men.
Abbreviations of countries: CHI: Chile, CHN: China, DEN: Denmark, EST: Estonia, FRA: France, HKG: Hong Kong, INA: Indonesia, JPA: Japan, KOR:
Korea, MAD: Madagascar, NED: The Netherlands, TUR: Turkey, RSA: South Africa, RUS: Russia, UK: United Kingdom, USA: United State of America.
781
Table 3 The detectionrates of causative pathogens fome urethritis in males with or without urethritis from recent published data.
782
Author Pub. year
Country Test year
n NG CT MG UU UP TV others n NG CT MG UU UP MH others
European countries
Dupin [53] FRA 2003 83 a 15.0 20.5 21.7 25.9 - 0 60 b 2.9 3.3 0 21.6 - -
2001
50c 4.0 1.0 0 - - 0
Varela [69] ESP 2003 1116d 2.4 3.9 - 33.5 - 0.9 HSV 0.2 - - - - - - - -
1995–2000 GV 0.4
Leung [75] UK 2006 302e 8.9 20.9 10.9 - - - - 378f 0.5 0.8 3.2 - - - -
unknown
Massari [57] FRA 2006 859g 21 25 8 5 - 3 - - - - - - - -

1997–2003
Vesic [66] Serbia 2007 320h 17.5 25.6 - 24.1 - 31.6 - - - - - - -

2004–2006
310i 0 14.5 - 18.7 - 26.5 - - - - - - - -
Asian countries
Deguchi [62] JPN 2004 572a 44.6 37.9 9.1 12.2 5.6 - - 141f 0 3.5 1.4 7.8 13.5 - -
1999–2002
Dolapci [74] TUK 2005 63a 9.5 6.3 6.3 4.8

2003–2004
Lee [77] KOR 2007 70d 32.9 22.9 27.1 7.1 - - - - - - - - - -

unknown
Yokio [78] JPN 2007 380j 10.0 21.8 4.2 8.5 2.1 - - - - - - - - -
1999–2005
Davies [79] INA 2007 273d 18.2 10.1 - - - - - - - - - - - -

1999
Author Pub. year
Country Test year
n NG CT MG UU UP TV others n NG CT MG UU UP MH others
Schlicht [59] 2004 26g 11.5 15.4 11.5 Ureaplasma - 67k 0 0 2.2 - - -
USA 1999–2000 sp. 61.5
Geisler [55] USA 2005 2266g 28.1 23.3 - - - - -

1998–2002
Kohl [60] USA 2005 20451g 34.7 12.5 - - - - - 23188f 3.8 6.7
1995–1999
Gaydos [64] USA 2006 8629 20.4 22.6 - - - - 16850f 1.4 6.4 - - - - -
1999–2003
South American
Gubelin [76] CHI 2006 37g 37.8 21.6 8.1 Ureaplasma - - - - - - - -

unknown sp. 35.1
-
African countries
Sturm [61] RSA 2004 335a 51.9 16.4 5.1 36.1 - 5.7 HSV 5.7 100k 0 8.0 3.0 30.0 - - HSV
2000 31.0
Lewis [67] RSA 2008 27g 22.2 3.7 7.4 - - 22.2 - 274c 4.7 9.1 6.6 - - -
2006
screening for pathogens of urethritis among the general population of men
Lee [82] KOR 2005 - - - - - - - 202k 0.5 5.0 - - - - -

unknown
Kahn [80] USA 2005 - - - - - - - 31263k 1.8 6.2 -

2002
Leutscher [81] 2005 - - - - - - - - 240k 4.6 4.6 4.6 - - -

MAD unknown
Amirkhanian [83] 2006 - 125l 2.4 4.8 - - - -

RUS 2003
783
continued
Table 3 The detectionrates of causative pathogens fome urethritis in males with or without urethritis from recent published data – cont'd
784
Chen [84] CHN 2006 - - - - - - - - 530m 10.6 8.1 - - - - -
2000
Benn [85] USA 2007 613i 7.2 4.3

1999–2001
Gunn [86] USA 2008 7333l 10.8

1997–2003
a
Patients with urethral symptoms and with microscopic signs of urethritis.
b
Patients with urethral symptoms and without microscopic signs of urethritis.
c
Asymptomatic men.
d
Patients who were screened for sexually transmitted infection.
e
Asymptomatic patients with microscopic signs of urethritis.
f
Patients without clinical signs of urethritis.
g
Patients who were diagnosed as urethritis by clinician.
h
Patients who were diagnosed as urethritis and with urethral discharge.
i
Patients who were diagnosed as urethritis and without urethral discharge.
j
Patients with gonococcal urethritis.
k
Men in general population.
l
Men who have sex with men (MSM).
m
Male military recrut.
Abbreviations: NG: Neisseria gonorrhoea, CT: Chlamydia trachomatis, MG: Mycoplasma genitalium, UU: Ureaplasma urealyticum, UP: Ureaplasma parvum, TV: Trichomonas vaginalis, HSV: Herpes simplex virus, GV: Gardnerella
vaginalis, AV: Adenovirus.
Abbreviations of countries: CHI: Chile, CHN: China, ESP: Spain, EST: Estonia, FRA: France, INA: Indonesia, JPN: Japan, KOR: Korea, MAD: Madagascar, RSA South Africa, RUS: Russia, TUR: Turkey, UK: United Kingdom, USA: United
State of America.
Table 4 Clinical studies of the presence of M. genitalium by nucleic acid amplification tests.
Published Country No with No with No w/o Evidence

Author year for test NGU Mg(+) %MG NCNGU Mg(+) %MG NGU MG(+) %Mg Study type level
Jensen [7] 2005 2261 470 20.8 1336 290 21.7 2107 124 5.9 Meta-analysis 1
OR 4.20 (3.41–5.17)
P<0.001*
Salari [58] 2003 IRI 125 9 7.2 125 1 0.8 Case control 3
OR 9.62 (1.20–77.12)
P:0.024
Jensen [70] 2004 SWE 1852 126 6.8% 1610 116 7.2 Case series 3
Maeda [72] 2004 JPN 153 26 17.0 80 19 23.8 Case series 3

a
Taylor-Robinson [71] 2004 UK 52 11 21.2 Case series 3
Sturm [61] 2004 RSA 45 5 11.1 16 3 18.8 100 3 3.0 Case control 3
OR 4.04 (0.92–17.72) OR 7.46 (1.36–40.9)

P:0.11 P:0.043
Deguchi [62] 2004 JPN 317 40 12.6 161 28 17.4 141 2 1.4 Case control 3
OR 7.26 (1.71–30.85) OR 14.63 (3.42–62.63)

P:0.004 P<0.001
Anagurius [73] 2005 SWE 276b 26 9.4 252 26 10.3 222c 2 0.9 Case control 3
OR 11.44 (2.68–48.75) OR 12.65 (2.97–53.96)

P<0.001 P<0.001
Iser [63] 2005 AUS 80 5 6.0 79 1 1.3 Case control 3
OR 5.20 (0.59–45.56)
P:0.22
Bradshow [65] 2006 AUS 329 31 9.4 307 3 1 Case control 3
OR 10.54 (3.19–34.85)
P<0.001
Gubelin [76] 2006 CHI 23 3 13.0 Case series 3
785
continued
Table 4 Clinical studies of the presence of M. genitalium by nucleic acid amplification tests. – cont'd
786
Published Country No with No with No w/o Evidence
Author year for test NGU Mg(+) %MG NCNGU Mg(+) %MG NGU MG(+) %Mg Study type level
Stamm [38] 2006 USA 111 28 25.2 Case series 3
Yu [68] 2008 HKG 98 10 10.2 236 5 2.1 Case control 3
OR 5.25 (1.75–15.79)
P:0.003
subtotal 3461 320 9.2 2119 192 9.1 1210 17 1.4
OR 7.15 (4.37–11.70) OR 6.99 (4.24–11.54)

P<0.001 P<0.001
Total 5722 790 13.8 3455 482 14.0 3317 141 4.3
OR 3.61 (3.00–4.34) OR 3.65 (3.01–4.43)

P<0.001 P<0.001
* Odds ratio (95% CI: conficence interval).

Abbreviations: MG: Mycoplasma genitalium, NGU: non-gonococcal urethritis, NCNGU: non-chlamydial non-gonococcal urethritis.
a
recurrent or persistent non-gnococcal urethritis.
b
Patients with more than 5 polymorphonuclear leukocytes in the urinary sediment of the first pass urine.
c
Patients with less than 4 polymorphonuclear leukocytes in the urinary sediment of the first pass urine.
Abbreviations of countries : AUS: Australia, CHI: Chile, DEN: Denmark, HKG: Hong Kong, IRI: Iran, JPN: Japan, SWE: Sweden, UK: United Kingdom, USA: United State of America.
Urethritis | 14.3 |
analyse the data on the antimicrobial strains have been increasing [26–28].
susceptibilities of the causative bacteria, We do not have sufficient information to
e.g. N. gonorrhoeae, and M. genitalium. determine the grading of AZM-regimens
In many countries, rates of fluoroqui- for GU [29–30] and this represents an
nolones-resistant N. gonorrhoeae are important concern.
increasing. The CDC announced that We identified four papers that evalu-
fluoroquinolones are no longer recom- ated antimicrobial susceptibilities of
mended for gonococcal infections in 2007 M. genitalium including three experimen-
[2]. Therefore, the susceptibility rates of tal papers and one case report describing
N. gonorrhoeae against fluoroquinolones an azithromycin (AZM)-resistant M. gen-
in particular were examined. In addition, talium strain[31]. Papers of antimicrobial
some reports about less susceptible strains susceptibility testing were very limited.
of N. gonorrhoeae against cefixime or Antimicrobial susceptibility testing for
ceftriaxone are very important to detem- M. genitalium has been performed by
ine the recommended regimens for GU. the broth-dilution method, but a newer
Regarding the antimicrobial suscep- method by using real-time PCR is being
tibilities of N. gonorrhoeae, we identi- trialled [31–32] as the isolation of M.
fied one systematic review [12] and 32 genitalium strains which can grow in the
papers that met the inclusion criteria mycoplasma-broth has been difficcult and
including: five case reports of cefixime- time-consuming [32]. M. genitalium was
resistant strains and two experimental more susceptible to macrolides such as
papers (Table 5). The prevalence rates of AZM or clarithromycin (CLR) and newer
fluoroquinone-resistant N. gonorrhoeae fluoroquinolones as moxifloxacin (MXF)
were shown in Newman’s review [12]. or sitafloxacin in vitro [32–34]. However,
Geographic regions reporting the high- azithromycin-resistant strains have been
est rates of ciprofloxacin (CIP)-resistance reported [31, 35].
were Asian countries where resistance We identified only one paper describ-
rates are up to 40–100% (Table 6). In ing the antimicrobial susceptibility of
Europe, resistance rates varied from C. Trachomatis. This paper was a case
10–50%. In the USA, a nationwide survey report describing one AZM-resistant
found 13.8% resistance rates in 2006. In strain [36]. We found another case report
New Caledonia, the CIP resistant strains describing multiple drug-resistant C. tra-
were not detected in 2006. These obser- chomatis strains published in 2000 [37].
vations suggest that CIP-resistant N. This study showed three clinical strans
gonorrhoeae strains are spreading world- resistant to DOX, AZM and ofloxacin.
wide. Resistance rates of N. gonorrhoeae
strains to penicillins or tetracyclines are
over 15% in many regions. In some coun- 5. TREATMENT
tries such as Japan, Sweden or Australia,
cases of treatment failure after cefix- All clinical trials of antibiotics against male
ime therapy and detection of cefixime- urethritis were also listed. The clinical effi-
resistant strains were reported [13–17]. cacy of antimicrobials against each patho-
In addition, less susceptible strains to gen, e.g. N. gonorrhoeae, C. trachomatis
ceftriaxone were reported from Italy [9], and M. genitalium was listed. Using these
Sweden [9, 18], Russia [19] Japan [16] and data for antimicrobial susceptibilities and
South Africa [20]. Fortunately, N. gonor- clinical treatment trials, the recommended
rhoeae resistance rates to ceftriaxone or regimens for male urethrits and their
spectinomycin remain very low [21–25]. grade of recommendation grade according
Recently, AZM-resisitant N. gonorrhoeae to ICUD standards [10–11] are shown.
787
Tabel 5 Evidence table for recent studies of antimicrobial susceptibilities of N. gonorrhoeae or M. genitalium that include
original data (susceptibility data), systematic reviews or meta-analysis, expert opinionand case reports of antimicrobial-resistant
strains of N. gonorrhoeae, M. genitalium or C. trachomatis, (2003–2008).
Lead author
Year Level of
Systematic review
(N. gonorrhoeae) Newman [12], 2007 Systematic review of fluoroqu- 1

inolone-resistant NG
Non-randomized
cohorting study
(N. gonorrhoeae) Martin [9], 2006 Western Europe susceptibilities of NG in 2

coountries of Western Europe,
2004
GRASP [87], 2006 Western Europe, UK Susceptibilities of NG in UK, 2

2006
Tapsall [88], 2006 Western Pacific susceptibility of NG in 16 2

countries of the Western
Pacific Region, 2005
GISP-2005 [89], 2006 North America, USA Susceptibilities of NG in USA, 2

2005
Euro-GASP [90] 2007 Western Europe Suceptibilities of NG in 16 2

Western European counties,
2006–2007
AUS-GSP [91], 2007 Oceania, AUS Susceptibility of NG in AUS, 2

2006
CDC up-date [2], 2007 North America, USA CDC guideline up-date 2
GISP-2006 [92], 2007 North America, USA Susceptibilities of NG in USA, 2

2006
AUS-GSP [93], 2008 Oceania, AUS Susceptibility of NG in AUS, 2

2007
Case series (in vitro

susceptibility)
(N. gonorrhoeae) Arreaza [26], 2003 Western Europe, ESP MICs of NG against AZM, 3
1991–2001. AZM-resistant
strains were incresing.
Llanes [25], 2003 Central America, CUB MICs of NG in Cuba, 3

1995–1999
Su [22], 2004 Asia, CHN susceptibility of NG in China, 3

1999–2006
Yoo [94], 2004 Asia, KOR susceptibility of NG in KOR, 3

1999–200
Shigemura [95], 2004 Asia, JPN susceptibility of NG in Japan, 3

2002
Aydin [96], 2005 Asia, TUR MICs of NG in TUR 3

1998–2002
Enders [97], 2006 Western Europe, GER MICs of NG in GER 3

2004–2005
788
Urethritis | 14.3 |
Lead author
Year Level of
Stathi [98], 2006 Western Europe, GRE suceptibility and MICs of NG 3

in GRE, 1994–2004
Wang [23], 2006 Asia, CHN MICs of NG in CHN, 2003 3
Yang [99], 2006 Asia, CHN MICs of NG in CHN, 2004 3
Donegan [100], 2006 Asia, INA MICs of NG in INA 2004 3

Shigemura Shigemura
Moodley [20], 2006 Africa, RSA susceptibilities of NG in RSA, 3

2003
Vazquez [101], 2007 Western Europe, ESP susceptibility of NG in ESP, 2005 3
Vorobieva [19], 2007 Eastern Europe, RUS Susceptibility of NG in RUS, 3

2004
Hovhannisyan [102], Eastern Europe, ARM susceptibilities of NG in ARM, 3

2007 2003–2004
Belda Junior [24], 2007 South America, BRA MICs of NG in BRA 3

2004–2005
De Jongh [103], 2007 Africa, RSA susceptibility of NG in RSA, 3

2004–2005
Olsen [104], 2008 Western Europe, SWE susceptibility of NG in 3

Sweden, 2005
Palmer [27], 2008 Western Europe, UK AZM-resistant strains are 3

increasing in UK.
Kubanova [21], 2008 Eastern Europe, RUS susceptibilities of NG in RUS, 3

2005–2006
Ilina [105], 2008 Eastern Europe, RUS MICs of NG against in RUS, 3

2004
Khaki [30], 2008 Asia, IND susceptibility of NG in India, 3

2005–2006
Muratani [42], 2008 Asia, JPN Susceptibility of NG in JPN, 3

2004–2006
Case reports
(N. gonorrhoeae) Ito [13], 2006 Asia, JPN Cefixime-resistant NG in JPN 3
Lindberg [18], 2007 Western Europe, SWE reduce susceptible Ng strains 3

to Cefixime or ceftriaxone
Yokoi [14], 2007 Asia, JPN cefime-treatment failure in GU 3
Ochiai [15], 2008 Asia, JPN reduced susceptible NG to 3

cepharosporins in JPN
Osaka [16], 2008 Asia, JPN less susceptible strains to 3

cefixime or ceftriaxone
(C. trachomatis) Magbanua [36], 2007 Western Europe, UK A variant CT and AZM- 3
resistant in UK
(M. genitalium) Jensen [31], 2008 Western Europe, Analysis of AZM-resistant stra- 3
DEM ins, mutation in 23S rRNA
continued
789
Tabel 5 Evidence table for recent studies of antimicrobial susceptibilities of N. gonorrhoeae or M. genitalium that include
original data (susceptibility data), systematic reviews or meta-analysis, expert opinionand case reports of antimicrobial-resistant
strains of N. gonorrhoeae, M. genitalium or C. trachomatis, (2003–2008) – cont'd
Lead author Level of

Study type Year Study area Design evidence
Reference
Experimental study
(N. gonorrhoeae) Lundback [28], 2006 Western Europe, SWE 10 AZM-resistant NG strains 4
Whiley [17], 2007 Oceania, AUS penA mutation of NG 4

strains with less susceptible to
cefixime
(M. genitalium) Yasuda [34], 2005 Asia, JPN MICs of MG against 4

fluoroquionolones
Hamasuna [32], 2005 Asia, JPN MICs of MG 4
Bebear [33], 2008 Western Europe, FRA MICs of MG 4
Expert opinion
(N. gonorrhoeae) Geisler [55], 2005 North America, USA CDC guideline 4
Abbreviations:
CT: Chlamydia trachomatis, NG: Neisseria gonorrhoeae, MG: Mycoplasma genitalium, GU: gonococcal urethritis, AZM: azithromycin, MICs:
minimum inhibitory concentrations, GRASP The Gonococcal resistance to Antimicrobials Surveillance Programme, GISP: Gonococcal Isolate
Surveillance Project, Euro-GASP: European Gonococcal Antimicrobial Surveillance Program, AUS-GSP: Australian Gonococcal Surveillance Programme.
Abbreviations of countries:
ARM: Armenia, AUS: Australia, BRA: Brazil, CHN: China, CUB: Cuba, DEN: Denmark, ESP: Spain, FRA: France, GER: Germany, GRE: Greece, HKG:
Hong Kong, IND: India, INA: Indonesia, JPA: Japan, KOR: Korea, NOR: Norway, SWE: Sweden, TUR: Turkey, RSA: South Africa, RUS: Russia,
UK: United Kingdom, USA: United State of America.
5.1 Clinical studies [29–30], CIP [40], ceftibuten [41], ceftriax-

We identified 24 studies on antimicrobial one [42] and cefodizime [43–44] for treat-
therapy of male urethritis that met our inclu- ment of GU.
sion criteria: 11 papers evaluating treatment For chlamydial urethrits, we identi-
of GU, three papers for chlamydial urethri- fied one meta-analysis [45], two RCT [38,
tis, 10 papers for M. genitalium urethritis 46] and one case series [47]. Lau’s meta-
and one paper for the three causative bacte- analysis [45] was important to determine
ria (Table 7). For gonococcal urethritis, one the recommendation for treatment with
sytematic review, one randomized controlled AZM or doxycycline (DOX) for chlamydial
study and eight case-series were included. urethritis. The RCTs compared Rafalazil
Newman performed a systematic review to AZM [38] and travafloxacin to DOX
of clinical studies of oral cephalosprins and [46]. A case series was reported of travo-
macrolides for gonorrhea, which were pub- floxacin for treatment of chlamydial ure-
lished between 1988 and 2001. The RCT thritis [47]. For M. genitalium urethritis,
compared Rafalazil to AZM [38]. Kojima et we identified one review [7], two RCTs
al. conducted a case-series of 2 g spectino- [38, 48], three case-controlled studies
mycin for GU [39], providing an important [35, 49–50] and four case series [51–54].
evaluation of the alternative regimen for The most important RCT was written by
GU recommmended in most guidelines. Jernberg et al., who evaluated the clinical
Other papers reported results of AZM efficacy of AZM and MXF in Norway [48].
790
Table 6 Antimicrobial susceptibilities of N.gonorhoeae isolated from any regions in recent published studies.
Penicillin (%) Tetracycline (%) Ciprofloxacin (%) Ceftriaxone (%) Spectinomycin (%) Azithromycin (%)
Less Less Less Less Less

Tested Tested Resistant susceptible Resistant susceptible Resistant susceptible susceptible Resistant susceptible Resistant
Country year strains ≥2 mg/l 0.12–1 mg/l ≥2 mg/l 0.5–1 mg/l ≥1 mg/l 0.12–0.5 mg/l >0.25 mg/l ≥125 mg/l 64 mg/l ≥1 mg/l Others Author
Western Europe
ESSTI 2006– PPNG:12.3,

2246 TRNG 16.5 52.0 0 0 NT NT 7.0 EGASP [90]
2007 CMRNG:31.1
AUT 2004 96 22.9a nd 55.2b nd 53.1 0 0 nd nd 31.2 Martin [9]
BEL 2004 64 26.5a nd 70.2b nd 46.9 0 0 nd nd 1.6 Martin [9]
a b
DEN 2004 98 28.3 nd 76.5 nd 46.0 5.1 0 nd nd 8.2 Martin [9]
ENG 2006 1313 9.5 nd 36.9 nd 26.5 1.7 0 0 0 2.0 GRASP [87]
ENG+WAL 2004 100 13.0a nd 72.0 b nd 12.0 0 0 nd nd 1.0 Martin [9]
FRA 2004 101 12.9a nd 75.2b nd 32.7 2.0 0 nd nd 0 Martin [9]
GER 2004–
65 21.5 70.5 29.2 63.1 47.7 0 0 0 0 7.7 Enders [97]
2005
GRE 2005 142 16.2 73.2 12.7 83.1 11.3 0 0 0 0 nd Stathi [98]
GRE 2004 79 14.0a nd 51.9 b* nd 7.6 1.3 0 nd nd 0 Martin [9]
a b
ITA 2004 42 19.0 nd 52.4 nd 33.3 4.8 4.8 nd nd 9.5 Martin [9]
NED 2004 81 25.9a nd 59.2b nd 16.0 0 0 nd nd 17.3 Martin [9]
POR 2004 17 11.8a nd 70.6b* nd 17.6 0 0 nd nd 0 Martin [9]
a b
SCO 2004 99 29.4 nd 48.6 nd 30.3 1.0 0 nd nd 5.1 Martin [9]
ESP 2005 204 31 59 36 49 43 7 0 nd nd nd Vazquez [101]
791
continued
Table 6 Antimicrobial susceptibilities of N.gonorhoeae isolated from any regions in recent published studies – cont'd
792
Spectinomycin Azithro-
Penicillin (%) Tetracycline (%) Ciprofloxacin (%) Ceftriaxone (%)
(%) mycin (%)

Tested Tested Resistant susceptible Resistant susceptible Resistant susceptible susceptible >0.25 Resistant susceptible Resistant
Country year strains ≥2 mg/l 0.12–1 mg/l ≥2 mg/l 0.5–1 mg/l ≥1 mg/l 0.12–0.5 mg/l mg/l ≥125 mg/l 64 mg/l ≥1 mg/l Others Author
ESP 2004 92 10.9a nd 54.4b nd 15.2 8.7 0 nd nd 2.2 Martin [9]
a b
SWE 2004 96 32.5 nd 71.8 nd 48.0 3.1 1.0 nd nd 13.5 Martin [9]
Eastern Europe
ARM 2003– Hovhannisyan

101 5.9 56.4 3.0 71.3 4.0 1.0 0 0 0 0
2004 [102]
RUS 2006 521 17.5 57.3 40.3 34.2 48.6 2.9 0 0.8 7.1 nd Kuvanova [21]
RUS 2004– Ilina [105]

464 11.9 62.2 38.1 26.0 45.5 0.4 nd nd nd nd
2005
RUS 2004 76 18.4 57.9 11.8 80.3 17.1 0 2.6 0 0 14.5d Vorobieva [19]
Asia
BRU 2006 PPNG:38.6,

208 nd nd 57.7 24.0 nd nd nd nd WP-GSP [88]
CMRNG:25.6
CHN 2006 TRNG:11.1

196 87.3 12.7 98.9 1.0 38.8e 2.0 0 nd Su [22]
PPNG/TRNG*21.7
CHN 2006 1134 PPNG:47.7 TRNG:35.2 94.2 5.4 nd nd nd nd WP-GSP [88]
CHN 2004– 159

81.2 6.9 56.6 26.4 98.7 0.6 0 0 1.9 nd Yang [99]
2005
CHN 2003 96 68.4 31.6 78.9 20.0 100 0 0 1.1 4.2 nd Wang [23]
HKG 2006 1622 PPNG:34.1,

TRNG:48.9 75.8 2.0 nd nd nd nd WP-GSP [88]
CMRNG:28.6
IND 2005– 75
32.0 66.7 30.1 22.7 98.7 1.3 0 0 0 0 Khaki [30]
2006
INA 2004 147 81.6 18.4 100 0 40.1 2.0 0 0 0 0 Donegan [100]
JPN 2006 211 PPNG:0.9,CMRNG:21.8 TRNG:0.9 75.8 7.0 nd nd nd nd WP-GSP [88]
h
JPN 2002 87 CFX-LS
19.5 70.1 19.5 39.1 69.0 21.7 0 0 0 nd Shigemura [95]
:9.2%
KOR 2002 209 58.9 36.8 82.8 14.8 48.8 35.9 0 0 0 Nd Yoo [94]
MAS 2006 34.4 nd nd nd 44.8 17.2 nd nd nd nd WP-GSP [88]
PHI 2006 42 PPNG:50.0,

TRNG:31.0 69.0 0 nd nd nd nd WP-GSP [88]
CMRNG:28.5
SIN 2006 160 PPNG:49.4,

TRNG:76.8 61.8 8.2 nd nd nd nd WP-GSP [88]
CMRNG:10.0
TUR 1998– 78
25.6 38.5 18.0 57.7 1.3 1.3 0 nd nd nd Aydin [96]
2002
VIE 2006 212 PPNG:30.7,CMRNG:0.5 TRNG:16.5 56.6 25.5 nd nd nd nd WP-GSP [88]
North America
CFX-LS GISP-2006
USA 2006 6089 11.4f nd 20.1b nd 13.8 1.2 0 0 0 0.2g
1 strain [92]
USA 2005 6199 GISP-2005

13.0 f Nd 17.2 b Nd 9.4 1.1 0 0 0 2.9
[89]
South America or Caribbean countries
BRA 2004– 65
23.1 76.9 30.8 61.5 nd nd nd 0 9.2 nd Belda [24]
2005
CUB 1995– 120

60.2 5.0 54.2 10.0 0 0.9 0 0 1.7 0 Llanes [25]
1999
Africa
RSA 2003 139 35.4 60.6 79.0 15.0 22.0 0 2.0 0 0 nd Moodley [20]
RSA 2004– 141 De Jongh

29.1 53.9 nd 7.1 0 0 0 0 0 nd
2005 [103]
Oceania
AUS 2007 3042 PPNG:12.1,

TRNG:16.6 47.9 1.2 0 0 0 nd AUS-GSP [93]
CMRNG:26.2
NC 2006 93 PPNG:0,CMRNG:0 TRNG:2.1 0 0 nd nd nd nd WP-GSP [88]
793
continued
Table 6 Antimicrobial susceptibilities of N.gonorhoeae isolated from any regions in recent published studies – cont'd
794
Spectinomycin Azithro-
Penicillin (%) Tetracycline (%) Ciprofloxacin (%) Ceftriaxone (%) (%) mycin (%)

Tested Tested Resistant susceptible Resistant susceptible Resistant susceptible susceptible >0.25 Resistant susceptible Resistant
Country year strains ≥2 mg/l 0.12–1 mg/l ≥2 mg/l 0.5–1 mg/l ≥1 mg/l 0.12–0.5 mg/l mg/l ≥125 mg/l 64 mg/l ≥1 mg/l Others Author
NZL 2006 284 PPNG:1.0,CMRNG:20.4 TRNG:25.0 13.7 0 nd nd nd nd WP-GSP [88]
PNG 2006 53 PPNG:43.4 nd nd 1.8 0 nd nd nd nd WP-GSP [88]
nd: no description
a
Strains of PPNG, PP/TRNG or CMRNG.
b
Strains of TRNG, PP/TRNG, CMRNG or TetR.
c
Resistant rate to ampicillin.
d
Azithromycin less susceptible.
e
Strains with ≥0.06 of MIC were determined less susceptible.
f
Strains of PPNG, PPNG/TRNG, CMRNG or PenR.
g
Strains with ≥2 of MIC were determined resistant.
h
Cefixime-less susceptible strains.
PPNG: Penicillin:β-lactamase +ve and tetracycline:MIC< 16 mg/l.
TRNG: Tetracycline:MIC≥ 16 mg/l and paenicillin β-lactamase –ve.
PP/TRNG: Penicillin:β-lactamase +ve and tetracycline:MIC≥16 mg/l.
CMRNG: Penicillin:MIC≥1 mg/l but β-lactamese –ve and tetracycline:MIC between 2–8 mg/l.
PenR: Penicillin: ≥1 mg/l but β-lactamase –ve and tetracycline:MIC <2 mg/l.
TetR: Tetracycline:MIC between 2–8 mg/l and penicillin: <1 mg/l.
EGASP: Europe Gonococcal Antimicrobial Surveillance Programme. Euro-GASP Annual report No.2 2007[90].
GRASP: the Gonococcal Resintance to Antimicrobials Surveillance Programme, GRASP Annual report 2006[87].
GISP-2006: Gonococcal Isolate Surveillance Project (GISP), Annual Report 2006[92].
GISP-2005: Gonococcal Isolate Surveillance Project (GISP), Annual Report 2005[89].
WP-GSP: Surveillance of antibiotic reisistace in Neissseria gonorrhoeae in the WHO Western Pacific Region, 2006[88].
Aus-GSP: Annual report of the Australian Gonococcal Surveillance Program, 2007[93].
Aus-GSP: Annual report of the Australian Gonococcal Surveillance Program, 2006[91].
ARM: Armenia, AUS: Australia, AUT: Austria, BEL Belgium, BRA: Brazil, BRU: Brunei, CHN: China, CUB: Cuba, DEN: Denmark, ENG: England, ESP: Spain, FRA: France, GER: Germany, GRE: Greece, HKG: Hong Kong, IND: India, INA:
Indonesia, ITA: Italy, JPA: Japan, KOR: Korea, MAS: Malaysia, NC: New Caledonia, NED: The Netherlands, NZL: New Zealand, PHI: Philippines, PNG: Papua New Guinea , POR: Portugal, SCO: Scotland, SWE: Sweden, SIN:　Singapore,
TUR: Turkey, RSA: South Africa, RUS: Russia, USA: United State of America, VIE: Vietnam, WAL: Wales.
Urethritis | 14.3 |
Tabel 7 Evidence table for recent studies of clinical trials of antibiotics to male urethritis that include systematic reviews or
meta-analysis, randomized controlled studies, case controlled studies, case series and expert opinion (1998–2008).
Study type Lead author Study area Design Level of

Year evidence
Reference
Systematic review,
meta-analysis
(N. gonorrhoea) Newman [12], 2007 Systematic review for treat- 1

ment of gonococcal infections
(C. trachomatis) Lau [45], 2002 Metaanalysis of treatment of 1

AZM and DOX for chlamydial
infection
(M. genitalium) Jensen [7], 2006 Review of MG studies 1
Randomized control-
led study
(N. gonorrhoea) Stamm [38], 2007 North America, USA Rafalazii, vs AZM, 111 men 1
with urethritis
(C. trachomatis)
(M. genitalium)
(C. trachomatis) MaComack [46], North America, USA Travafloxacin vs DOX, men 1
1999 202 with chlamydial urethritis
(M. genitalium) Jernberg [48], 2008 Western Europe, NOR Macrolides and moxyfloxacin, 1
234 MG-positive men
Case controlled study
(M. genitalium) Falk [49], 2003 Western Europe, SWE Clinical study of tetracyclines 2
(DOX or lymecycline) or AZM
1g, 16 men with NGU
Bradshaw [35], 2006 Oceania, AUS Clinical study of AZM 1g, 2

34 MG-positive men with or
without urethritis
Bjornelius [50], 2008 Western Europe, SWE Clinical study of AZM 1g and 2
DOX, 115 MG-positive men
Case series
(N. gonorrhoeae) Chong [41], 1998 Asia, HKG Clinical trial of ceftibuten, 112 3
men with G
Moodley [40], 2002 Africa, RSA Low dose of Ciprofloxacin, 3

442 men with GU
Matsumoto [43], Asia, JPN Clinical trial of cefodizime 1g, 3

2006 10 men with GU
Matsumoto [44], Asia, JPN Clinical trial of cefodizime 3

2006 1g for the NG-pharyngeal
infection
Habib [29], 2006 Asia, IND Clinical trial of AZM 1g, 135 3
men with GU
Kojima [39], 2008 Asia, JPN Clinical study of spectinomy- 3

cin 2g, 210 men with GU
Khaki [30], 2008 Asia, IND Clinical trial of AZM 2g, 52 3

men with GU
795
Tabel 7 Evidence table for recent studies of clinical trials of antibiotics to male urethritis that include systematic reviews or
meta-analysis, randomized controlled studies, case controlled studies, case series and expert opinion (1998–2008) – cont'd
Lead author
Year Level of
Muratani [42], 2008 Asia, JPN Clinical trial of ceftroaxone 3
1g, 27 men and 40 women
with gonorrhoeae
(C. trachomatis) Martin [47], 1999 North America, USA Clinical trial of travafloxacin,
64 men with CU
(M. genitalium) Johannisson [51], Western Europe, SWE Clinical trial of tetracycline 22 3
2000 MG-positive men
Maeda [52], 2001 Asia, JPN Clinical trial of levofloxacin, 3

12 men with NGU
Dupin [53], 2003 Western Europe, FRA Clinical trial of minocycline or 3

DOX, 8 MG-positive men
Wikstrom [54], 2006 Western Europe, SWE Clinical trial of AZM, 22 men 3
with recurrent or persistent
urethritis
Expert opinion
(N. gonorrhoeae) CDC up-date [2], North America, USA CDC guideline up-date 4
2007
Geisler [55]　2005 North America, USA CDC guideline 4
Abbreviations:
MG: Mycoplasma genitalium, GU: gonococcal urethritis, CU: chlamydial urethritis, NGU: non-gonococcal urethritis, AZM: azithromycin,
DOX: doxycycline.
Abbreviations of countries:
AUS: Australia, DEN: Denmark, HKG: Hong Kong, IND: India, FRA: France, JPA: Japan, NOR: Norway, RSA: South Africa, SWE: Sweden.
5.2 Recommendations for the • Cefixime 400 mg orally in a single dose

treatment of male patients • (Quinolone regimens no longer recom-
with urethritis mended [2])
The recommended management of male Alternative regimens
patients with urethritis is based on the
• Spectinomycin 2 g intramuscurally in
CDC 2006 guidelines [1] and on our review
a single dose
of the literature described above.
• Single-dose cephalosporin regimens
5.2.1 Definition of GU and NGU
The presence of Gram-negative intracel-
5.2.3 Treatment of NGU
lular diplococci (GNID) on urethral smear
is indicative of GU. NGU is diagnosed Recommended regimens
when microscopy indicates inflammation
• AZM 1g orally in a single dose
without GNID.
• DOX 100 mg orally twice a day for
5.2.2 Treatment of GU 7 days
Recomended regimens Alternative regimens
• Ceftriaxone 125 mg intramuscurally • Erythromycin base 500 mg orally for
in a single dose times a day for 7 daya
796
Urethritis | 14.3 |
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803
|14.4|
Pelvic infections in women

Gilbert G.G. Donders1,2,3, Jasper Verguts1
1
Department of Obstetrics and Gynaecology, University Hospitals Gasthuisberg, Leuven University, Belgium
2
Regional Hospital Heilig Hart, Tienen, Belgium
3
Citadelle Hospital, Liège University, Belgium
Corresponding author: Gilbert GG Donders MD PhD, Department of Obstetrics and Gynecology, University Hospital
Gasthuisberg, Herestraat 45, 3000 Leuven, Belgium
Tel +32344204, Fax +32813440, E mail: gilbert.donders@femicare.net
ABSTRACT these areas and often accounts for a major

part of healthcare expenses. Therefore,
Pelvic Inflammatory Disease (PID) is diffi- ambulatory treatment with oral antibiot-
cult to define, and therefore difficult to diag- ics is preferred in most cases, to be followed
nose and to treat. In order to be complete, by hospitalisation and laparoscopy only in
we include the diagnosis and treatment those cases where the response to therapy
of cervicitis, endometritis, salpingitis and is inadequate or the likelihood of compli-
pelvic/ovarian abscesses in the discussion. cations is high. Finally, screening, preven-
PID is caused by the ascension of bacte- tion and treatment of etiologic factors of
ria present or deposited in the vagina, and PID are most cost effective and should be
the most important risk factors for severe encouraged wherever possible.
disease are related to sexual behaviour. As Key words: pelvic infection, ascending
long term sequalae such as infertility, extra- infection, vaginitits, complications, infer-
uterine pregnancy and chronic pelvic pain tility, syndromic management
can be a consequence, increased considera-
tion of upper genital tract infection and low
threshold treatment are recommended,
however, not without extensive prior efforts SUMMARY OF RECOMMENDATIONS
to have a proper well documented and
refined diagnosis, as this greatly helps in 1. Former definitions of PID suggest
adjusting treatment if the response to syn- sexual activity is the obligate cause
dromic management is not optimal. Care of the disease, but in a vast number
was taken to leave open adequate diagno- of women with PID, no STI can be
sis and treatment in low resource settings, discovered; often Gram-positive
as PID is more frequently encountered in cocci, Gram-negative bacilli and
Pelvic infections in women | 14.4 |
mycoplasmata such as the newly 2. METHODS

discovered M. genitalis, are associated
with PID and also have to be This review aims to summarize in a
considered (GoR A). structured way an enormous body of lit-
2. Clinical diagnosis is not always erature on pelvic inflammatory disease
straightforward. However, it is crucial in women. We focused on recent dis-
to invest in a proper diagnosis of PID: coveries and insights in an effort to fill
laparoscopy should be performed in some of the huge number of gaps and
case of doubt (GoR A). missing links of a syndrome that used to
be ill-defined and lacked coherent treat-
3. Antibiotic treatment should be started
ment guidelines. Using the terms: pelvic
as soon as PID is suspected, however,
infection, supracervical infection, genital
if an insufficient clinical response is
infection and pelvic inflammatory disease
obtained after 48 hours, the diagnosis
as basic keywords, differential lists of
should be reconsidered and therapy
searches about pathogenesis, risk factors,
adjusted (GoR A).
diagnosis and management were saved
4. Perioperative antisepsis and antibiotics, and scanned for proper manuscripts. If
sexual education, and systematic decent papers containing evidence based
screening in adolescent women are the data (LoE 1, 2) were found during the
mainstays of prevention (GoR B) last 10 years, no further reading of older
papers was encouraged. Only if those
were not available, were older litera-
1. INTRODUCTION ture data from publications or textbooks
used. The recommendations given were
Pelvic Inflammatory disease (PID) is one therefore based on recent Level 1 or 2
of the first and most prominent infec- evidence.
tious syndromes ever described in the The studies were rated according
discipline of obstetrics and gynecology. to the level of evidence (LoE) and the
Before the discovery of the transmission grade of recommendation (GoR) using
mode of bacterial infection, PID was a ICUD standards (for details see Preface)
frequent condition and a major killer, [1–2].
especially amongst postpartum women,
caused by medical staff examining con-
secutive women without what is now con-
3. DEFINITION AND CLASSIFICATION
sidered proper antiseptic hand care. Soon
after this the ascending nature of these
bacterial infections, mainly by sexually 3.1 Definition
transmitted microorganisms, led to effi- Pelvic inflammatory disease (PID) is
cient antibiotic treatment. However, even defined as an infection of the uterus, fal-
now, the diagnosis of PID may be diffi- lopian tubes or ovaries related to sexual
cult and the clinical presentation vari- contact. Therefore, other pelvic infections
able, often causing delay in recognition caused by surgery, during pregnancy or
and the timely commencement of proper due to other abdominal processes are not,
antibiotherapy, leading to major seque- strictly considered, ‘PID’. This stringent
lae like pelvic pain, tubal infertility and diagnosis implying the need for sexual
extrauterine pregnancies. Hence a sys- contact is controversial because very often
tematic overview of the known and less only endogenous intestinal microorganisms
well known pitfalls and diagnostic tips can be recovered from the genital tracts
may be useful, and an update of a practi- of women with pelvic infections, espe-
cal therapeutic algorithm is given. cially in IUCD users and post-pregnancy
805
complications, and their sexual partners aerobic vaginitis (AV) intestinal faculta-
do not seem to be infected [3–8]. tive aerobic bacteria are mostly present,
usually accompanied by a more or less
3.2 Classification severe inflammatory response [9–10]. In
both conditions lactobacilli are depressed
PID has characteristically been consid- and the vagina has an increased pH. In
ered to have three grades of severity one out of seven women with BV, a sub-
based on laparoscopic findings. PID grade clinical PID can be diagnosed, charac-
1 means there is either endometritis or terized by endometritis on subsequent
erythema of the salpinx, or a combina- biopsy [11]. However, the precise role of
tion of both. In a grade 2 PID, the salp- BV in the pathogenesis of PID remains
inges are dark red and swollen (edema). controversial.
In a grade 3 PID the salpinx is filled with Whenever the cervical barrier becomes
pus (pyosalpinx) and exudation is found damaged, bacteria can ascend from the
in the pelvis. Tubo-ovarian abcedation vagina to infect the upper genital tract
(TOA) is also PID grade 3 according to [12]. The importance of this ascending
the definition. A tubo-ovarian complex is route is emphasized by the finding that
a name used for oedema of the salpinx 75% PID of cases begin during the first
which is adherent to the ovaria, uterus, seven days after menstruation [13–14].
pelvic wall, and/or bowel, but without
abscedation. In clinical practice the grad- 4.1 Etiology
ing is not always clear.
A number of urogenital pathogens have
established roles in PID.
4. ETIOLOGY, PATHOGENESIS AND
RISK FACTORS 4.1.1 Chlamydia trachomatis
C. trachomatis is a non motile, obliga-
In the US about one million women suf- tory intracellular bacterium. In the mid
fer from a symptomatic PID each year. Of 1970s it became clear that this micro-
women with symptomatic PID, 15–20% organism was a frequent cause of PID.
suffer complications requiring surgical After a dramatic decline in prevalence of
intervention. The prevalence of asympto- both incidence and complications (neona-
matic PID is unknown. tal conjunctivitis, tubal factor infertility,
The normal vaginal micro-flora con- ectopic pregnancy) as was noted in Europe
sists of a large spectrum of commensal [15–21], and in many developing coun-
and/or potentially pathogenic bacteria tries [22–23] a resurge of C. trachomatis
and fungi. These flora include different infected women appeared first in Sweden,
types of lactobacilli that contribute to a and subsequently in other European coun-
healthy environment of the vagina not tries [24–26]. This apparent increase may
allowing pathogenic bacteria to overgrow reflect better detection methods, higher
and transcend through the cervical canal. sampling frequencies, or an increase in
These normal vaginal lactobacilli have unsafe sexual practices in at risk popula-
varied properties that serve to maintain tions [27]. Also, some formerly unknown
the normal vaginal microenvironment, strains were detected in Scandinavia
including: adhesive capacity, produc- that were not detected using routine PCR
tion of H2O2, bacteriocins and lactic acid. techniques, including PCR [24]. Recently
Disturbance of the normal flora can some fluoroquinolone-resistant strains
cause anaerobic bacterial vaginosis (BV), have been discovered [28].
with typical absence of the inflammatory The incubation period for C. tracho-
immune response [9]. In patients with matis infection is 2 to 3 weeks. Once
806
infected, C. trachomatis can remain silent doxycycline (100 mg by mouth twice

for months if left untreated. The PID daily). During pregnancy, C. trachomatis
rate after an untreated infection is esti- can cause amnionitis and post-partum
mated to be 8-to-40% [14]. It is estimated endometritis (see below). Although off-
that approximately 70% of C. tracho- label, azithromycin can be used safely
matis infections remain asymptomatic. during pregnancy, and represents the
Asymptomatic salpingitis can cause tubal treatment of choice [36–37].
damage and subfertility without any
clinical signs.
After initial infection with C. tracho- 4.1.2 Neisseria gonorrhoeae
matis the risk of silent progression with N. gonorrhoeae is a Gram-negative aero-
intra-tubal scarring is high, in part due bic diplococus that was the first identi-
to upregulation of heat shock proteins fied cause of PID. Following availability
[29–30]. Chlamydial antigens can mimic of penicillin, gonorrhoea became less fre-
the autologous human antigens triggering quent. However, worldwide 1/3 of all PID
reflex production of heat shock proteins cases are caused by N gonorrhoeae.
that normally provide a useful defense Although 30–60% of women harbour-
against nonspecific challenges such as ing N. gonorrhoeae have no symptoms,
extreme temperatures or environmental such asymptomatic carriers can transmit
toxins. With recurrent infections and pro- the infection to others. If not detected and
duction of heat shock proteins nonspecific treated, N. gonorrhoeae will cause PID in
inflammation may be triggered by various 10–30% of infected women [14]. 20–30%
causes, resulting in extensive scarring, of the women harbouring N. gonorrhoeae
even if no active Chlamydial organisms are also infected with C. trachomatis [38].
are present. The result is an increased The most frequent symptoms include a
risk of ectopic pregnancies and infertility yellow-green leucorrhoea and pelvic pain;
[31–32]. Besides salpingitis, Chlamydia on inspection a mucopurulent cervicitis is
may also cause mucopurulent cervicitis, often visualized.
urethritis and endometritis. Although PCR is very reliable and
The diagnostic method of choice for much faster, culture remains the best
detection of C. trachomatis is polymer- test for N. gonorrhoeae as it also allows
ase chain reaction’ (PCR)-based testing. sensitivity testing for antibiotics [34–35].
These tests have an estimated sensitivity Ideally, Thayer-Martin medium (choco-
of 86%, a specificity of 99.5%, and provide late agar with antibiotics inhibiting other
the opportunity for simultaneous testing bacteria) is used, providing 65–85% sen-
for N gonorrhoea [33–35]. Testing can be sitivity for asymptomatic infections and
performed on urethral or cervical swabs, 100%, specificity of but a regular choco-
or on urine, produced without washing late agar can also be used. Fast transport
or disinfecting the urethra, preferably is crucial, due to the short ex vivo sur-
from the first void in the morning, or at vival time of N. gonorrhoeae. To increase
least four hours after micturition. Care sensitivity, the endocervical and/or (ure-
has to be taken that the first part of the thral swab should be inoculated into a
sample is included. Alternative, but less specific transport medium.
accurate testing is antigen detection by In some areas, treatment options
ELISA. Culture methods have a specifi- include: 500 mg ciprofloxacin, 1g azy-
city of 100%, but their sensitivity is only thromicin, or ceftriaxone 125 mg IM of
50 to 80%. IV. However, also increasing fluoroqui-
Chlamydial cervicitis or urethritis nolone resistance (up to 30%) has limited
can be treated by single oral dose of 1 g oral options in many areas [39–43]. For
azithromycin or seven days of oral example, in the US the CDC recommends
807
ceftriaxone 125 mg IM or IV as the treat- infection [59], misoprosotol should only

ment of choice. In Belgium ceftriaxone is be used orally, as is common in Europe.
only available in a 1g formulation.
4.1.6 Tuberculosis
4.1.3 Facultative aerobic Gram-negative Genital tuberculosis characteristically
bacteria
presents as a chronic, latent infection
Gram-negative rods, such as Escherichia diagnosed an an infertility evaluation. The
coli, Enterobacter spp., Klebsiella spp., infection is often secondary to hematog-
Proteus spp., Gardnerella vaginalis are enous spread from a non-genital source.
often recovered in PID cases [38] and The fallopian tubes and endometrium are
Pseudomonas spp. rather seldom and only most often infected. When associated with
after surgery. The etiology is unclear, as ascites and peritonitis, genital tubercu-
these organisms can also be seen as fac- losis can present a diagnostic dilemma
ultative pathogens and in cluster analy- often confused with carcinomatosis peri-
sis their presence in the vagina was not a tonitis or ovarian malignancies [60–65].
primary risk factor for PID [44]. Recently Confirmation requires biopsy with spe-
Salmonella spp. were also found to be cific endometrial cultures, preferably
associated with PID [45–49]. during menstruation. Specific cultures
of intra-abdominal abscesses may also
4.1.4 Aerobic Gram-positive cocci lead diagnosis. If suspected, detection of
Staphylococcus spp, Streptococcus spp tuberculosis in other organs such as the
(especially Streptococci Lancefield groups lungs can be helpful. Patients at high risk
A and B) and Enterococcus sp. (Streptococci are immigrants, HIV-infected patients,
groups D and F) are often found as sole imprisoned women, or patients with a his-
pathogens [50], but as with Gram-negative tory of alcohol or injection drug use.
rods, their exact role in the etiology is
unclear. The importance Gram-positive 4.1.7 Actinomyces
cocci clinical management, however, is Actinomyces israelii is a Gram-positive
emphasized by the fact that presence of anaerobic bacterium usually recovered
beta-lactamase producing enterococci may from the upper respiratory or gastrointes-
require adjust of treatment by addition of tinal tracts. PID is rarely caused by this
clavulanate to tricarcillin regimens to pre- organism due to hematogeneous spread
vent clinical failures [51]. from another location, or ascending infec-
tion from the vagina in women with cop-
4.1.5 Anaerobes per-containing intrauterine contraceptive
Anaerobic bacteria, such as Bacteroides devices (IUCDs) [66]. Colonization of
fragilis, Clostridium spp, and Peptostre- the lower genital tract is frequent in the
ptococcus, are present in many PID presence IUCDs and increases with dura-
patients and are always treated [44, tion of use [66–68]. In rare cases severe
52–54]. Most, if not all, of these anaerobic pelvic infections may occur, mimick-
bacteria are highly sensitive to nitroimi- ing pelvic malignancies [69]. Incidental
dazol derivates (i.e., metronidazole, detection of Actinomyces spp. on Pap
ornidazole, and tinidazole) and to amoxi- smears does not need to be treated if
cillin/clavulanic acid. In the US, several asymptomatic. In contrast, if the IUCD is
life-threatening cases with ascending in place for longer than four years, or if
Clostridium spp. were observed after the infection is found on more than one
the use of vaginal misoprostol to induce occasion during 12 months, then IUCD
an abortion [55–58]. Because vaginally removal should be considered. After
applied misoprostol may cause this lethal removal of the IUCD, infection usually
808
disappears spontaneously without com- present, antibiotics should be adjusted to

plications. A new IUCD can be inserted cover the organism [85–86].
one or two months later. A. israelii is sen-
sitive to penicillin, but once endometri- 4.1.8.1 Mycoplasma genitalium
tis is present, treatment with low dose Taylor-Robinson and co-workers showed
penicillin should be continued for weeks that M. genitalium (Mg), a former
to months. Care has to be taken not to Mycoplasma, was ubiquitous worldwide
misdiagnose pelvic actinomycosis as and was associated with pelvic infections
a pelvic cancer, because infection can [87–88]. Later studies clearly confirmed
mimic locally extensive ovarian cancer, the link between Mg and clinical PID in
both on diagnostic imaging, or during the absence of concomitant STIs, such as
surgical procedures like laparoscopy and Ct and gonorrhea [89–92]. In a study of
laparotomy [69–73]. Attempts to remove 722 women with suspicion of PID, women
the ovaries and uterus in patients with with M. genitalium infection were less
actinomyces have led to lethal complica- likely to have elevated systemic inflam-
tions [74–75]. matory markers (erythrocyte sedimen-
tation rate >15 mm/hr, (p = .002), white
blood cell count >10,000 cells/mL (p = .018),
4.1.8 Mycoplasmata oral temperature ≥ 38.3 °C (p = .001)) than
Mycoplasma hominis (Mh) is one of the women with gonococcal PID. In addi-
smallest known bacteria. Because these tion, they were less likely to present with
bacteria do not have a cell wall, diagno- mucopurulent cervicitis (p = .001), elevated
sis cannot be made by microscopic exam- vaginal pH (p = .018), and high pelvic pain
ination of fresh vaginal fluid or Gram score (p = .014). In contrast, women with
stains. Also, antibiotics inhibiting cell chlamydial PID had signs and symptoms
wall synthesis have no effect, and antibi- that were similar to those in women with
otics targeting protein synthesis are rec- M. genitalium infection [93]. These find-
ommended. The treatment of choice is 1g ings supported different PID treatment
azithromycin once or doxycycline 100mg regimens for women harbouring M. geni-
twice daily for seven days [76]. Studies talium, because metronidazole – doxycy-
from the 1970s found Mh more often in cline regimens had success rates of only
fallopian tubes of women with clinical PID 35-to-55% [94]. Furthermore, treatment
(4/50), but not in asymptomatic women with cefoxitin and Doxycycline plus azy-
(0/50) [77] and serologic evidence linked thromycin do not provide reliable eradica-
Mycoplasma with PID [78–79]. Also, Mh tion of M. genitalium [95–96]. Hence more
in relation to BV posed an increased risk studies about the pathogenesis and treat-
of PID [44]. Still, the exact role of Mh in ment of this novel microorganism seem
PID remains controversial [44]. warranted [89].
Ureaplasma urealyticum (Uu) is also a
intracellular bacterium of the Mycoplasma
4.2 Risk factors
group that is frequently encountered in
the cervix and endometrium of patients The risk of PID is related to the number
with pelvic infection and/or bacteriemic of lifetime sexual partners of both the
sepsis [80]. However, Uu is found so uni- woman and her sexual partners [97].
versally in both men and women, in the Apart from this, the frequency of sexual
urethra, vagina, cervix, endometrial contact increases the risk of bacterial
cavity and pouch of Douglas, and with- vaginosis, a condition linked to STIs, such
out a clear link to pathogenesis, that it as C trachomatis, trichomoniasis and gon-
is doubtful whether Uu has any causa- orrhea [98] and with PID [44]. PID due to
tive link with PID [81–84]. Still, if it is Chlamydia is primarily found in young
809
women (15–25 years of age). In general metrorrhagia, postcoital or intermen-

PID is seldom encountered in women strual bleeding and/or menorrhagia, PID
older than 35 years of age [99–100]. should always be considered [111–112].
Possible explanations include an
increased immunity, differences in sexual 5.2 Clinical findings
behaviors, or other factors. There is no clear consensus on the con-
Use of barrier methods (e.g., condom, firmatory clinical criteria supporting PID
pessary, etc) is largely protective against diagnosis. Minimal diagnostic criteria
PID. However, in some studies barrier should include: 1) lower abdominal sensi-
contraception reduces transmission of C. tivity and 2) painful adnexae or cervix on
trachomatis and N. gonorrhoeae only by palpation. Urinary infection, lumbar disk
50% [101–102]. This can be explained by disease and torsion of an ovary have to be
the fact that protection against transmis- excluded. Additional criteria supporting
sion is only significant in perfect users, an PID diagnosis are: T >38.5°C, purulent
aim that is seldom achieved even in well cervical discharge (microscopy), pelvic
controlled studies incorporating extensive imaging (sonar, CRT scan) suggesting
counseling [101–102]. Oral contraceptives tubo-ovarian abscess, increased inflamma-
and intramuscular depot medroxyproges- tory parameters (e.g., elevated C-reactive
terone also seem to protect against ascend- protein, leucocytosis >10.000 /ml, elevated
ing infection and PID, but not against erythrocyte sedimentation rate, etc.),
Chlamydial cervicitis [103–104]. Copper- presence of C. trachomatis or N. gonor-
containing IUCDs do not increase PID risk, rhoeae, (Mycoplasma genitalium) or his-
unless the device is inserted in a women topathologic evidence of endometritis.
with an STI [105–106] or when an older In older studies, an elevated erythrocyte
type of IUCD was used [107]. Randomized sedimentation rate, temperature above
studies found a lower PID risk with 38°C and adnexal tenderness were pre-
levonorgestrel-containing IUCDs than with dictive for 65% of laparoscopy-confirmed
copper-containing IUCDs [108–110]. PID. C-reactive protein represents a more
accurate marker than the erythrocyte
sedimentation rate for assessing inflam-
5. CLINICAL PRESENTATION matory activity and is typically used for
monitoring patients [113–115].
5.1 Medical history
5.2.1 Abdominal examination
Specific information should be elicited
about presence of fever during the last During abdominal palpation, attention
two weeks, general malaise, bilateral must be given to muscular resistance,
lower abdominal pain, or pain when mov- rebound tenderness and pain on percus-
ing or being transported. Genital symp- sion. Pain localized in the right upper
toms should be evaluated including the abdomen suggests possible perihepatitis
amount and characteristics of vaginal dis- with formation of local adhesions, also
charge, post-coital bleeding, dyspareunia known as Fitz-Hugh Curtis syndrome of.
and abdominal pain with radiation to the In a first episode of PID, the pain never
interior thighs. Typically, the symptoms lasts longer than two weeks [116].
appear during the first seven days after
menses [14]. Presence of predisposing and 5.2.2 Genital examination
risk factors (described above) increase the Redness and edema of the vulva, vagina
likelihood of PID. At least one third of the and, most importantly, the cervix sug-
patients with PID have irregular vagi- gest an infectious process. The vaginal
nal bleeding. If a patient presents with discharge can vary from grayish watery
810
and foamy, to yellow green and muco- increased. CRP represents an excellent
purulent. An inflamed cervix has deep marker to follow the course of the disease
red to blue color, appears edematous and and the effect of treatment [113–115].
bleeds easily when touched. Typically, Even when clinical signs and leukocyto-
thick green-yellow mucus may be vis- sis resolve, persistence of elevated CRP
ible, but mucopurulent cervicitis can be suggests the beginning of abscess forma-
diagnosed microscopically even when the tion [118]. Human chorionic gonadotropin
mucus appears clinically normal. (b HCG) should be evaluated to exclude
Bimanual vagino-abdominal palpation ectopic pregnancy, imminent abortion or
may show motion tenderness of the uterus septic abortion, as these conditions may
and pain upon pushing the uterus towards mimic PID.
the abdomen. Tenderness and pain in the Serum CA-125 is in general a fol-
adnexal region is suspicious for PID grade low up marker to monitor the treatment
2 or 3; bilateral pain is more suggestive effect, but in menopause it can be used to
for this than unilateral tenderness or exclude malignant intra-abdominal proc-
pain. Sensitivity of this criterion of uter- esses of ovaries, uterus, stomach, liver or
ine and/or adnexal tenderness is 96%, but pancreas. However, CA-125 can be also be
specificity of this finding is extremely low elevated in patients with endometriosis,
(4%) [117]. Therefore, starting antibiotics PID and hepatitis, although the former
based on this symptom alone would lead two are only sporadically encountered
to a tremendous risk of over treatment after menopause. This test is only recom-
and should be discouraged. mended in case of doubt about the dif-
Clinical diagnosis of PID is imprecise ferential diagnosis, in which case further
and misses one third of cases proven by diagnostic workout is needed.
laparoscopy. Therefore, laparoscopic diag-
nosis remains the ‘gold standard’, and
in doubtful cases laparoscopy is advised 6.1.2 Microbiology
before starting therapy. Cultures from Cervical cultures for gonococci, aerobic
the vagina, cervix and urethra taken at bacteria, and PCR for Chlamydia (cervix,
the initial visit before starting therapy urethra and/or urine) should be performed,
are sometimes crucial for adjusting the as well as urinary cultures. In patients
antibiotic choice if to the patients does with PID, microscopic examination of a
not respond to treatment. fresh endocervical smear reveals more
than 30 leukocytes per high power field,
5.2.3 Fever or more than 10 per epithelium cell [9, 99].
Fever only occurs in 50% of women with Increased leukocytosis is very sensitive
PID. Therefore, fever not a reliable sign. (91%) and has a high negative predictive
Temperature above 38.5°C is always value (90%) for diagnosis of cervicitis [119].
alarming and requires intensive diagnos- However, this examination lacks specifi-
tic work-up. city (19%) thereby erroneously diagnosing
PID in four out of five women [119–120].
Two additional microscopic criteria can
6. DIAGNOSTIC TESTING provide additional help; the concomitant
finding of abnormal vaginal flora whereby
6.1 Laboratory tests the lactobacilli are replaced by cocci or
anaerobic morphotypes (AVF, Lactobacilli
6.1.1 Serum grade 3 [121], and the finding of palisades
Signs of acute infection are accompa- of leucocytes lining up in the cervical
nied by leucocytosis above 10.000/ml and mucus (Figure 1). Although the latter sign
C-reactive protein (CRP) is invariably is considered typical, it has not yet been
811
Figure 1 Cogwheel sign.
adequately validated in large clinical stud- that clinical diagnosis should have a low
ies. Absence of leukocytosis, certainly if in threshold. A number of tests may provide
the presence of Lactobacilli grade 1 (nor- further support for PID diagnosis.
mal), however, almost certainly excludes
cervicitis and PID [10, 122]. 6.2 Imaging techniques
During laparoscopy samples from
the retro-uterine pouch of Douglas and 6.2.1 Ultrasonographic examination
endotubal swabs are recommended for After clinical examination, pelvic ultra-
aerobic, anaerobic and Chlamydial cul- sound is the next step in the PID diagno-
tures or PCR. If there is a suspicion of sis. The level of severity of the infection
tuberculosis, a biopsy, with a specific is the basis of the sonographic grading of
request for the pathologist, is necessary. PID, but in studies neither sensitivity nor
Initially, PID should be considered a specificity are well defined. In resource
potential STI. Therefore screening for limited settings, sonographic examination
possible concomitant STI’s is recom- should therefore be limited to a subset of
mended. This includes blood tests for patients, e.g. the women not responding
HIV, hepatitis B and C, syphilis are to therapy.
required as well as cervical testing for In mild disease the uterus may be
HPV infection. As PID can originate from painful on palpation with the abdomi-
causes other than sexual contact (see nal or endovaginal probe, but adnexal
above), this is not obligatory for pelvic regions are normal and the pouch of
infections secondary to a surgical inter- Douglas (retrouterine area) may show
vention, delivery or a known gastrointes- some fluid at the most. If the fallopian
tinal infectious process. tubes can be visualized by a thicker
Clinical diagnosis of PID is difficult due tubal wall and increased vascularity
to the lack of accurate (in terms of sensi- on Doppler flow examination, then the
tivity and specificity) at present. However, disease is usually more severe. In typi-
the potential for severe sequelae means cal cases the “cog wheel sign,” can be
812
Figure 2 Beads-on-a-string sign.
visualized (Figure 1). In severe PID the they move ‘en bloc’ on pressure from the
fallopian tubes are extended with inho- vaginal probe. Pelvic adhesions can be
mogeneous purulent fluid, sometimes responsible for the “flapping sail” sign,
with fluid-air levels (pyosalpinx) and usually reflecting large amounts of pel-
pseudo-septation. In cases of chronic vic fluid confined by the loose adhesions.
salpingitis, the pyosalpinx will gradu- A painful, retroverted and fixated uterus
ally be replaced by anechogenic fluid and often result from reduced mobility of the
a “beads-on-a-string” image typical for a uterus caused by such adhesions. The
hydrosalpinx: the remnants of the endos- typical ultrasonographic appearance of
alpingeal plicae are seen as small excres- such a fixated retroplicated uterus is
cences against the tubal wall (Figure 2). sometimes called the “ear-sign”, due to
With extension, the tubal wall becomes the appearance of the uterus resembling
thinner (<3mm), Later in the process, an auricle.
peritoneal pseudo cysts form due to
inclusion of peritoneal fluid in pockets of 6.2.3 Computerized tomography
adhesions of the bowel, internal genitals (CT)-scan
and pelvic wall. By scanning a larger area CT can pro-
Patients with tubo-ovarian abscess vide additional information in selected
exhibit collections of pus with a thick, cases. Indications for a CT scan in
hypervascularised wall surrounding an the diagnosis of pelvic inflamma-
inhomogenous echogenic fluid, sometimes tory processes are outlined in Table 1.
with air /fluid levels. When a tubo-ovarian Thrombosis of the ovarian vein is most
complex has formed, the tubes, uterus often seen in the postpartum period,
and ovaries are all stuck together and (frequency 1/3000), but is also a known
cannot be moved or palpated separately: complication of pelvic surgery and PID.
813
Table 1 Indications for CT-scan in patient suspected of a pelvic infection.
Adequate sonography not possible (stenotic vagina)
Uncertain diagnosis on clinical and sonographical grounds
Failing antibiotic therapy
To complete full staging of inflammatory process like perihepatitis (Fitz-Hugh-Curtis)
Detection of possible complications, e.g. septic trombo-phlebitis
Differential diagnosis with other intra-abdominal conditions (e.g. appendicular plastron, dermoid cyst, avarian endometriosis. . .)
Figure 3 Microscopic sign of infected endocervcical mucus: palisades of polymorphonuclear leucocytes

lined up in mucus (Bioletz Leitz, Warfurt Germany, 400 times magnification, phase contrast). ©GGG
Donders, Femicare.
80 to 90% of thrombosis is encountered fuzzy hyper-intense zone (so called “halo”)

at the right side. To detect this compli- with intensification on T1 weighted
cation CT-scan is a superior technique to images. The formation of an abscess is
echo-Doppler [123]. seen as a thick-walled mass filed with
fluid in the adnexal area. The pyosalpinx
also presents a very clear appearance of a
6.2.4 Nuclear magnetic resonance (NMR) twisted and dilated fluid-filled structure.
NMR images showing parametrial inflam- The content of such abscesses are lightly
mation are very specific: T2 weighted hyper-intense on T1 weighted images
images suppressing fat densities show a and hypo-intense on T2 weighted images,
814
indicative of blood or inflammatory debris 8. MANAGEMENT

[124–125].
Treatment goals are to treat the most
important causative microorganisms and
7. LONG-TERM SEQUELAE minimize sequelae of PID. Because most
women with early PID do not have major
Tubal infertility represents a major complaints, diagnosis and effective ther-
worldwide outcome after PID [126]. The apy often increase the likelihood of adhe-
pathogenesis is best studied in women sions and late sequelae. It is important to
with recurrent Chlamydial infections examine and treat partners even if they
causing immune modulation (i.e., the have no symptoms.
immune system does not ‘see’ the latent
intracellular infection) and subsequent
8.1 Antibiotics
intratubal scarring. Because such recur-
rent infections often remain asympto- Empirical, antibiotic therapy based on
matic these infections typically often the expected microorganisms should
cause substantially more damage than start before the culture results are avail-
those that are clinically suspected (see able. Local resistance patterns vary in
above) [127]. A particular set of signs different areas. Most empiric treatment
and symptoms due to intra-abdominal regimens combine agents to treat aero-
adhesion formation is the so-called Fitz- bic and anaerobic bacteria as well as
Hugh-Curtis syndrome [128]. This syn- C. trachomatis.
drome reflects a peri-hepatitis with upper In Europe, the indications for intrave-
abdominal pain, and typical adhesions nous therapy coincide with those for hos-
found on laparoscopy. Other STIs, like pital admission (see below), but in the US
gonorrhea and perhaps M. genitalium patients do not need to be hopsitalised
(see above), may cause tubal infertility to get IV treatment. When the patient is
after a single PID episode. afebrile and C-reactive protein is decreas-
Ectopic pregnancy represents a second ing, the patient can be discharged and
important consequence of mucosal dam- oral therapy started for 14 days. Although
age to the fallopian tubes. Ectopic preg- other regimens may be effective, most
nancies are linked to a history of PID, guidelines are consistent with the recom-
presence of Chlamydia antibodies [129] mendations in Table 2 [137]. Some recom-
and Chlamydia induced heat shock pro- mended antibiotics may not be available
tein 60 and 70 reactivity [130–131]. The in all countries, necessitating other alter-
tubal damage or ectopic pregnancy risk native regimens. In general, therapy
after infection with M genitalium is not should be prolonged to limit the chance
yet fully elucidated [132], but identifica- of relapse. Reassessment is recommended
tion of Mycoplasma at laparoscopy for after 48 to 72 hours. If the patient is
PID, either in the lower genital tract or not responding as expected, the patient
the upper genital tract, is a risk factor for should be reassessed by additional diag-
later ectopic pregnancy [133]. nostic workout, after which alternative
Chronic pelvic pain is the third major therapy and/or hospital admission are
long-term complication of PID. Many considered. For mild to moderate PID,
women suffer from chronic pelvic pain antibiotics are given for 14 days, while
after a symptomatic or asymptomatic PID for grade 3 PID several weeks of therapy
episode of PID [134]. Differential diagno- may be necessary.
sis includes: interstitial cystitis, pelvic As noted above, increasing antibicrobial
congestion syndrome and endometriosis. resistance, especially to fluoroquinolones,
[135–136]. has been documented in N. gonorrhoeae
815
Table 2 Antibiotics of choice in women with pelvic infections.
Cervicitis
Daycare
Option 1 Azithromycin 1 g PO Single dose
5-nitro-imidazole* 500 mg PO 7 days
Option 2 Ceftriaxon 1 g IM or IV Single dose
Azithromycine* 1 g PO Single dose
* Association of metronidazole with azythromycin is a perfect alternative option on condition of low prevalence and/or exclusion of
N gonorrhoea. In other cases ceftriaxon is necessary.
Salpingitis / PID
Ambulatory
Option 1 Ceftriaxon 1 g IM or IV Single dose
Moxifloxacine 400 mg PO 10–14 days
5-nitro-imidazole (metronidazole, 2 × 500 mg PO 10–14 days

ornidazole, tinidazole)
duration of therapy may differ according to clinical / hematological evolution (i.e. abscess: therapy up to 6 weeks
recommended)
Option 2 Ceftriaxon 1g IM or IV Single dose
Levofloxacine 500 mg PO 10–14 days
5-nitro-imidazole 2 × 500 mg PO 10–14 days

(metronidazole, ornidazole,
tinidazole)
Hospitalisation
Option 1 Ceftriaxon 1 g IM of IV Single dose
Levofloxacine 500 mg IV 10–14 days
5-nitro-imidazole (metronidazole, 1 g IV 10–14 days

ornidazole, tinidazole)
Option 2 Ceftriaxon 1 g IM of IV Single dose
Amoxi-Clav 4 x 1 g IV 10–14 days
Levofloxacine 500 mg IV 10–14 days
Option 3 Ceftriaxon 1g IM of IV Single dose
Amoxi-Clav 4 x 1g IV 10–14 days
doxycycline 2 x 100 mg PO 10–14 days
Switch to ambulatory setting possible after 48 hours IV therapy in case of clinical / hematological improvement.
in many areas. Thus, the treatments of Recent reports suggest that moxi-
choice are 125 mg IM or IV or cefixime floxacin 400mg once daily is effective for
400mg orally (not available in the US). PID grade 1. this regimen has shown
This therapy should be included in all similar cure rates to ofloxacin plus met-
grades of PID. ronidazole and to ciprofloxacin plus
816
doxycycline and metronidazole for uncom- combined with hysteroscopy and endome-
plicated PID [138]. Future guidelines will trial sampling for histologic examination.
perhaps incorporate moxifloxacine, but However, in doubtful cases or when the
these need to be validated first. patient does not improve or deteriorates
Specific therapy determined by anti- (clinically or by increase of the infectious
microbial sensitivity testing is indicated parameters after 72 hours of antibiotic
when the microorganisms and their anti- therapy), laparoscopy is indicated. Intra-
biotic sensitivity are known. However, abdominal cultures can be taken, and
care has to be taken to assure anaerobic other possible pathology, such as endome-
coverage. Also, it is important to consider triosis, can be assessed. Excessive rins-
the possibility that non-cultivated germs ing with saline is advised and if abscesses
(i.e., those not detected by standard cul- are encountered they should be opened,
ture techniques) may also be present, rinsed and drained [140–142].
necessitating alternative therapy if the
patient does not improve as expected.
9. SPECIAL TYPES OF PID
8.2 Hospitalization
Indications for hospitalization are sum- 9.1 Tubo-ovarian abscess
marized in Table 3. For PID grade 1
A tubo-ovarian abscess (TOA) is the ulti-
and 2, cure rates were similar for ambu-
mate attempt of the body to conceal a life
latory treatment and hospitalization
threatening infection.
[139]. Intravenous fluids are indicated
for patients with vomiting or ileus.
9.1.1 Pathogenesis
Thrombosis prophylaxis is also indicated
with low molecular heparin for hospital- TOA can originate from either ascending
ized patients. PID (primary TOA) or as a consequence
of surgery or intestinal infectious proc-
esses. One has to be aware that a TOA
8.3 Indications for laparoscopy can always mimic or complicate a malig-
nant process, especially in postmenopau-
Laparoscopy is not very accurate in PID sal women (secondary TOA) [143]. There
grades 1 and 2, and is not able to diagnose are no known risk factors that promote
the presence of endometritis unless it is TOA development after PID.
The inflammatory reaction caused
by ascending aerobic bacteria causes
Table 3 Indications for hospitalization and intravenous
therapy. endothelial damage and intra-tubal adhe-
sions in which bacteria, debris and leu-
Surgical intervention not excluded kocytes accumulate. Once large enough,
Severe clinical picture this accumulation will not allow sufficient
oxygen to diffuse into the center of the
PID grade3 (including tubo-ovarian abces) abscess. Within 24 to 48 hours anaerobes
and facultative anaerobic microorganisms
Pregnancy
can thrive in this anaerobic environment
Failure to respond on oral antibiotics within 48 hours (the so-called ‘anaerobic shift’).
Immune compromised patients (HIV, transplantation,. . .)

9.1.2 Diagnosis
Intolerant for peroral antibiotics The most prominent clinical findings
Inconsequent patient not taking medication properly
include abdominal and pelvic pain,
present in over 90% of affected women,
817
followed by fever and leukocytosis in Patients should be instructed about

60–80% [144]. The “gold standard” for possible relapse of the TOA.
diagnosis is ultrasonography (see above).
TOA, with cystic structures and often air/ 9.2 Acute, subacute and chronic
fluid levels should be clearly distinguished endometritis
from a ‘tubo-ovarian complex’, where
edema, adhesions and inflammation are Endometrial inflammation is a histo-
present, leading to more heterogeneuous logic diagnosis and can be subdivided
and hypervascularized sonographic find- in acute, subcute, chronic and fibrotic.
ings. Patients with tubo-ovarian complex Fibrosis can occur with intracavitary
often respond well to sensitive to anti- adhesions between anterior and posterior
microbial therapy (>95%), in contrast to walls of the uterine cavity (Asherman
patients with TOA (see below). Differential syndrome).
diagnosis including a dermoïd or endome-
triosis cyst can be particularly difficult, 9.2.1 Acute endometritis
especially if secondary infection is present, True acute endometritis is rare and is
as often in the case of endometriosis. characterized by finding polymorpho-
nuclear neutrophils in the endometrial
glands. It may occur subsequent to intra-
9.1.3 Management: ubi pus, ibi
uterine surgery, during the postpartum
evacua (where there is pus,
you have to drain?) period when infected placental tissue rem-
nants are still in place, and can also be the
More than 80% of the women who do transient first phase of an ascending infec-
not respond to appropriate PID therapy tion leading to PID. In particular M. geni-
have TOAs. Still, some authors report talium and group A streptococci have been
cure rates as high as 75% with antibiot- found in association with acute endometri-
ics alone [145]. Therefore, the need for tis [92, 150]. Diagnosis requires endome-
laparoscopic intervention and timing of trial biopsy and cultures. Treatment is
this intervention remain controversial. outlined above. If placental remnants are
Surgical drainage is required if the suspected they have to be removed.
TOA does not respond to medical ther-
apy. This can be done laparoscopically 9.2.2 Subacute endometritis
[142], by CT- or ultrasound-guided per-
cutaneous aspiration [146–148], or more This is less known among pathologists but
recently also by transvaginal puncture is more common clinically. This condition
[149]. These procedures should only be is characterized by presence of lympocytes
done with broad antibiotic coverage, as around the endometrial glands that infil-
the drainage procedure may dissemi- trate both the surrounding stroma and
nate infection [149]. As diagnostic work- the glandular lumen, together with cellu-
up to exclude malignancy is crucial in lar debris. Typically, plasma cells are lack-
post-menopausal women, laparoscopy is ing. Subacute endometritis is often been
always mandatory in this group. associated with C. trachomatis infection
Conservative treatment is only possible and should be treated accordingly [151].
if the patient is well informed that close
follow up is needed and surgical interven- 9.2.3 Chronic endometritis
tion may still prove necessary. Resolution Chronic endometritis is characterized by
of a TOA can take weeks to months. typical plasma cells in the endometrial
Weekly follow up with bimanual exami- stroma [152–153]. Chronic endometritis
nation and ultrasonography are neces- can also be a consequence of placental rem-
sary, especially during the first weeks. nants [154], after insertion of a intrauterine
818
contraceptive device [155–157], pelvic radi- has proven effective for preventing
otherapy, ascending infection by Chlamydia endometritis and secondary post-surgery
[153–154, 157] or tuberculosis (granuloma- PID. The best studied intervention cae-
tous endometritis). In one third of women sarian section (C-section). However, rou-
no cause can be found. tine peri-operative antibiotics are still
Treatment is directed at known or sus- under discussion due to the possible dis-
pected pathogens. In other cases, empiric advantages like allergic reactions, and
use of doxycycline 100mg twice per day is resistance with the emergence of diffi-
advised for 10 to 14 days or azythromycin cult to treat Staphylococcus aureus and
1 g per week for two weeks, with a cure rate Clostridium difficile infections [160]. For
of 86 to 98% [158], although other stud- both elective and non-elective C-sections,
ies found lower cure rates for doxycyclin a Cochrane review concluded that pro-
and favour eiter azythromycin or quinolo- phylactic antibiotics are recommended
nes [94]. Biphasic estro-progestogens are because treatment results in a 30 to 80%
sometimes used for three months to induce decrease in maternal infectious morbid-
shedding of the endometrium (‘hormonal ity [63, 161]. In elective C-sections, some
curettage’). This type of therapy is most authors concluded in a meta-analysis
often used after postpartum endometritis. that early administration at the time of
incision instead of after cord-clamping
9.3 Post-abortion results in a reduced rate of postpartum
After instrumentation, especially in prim- endometritis, (RR 0.47) and wound infec-
igravidas, cervical stenosis can occur, tion (RR 0.60) [162]. They also found a
leading to retention, hematometra and difference in these complication rates
pyometra. Diagnosis is made by combin- when the policy in their hospital was
ing clinical findings of a painful enlarged changed with respect to timing of the
uterus and fever with a fluid filled uter- antibiotic delivery [163]. In contrast,
ine cavity. Dilatation and drainage are other authors did not find a difference
combined with amoxicillin with clavu- in infectious morbidity between early or
lanic acid and doxycycline. late (after cord clamping) administra-
tion of antibiotics [164]. Metronidazole
should be added to cefazolin because
9.4 Post-partum
combination therapy proved superior
Endometritis during the post-partum for preventing complications [160, 165].
period is associated with prolonged labor, Remarkably, none of the antibiotic regi-
preterm rupture of the membranes, or mens evaluated have been shown to
remnants of blood clots and/or placental benefit the neonate. Updated guidelines
tissue after delivery [154, 159]. Presence for other gynecological procedures are
of air in the uterine cavity is a normal summarized in the Practice Bulletins of
finding on ultrasound or CT scan for up the American College of Obstetrics and
to six weeks post-partum and should not Gynecology [166].
be mistaken for abscess or pyometra.
Treatment is similar to that described
above for post-abortion entometritis. 10.2 Screening
Standard STI screening and treat-
ment policies offer the potential for sub-
10. PREVENTION
stantially reducing a PID rates [167].
In high risk groups of women (e.g., sex
10.1 Perioperative antibiotics
workers, abused women, women with
Before or during certain surgical interven- a history of PID, women undergoing
tions, routine administration of antibiotics counseling for abortion, etc.) routine
819
screening for Chlamydia and other STIs 12. FURTHER RESEARCH

is recommended [168–170]. Another high
risk group that is likely to benefit from There is a great need of more research,
screening is teenagers at schools, during as new microbiological techniques have
visits in family planning clinics or where become available. Polymerase chain
contraception is discussed [171–172]. reaction allows detection of new and
formerly undetectable microorganisms,
10.3 Sexual education opening an interesting field to close the
gap of the ‘unexplained PID like syn-
Abstinence is the most secure guarantee dromes’ in which no causative organ-
of avoiding PID, at least according to the ism could be detected with conventional
strict definition wherein PID is consid- techniques. The epidemiology, which is
ered to be an STD [173]. The abstention, now increasingly mapping a growing
beware and condom use methods (ABC number of women in which non-sexually
policy) have been successful in some set- transmitted organisms are responsible
tings such Uganda [174] and in US mili- for ascending pelvic infection as well as
tary clinics [175]. However, many barriers the specific genetic susceptibility of cer-
must be addressed to make safe sex prac- tain women to certain complications like
tices an accepted and commonly adopted tubal infertility, needs more attention in
approach [176]. future studies. Finally, accessible and
more focused screening programs have
to be developed and exercised, espe-
11. FOLLOW UP cially in low resource countries, where
the sequelae of PID create a tremendous
After the initial PID episode, it is impor- burden for young women in their repro-
tant to monitor infectious parameters and ductive years. Although it is the only
any abscess or mass seen on ultrasound. system manageable at hoc, the adapta-
Officially, there is no need to retest for tion of ‘syndromic management’ does not
Chlamydia after recommended treatment. seem to be sufficient to stem the spread
However, some guidelines (i.e., Belgian of the disease.
Societies of Gynecology and Obstetrics)
test of cure testing is strongly advised
because persistence of a Chlamydia infec- 13. CONCLUSIONS
tion is seen in 10–15% of cases. Patients
with persistent symptoms or doubtful 1. PID still remains a silent cause of
compliance to therapy should also be major genital pathology worldwide
tested again three weeks post treatment.
False negative (still viable Chlamydia in 2. Diagnosis of PID may be difficult
low numbers) or false positive (shedding due to a blurry, composite definition
of non viable Chlamydia) testing may of the condition, and the lack of a
occur the first weeks after treatment. single cause. Instead a flexible and
Frequent complications of PID are attentive mind is needed to consider
chronic pelvic pain, dyspareunia, infertil- the diagnosis with a low treshold for
ity (RR × 6 after 1 episode, × 17 after 2 therapy.
episodes), and ectopic pregnancy. Every 3. Laparoscopy is still the ‘gold standard’
woman experiencing a PID episode should of diagnosis, but the increasing
be aware of these risks. Unfortunately, no technical resolution of imaging
study has compared rates of such long- techniques like sonography, CT scan
term sequelae after different treatment and MRI and the increasing
regimens. sensitivity of blood analysis allow
820
better non-invasive diagnostic Gesouli E, Dalkalitsis N, Korkontzelos

approaches than ever before. I, Mouzakioti E, and Lolis DE,
Bacteriological cultures of removed
4. However, the clinical syndrome intrauterine devices and pelvic inflam-
remains the cornerstone of the matory disease. Contraception, 2002.
presumed diagnosis of PID, and needs 65(5): 339–42.
treatment as soon as the diagnosis is 9. Donders GG, Definition and classifica-
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diagnosis is refined, or if the response 10. Donders GG, Vereecken A, Bosmans E,
to therapy is inadequate. Dekeersmaecker A, Salembier G, and
Spitz B, Definition of a type of abnormal
vaginal flora that is distinct from bacte-
rial vaginosis: aerobic vaginitis. BJOG,
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|14.5|
HIV Infection in urological practice

Seung-Ju Lee
Department of Urology, The Catholic University, College of Medicine, Seoul, Korea
Corresponding author: Seung-Ju Lee, MD, PhD Urology, St. Vincent’s Hospital, The Catholic University,
93-6 Ji-dong, Paldal-gu, Suwon 442-723, Korea
Tel: +82-31-249-8305, Fax: +82-31-253-0949, E mail: lee.seungju@gmail.com
This review evaluates the scientific evi- 1. Control of sexually transmitted infec-
dence suggesting that urological factors tions (STI) can reduce HIV incidence
increase the efficiency of human immu- (GoR B).
nodeficiency virus (HIV) transmission 2. Immediate diagnostic evaluation and
and discusses the important urological appropriate treatment of an indi-
manifestations of HIV infection. Level 1 vidual with any symptomatic STIs can
evidence suggests that sexually trans- reduce HIV acquisition (GoR B).
mitted infections (STIs) are substantially
3. Prompt and effective treatment of
associated with an increased risk of HIV
HIV-infected individuals experiencing
infection. Several randomized control-
genital symptoms can limit the trans-
led trials show that improved STI control
mission of HIV (GoR B).
can play a vital role in comprehensive
programs to prevent sexual transmis- 4. Behavioral interventions can reduce
sion of HIV. However, there is limited HIV-related sexual risk behavior
evidence that control of STIs reduces HIV (GoR B).
incidence at a population level. HIV has 5. Interventions targeting people living
become a chronic manageable condition with HIV are efficacious in reducing
thanks to highly active antiretroviral unprotected sex and acquisition of
therapy. Urologists face a challenge in STIs (GoR B).
trying to manage the genitourinary mani-
festations of HIV infection. 1. INTRODUCTION
Key words: HIV infection, sexually trans- Acquired immunodeficiency syndrome

mitted infection, transmission, urology. (AIDS) is defined by the development of
HIV infection in urological practice | 14.5 |
serious opportunistic infections, neoplasms, 3. EPIDEMIOLOGY OF HIV/AIDS1

or other life-threatening conditions result-
ing from progressive immunosuppression The global percentage of people liv-
caused by human immunodeficiency virus ing with HIV has stabilized since 2000.
(HIV) infection. However, the overall number of people
Although deaths attributed to AIDS living with HIV has increased as a result
have declined in the Western world with of the ongoing number of new infec-
the introduction of effective antiretroviral tions each year and the beneficial effects
therapy, AIDS remains the leading cause of more widely available antiretroviral
of death in many African cities [1]. The therapy. Sub-Saharan Africa remains
three main modes of HIV transmission most heavily affected by HIV, account-
have changed little: unprotected inter- ing for 67% of all people living with HIV
course, contact with blood, and trans- and for 72% of AIDS deaths in 2007. The
mission from mother to child [2]. Among global epidemic is stabilizing but at an
them, HIV acquired through unprotected unacceptably high level. Globally, there
heterosexual intercourse is on the rise were an estimated 33 million (30.3 mil-
and considered to be a urological factor lion–36.1 million) people living with HIV
for HIV transmission [1]. This review in 2007. The annual number of new HIV
evaluates the scientific evidence suggest- infections declined from 3.0 million (2.6
ing that urological factors increase the million–3.5 million) in 2001 to 2.7 mil-
efficiency of HIV transmission and dis- lion (2.2 million–3.2 million) in 2007. The
cusses the important urological manifes- rate of new HIV infections has fallen in
tations of HIV infection. several countries, although globally these
favorable trends are at least partially off-
set by increases in new infections in other
countries [1].
2. METHODS
A systematic literature search and 4. DYNAMICS OF HIV TRANSMISSION

review of existing scientific evidence
published in peer reviewed journals HIV is transmitted from person to per-
was performed in MEDLINE/PubMed son via bodily fluids because the virus is
for the last 20 years with the following present in varying concentrations in the
key words: HIV transmission, sexually blood, sexual fluids such as semen and
transmitted infection; and the follow- vaginal fluid, and breast milk. Risk and
ing limitations: human, clinical studies, exposure varies dramatically depending
randomized controlled trials (RCTs) or on many systemic factors as well as local
studies, meta-analysis, English. 173 arti- urogenital factors. Potential explanations
cles were found and screened by the title for this variability include biological dif-
and abstract of each electronic citation. ferences in infectiousness, susceptibility
Full-text copies of potentially relevant or both, or differences in sexual behav-
studies were obtained and 20 articles iors [2, 5–6]. The concentration of HIV
were finally included in this review. in genital tract secretions from males
References from retrieved study reports and females is increased at times when
and reviews were also screened for addi- enhanced transmission is suspected, such
tional studies. as in primary infection or in later stages
The studies were rated according to the of HIV disease and in patients with sexu-
level of evidence (LoE) and the grade of ally transmitted infections (STIs) [7–11].
recommendation (GoR) using ICUD Chakaraborty et al. estimated the effects
standards (for details see Preface) [3–4]. of semen viral burden on heterosexual
831
transmission [12]. They concluded that subtypes and CRFs are progressively being
when HIV RNA in semen was low (<5000 introduced in association with increased
copies/mL) transmission was unlikely heterosexual transmission of HIV-1
to occur, at one per 10,000 episodes of between migrants and/or immigrants
intercourse. Conversely, when the con- from regions where HIV-1 is endemic and
centration of HIV in semen was high their European partners [28–30].
(eg, 1 million copies/mL) the probabil-
ity of transmission rose to three per 100
episodes of intercourse. In general, viral 5. RELATIVE RISK FOR SPECIFIC
levels in the female genital tract [13] and EXPOSURE
in semen [14–15] correlate with systemic
viral loads. The probability of HIV trans- Evidence studies for STIs as a risk fac-
mission per episode of vaginal intercourse tor of HIV transmission are summarized
has been estimated from studies of HIV- in Table 1. Classic sexually transmit-
discordant couples: such estimates vary ted diseases (STDs) (genital ulcers and
from one per 7,000 to one per 700 in the mucosal inflammatory diseases) occur
USA, Europe and Africa [5, 16–19] and to in the same geographic areas as HIV,
one per 500 in Thailand [20]. As will be and compelling epidemiological evidence
discussed further below, one of the most supports the view that such diseases
important determinants of genital viral increase HIV transmission; indeed, the
load is the presence of STIs [21–23]. In interaction between classic STDs and
women, bacterial vaginosis (BV), herpes HIV is referred to as “epidemiologi-
simplex virus (HSV), human papilloma- cal synergy” [21]. Several large RCTs
virus, Chlamydia trachomatis, Neisseria were undertaken to investigate whether
gonorrhoeae, Candida, genital ulceration controlling STIs can reduce the inci-
and vaginal discharge have been associ- dence of HIV in a community. The first
ated with increased HIV shedding. In RCT enrolled 12,537 adults aged 15–54
men, N. gonorrhoeae, Trichomonas vagi- years from six intervention communi-
nalis, cytomegalovirus (CMV), urethri- ties and six pair-matched comparisons
tis and genital ulcer disease have been [31]. Baseline HIV prevalence was 3.8%
linked to HIV shedding in semen [23]. and 4.4% in the intervention and con-
The risk and exposure may also depend trol communities, respectively. There
on the particular viral clade and circu- was a reduction in syphilis and symp-
lating recombinant form (CRF) [24]. The tomatic urethritis in the intervention
cocirculation of subtype B among intrave- group. The incidence of HIV infection
nous drug users (IDUs) and CRF01_AE was 1.2% and 1.9% in the intervention
(originally defined as subtype E) among and control groups, respectively (odds
heterosexuals was originally described ratio (OR) 0.58, 95% confidence inter-
in Thailand [25]; the segregation of sub- val (CI) 0.42–0.70), corresponding to a
type B to homosexuals and subtype C to 38% reduction (95% CI 15–55%) in the
heterosexuals was described in South intervention group. The intervention
Africa [26]; more recently, two concur- reduced both the incidence/prevalence of
rent epidemics in Argentina have been STIs and the incidence of HIV infection.
reported, one among men who have sex Since then, other trials in Rakai [32–33]
with men, sustained by subtype B, and and Masaka [34] showed that there was
the other among heterosexuals and IDUs, no significant effect on HIV prevention.
sustained by BF recombinants [27]. In Possible hypotheses have been suggested
Europe, where subtype B has sustained to explain these contrasting results. The
the HIV-1 epidemic among the “historical” relative contribution of individual STIs
IDU and homosexual risk groups, non-B to an epidemic varies at different times
832
Table 1 Evidence Table for Studies of Sexually Transmitted Infections (STIs) as Risk Factor of both HIV Transmission and
Acquisition that Include Original Data, Systematic Reviews, Meta-analyses, or Other Human Data (1988–2008).
Level of Evidence
Positive (role of
Lead author, a risk factor) or
Study Type STI type year, reference Design Negative
Systematic reviews, Meta-analyses and Modeling
STIs Sangani, 2004 [101] Systematic review and 1, Positive

meta-analysis of the five
RCTs
STIs Hay, 2008 [35] Systematic reviews 1, Positive
Bacterial vaginosis Atashili, 2008 [102] Systematic review and 2, Positive

meta-analysis of the 23
eligible publications
Randomized-controlled trials
STIs Grosskurth, 1995 12,537 adults aged 1, Positive

[31] 15–54 in six intervention
communities and six pair-
matched comparisons
communities in Mwanza,
Tanzania
STIs Wawer, 1999 [32] 12,726 adults aged 15–59 1, Negative

in Rakai, rural Uganda
STIs Gray, 2001 [33] 2,070 pregnant women in 1, Positive

Rakai, Uganda
STIs Kamali, 2003 [34] 12,819 individuals aged 1, Negative

13 and older in Masaka,
rural Uganda
HSV-2 Nagot, 2007 [36] 140 seropositive women 1, Positive

for HIV-1 and HSV-2 in
Burkina Faso
CMV Casper, 2008 [40] 16 HIV-positive men and 1, Positive

10 HIV-negative men in
Seattle, USA
Non-randomized cohort studies
Genital ulcers Cameron, 1989 [103] Prospective study of 422 2, Positive

men who had acquired
STD from female CSWs in
Nairobi
Genital ulcers, Plummer, 1991 [104] 124 seronegative female 2, Positive

Chlamydia CSWs in Nairobi
trachomatis
Neisseria gonor- Laga, 1995 [105] Cohort study of 431 HIV- 2, Positive
rhoeae, Chlamydia negative female CSWs in
trachomatis, Kinshasa, Zaire followed
Trichomonas for 2 years
vaginalis
continued
833
Table 1 Evidence Table for Studies of Sexually Transmitted Infections (STIs) as Risk Factor of both HIV Transmission and
Acquisition that Include Original Data, Systematic Reviews, Meta-analyses, or Other Human Data (1988–2008). – (Cont’d)
Level of Evidence
Positive (role of
Lead author, a risk factor) or
Study Type STI type year, reference Design Negative
Bacterial vaginosis Taha, 1998 [106] 1,196 antenatal pregnant 2, Positive

and 1169 postnatal
seronegative women in
Malawi
Bacterial vaginosis Martin, 1999 [107] 657 seronegative female 2, Positive

CSWs in Kenya
Bacterial vaginosis Myer, 2005 [108] 410 women screened 2, Positive

for cervical cancer in
South Africa
CMV Sheth, 2006 [39] 26 HIV-infected MSMs 2, Positive

and 15 uninfected con-
trols (6 MSMs; 9 heterose-
xuals) in Toronto, Canada
HSV-2 Rebbapragada, 2007 55 HIV-infected and 36 2, Positive

[37] uninfected female CSWs
in Nairobi, Kenya
Case-control studies
Urethritis Cohen, 1997 [109] 135 HIV-1-seropositive 3, Positive

men in Malawi
Neisseria gonor- Ghys, 1997 [110] 609 HIV-1-seropositive 3, Positive

rhoeae, Chlamydia women in Abidjan, Côte
trachomatis, geni- d’Ivoire
tal ulcers
Case-series
HSV, syphilis Stamm, 1988 [111] 200 homosexual men 3, Positive

with acute proctitis
and 111 asymptomatic
homosexuals
The hierarchy of study types was: systematic reviews and meta-analysis of randomized controlled trials, non-randomized cohort studies,
case-control studies, case series, and expert opinion (as the lowest level).
and places depending on the maturity of among women who were seropositive for
the epidemic and the relative prevalence HIV-1 and HSV-2 [36]. All were ineligible
of HIV and STI infection in the commu- for highly active antiretroviral therapy
nity [35]. Although they did not show a and followed for 24 weeks with 12 weeks
reduction in HIV acquisition, there were before and 12 weeks after randomization.
reductions in adverse other outcomes Valacyclovir therapy was found to be asso-
such as neonatal mortality. ciated with a significant decrease in the
Recently, a randomized, double-blind, frequency of genital HIV-1 RNA (OR 0.41,
placebo-controlled trial of herpes simplex 95% CI 0.21–0.80) and in the mean quan-
virus (HSV) suppressive therapy with val- tity of the virus (log(10) copies per millili-
acyclovir was undertaken in Burkina Faso ter -0.29, 95% CI -0.44 – -0.15). Genital
834
herpes infection is now thought to be the 6. SCREENING FOR STIs

most important cofactor in mature epi-
demics of HIV [35]. Interestingly, HSV-2 STIs facilitate both transmission and
also drives secondary transmission of acquisition of HIV with relative risks of
HIV from HSV2-HIV co-infected individu- 2 to 5 [21]. Presence of any symptoms or
als. Rebbapragada et al. [37] conducted a signs suggestive of STIs should prompt
well-defined cohort study among 55 HIV- immediate diagnostic evaluation and
infected and 36 uninfected Kenyan female appropriate treatment [46]. Because
commercial sex workers (CSWs). HSV-2 STIs are frequently asymptomatic, rou-
shedding is much more common in HIV- tine laboratory screening for STIs should
infected than HIV-uninfected women, be undertaken in high-risk populations
perhaps due to HIV-induced depletion of where resources are available [47].
mucosal immature dendritic cells exerting
local HSV-2 immune control.
CMV may act as an important factor in 7. HIV COUNSELING AND TESTING
HIV secondary transmission [38]. Sheth
et al. [39] enrolled 26 HIV infected men who Since the first diagnostic HIV test in 1985,
have sex with men (MSMs) and 15 unin- HIV testing has become easier, more sen-
fected controls (six MSMs; nine heterosexu- sitive, more accessible and less invasive.
als). CMV shedding was associated with Unfortunately, national data indicate that
a 10-fold increase in HIV levels in semen, a large percentage of new human immuno-
independent of HIV blood viral load and deficiency virus (HIV) diagnoses are made
CD4+ T cell count, and there was a strong in the late stages of disease. In the United
linear correlation between the semen lev- States, 40% of patients with newly diag-
els of HIV RNA and CMV DNA. In the US nosed HIV infection develop AIDS within
RCT trial, anti-CMV treatment reduced one year of testing [25]. Furthermore,
shedding of human herpesvirus-8 (HHV-8) it has been estimated that one-fourth
and CMV [40]. A total of 16 HIV–positive of the people living with HIV infection
men and 10 HIV-negative men were ran- in the United States do not know they
domized to receive valganciclovir or pla- are infected and, thus, miss the opportu-
cebo administered orally. Valganciclovir nity to receive life-saving antiretroviral
reduced oropharyngeal shedding of HHV-8 therapy [48]. That lack of awareness of
by 46% (OR 0.54, 95% CI 0.33–0.90) and infection is critical from the public-health
cytomegalovirus by 80% (OR 0.20, 95% perspective as it is estimated that over
CI 0.08–0.48). Lack of male circumcision 50% of new sexually transmitted HIV
[41–43] can be considered as a facilitating infections are due to people unaware of
factor or high levels of male circumcision their HIV infection; and evidence strongly
and condom use can be considered as pro- suggests that once individuals are made
tective factors (please refer to the chapter aware of their infection, they reduce their
on male circumcision). Facilitating factors risk behavior and decrease the prob-
are virtually all positively correlated with ability of transmitting infection [49]. In
high-risk sex behaviors and are essential addition, people with acute HIV infection
for epidemic HIV transmission, but they (which is defined as the first three weeks
are difficult to quantify. Anal intercourse of infection) or early infection (the first six
poses a higher risk of HIV transmission months) represent the greatest risk for
compared with vaginal intercourse because transmission [2]. Therefore, HIV testing
of the greater amount of tissue trauma provides an opportunity for decreasing
that may occur [44–45] (please refer to the the continued incidence of HIV infection
recent NEJM review on this and male cir- and for providing life-saving therapy to
cumcision in homosexual men). newly diagnosed patients. To decrease the
835
number of people unaware of their HIV the superiority of HAART to single

infection, in 2006, the Center for Disease agents). These continued improvements
Control and Prevention (CDC) expanded have prompted a change in HIV from an
its HIV-testing recommendations [50]. almost uniformly fatal disease to one that
The new CDC recommendations advo- is a manageable chronic illness requiring
cate voluntary “opt-out” HIV screening in continued evaluation and therapy.
healthcare settings for all adults instead
of just screening traditionally “high-risk”
patients. The recommendations also sug- 9. UROLOGICAL MANIFESTATIONS
gest eliminating requirements for written OF HIV INFECTION
consent for HIV testing, annual re-testing
HIV infection in either early or late
for persons with known risk factors, and
stages affects each of the major organs in
third-trimester screening for women who
the genitourinary system.
test negative for HIV early in pregnancy.
To date, the enzyme immunoassay
9.1 Urinary tract infections
(EIA) format is still the primary HIV
antibody screening test in most settings. The risk of bacterial and opportun-
Assays are available to assess HIV-1 and istic infection, including UTIs, rises
HIV-2 separately or in combination [51]. dramatically when the CD4 counts
The recent introduction of alternative fall below 500/mm3 [57–58]. The most
fluids as suitable samples has allowed common bacterial pathogens in HIV-
testing to go beyond the clinic setting. infected patients are Escherichia coli,
Oral fluid (mucosal transudate) testing Enterobacter (Enterococci), Pseudomonas
is a valuable tool for outreach projects aeruginosa, Proteus spp, Klebsiella,
[52]. These noninvasive sample collec- Acinetobacter, Staphylococcus aureus,
tions such as oral fluid and urine tend to group D Streptococcus, Serratia, and
decrease the chance of occupational expo- Salmonella spp [58–62]. Atypical patho-
sure among health care workers. gens including fungi (Candida albicans,
Aspergillus, Blastomyces, Cryptococcus
neoformans, Cryptosporidia, Histoplasma
8. HIGHLY ACTIVE ANTI-RETROVIRAL capsulatum), parasites (Toxoplasma
THERAPY (HAART) gondii, Pneumocystis carinii), myco-
bacteria (Mycobacterium tuberculosis,
Taking a combination of three or more Mycobacterium avium complex), and
anti-HIV drugs is sometimes referred to viruses (cytomegalovirus and adenovirus)
as highly active anti-retroviral therapy are often widely disseminated in patients
(HAART). If only one drug was taken, with very low CD4 counts (usually <100/
HIV could quickly become resistant to it mm3) [61–65]. They may potentially affect
and the drug would stop working. Taking any portion of the genitourinary tract,
two or more anti-retrovirals at the same including the adrenals kidneys, bladder,
time vastly reduces the rate at which prostate, testes and epididymedes. When
resistance might develop, making treat- urinary cultures from 98 HIV-infected
ment more effective in the long-term men were collected prospectively at six-
[53]. There are five groups and more monthly intervals over two years, and
than 20 approved anti-retroviral drugs when they had signs and symptoms of
(Table 2). Each of these groups attacks UTI, one or more positive urinary cultures
HIV in a different way. Thus, combin- were found in 30% whose CD4 count was
ing different treatment approaches can <200/mm3 and in 11% with a CD4 count
provide synergy [54–56] (please refer to of 200–500/mm3. No bacteriuria or symp-
the numerous studies that demonstrate tomatic infective episodes were found
836
Table 2 FDA-Approved Antiretroviral Drugs for Treating HIV/AIDS.
Anti-retroviral drug class Abbreviation Generic name Mechanism of Action
Nucleoside/Nucleotide Reverse 3TC lamivudine NRTIs interfere with the action of an HIV pro-
Transcriptase Inhibitors (NRTIs, tein called reverse transcriptase, which the
ABC abacavir
nucleoside analogues) virus needs to make new copies of itself.
AZT or ZDV zidovudine
d4T stavudine
ddC zalcitabine
ddI didanosine
FTC emtricitabine
TDF tenofovir
Non-Nucleoside Reverse DLV delavirdine NNRTIs also stop HIV from replicating within
Transcriptase Inhibitors cells by inhibiting the reverse transcriptase
EFV efavirenz
(NNRTIs, non-nucleosides) protein.
ETR etravirine
NVP nevirapine
Protease Inhibitors (PIs) APV amprenavir PIs inhibit protease, which is another protein
involved in the HIV replication process.
FOS-APV fosamprenavir
ATV atazanavir
DRV darunavir
IDV indinavir
LPV/RTV lopinavir +
ritonavir
NFV
nelfinavir
RTV
ritonavir
SQV
saquinavir
TPV
tipranavir
Fusion or Entry Inhibitors T-20 enfuvirtide Fusion or entry inhibitors prevent HIV from
binding to or entering human immune cells.
MVC maraviroc
Integrase Inhibitors RAL raltegravir Integrase inhibitors interfere with the integrase
enzyme, which HIV needs to insert its genetic
material into human cells.
Data from U.S. Food and Drug Administration. Drugs used in the treatment of HIV infection. http://www.fda.gov/oashi/aids/
virals.html. Accessed 31 December 2008.
in those with CD4 counts of >500/mm3 at least three and sometimes four agents,
[57]. In autopsy studies of patients with including rifampicin, isoniazid, pyrazi-
AIDS, renal tuberculosis was identified in namide and ethambutol for six to nine
6–23%. Although most of these patients months, depending on sensitivity results
had symptoms and signs of pulmonary [58, 61]. The incidence of acute bacte-
tuberculosis, 20% had subclinical disease. rial prostatitis is 1% to 2% in the general
The clinical diagnosis is made with urine population, whereas it is 3% in asympto-
tuberculosis culture, excretory urogra- matic, HIV-infected patients and 14% in
phy, cystoscopy and biopsy with staining patients who have AIDS [66]. The inci-
for acid-fast bacilli. Treatment requires dence of prostatic abscesses in AIDS has
837
decreased significantly with the advent including the kidneys and testes [74–75].
of HAART, because they occur only in A new herpes virus, called KS herpes
patients with very low CD4 counts [59]. virus or human herpes virus type 8,
In autopsy studies of patients with AIDS transmitted by sexual contact or through
and systemic opportunistic infections, the blood may be related to the develop-
prevalence of concomitant testicular infec- ment of KS in the HIV-positive popu-
tion is 25–39%. The causative organisms lation [59, 63]. Genital lesions appear
include Salmonella, Cytomegalovirus in approximately 20% of patients who
(CMV), Mycobacterium avium intracellu- have KS, with <3% having the initial
lar (MAI), Toxoplasma, Histoplasma and lesion on the penis [76]. Renal involve-
Candida albicans [62, 67]. ment of NHL in patients who have AIDS
is 6% to 12%, and presentation may be
bilateral [59, 61]. Renal cell carcinoma
9.2 Malignancies
carries an 8.5-fold greater risk for HIV-
Many malignancies occur in HIV-infected infected patients compared with non-
patients. Possible mechanisms proposed infected patients [77]. Retrospective
that support malignancy formation review of 3,000 patients enrolled in an
include decreased immune surveillance, HIV clinic found a 50 times greater rate
a direct effect of viral proteins, cytokine of testicular malignancy in the general
dysregulation, or other immunologic or population [78]. Compared with HIV
viral cofactors [68–69]. Vascular and noninfected patients, there is a greater
lymphoreticular malignancies have been risk of tumor bilaterality and a greater
associated most strongly with HIV infec- risk of high-grade testicular lymphoma
tion, particularly Kaposi’s sarcoma (KS) [79]. Recently, Vianna and colleagues
and non-Hodgkin’s lymphoma (NHL). [80] examined a cohort of 534 men aged
The risk of KS and NHL are increased 49 years and older who had risk fac-
1000- and 100-fold, respectively, among tors for HIV. Among older men, PSA
HIV-infected patients compared with the levels increased with age but did not
general population [70]. KS, systemic differ by HIV status. The study recom-
intermediate/high-grade B-cell NHL, and mended that standard prostate-specific
invasive cervical cancer are considered antigen evaluations can be made with
to be AIDS-defining malignancies. Many HIV-positive patients without the need
non-AIDS-defining malignancies have, for adjustments. HIV infection is associ-
however, also been found in greater fre- ated with human papillomavirus (HPV)-
quency among those with HIV, includ- related anogenital malignancies. HPV
ing germ cell testicular tumors, renal types 16 and 18 are considered high risk
cell carcinoma, and prostate cancer [71]. in anogenital malignancy formation of
HAART radically changed the clinical carcinoma in situ and squamous cell car-
spectrum of HIV infection in industrial- cinoma [81]. Bowen’s disease (Carcinoma
ized countries. The incidence of AIDS- in situ) of the penis, considered a prema-
associated malignancies decreased lignant lesion, appears more common in
significantly after the introduction the HIV-infected population [82].
of HAART [72]. Systemic NHL inci-
dence decreased less than KS and later
9.3 HIV-associated nephropathy
than the other AIDS-defining illnesses.
(HIVAN)
Consequently, lymphoma has become the
most common AIDS-associated malig- HIV-associated nephropathy (HIVAN)
nancy among patients receiving HAART is the most well-known and aggressive
[73]. KS can present as a systemic kidney disease in HIV-infected patients.
disease that affects internal organs, With the widespread use of HAART, its
838
prevalence is declining in industrialized patients [94]. This adverse effect may be

countries [83]. The prevalence of HIVAN managed by the discontinuation of indi-
is reported to be 3.5% in HIV-infected navir administration, urine acidification,
clinic patients and 6.9% in autopsy series hydration, alpha-blockers to facilitate
of HIV-infected patients [84]. Scientific stone passage, as well as the possible
evidence suggests that HAART can pre- early insertion of bilateral double-J ure-
vent the development of HIVAN [85–87]. teral stents [95]. HAART, especially pro-
Furthermore, HAART, corticosteroids and tease inhibitor-based therapy, also plays
inhibition of the renin-angiotensin axis a role in sexual dysfunction [96–97].
are potentially helpful in delaying disease In a cohort study [98], the incidence of
progression, as well as the need for renal erectile dysfunction (ED) and decreased
replacement therapy [88]. libido in HIV-positive homosexual men is
26%. In that study, in patients who were
9.4 Voiding dysfunction taking HAART, the incidence of reduced
libido was 48% and the rate of ED was
Of patients with AIDS, 30–40% have neu- 25%. Decreased libido may be a result of
rological involvement, and in 20% this is raised estradiol level, low testosterone
the initial manifestation. In HIV-infected level, fatigue, depression and hypogo-
patients who present with voiding dis- nadism. However, Lallemand et al. [99]
turbances, an underlying neurological oppose the occurrence of sexual dysfunc-
cause is present in 60%, and 90% of those tion in HIV-positive men taking protease
already have AIDS-associated infections or inhibitors in their cross-sectional study.
tumors [61]. Urinary retention is the most Phosphodiesterase type-5 (PDE-5) inhibitors
common voiding dysfunction (54%) seen also may interact with protease inhibitors,
by urologists, although detrusor hyper- which increase the blood concentrations of
reflexia (27%) and outflow obstruction PDE-5 inhibitors. Starting PDE-5 inhibitors
(18%) have been documented during uro- at a lower dose with a caution for side-effect
dynamic study of AIDS patients with void- may be more appropriate in patients taking
ing symptoms [89–90]. Voiding complaints protease inhibitors [100].
often reflect the degree of systemic impair-
ment and poor prognosis, although such
symptoms often improve substantially 10. FURTHER RESEARCH
after effective antiretroviral therapy [61].
Further community-based RCTs should
9.5 Other urological manifestations
carefully test a range of alternative STI
Several complications related to HAART control strategies in a variety of differ-
such as urolithiasis and sexual dysfunc- ent settings. Improved trials - especially
tion have been reported. The strongest more detailed estimates that measure a
association is with protease inhibitors, range of factors that include health seek-
especially indinavir [91]. Current lit- ing behavior and quality of treatment, as
erature have reported that 10–28% of well as HIV, STI and other biological end-
patients receiving indinavir may develop points - will help us to identify the best
a new form of urinary stones, known as possible intervention strategies for slow-
‘‘indinavir urolithiasis’’ [91–93]. Pure ing the epidemic’s spread.
indinavir stones are radiolucent and can-
not be detected with either conventional
radiography or CT. However, mixed 11. CONCLUSIONS
stones consisting of indinavir and calcium
oxalate or phosphate salts have occa- The current world-wide expansion of the
sionally been reported in HIV-positive AIDS epidemic is primarily driven by
839
the sexual transmission of HIV. Evidence prevention and control. Int J STD AIDS,
from intervention studies indicates that 2007. 18(8): 509–13.
in the presence of other STIs, individuals 7. Dyer JR, Gilliam BL, Eron JJ, Jr., Grosso L,
are more likely to acquire HIV if exposed Cohen MS, and Fiscus SA, Quantitation
to the virus through sexual contact. of human immunodeficiency virus type
Therefore, early detection and treatment 1 RNA in cell free seminal plasma: com-
parison of NASBA with Amplicor reverse
of curable STIs can play a vital role in
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primarily and secondarily affects virtually tion with antiviral treatment and immune
every part of the genitourinary system. status. AIDS, 1997. 11(8): 987–93.
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in prolonging time to development of human immunodeficiency virus secretion
AIDS and improving AIDS survival rates. and plasma viral load in human immu-
Urologists who treat genitourinary mani- nodeficiency virus-seropositive women.
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Peterson G, Hooton TM, Collier AC,
Corey L, Koutsky L, and Krieger JN,
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846
|14.6|
Male circumcision and HIV

infection risk
John N. Krieger
John N. Krieger, M.D., Department of Urology, University of Washington, School of Medicine,
Seattle, WA USA 98195
Tel: 206-543-3640, FAX: 206-764-2239, E mail: jkrieger@u.washington.edu
This review evaluates the scientific evi- There is a need to provide safe male cir-
dence suggesting that male circumcision cumcision services for high-risk popu-
reduces the risk of human immunodefi- lations because this is one of very few
ciency virus type 1 (HIV) infection risk. proven HIV prevention strategies (GoR A).
Level 1 evidence that male circumcision
substantially reduces the risk of HIV
infection is summarized below. Three 1. INTRODUCTION
lines of evidence support this conclusion:
biological evidence, data from observa- This review evaluates the scientific evi-
tional studies supported by high-quality dence suggesting that male circumcision
meta-analysis, and the results of three reduces the risk of human immunodefi-
randomized clinical trials supported ciency virus type 1 (HIV) infection risk.
by high quality meta-analysis. The evi- First, we present an executive summary
dence from biological studies, observa- of the best available scientific data sup-
tional studies, randomized controlled porting our findings, then we discuss
clinical trials, meta-analyses, and cost- the methods and detail the supporting
effectiveness studies is conclusive. The evidence.
challenges to implementation must now One major question was defined, “How
be faced. strong is the scientific evidence that male
Key words: Male circumcision, HIV circumcision reduces the risk of HIV
infection, risk, complications. infection?” If the evidence supporting
male circumcision as an HIV preven- systematic reviews and meta-analysis

tion strategy is robust, then a number or modeling, randomized controlled tri-
of secondary issues merit consideration, als, non-randomized cohort studies, case-
such as, cost-effectiveness, potential for control studies, case series, and expert
adverse events or behavioral changes and opinion (as the lowest level). In addition,
other important issues. we included other relevant biological
studies that and cost-effectiveness stud-
2. METHODS ies. We reviewed the titles and abstracts
of the articles identified in the initial
search to identify 278 articles meriting
We searched for papers published, or
detailed review.
accepted for publication in the peer
This detailed review considered how
reviewed issues of journals, papers
well individual studies were designed
accepted for publication by the peer
and carried out using a standard check
reviewed journals but not yet published,
list to assure that a consistent approach
but excluded papers published in non
was used in the methodological assess-
peer reviewed supplements. The search
ment of the evidence. The objective of
included the last 10 years of data in the
the checklist was to provide a system-
major databases (e.g., Medline, Embase,
atic quality rating for individual stud-
Cochrane Library, Biosis, and Science
ies. The checklist included items rating
Citation Index). We reviewed the table of
how well the study was conducted and
contents of the major urology journals and
reported using the CONSORT state-
other relevant journals, for the last three
ment and its widely accepted checklist
months, to take into account the possible
(http://www.consort-statement.org). This
delay in the indexation of the published
process identified a total of 80 papers,
papers in the databases. In addition, we
representing every study type category
reviewed critical articles that were more
(Table 1).
than 10 years old to provide relevant
background and context for this analysis.
For inclusion in the final analysis, we
recommendation (GoR) using ICUD
required papers published within the last
10 years that either contained original
After selecting the 79 papers and rat-
data or original data analyses, such as
ing of the level of evidence of each study,
systematic reviews or meta-analyses. We
a table was constructed to summarize the
also included relevant articles on possi-
evidence of the individual studies and the
ble biological mechanisms and published
overall direction of evidence in an evi-
articles that reviewed selected data and
dence table (Table 1).
opinion to represent the full range of
expert opinion. The search strategy used
the term male circumcision combined 3. BEST EVIDENCE THAT MALE
with the terms: HIV infection, complica- CIRCUMCISION REDUCES THE
tions, acceptability and sexually transmit- RISK OF HIV INFECTION
ted infection, plus the combination of the
search terms foreskin and HIV receptor to The highest quality evidence that male
identify 1,048 unique articles. circumcision substantially reduces the
Because papers in peer-reviewed risk of HIV infection is summarized
journals differ in quality and level of below. Three lines of evidence support
evidence, included papers were rated this conclusion: biological evidence, data
according to levels of evidence (see from observational studies supported
below). The hierarchy of study types was: by high-quality meta-analysis, and the
848
Male circumcision and HIV infection risk | 14.6 |
results of three randomized clinical trials 3.3 Randomized controlled clinical

supported by high quality meta-analysis. trial evidence
While statistically significant and pro-
3.1 Biological evidence
vocative, observational studies can-
Plausible biological mechanisms could not prove causality. Three randomized
explain the increased risk of HIV and clinical trials of adult male circumci-
other sexually transmitted infections (STI) sion among consenting, healthy men
among uncircumcised men. These mecha- in South Africa [12], Kenya [13], and
nisms include: an increased rate of inflam- Uganda [14], were started in 2002–2003.
matory conditions, susceptibility of the All three trials were stopped early fol-
mucosal surface of the prepuce to trauma, lowing recommendations by independ-
and the longer survival of pathogens in ent Data and Safety Monitoring Boards
the warm, moist subpreputial space. The after interim analyses found highly sig-
inner foreskin is especially susceptible to nificant decreases in HIV infection risk
HIV infection due to lack of keratinization among participants randomly assigned
and the high density of HIV target cells to circumcision.
that are relatively accessible to infection The three trials enrolled a total of
compared with their deeper location [3] 10,908 uncircumcised, HIV-negative adult
under the keratinized surface of the outer men. Participants were randomly assigned
foreskin and the glans [4–6]. to circumcision or control arms and
then followed for up to 2 years (Table 2).
3.2 Observational study evidence
Retention rates were high (86–92%).
The hypothesis that male circumcision Table 2 shows the cumulative HIV infec-
might protect against HIV infection was tion risk among men estimated using
first suggested in 1986 [7]. Subsequent intention-to-treat Kaplan-Meier analy-
support was provided by ecological stud- sis. Subsequent meta-analysis using a
ies in areas with low prevalence of male random-effects model of the trial results,
circumcision and high HIV prevalence following the QUORUM statement rec-
in sub-Saharan Africa in the late 1980s ommendations found no evidence of het-
[8], and later across 118 developing coun- erogeneity among the trials.[11] The
tries.[9] Further evidence comes from overall rate ratio (RR) was 0.42 (95%
two well-done systematic reviews of the confidence interval (CI) 0.31–0.57), cor-
observational study data comparing HIV responding to a protective effect of 58%
infection rates in circumcised and uncir- (95% CI 43–69%), identical to that found
cumcised men from the same populations in the observational studies (58%, 95% CI
[3, 10]. One review was restricted to 27 46–66%).
studies from sub-Saharan Africa, [3] and The true protection provided by male
the other was a global review including circumcision may be better estimated
37 studies [10]. Circumcised men had by an “as-treated” analysis, assigning
substantially lower risk of HIV infection. outcomes according to the actual cir-
A well-done meta-analysis of the 15 stud- cumcision status of participants. All
ies that adjusted for potential confound- participants did not adhere to the arm
ers showed this reduction to be large and they were randomly assigned to. Meta-
highly significant (adjusted risk ratio analysis of the “as-treated” results of the
(RR) 0.42, 95% confidence interval (CI) three trials shows even stronger protec-
0.34–0.54) [3]. Subsequent studies have tion against HIV infection in the circum-
found similar large risk reductions among cision group (summary RR 0.35, 95% CI
circumcised men [11]. 0.24–0.54) [11].
849
Table 1 Evidence Table for Studies of Male Circumcision and HIV Infection Risk that Include Original Data, Systematic Reviews
or Meta-analysis, Expert Opinion, or Other Human Data (1999–2008).
Level of Evidence
Positive (favoring
Lead author, year, circumcision) or
Study Type reference Design Negative
Systematic reviews, Meta-analyses and Modeling
Van Howe, 1999 [19] Meta-analysis of 29 published articles 4, Negative

with serious technical flaws.
O’Farrell, 2000 [20] Meta-analysis of 33 diverse obser- 2, Positive

vational studies, stratifying by study
type.
Weiss, 2000 [3] Systemic review and meta-analysis of 2, Positive

27 studies
Siegfried, 2003, 2005 Systematic reviews [10] 3, Positive

[10, 21]
Desai, 2006 [22] Stochastic prevention trial simulator 2, Positive

and RCT* data.
Williams, 2006 [23] Dynamical simulation models using 2, Positive

country level data.
Drain, 2006 [9] Country-specific data from 118 2, Positive

developing countries evaluated with
multivariate linear regression.
Orroth, 2007 [24] Individual-based stochastic model 3, Positive

fitted to characteristics four urban
African populations.
Hallet, 2008 [25] Mathematical model parameterised 3, Positive

RCT findings.
Londish, 2008 [26] Mathematical model simulated obser- 3, Positive

ved levels of HIV prevalence in sub-
Saharan Africa
Weiss, 2008 [11] Systematic review and meta-analysis 1, Positive

of the three RCTs.
Randomized-controlled trials
Auvert, 2005 [12] 3,274 uncircumcised men randomi- 1, Positive

zed 1:1
Bailey, 2007 [13] 2,784 uncircumcised HIV-negative 1, Positive

men randomized 1:1
Gray, 2007 [14] 4,996 uncircumcised, HIV-negative 1, Positive

men randomized 1:1
Non-randomized cohort studies
Kelly, 1999 [27] Survey of 6,821 men aged 15–59 3, Positive

years in rural Uganda
Quinn, 2000 [28] 415 Ugandan couples in which one 2, Positive

partner was HIV-positive and one was
initially HIV-negative followed pro-
spectively for up to 30 months
850
Level of Evidence
Positive (favoring
Reynolds, 2004 [29] Prospective study of 2,298 HIV- 2, Positive

negative men attending sexually
transmitted infection clinics in India.
Meier, 2006 [30] 150 Kenyan sex partners of women 3, Positive

with genital symptoms,
Shaffer, 2007 [31] Prospective cohort of 1,378 men in 2, Positive

rural Kenya followed for 2 years.
Millet, 2007 [32] Respondent-driven sampling of 1154 3, Negative

black and 1091 Latino men who have
sex with men in the US.
Case-control studies
Auvert, 2001 [33–34] Random population samples from 3, Positive

2 circumcising African populations
compared to 2 non-circumcising pop-
ulations (approximately 4,000 men)
MacDonald, 2001 [35] 38 HIV-positive and 94 HIV-negative 3, Positive

Kenyan men with genital ulcers.
Gray, 2004 [36] Rural Uganda 3, Positive
Agot, 2004 [37] 398 circumcised and 447 uncircum- 3, Positive

cised Kenyan men
Jewkes, 2006 [38] 1277 sexually experienced men from 3, Positive

70 villages in South Africa
Kapiga, 2006 [39] Community-based study of 1,418 3, Positive

women and 566 of their regular male
partners in Tanzania
Johnson, 2006 [40] Cross-sectional, population-based 3, Positive

survey including 2,941 Kenyan men.
Talukdar, 2007 [41] Probability sample of homeless men 3, Positive

aged in Kolkata, India
Mishra, 2007 [42] Data are from eight national surveys 3, Positive
in sub-Saharan Africa.
Klavs, 2008 [43] National probability sample of the 3, Negative

general population in Slovenia.
Foglia, 2008 [44] Population-based study of Kenyan 3, Positive

men
Mermin, 2008 [45] Cross-sectional nationally representa- 3, Positive

tive survey 10,227 women and 8,298
men in Uganda.
Case-series
Halpern, 2005 [46] Zimbabwe 3, Positive
Buchbinder, 2005 [47] 3257 men who have sex with men in 3, Positive
6 US cities
continued
851
Table 1 Evidence Table for Studies of Male Circumcision and HIV Infection Risk that Include Original Data, Systematic Reviews
or Meta-analysis, Expert Opinion, or Other Human Data (1999–2008) – (Cont’d)
Level of Evidence
Positive (favoring
Expert opinion
Moses, 1999 [8] Review 3, Positive
Halpern, 1999 [48] 4, Positive
Green, 2000 [49] 4, Positive
Szabo, 2000 [50] 4, Positive
Quigley, 2001 [51] Review 4, Positive
Lerman, 2001 [52] Review 4, Positive
Shapiro, 2002 [53] Social perspective 4, Positive
Gisselquist, 2004 [54] 4, Negative
Sahasrabuddhe, 2004 [55] Review 3, Positive
Short, 2004, 4, Positive

2006 [56–57]
Nyindo, 2005 [58] Review 3, Positive
Inungu, 2005 [59] 4, Neutral
Jones, 2005 [60] 4, Positive
Flynn, 2005 [61] Review 3, Positive
Van Howe, 2005 [62] 4, Negative
Auerbach, 2006 [63] Review 3, Positive
Chan, 2006 [64] 4, Positive
Mboto, 2006 [65] 4, Positive
Islugo-Abanlhe, 2006 4, Positive

[66]
Weiss, 2007 [67] Review 3, Positive
Sawires, 2007 [68] Review 3, Positive
Schenker, 2007 [69] Data on complications of infant 3, Positive

and adult complications in Israel
Sharp, 2007 [70] Conference review 4, Positive
Quinn, 2007 [71] Review 3, Positive
Schoen, 2007 [72] 4, Positive
Clark, 2000, 2007 4, Positive

[73–74]
Morris, 2007 [75] Review 4, Positive
Mor, 2007 [76] 3, Positive
852
Level of Evidence
Positive (favoring
Jayasuriya, 2007 [77] Review 3, Positive
Landovitz, 2007 [78] Review 3, Positive
Vardi, 2007, 2008 [79] 4, Neutral
Cohen, 2008 [80] Review 3, Positive
Gray, 2008 [81] Review of RCT data 3, Positive
Potts, 2008 [82] 3, Positive
Cost-Effectiveness Studies
Kahn, 2006 [17] Cost-effectiveness models for a gen- 2, Positive

eral adult male population in South
Africa.
Gray, 2007 [18] Stochastic simulation model with 2, Positive

empirically derived parameters.
Fieno, 2008 [83] Cost-effectiveness models for 2, Positive

Mozambique.
Pertinent Biological Studies
Patterson, 2002 [4] Immunological and in vivo infection 4, Positive

of human foreskins.
Soilleux, 2004 [5] HIV-receptor studies of human 4, Positive

foreskins.
McCombe, 2006 [6] HIV-receptor studies of human 4, Positive

foreskins.
The hierarchy of study types was: systematic reviews and meta-analysis of randomized controlled trials, randomized controlled trials,
non-randomized cohort studies, case-control studies, case series, and expert opinion (as the lowest level).
3.4 Complications of male negative men [12]. In the Ugandan trial,

circumcision the surgery-related adverse event was
Complications of adolescent or adult cir- 7.6% (178/2328) [14]. This may reflect dif-
cumcision include bleeding, wound infec- ferences in management. The risk of mod-
tions, delayed wound healing and other erate adverse events related to surgery
less common events. Comparing the was 3% in the Uganda trial, including
adverse event rates in the three trials five severe adverse events (0.2%). All of
is complicated. The studies had differ- these events were managed successfully.
ent visit schedules, adverse event defini-
tions and criteria. In the Kenyan trial, 3.5 Cost-effectiveness
adverse events possibly, probably or defi- Detailed analyses of the African trials
nitely related to circumcision occurred indicate that male circumcision is likely
in 23 of 1,334 circumcised participants to be very cost-effective, likely even cost-
(1.7%) [15–16]. All adverse events were saving [17]. The South African estimate
mild or moderate and resolved quickly. In modeled using data from their trial found
the South African trial, the adverse event the cost per HIV infection averted was
rate was 54 per 1,495 (3.6%) in HIV- US$181 (80% CI US$117–306), with net
853
Table 2 Summary of the Three Randomized Controlled Trials of Male Circumcision on HIV Infection in sub-Saharan Africa.
South Africa [12] Kenya [13] Uganda [14]
Participants 1,582 1,393 2,522

Control 1,546 1.391 2,474
Circumcision
Age range (years) 18–24 18–24 15–49
Setting Peri-urban Urban Rural
Circumcision method Forceps-guided by local Forceps-guided by study Sleeve method by study

general practitioners, clinicians, clinicians
Monopolar cautery
No cautery Bipolar cautery
Visit schedule (months) 3, 12 and 21 1, 3, 6, 12. 18 and 24 6, 12 and 24
Retention rate 92% at 21 months 86% at 24 months 90% at 24 months
Person-years of follow-up 4,693 4,428 6,744
HIV infections 20:49 19:46 22:45

(circumcision:control)
Risk ratio (95% CI) 0.41 (0.24–0.69) 0.41 (0.24–0.70) 0.43 (0.24–0.75)
Summary risk ratio for all three 0.42 (0.31–0.57)

trials (95% CI)
CI = confidence interval.
Modified from Weiss, et al.[11]
savings of US$2.4 million over 20 years expanding male circumcision services,

(cost savings of US$2,631 per circumci- and the relevance of the findings for other
sion). Using data from the Kenyan trial, populations. Below we will briefly con-
the estimated cost was $200 per HIV sider two important issues that require
infection averted [11]. Costs were higher resolution, the potential differences
in Uganda, where 39 circumcisions would between clinical trial and field condi-
be needed to prevent one HIV infections, and the potential for ‘behavioral
tion over 10 years at a cost of US$2,631 disinhibition.’
per HIV infection averted over 10 years
[18]. Because benefits of circumcision are
life-long, and economies of scale should 5. DIFFERENCES BETWEEN CLINICAL
decrease costs, male circumcision is very TRIAL AND FIELD CONDITIONS
likely to prove extremely cost-effective in
high-risk African settings. These trial data indicate that adult
male circumcision can be safe in limited-
resource settings when performed by
4. OUTSTANDING ISSUES experienced, well-trained providers.
However, when male circumcision is
Many issues remain, including the cul- undertaken in septic conditions by inex-
tural acceptability of male circumcision perienced providers or with poor after-
in non-circumcising African communi- care, serious complications or even death
ties, socio-cultural and economic issues of can result. Thus, implementation safe
854
adult male circumcision in many African and benefits of male circumcision in

settings will require considerable effort settings in addition to the high-risk het-
and national policies. erosexual populations that have been
extensively investigated to date.
6. POTENTIAL FOR ‘BEHAVIORAL

DISINHIBITION’ 8. CONCLUSIONS
The potential for an increase in unsafe sex The positive findings in the male cir-
practices (known as, ‘risk compensation’ or cumcision trials are in stark contrast to
‘behavioral disinhibition’) after circumci- recent negative of other HIV prevention
sion could potentially offset the protective interventions, including: microbicides, the
effect of male circumcision. The Ugandan female diaphragm and gel, treatment to
trial found no difference in sexual behavior suppress genital herpes infections, and,
during the trial by circumcision status [14]. most recently, an andenovirus-based HIV
The South African trial showed a signifi- vaccine. There is a need to provide safe
cantly increased mean number of sex acts male circumcision services for high-risk
between four and 21 months among men populations because this is one of very
in the circumcision arm, but no increase in few proven HIV prevention strategies.
the number of sexual partners or a change In addition to other health benefits, male
in condom use [12]. The Kenyan trial circumcision provides a much-needed
reported a decrease in reported risk-taking addition to the limited HIV prevention
behaviors during the 24 months of follow-up armamentarium. Male circumcision is
in both study arms [13]. possibly the oldest, and certainly the
The trial findings are reassuring but most common surgical procedure. The
these data may not be generalizable. The evidence from, biological studies, obser-
trials provided the highest standards of vational studies, randomized controlled
preventative care, with intensive individ- clinical trials, meta-analyses, and cost-
ual counseling. Further, participants did effectiveness studies is conclusive. The
not know that circumcision reduced their challenges to implementation must now
risk of HIV infection. The challenges of be faced.
expanding services within already over-
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859
Chapter |15|
Special urogenital
infections
Chair: Tetsuro Matsumoto
CHAPTER OUTLINE
15.2 Urinary tuberculosis 864
15.3 Male genital tuberculosis 877
15.4 Genitourinary tuberculosis in a developing country
(Vietnam): diagnosis and treatment 892
15.5 Guidelines for the treatment of fungal urinary
tract infections 903
15.6 Vulvovaginal candidosis 912
15.7 Viral genitourinary infections 928
15.8 Genitourinary schistosomiasis 943
15.9 Brucellosis: genitourinary involvement 959
15.10 Echinococcus/hydatid disease: genitourinary involvement 968
|15.1|
Introduction
Tetsuro Matsumoto
Professor of Urology, Chairman of the Department of Urology, School of Medicine,
University of Occupational and Environmental Health, 1-1, Iseigaoka, Yahatanishi-ku, Kitakyushu, 807–8555 Japan
Fax +81-93-6038724, Tel +81-93-6031611/7446, t-matsu@med.uoeh-u.ac.jp
This section includes various infectious rare type of TB and its diagnosis is based
diseases of the urinary tract, such as on aseptic pyuria, culture method and/
tuberculosis, fungal infections, para- or PCR. The treatment for urogenital TB
site infections, viral infections and bru- consists of a combination therapy with 3
cellosis. While some of these infections or 4 antituberculous antibiotics.
are not so common, some infections are Candida infection of the urinary tract
very bothersome in specialist areas or is common and is diagnosed by the pres-
in patients with special conditions, e.g. ence of fungi in urine and a positive urine
immunodeficiency. The authors of this culture of candida species. Candida albi-
section developed general guidelines for cans is the most common pathogen of
diagnosis, treatment and follow-up of funguria followed by C. tropicalis, C. kru-
infectious diseases based on the evidence sei and C. parapsilosis. In general, treat-
available. However, most of the guide- ment of asymptomatic candiduria is not
lines are expert opinions, because studies recommended, but high risk patients may
with higher evidence are quite limited. be treated to prevent dissemination and
Tuberculosis (TB) is not so rare. The symptomatic patients can be treated with
World Health Organization (WHO) esti- antifungal agents or surgical intervention
mated that one third of the world’s pop- to remove a fungal ball.
ulation is infected with Mycobacterium Parasitic diseases including urogeni-
tuberculosis and there are 8 to 10 million tal schistosomiasis and echinococcocis
new active cases of TB each year. The are a major health problem, especially in
most important problems in TB are its developing countries. Schistosomiasis is
increase in patients with human immu- diagnosed by the presence of eggs in uri-
nodeficiency virus (HIV) infection and nary sediment. The adequate treatment
the emergence and increase of multid- is praziquantel. Hydatid cysts caused by
rug resistant strains. Urogenital TB is a Echinococcus granulosus, E. multilocularis
or E. vogeli are seldom seen in the kidney involvement is seen in the male genital
and the urogenital area. organ, female pelvic inflammatory dis-
Several kinds of viral infections involve eases and/or pyelonephritis. Brucellosis is
the urinary tract. Hemorrhagic cystitis usually treated by a combination of doxy-
is sometimes caused by viruses includ- cycline plus streptomycin, rifampcin or
ing BK virus, adenovirus and cytomega- gentamycin.
lovirus. HIV, Herpes simplex virus and We thank all authors of this section for
human papilloma virus cause sexually their hard work on developing general
transmitted infections of the urogenital guidelines for relatively rare and special
area. infections of the urogenital tract and we
Brucellosis is a zoonotic infection of the hope that these recommendations are
urinary tract caused by Brucella melitensis, useful for all urologists taking care of
B. abortus, B. suis, B. canis etc. Urogenital such patients.
863
|15.2|
Urinary tuberculosis
Severin Lenk1*, Mitsuru Yasuda2
*Corresponding author:
1
Prof. Dr. med. Severin Lenk, MD, PhD, Professor, Private practice for Urology/Andrology, Reinhardtstraße 3, D-10117 Berlin
Telephone: 0049/30/4251229, Fax: 0049/30/64169096, e-mail: privatpraxis_prof.lenk@yahoo.de
2
Dr. Mitsuru Yasuda, Department of Urology, Division of Disease Control, Research Field of Medical Sciences,
Graduete School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501194, Japan
Tel.: +81-58-230-6338, Fax: +81-58-230-6339, super7@gifu-u.ac.jp
ABSTRACT The diagnosis of tuberculosis of the

urinary tract is based on the finding of
More than 100 years after Robert Koch pyuria in the absence of infection as judged
discovered the acid-fast bacillus, tuber- by culture on routine media.
culosis is still counted amongst the most Radiological imaging can be helpful to
important infectious diseases in the world, detect urinary tuberculosis by intravenous
especially in the context of HIV infection. pyelogram and/or computertomography.
In 2006 there were 9.6 millon new A positive yellow egg culture and/or histo-
cases of tuberculosis and 1.7 million fatal- logical analysis of biopsy specimens possibly
ities from disease worldwide. combined with polymerase chain reaction
In contrast to this, as the result of (PCR) is still required in most patients to
intensive tuberculosis control measures, establish a definitive diagnosis of GUTB.
the incidence of tuberculosis in Germany In GUTB drug treatment is the first
has constantly decreased. line therapy.
However, the rate of new cases of According to the World Health
extrapulmonary manifestations includ- Organisation (WHO), antituberculous
ing genitourinary tuberculosis (GUTB) drug treatment is based on an initial
decreases rather slowly. 2-month intensive phase with three or
GUTB usually results from the reac- four drugs daily (rifampicin, isoniazid,
tivation of old, dormant tuberculous dis- pyrazinamide, and ethambutol or strepto-
ease by members of the Mycobacterium mycin) followed by a four-month continu-
(M.) tuberculosis complex. ation phase with only two drugs, mostly
Renal tuberculosis mostly presents uni- rifampicin and isoniazid.
laterally, but post mortem studies show These two drugs may be given twice or
the disease is bilateral. thrice weekly.
Urinary tuberculosis | 15.2 |
Surgery as a treatment option in Diagnosis

GUTB has clearly lost its importance. It
might be indicated in complicated uri- 6. Around 40% of patients with GUTB
nary tuberculosis (obstruction, abscess) in the developed countries and 50%
or secondary urinary tract infection such in the developing countries have a
as pyelonephritis or urinary stones. history of tuberculosis. The case
After antituberculous treatment of uri- history must be an important step
nary tuberculosis, follow-up surveillance in the diagnostic procedure of GUTB
over five years is recommended. (GoR A).
Although the incidence of GUTB in 7. The main symptoms in urinary
Germany is relatively low, it is still nec- tuberculosis are voiding problems
essary to impart and deepen scientific and chronic urgency non-responding
knowledge of the diagnosis and therapy to antibacterial drug treatment regi-
of GUTB. mens. In such cases a screening for
Special problems present themselves GUTB is recommended (GoR A).
with patients with immunosuppres- 8. The diagnosis of tuberculosis of the
sion (AIDS or after transplantation) and urinary tract is based on the findings
migrants with tuberculosis from the so- of pyuria in the absence of infec-
called Third World. tion as judged by culture on routine
Key words: tuberculosis epidemiology, media (GoR A).
urinary tuberculosis: pathogenesis, diag- 9. Characteristic signs on intravenous
nosis, medical treatment, surgical treat- pyelogram and computer tomography
ment, follow-up are useful in depicting GUTB (GoR B).
10. Relatively few studies have spe-
cifically evaluated polymerase chain
SUMMARY OF RECOMMENDATIONS reaction (PCR) for detection of GUTB,
but these show the technique to be
Epidemiology and pathogenesis sensitive and specific. Especially, PCR
should be used to detect mycobacte-
1. In 2006 there were 9.6 million new rial DNA in urine in HIV related
cases of tuberculosis and 1.7 million disseminated tuberculosis (GoR B).
fatalities from the disease (LoE 2).
11. A positive yellow egg culture or
2. Of the 1.7 million people who died histological analysis of biopsy speci-
from tuberculosis, 229,000 were mens possibly combined with PCR
co-infected with HIV (LoE 2). is still required in the majority for a
3. As a result of intensive control meas- definite diagnosis (GoR A).
ures, the incidence of tuberculosis in 12. The biological activity of tuberculo-
Germany has constantly decreased, sis should be assessed by cultivating
whereas the incidence of GUTB shows mycobacteria (urine, smear, secretion,
only a slow downward trend (LoE 1). ejaculate, tissue samples) (GoR A).
4. The kidney usually is infected by a
hematogenous spread of bacilli of the
Treatment
Mycobacterium tuberculosis complex
from a focus of infection in the lungs 13. According to the World Health
and/or bowel (LoE 1). Organization (WHO), antitubercu-
5. Usually, GUTB is a reactivation lous drug treatment is based on an
of the tuberculosis from a period of initial two-month intensive phase of
dormancy (LoE 1). treatment with three or four drugs
865
Chapter | 15 | Special urogenital infections
daily (rifampicin, isoniazid, pyrazina- with tuberculosis. Tuberculosis is the

mide and ethambutol), followed by a most common extrapulmonary manifes-
four-month continuation phase with tation after tuberculosis of the peripheral
only two drugs, mostly rifampicin lymph nodes [2, 6].
and isoniazid (GoR A).
14. Drug treatment is recommended
2. METHODS
as the first line therapy in GUTB
(GoR A).
Up to 1997 meta-analysis of genitouri-
15. Only in complicated cases (recur- nary tuberculosis publications was done
rences of tuberculosis, immunosup- of the basis of journals. A systematic lit-
pression and HIV/AIDS) is nine- to erature search up to 2008 was performed
12-month therapy recommended in MEDLINE and PubMed with the key
(GoR B). words: tuberculosis, genitourinary tuber-
16. Surgery has clearly lost its importance culosis, extrapulmonary tuberculosis,
as a treatment option. It must be done non-pulmonary tuberculosis, tuberculosis
in complicated GUTB (obstruction, and HIV-infection with the following limi-
abscess) or secondary urinary tract tations: English abstract available.
infections such as pyelonephritis or A total of 225 publications were iden-
nephrolithiasis (GoR B). tified, which were screened by title and
abstract. After exclusion of duplicates, a
total of 25 publications were included in
1. INTRODUCTION the review.
Since Robert Koch’s discovery of the acid- level of evidence (LoE) and the grade of
fast bacillus in 1882, intensive research recommendation (GoR) using ICUD
of the diagnosis and treatment modalities standards (for details see Preface) [7–8].
of tuberculosis has taken place [1–3].
Currently, in most industrial countries,
the incidence of newly diagnosed cases of 3. EPIDEMIOLOGY
tuberculosis is decreasing each year, but
the worldwide prevalence of tuberculo- In 2006 there were 9.6 million new cases
sis has remained almost as it was at the of tuberculosis and 1.7 million fatalities
beginning of the 20th century. due to the disease worldwide. Besides
More than 95% of patients diagnosed social poverty and insufficient medi-
with tuberculosis live in the so-called Third cal care, tuberculosis mainly still counts
World countries. In these countries, a dra- among the most important infectious dis-
matic increase in the incidence of tuber- eases of the world because of HIV infec-
culosis has been observed, which appears tions. Of the 1.7 million people who died
to be closely linked to infection with HIV. of tuberculosis, 229,000 were co-infected
Patients with AIDS are at a high risk of with HIV [9].
developing secondary infections such as There were 445.000 new TB cases in
tuberculosis. Prospective real-time sur- Europe in 2005, representing 6% of the
veillance of tuberculosis in HIV patients is global TB burden [10].
needed in order to detect case-clustering The Russian Federation had the
and to improve control of tuberculosis [4–5]. ninth highest burden of TB in the world.
Nearly 20% of patients with tubercu- Within Europe, TB incidence varies enor-
losis develop extrapulmonary manifesta- mously, from 2.9 per 100.000 population
tions. Involvement of the genitourinary in Monaco to 208.4 per 100.000 popula-
system is seen in 4–8% of all patients tion in Kazakhstan in 2003 [9–10].
866
The female/male ratio was 0.4 among Germany has been constantly decreasing.
new pulmonary TB cases with a positive The incidence of pulmonary tuberculosis
sputum smear. This may require research especially was reduced, whereas the rate
on gender inequality in accessing TB of new cases of extrapulmonary tuber-
services in some settings. culosis failed to decrease. The same ten-
High rates of TB are associated with dency can be observed with GUTB, the
socioeconomic crisis, weaknesses in health incidence of which shows an only a slow
systems, epidemics of HIV and multidrug- downward trend [6, 11].
resistant TB, and poor interventions to Over the last 40 years, the incidence of
control TB among vulnerable populations. tuberculosis in Germany decreased more
Recent analysis shows that 2.6% of all rapidly. In 1999, for the first time, less
new TB cases in Europe in 2000 were than 10,000 new cases were registered
attributable to HIV co-infection. In the and up to 2006 (5280 new cases, inci-
Russian Federation, 1% of all new cases dence 6.6/100.000 inhabitants) the posi-
of TB were estimated to be HIV-positive tive trend was continuing [9, 12].
and 35% of adults with AIDS died from In contrast to this, the proportion of
TB [9–10]. tuberculosis in the foreign population
In Europe and in the United States did not decrease (incidence 45.2/100.000
after lymphadenopathy, the most com- foreigners).
mon form of non-pulmonary tuberculosis The rate of new cases of extrapul-
is GUTB, accounting for 27% (range from monary tuberculosis barely dropped at
14 to 41%) of non-pulmonary cases. all over the last 20 years (figure 1). In
As a result of intensive control meas- Germany, GUTB ranks second amongst
ures, the incidence of tuberculosis in extrapulmonary forms of tuberculosis,
Non-pulmonary
(extrapulmonary)
tuberculosis
1091
(20.7%)
Pulmonary
tuberculosis
4189
(79.3%)
Figure 1 Tuberculosis in Germany 2006.
867
180 46
(3.4%) (0.9%)
411
(7.8%)
46
(0.9%) Peripheral lymphnodes
Bones and spinal
medullary
Urogenital system
Gastrointestinal tract
21 Meningitis and central

(0.4%) nervous system
Others (pleura,
114 mediastinum)
(2.2%) Dissiminated
132
(2.5%)
Figure 2 Non-pulmonary (extrapulmonary) tuberculosis in Germany 2006.
after tuberculosis of the peripheral lymph bacillus. Tuberculosis caused by the

nodes (figure 2). bovine tubercle bacillus M. bovis is now
However, the proportion of foreigners uncommon in industrially developed
with GUTB (16.5%) as opposed to tuber- nations. It is usually due to reactiva-
culosis of the peripheral lymph nodes tion of old, dormant disease, although
(62.5%) is comparatively low [12]. cases have occurred in younger, HIV-
In our own case material the aver- positive patients. In approximately 25%
age age of patients (52 years) clearly of cases caused by reactivation of M.
increased over the course of 40 years, as bovis infection, the genitourinary system
did the latency period (30 years), whilst is involved.
the yearly number of cases and the time Other species of mycobacterium, the
of treatment decreased. so-called environmental mycobacteria,
occasionally cause human disease similar
to the tuberculosis disease, particularly
4. ETIOLOGY AND PATHOGENESIS in immunosuppressed individuals includ-
ing transplant patients. Tuberculosis
Tuberculosis of the kidney, the urinary may involve the kidney as part of gener-
tract, and the male genital tract, like alized disseminated infection or as local-
other forms of tuberculosis (pulmonary ized genitourinary disease. The kidney is
and non-pulmonary), is caused by mem- usually infected by hematogenous spread
bers of the Mycobacterium (M.) tubercu- of bacilli from a focus of infection in the
losis complex. By far the most common lungs and/or bowel. Mostly, GUTB is a
causative organism is the human tubercle reactivation of dormant tuberculosis.
868
Clinically, renal tuberculosis usually the male genital tract, mostly combined
presents unilaterally, but post mortem with scrotal fistulas.
studies show that the disease is fre- Other symptoms that sometimes occur
quently bilateral [2]. include back, flank, and suprapubic
Genital tuberculosis in males most pain, hematuria, frequency, and noctu-
commonly involves the epididymis fol- ria. Renal colic is uncommon, occurring
lowed by the prostate. Testicular involve- in fewer than 10% of patients, and con-
ment is less common and usually a result stitutional symptoms such as fever,
of direct invasive epididymitis. weight loss, and night sweats also are
Tuberculous prostatitis results from unusual.
antegrade infection within the urinary Only one third of patients have an
tract; tuberculous epididymitis is prob- abnormal chest X-ray.
ably a result of blood-borne infection Physical examination should include
because it is often an isolated finding the male genital tract (testes, epidi-
without urinary tract involvement. It is dymides) and digital-rectal examination
important to be aware that a high propor- (prostate gland) to differentiate between
tion (50–75%) of men with genital tuber- unspecific inflammatory diseases, tuber-
culosis have radiologic abnormalities in culosis and tumours, respectively.
the urinary tract. The urinary tract of The diagnosis of tuberculosis of the uri-
all patients with primary tuberculous nary tract is based on the finding of pyu-
infection of the epididymis should be ria in the absence of infection as judged
investigated [13]. by culture on routine media.
Radiological imaging can be helpful
to detect GUTB. Characteristic signs on
5. DIAGNOSTIC PROCEDURES intravenous pyelogram and computed
tomography are useful in depicting
The diagnosis of GUTB is difficult GUTB. Radiologically detectable mani-
because its symptoms are non-specific. festations of tuberculosis allow for ear-
The most important step in diagnosis lier diagnosis and the timely initiation
is the patient history. Knowledge of an of appropriate therapy, thus reducing
earlier tuberculosis infection either asp- patient morbidity [16–17].
rimary pulmonarymanifestation or as In the early course of disease it is
an extrapulmonary manifestation is an often possible to detect changes in a sin-
important clue in a large number of cases. gle calyx with evidence of parenchymal
Around 40% of patients with GUTB in necrosis on intravenous urography, and
developed countries and 50% in develop- typically there is calcification on the
ing counties have a past history of tuber- plain film. In more advanced disease
culosis [14]. urography will show calyceal distortion,
One has to be aware that the latency ureteric strictures, and bladder fibrosis
between pulmonary manifestation and (figures 3–5).
GUTB is enormous. In some cases it could Ultrasound examination of the uri-
take more than 30 years before GUTB nary tract may reveal renal calyceal
becomes evident [2, 15]. dilation and more overt evidence of
Symptoms suggestive of GUTB, obstruction.
especially in urinary tuberculosis, are Computed tomography (CT) and
voiding problems and chronic urgency non- nuclear magnetic imaging are impor-
responding to antibacterial drug regi- tant for differential diagnosis (renal
mens. In men, chronic epididymitis is the parenchymal masses, scarring, auton-
typical manifestation of tuberculosis of ephrectomy).
869
Figure 3 Intravenous pyelogram: plain film showing

abnormal upper calyx with intrarenal stricture, dilatation of the
right renal pelvis and a dilated right ureter (M. tuberculosis was
isolated from the urine).
Figure 5 Progressive bladder tuberculosis with scarring

and vesicoureteral reflux on both sides.
A positive skin test supports the diag-

nosis of tuberculosis, but a negative
skin test does not necessarily exclude an
extrapulmonary manifestation. This is
especially true in cases of GUTB.
A microbiologic diagnosis of tubercu-
losis is usually made by isolation of the
causative organism from urine or biopsy
material on conventional solid media or
by an automated system such as radiom-
etry [18].
In recent years, nucleic-acid ampli-
fication techniques, such as polymer-
ase chain reaction (PCR), have been
investigated extensively for the detec-
tion of M. tuberculosis complex (M.
tuberculosis, M. bovis, M. microti, M.
africanum) and other mycobacteria in
clinical specimens, notably sputum.
Relatively few studies have specifi-
cally evaluated PCR for detection of
Figure 4 Intravenous pyelogramm: progressive renal
tuberculosis on both sides, strictures and dilatations on the GUTB, but these show the technique
right side, intrarenal strictures of the calices on the left side. to be sensitive and specific, although
870
some urine specimens contain inhibi- In a study of 118 patients mostly suf-
tory substances [13, 19–20]. fering from renal tuberculosis, tissue
In addition, PCR has been used to specimens were minced and dispersed
detect mycobacterial DNA in urine in in 0.9% sterile saline and examined by
cases of HIV-related disseminated tuber- microscopy, culture and animal experi-
culosis [19, 21]. ment. Mycobacteria were detected in
A positive culture or histological 34 of 118 tissue samples (29%). The
analysis of biopsy specimens possibly renal tissue samples were divided into
combined with PCR is still required in two groups, one before and one after a
most patients for a definite diagnosis. three-month course of antituberculo-
In 25–30% the diagnosis of GUTB is sis treatment. Interestingly, the latter
established on the basis of the histologi- group demonstrated a higher amount
cal pattern and/or by detection of the of detected mycobacteria (table 1).
Mycobacterium tuberculosis complex by This finding clearly questions the use
PCR [19]. of short-term treatment modalities in
Detection of acid-fast bacilli from urine UGT. The results also show that direct
samples by microscopy (Ziehl-Neelson proof of the presence of mycobacteria
acid-fast stain) is not reliable because of enables a reliable assessment of the bio-
the possible presence of M. smegmatis, logical activity of GUTB, which is desir-
which are acid-fast bacilli too. able for treatment planning and therapy
However, the biological activity of control. In all cases suspected for GUTB
tuberculosis can only be assessed by cul- a diagnostic algorithm is recommended
tivating mycobacteria [22]. (table 2).
Table 1 Detection of mycobacteria from renal tissue specimens before and

after a 3-month course of anti-tuberculosis treatment.
Anti-tuberculosis Mycobacteria No mycobacteria

treatment present present
No (n = 26) 7 (27%) 19 (73%)
Yes (n = 40) 14 (35%) 26 (65%)
Summary (n = 66) 21 (32%) 45 (68%)
Table 2 Diagnostic procedures of GUTB.
Suspected diagnosis Definite diagnosis
• Case history (earlier pulmonary or extrapulmonary • Microscopic examination (Ziehl-Neelson

tuberculosis) acid-fast stain)
• Symptoms • Yellow egg culture media (urine, smear,
• Physical examination secretion, ejaculate, tissue samples)
• Skin test • PCR
• Urine analysis (leucocytes, erythrocytes, bacteria) • Histological examination (tissue samples)
• Radiological imaging • Combined with Ziehl-Neelson acid- fast stain
• intravenous pyelogram and/or PCR
• CT
• Cystoscopy (only for differential diagnosis, figure 6)
871
sequenced to study the mechanism of

rifampicin resistance [23].
Drug resistance was detected in 33
patients out of the 50 from whom cul-
tures were isolated. Most of the isolates
were resistant to rifampicin (n=25), iso-
niazid (n=14), and streptomycin (n=7).
Multi-drug resistance was common. Only
6% of the isolates were resistant to one
drug, whereas resistance to two, three,
four, and five drugs was seen in 14, 32,
40, and 8%, respectively. Fully suscep-
Figure 6 Endophotography of the urinary bladder shows
tible isolates were derived from only 17
typical tubercle near the orifice of the ureter. patients. ln rifampicin-resistant strains,
a number of previously unrecognized
genetic alterations (point mutations and
6. MEDICAL TREATMENT deletions) were found in the rpoB locus.
The rpoB locus is responsible for a high
Modern short-course antitubercuIous level of rifampicin resistance (>500 ug/ml
drug regimens are effective in all forms in egg-based medium).
of tuberculosis. According to the World ln cases with multi-drug-resistant tuber-
Health Organization (WHO), anti-tuberculosis by definition (WHO), caused by bacilli
culous drug treatment is based on an resistant to rifampicin and isoniazid, with or
initial two-month intensive phase of without resistance to other drugs, therapy
treatment with three or four drugs daily, requires the use of at least four drugs that
including rifampicin, isoniazid, pyrazina- are selected on the basis of a drug suscep-
mide, and ethambutol (or streptomycin), tibility test (ethionamide, prothionamide,
to destroy almost all tubercle bacilli. This quinolones, clarithromycin, cycloserin, kan-
is followed by a four-month continua- amycin, viomycin, capreomycin, thiaaceta-
tion phase with only two drugs, usually zone, and para-amino-salicide acid). These
rifampicin and isoniazid. In the continua- drugs are less effective and often more toxic
tion phase the drug may be given twice or than the first line drugs [24].
thrice weekly. The duration of therapy is based on
In GUTB, drug treatment is the first the bacteriologic response but may be 18
line therapy. Over the course of a fol- months and longer.
low-up of more than 40 years the treat- Mycobacterium bovis harbours a pri-
ment time was reduced from 24 months mary resistance to pyrazinamide and
to six months [9, 12]. is found in a high percentage of elderly
Only in complicated cases (recurrences patients with GUTB.
of tuberculosis, immunosuppression and In clinical practice, pyrazinamide should
HIV/AIDS) is a nine- to 12-month ther- be avoided in those cases not only because
apy necessary [2]. of the likelihood of primary resistance but
A serious problem at present is the also because of the induction of hyperuri-
high percentage of primary drug resist- caemia and hyperuricuria which might be
ance in patients with tuberculosis. In detrimental in patients with GUTB.
a study from the Russian Research Patients with GUTB caused by M.
Institute of Phthisiopulmology, 50 iso- tuberculosis who are treated with pyrazi-
lates of M. tuberculosis obtained from namide in the intensive treatment phase
patients referred from various parts should be given a xanthinoxydase-inhibi-
of Russia were analysed by PCR and tor in addition.
872
Table 3 First line antituberculous drug therapy.
Antituberculous Dose Body Daily

drug mg/kg BW weight (BW) dose
Isoniazid (INH) 5 <50 kg 300 mg
Rifampicin (RMP) 10 >50 kg 450 mg

600 mg
Pyrazinamide (PZA) 25–35 <50 kg 1,5 g

<50 kg 2,0 g
>75 kg 2,5 g
Streptomycin (SM) 15–20 >50 kg 0,75 g

>50 kg 1,0 g
Ethambutol (EMB)¹ 25² 0,8–2,0 g
Prothionamide (PTA) 5–15 0,5–1,0 g
¹not for children younger than 10 years.

²after two months 20 mg.
A six-month short course of antituber-

Table 4 six-month regimes for the treatment of
culous drug regimen is also effective in
uncomplicated GUTB.
uncomplicated GUTB [2, 12, 25–26].
Special considerations apply to the Intensive phase Continuation phase
treatment of tuberculosis in patients with
impaired renal function. Rifampicin, iso- 3 months 3 months
niazid, pyrazinamide, prothionamide, INH, RMP, EMB (or SM) INH, RMP
and ethionamide may be given in nor- daily twice or thrice per week
mal dosage. They are eliminated in the
bile or broken down to metabolites that 2 months 4 months
are not excreted by the kidney. Care is INH, RMP, PZA, EMB INH, RMP
required in the use of streptomycin, other daily twice or thrice per week
aminoglycosides, and ethambutol. These
are wholly excreted via kidney.
Ethambutol causes optic neuritis, which
may be irreversible, and reduced dose Regular measurements of the concen-
should be given according to the glomeru- tration of cyclosporine and Iacrolimus
lum fitration rate (GFR). Streptomycin in the blood of such patients (mostly
and other aminoglycosides are ototoxic and patients after transplantation) are
nephrotoxic, and should not be given to recommended.
patients with renal failure, especially after In HIV-patients, antiretroviral therapy
renal transplantation, because cyclosporine interacts adversely with rifampicin. When
involves also a high risk of nephrotoxity. rifabutin is given instead of rifampicin
Encephalopathy is an uncommon compli- the therapy must be extendend to nine to
cation of isoniazide and can be prevented 12 months.
by pyroxidine (25 to 50 mg per day). The drug treatment recommendations
Rifampicin increases the rate of metab- for GUTB are summarized (according to
olism, of corticosteroids, cyclosporine, and pulmonary tuberculosis) in tables 3 and
lacrolimus. table 4.
873
7. SURGERY • reconstruction of the upper urinary

tract (pyeloureterostomy, ureterocysto-
Surgery as a treatment option has clearly neostomy, ureter replacement)
lost its importance, but it might be indi- • bladder augmentation
cated in complicated GUTB (obstruc-
• reconstruction of the urethra (seldom)
tion, abscess, etc.) or secondary urinary
tract infections such as pyelonephritis or • management of genital tuber-
nephrolithiasis. culosis (orchiepididymectomy /
Surgical excision of non-functioning epididymectomy)
kidneys (figure 7) or because of extensive Over the course of more than 40 years
lesion in partiallly functioning kidneys is of investigation of our case material
controversial. Nephrectomy is indicated with GUTB (n=764) the operation rate
by complications such as upper urinary decreased from 80.4% (1961) to 24.5%
tract infection (UTI) with Gram-negative (2007), whereas the nephrectomy rate
or Gram-positive bacteria and/or urinary was unchanged (approximately 20 to 25%
stones, and hypertension. of all patients with GUTB).
Early stenting or percutaneous neph-
rostomy may aid functional recovery of
disturbed renal function in patients with 8. FOLLOW-UP
tuberculous ureteric obstruction [2].
Overall, open surgical management Normally no tuberculous infection is
and minimally invasive procedures [27] found in uncomplicated cases of GUTB
in UGT can be categorized into seven after a treatment period of six months
groups [15]: with antituberculous drugs.
Only in high risk patients with GUTB
• drainage for hydronephrosis (ureter
(HIV/AIDS, immunosuppressed patients,
stenting, percutaneous nephrostomy)
drug resistance) is a longer treatment
• drainage for abscesses/caverns (only in period (nine to 12 months or more)
septic cases) necessary.
• definitive local treatment of kid- In the follow-up of patients with GUTB
ney tuberculosis (partial or total after antituberculous drug treatment,
nephrectomy) five-year surveillance is recommended.
Urine examination and urine cultures
should be done twice a year for the first
two years, afterwards once a year.
Blood examinations (creatinine, uric
acid), urosonography, and if necessary,
x-ray controls (intravenous pyelogram,
chest) are important to detect complica-
tions as early as possible (renal insuffi-
ciency, obstruction, renal damage).
9. FURTHER RESEARCH
The main problems of tuberculosis are the

high prevalence of mycobacterial infec-
tions and multi-drug resistance (MDR).
Figure 7 Tuberculous “pyonephrosis“ with extensive caseous A better tuberculosis control (in
necrosis and renal parenchymal destruction. developing countries) and an effective
874
treatment of patients with HIV and 4. World Health Organization, Treatment

tuberculosis is a first step to reduce the of Tuberculosis: Guidelines for National
incidence of tuberculosis worldwide. Programs. Third Edition ed. 2003,
The development of new antitubercu- Geneva: WHO.
lous drugs for patients with multi-drug 5. World Health Organization, Global
resistance (MDR) is very important. Tuberculosis Control 2008: Surveillance,
Planning, Financing. 2008, Geneva:
Case control studies are necessary to
WHO. WHO/HTM/TB 2008.39.
detect patients with GUTB earlier, before
6. Lenk S, Epidemiology of genitourinary
their renal function is destroyed.
tuberculosis in Germany. Eur Urol, 2004.
Suppl 3(2): 206.
10. CONCLUSIONS 7. Abrams P, Khoury S, and Grant A,
Evidence – based medicine overview of the
More than 125 years after Robert Koch`s guideline recommendations. Prog Urol,
discovery of tubercle bacilli worldwide, 2007. 17(3): 681–4.
tuberculosis is still not eradicated. 8. U.S. Department of Health and Human
The main problems are insufficient Services Public Health Service Agency for
tuberculosis control and the high preva- Health Care Policy and Research, 1992:
lence of HIV infections in developing 115–127.
countries. Another important problem is 9. German “Zentralkommitee zur
MDR in patients with tuberculosis. Bekämpfung der Tuberkulose”: 31st
More than 4% of all new cases with Information Report 2008, Berlin.
tuberculosis are suffering from GUTB. 10. German “Zentralkommitee zur
Although the incidence of GUTB in Bekämpfung der Tuberkulose”: 30th
Germany is relatively low, it is still nec- Information Report 2007, Berlin.
essary to impart and deepen scientific 11. Forssbohm M, Zwahlen M,
knowledge of the diagnosis and therapy Loddenkemper R, and Rieder HL,
of GUTB. Demographic characteristics of patients
Special problems present themselves with extrapulmonary tuberculosis in
Germany. Eur Respir J, 2008. 31(1):
with patients with immunosuppres-
99–105.
sion (AIDS or after transplantation) and
12. Robert-Koch-Institute, Report of
migrants with tuberculosis from countries
Epidemiology of Tuberculosis in Germany
with a high prevalence of tuberculosis. 2006 2006, Berlin: Robert-Koch-Institute
13. Barisic Z, Vrsalovic-Carevic N, Milostic
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Zoranic V, Kaliterna V, and Carev M,
1. Harries AD, Robert Koch and the dis- Tuberculous orchiepididymitis diagnosed by
covery of the tubercle bacillus: the chal- nucleic acid amplification test: a case report.
lenge of HIV and tuberculosis 125 years Int Urol Nephrol, 2003. 35(2): 203–5.
later. Int J Tuberc Lung Dis, 2008. 12(3): 14. Figueiredo AA, Lucon AM, Junior RF,
241–9. and Srougi M, Epidemiology of urogenital
2. Lenk S and Schroeder J, Genitourinary tuberculosis worldwide. Int J Urol, 2008.
tuberculosis. Curr Opin Urol, 2001. 11: 15(9): 827–32.
93–96. 15. Carl P and Stark L, Indications for surgi-
3. Migliori GB, Loddenkemper R, Blasi cal management of genitourinary tubercu-
F, and Raviglione MC, 125 years after losis. World J Surg, 1997. 21(5): 505–10.
Robert Koch’s discovery of the tubercle 16. Engin G, Acunas B, Acunas G, and Tunaci
bacillus: the new XDR-TB threat. Is “sci- M, Imaging of extrapulmonary tuberculo-
ence” enough to tackle the epidemic? Eur sis. Radiographics, 2000. 20(2): 471–88;
Respir J, 2007. 29(3): 423–7. quiz 529–30, 532.
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17. Harisinghani MG, McLoud TC, Shepard chain reaction and non-radioactive DNA
JA, Ko JP, Shroff MM, and Mueller hybridization. J Urol, 2000. 164(2): 584–8.
PR, Tuberculosis from head to toe. 22. Lenk S, Detection of mycobacterica in
Radiographics, 2000. 20(2): 449–70; quiz specimens of genitourinary tract. J Urol
528–9, 532. Urogynäkologie, 2000. 7: 7–13.
18. Watterson SA and Drobniewski FA, 23. Stepanshina VN, Panfertsev EA,
Modern laboratory diagnosis of myco- Korobova OV, Shemyakin IG, Stepanshin
bacterial infections. J Clin Pathol, 2000. YG, Medvedeva IM, and Dorozhkova IR,
53(10): 727–32. Drug-resistant strains of Mycobacterium
19. Hemal AK, Gupta NP, Rajeev TP, Kumar tuberculosis isolated in Russia. Int J
R, Dar L, and Seth P, Polymerase chain Tuberc Lung Dis, 1999. 3(2): 149–52.
reaction in clinically suspected genitouri- 24. World Health Organization,
nary tuberculosis: comparison with intra- Antituberculosis drug resistance in the
venous urography, bladder biopsy, and world. Report No.4 (2008). 2008, Geneva:
urine acid fast bacilli culture. Urology, WHO. WHO/HTM/TB/2008.394.
2000. 56(4): 570–4. 25. Gow JG, Genitourinary tuberculosis: a
20. Takahashi S, Hashimoto K, Miyamoto S, study of short course regimes. J Urol,
Takeyama K, Takagi Y, and Tsukamoto T, 1997. 115: 707–711.
Clinical relevance of nucleic acid amplifi- 26. Skutil V, Varsa J, and Obsitnik M, Six-
cation test for patients with urinary tuber- month chemotherapy for urogenital tuber-
culosis during antituberculosis treatment. culosis. Eur Urol, 1985. 11(3): 170–6.
J Infect Chemother, 2005. 11(6): 300–2. 27. Kim HH, Lee KS, Park K, and Ahn H,
21. Moussa OM, Eraky I, El-Far MA, Osman Laparoscopic nephrectomy for nonfunc-
HG, and Ghoneim MA, Rapid diagnosis of tioning tuberculous kidney. J Endourol,
genitourinary tuberculosis by polymerase 2000. 14(5): 433–7.
876
|15.3|
Male genital tuberculosis
1
Ekaterina Kulchavenya, 2Chul-Sung Kim
1
Novosibirsk Research TB Institute, Novosibirsk, Russia
2
Department of Urology, Chosun University Hospital, Gwangju, Korea
Address of Corresponding Author: Ekaterina Kulchavenya, MD, Professor and Head of Urogenital Department of Research TB
Institute, Okhotskaya 81-a, Novosibirsk 630040, Russian Federation
Tel +7-383-203-79-89, Fax +7-383-203-68-75, ku_ekaterina@mail.ru
The diagnosis Male Genital Tuberculosis
is rare, but the disease is not
ABSTRACT MGTB presents non-specific symptoms

and laboratory findings, except for a posi-
Tuberculosis (TB) and HIV/AIDS have tive MBT culture, but only about 36% of
reached such proportions worldwide that cases are culture-positive. Co-morbidity
the development of civil societies is seri- with other forms of TB is common for
ously endangered. TB caused by immuno- MGTB (45–79%), but isolated tubercu-
deficiency due to HIV or malnutrition is lous epididymitis was diagnosed in 21.5%
enhanced by more aggressive tuberculous of cases in one study.
Mycobacteria (MBT). 425,000 multi-drug In countries with low incidence of TB,
resistant (MDR) TB cases emerge every three antituberculous drugs may be suf-
year throughout the world. 67% of the ficient for treatment. In epidemic regions
estimated MDR-TB cases exist in China, MGTB should be treated with four to five
India and the Russian Federation. The antituberculous drugs such as isoniazid
highest MDR-TB prevalences are found 10 mg/kg, rifampicin 10 mg/kg, pyrazi-
in the former USSR and China. namid 20 mg/kg, streptomycin 15 mg/kg
Urogenital TB is the second most com- and PAS 150 mg/kg (or ofloxacin 800 mg
mon form of TB in countries with severe or levofloxacin 500 mg), simultaneously
epidemic situation and the third most over two to four months, followed by six
common form in regions with low inci- to eight months of chemotherapy with
dence of TB. Male genital TB (MGTB) isoniazid and rifampicin only.
seems to be a rare disease. Nevertheless, A caseating abscess with firm swell-
77% of men who died from TB of all locali- ing not responding to chemotherapy and
zations had prostate TB, which had mostly remaining unchanged or slowly increas-
been overlooked during their life time. ing in size despite the administration of
antibiotics and antituberculous chemo- examination to avoid contamination

therapy is an indication for surgery. of urine with prostatic fluid (GoR B).
Key words: male genital tuberculo- 7. At least three, but preferably five
sis, Mycobacterium tuberculosis, diag- serial microbiologic studies with
nosis, antituberculous chemotherapy, urine, ejaculate and prostate secretion
urogenital. including smears, cultures (GoR A)
and PCR (GoR B) should be performed
to make the diagnosis of MGTB.
SUMMARY OF RECOMMENDATIONS 8. In isolated external genital TB with-
out renal and prostate involvement,
diagnosis of MBT is often only possi-
Epidemiology and Pathogenesis
ble by pathomorphology (GoR B).
1. Male genital tuberculosis (MGTB) 9. In difficult cases a provocative sub-
is a rare form of tuberculosis (TB), cutaneous tuberculin test is recom-
but in countries with epidemic TB mended (GoR B).
a large proportion of patients are
10. Radiologic studies including renal
underdiagnosed (LoE 2).
ultrasonography, TRUS, CT, and
2. MGTB is usually (over 50%) associ- MRI may be helpful to visualize a
ated with lung and/or renal TB (actual prostate cavern (GoR C).
or cured), but isolated forms are also
11. For cavernous prostate tuberculosis
possible. Usually the epididymis and
retrograde urethrography is crucial
prostate are involved (LoE 1).
(GoR A)
3. The main route of infection is via
12. Fine needle aspiration cytology
hematogenous spread, but direct
(FNAC) is an accurate and rapid
extension from infected urine and lym-
diagnostic tool for scrotal TB (GoR C).
phatic spread is also possible (LoE 1).
Treatment
Diagnosis
Comment: The principles of antitubercu-
4. All patients with genital TB should lous chemotherapy in MGTB are different
be screened for chest and upper between various forms and between coun-
urinary tract involvement and HIV tries with different epidemic situations.
infection (GoR A).
13. Short term treatment for six to nine
5. The urine should be examined for months is suitable in uncomplicated
red blood cell and leucocytes in three cases in regions with low incidence of
consequent portions (three-glass-test) TB (GoR B).
during urine voiding without inter-
14. In complicated cases (retreatment,
ruption (GoR A). Leucocyturia in the
immunosuppression, drug-resistance
first portion means an inflammation
and HIV/AIDS) and in epidemic
in the urethra, in the second portion
regions it should be longer, up to
an inflammation in the urinary blad-
12–14 months with four to five drugs
der or upper urinary tract, and in the
(GoR B).
third portion an inflammation in the
prostate. Leucocyturia in all three
portions mirrors a severe inflamma- 1. INTRODUCTION
tion of the total urinary system.
6. The three-glass-test should be Urogenital tuberculosis (UGTB) is the sec-
performed before digital rectal ond most common form of TB in countries
878
Male genital tuberculosis | 15.3 |
with a severe epidemic situation and the The studies were rated according to the
third most common form in regions with level of evidence (LoE) and the grade of
low incidence of TB. MGTB seems to be recommendation (GoR) using ICUD
a rare disease. Nevertheless, 77% of men standards (for details see Preface) [2–3].
who died from tuberculosis of all locali-
zations had prostate tuberculosis which
had mostly been overlooked during their 3. TERMS AND CLASSIFICATIONS
life time [1]. In actual figures, this means
about 19,000 men yearly in Russia. The first note of urogenital TB was
MGTB presents non-specific symptoms made by Porter in 1894 [4]; later in 1937
and laboratory findings, except for posi- Wildbolz [5] suggested the term genitouri-
tive Mycobacteria tuberculosis (MBT) nary TB. We prefer the term urogenital
culture, but only about 36% cases are TB (UGTB), because kidney TB, which is
culture-positive. This is one of the main usually primary, is diagnosed more often
reasons for late and poor diagnosis of than genital TB. Only 53% of patients
MGTB. The significance of genital TB may with kidney TB have genital lesions, but
be considerable when the high prevalence in 61.9% patients with epididymorchitis
of overall TB and the asymptomatic nature and in 79.3% patients with TB of the pros-
of genital TB are taken into account. tate a renal lesion can be diagnosed [6].
MGTB includes tuberculous epididy-
morchitis (uni- and bilateral), TB of the
2. METHODS prostate, TB of a seminal vesicle (only in
combination with other forms of UGTB),
A Medline/PubMed research with key unilaterally or bilaterally, and TB of the
words “male genital tuberculosis” resulted penis (very rarely).
in a total of 825 titles, 159 within the last
10 years (since 1999). Among the articles
of the last 10 years, 63 (39.6%) were case 4. EPIDEMIOLOGY
reports, including cases of tuberculous
epididymorchitis and prostatitis follow- TB and HIV/AIDS have reached such
ing intravesical BCG for superficial blad- proportions worldwide that the develop-
der cancer, 16 (10.1%) were associated ment of civil societies is seriously endan-
with AIDS, 32 (20.1%) mentioned MGTB gered. It is therefore mandatory that the
in the context of other diseases, and only fight against infections should be a mat-
48 were specifically dedicated to MGTB, ter of concern to all, including “big poli-
describing the experience of single cent- ticians”. Consequently, these infections
ers. To estimate the real prevalence of have been on the agenda of both the G-8
MGTB worldwide is almost impossible, summit in 2006 and 2007. At both meet-
since genital tuberculosis accounts for ings, the G-8 nations committed them-
relatively small fractions of tuberculosis. selves to act now [7].
Most studies have been published under According to the World Health
the topic of ‘genitourinary tuberculosis’, Organization (WHO) 425,000 multi-drug
but focus mainly on urinary tract tuber- resistant (MDR) TB cases emerge every
culosis and the proportion of genital year throughout the world [8]. With inad-
involvement varying by region. Only one equate and poor quality treatment or with-
meta-analysis was found and two guide- out treatment at all, MDR-TB can develop
lines (one in Russian), also seven mono- and spread throughout communities. 67%
graphs in Russian, but all of them were of the estimated MDR-TB cases are found
dedicated to urogenital TB or extrapul- in China, India and the Russian Federation
monary TB, but none to MGTB exactly. [8], with the highest MDR-TB prevalences
879
in the former USSR and China. The most of the world more than 100 years after
severe drug resistance patterns are found Robert Koch discovered its pathogen in
in the former USSR. Now a new threat to 1882. In Africa and Eastern Europe, the
TB control has appeared – the extensively incidence of TB is increasing as a result
drug resistant TB (XDR-TB), which is of AIDS spreading widely, emergence of
completely resistant to all antituberculous resistant organisms, low socioeconomic
chemotherapeutics [8]. status, and of human migration [11–13].
Based on surveys and death registra- 25–50% of HIV patients worldwide have
tions, 8.9 million new cases of TB were esti- active TB. Pulmonary TB is more danger-
mated in 2004, less than half of which were ous and obvious, but extrapulmonary TB
reported to public health authorities and to is also contagious and potentially lethal,
WHO [7]. Approximately 3.9 million cases and it affects the quality of life much
were sputum-smear positive, the most more than pulmonary TB [14].
infectious form of the disease. The WHO BCG-therapy of bladder cancer and
African region has the highest estimated kidney transplantation may also play a
incidence rate (356 per 100,000 habitants role in the incidence of urogenital tuber-
per year) but the highest number of TB culosis [15].
patients live in the most densely populated In countries with severe epidemic
countries of Asia. Bangladesh, China, India, TB, UGTB is the most common form of
Indonesia and Pakistan together account extrapulmonary TB. In countries with low
for half of the new cases arising each year incidence lymphonodal TB predominates.
[7]. According to the WHO report 2008, the
worldwide estimated incidence of new cases
of TB increased in 2006 to 9.2 million (139 5. PATHOPHYSIOLOGY
per 100 000 on average). Large proportions
of cases occur in Asia (South-East Asia and The lungs are the most common primary
Western Pacific region) and Africa; 55% and entry site for Mycobacterium tuberculosis.
31%, respectively [9]. The renal seeding of mycobacteria occurs
One-third of the world’s population is via haematogenous route. However, ini-
currently infected with MBT. tiation of genital organ involvement by
TB kills more youths and adults than mycobacteria has several routes, the
any other infectious disease. main one is also haematogenous. The fact
Every four seconds someone falls ill that over 50% of patients with MGT have
with TB and every 10 seconds someone renal lesions suggests that MGTB origi-
dies from TB. nates from direct extension of infected
Left untreated, a person with active urine by reflux into the prostate. But hae-
TB can infect between 10 and 15 people matogenous spread may also be signifi-
every year. cant in isolated genital TB [16].
TB accounts for 9% of deaths among TB when induced by immunodefi-
women between 15 and 44 years of ages ciency due to HIV infection or malnutri-
compared with war, which accounts for tion shows enhanced aggression of MBT.
4%, HIV for 3% and heart diseases for 3% A weakened human organism with lack
of deaths. Of all causes of death TB holds of antibodies and not enough sensitized
the eighth place, of all infectious diseases immunocompetent cells is not able to
the fourth place and of infectious diseases resist a causative agent with extreme
in adults the first place [10]. reproduction. Generalized and polycav-
Besides social property and insufficient ernous processes increase the mycobacte-
medical care, the HIV/AIDS epidemic is rial population rapidly and consequently
the main cause of TB, which is still one also mutants accumulate which may be
of the most important infectious diseases resistant to antibiotics or chemodrugs [7].
880
In MGTB the epididymis and the pros- [22] or via a direct infection through a
tate are the most common sites, followed penile wound during ritual circumcision.
by the seminal vesicles, and the testicles Penile lesions present as ulcers on the
[17–18]. Tuberculous foci in the epidi- glans or penile skin [23].
dymis are caused by metastatic spread of
MBT via the blood stream. The disease
usually starts in the lobus minor, because 6. CLINICAL FEATURES
it has a greater blood supply than other
parts of the epididymis. During mycobac- TB of the epididymis may involve the tes-
teriaemia there is an inoculation of myco- tis, in which case the lesion mimics acute
bacteria both in the epididymis and in non-specific epididymorchitis. Tuberculous
the testicle. But the pathological process epididymorchitis has local rather than
originally develops in the epididymis and systemic symptoms, which may be mild,
then passes on to the testicle. The absence intermittent and often asymptomatic.
of visual signs of an orchitis in a patient TB of the scrotal organs may be the first
with tuberculous epididymitis however and only symptom of UGTB. In 66.7%
does not mean that he has healthy tes- the onset of the disease was acute, with
ticles. Therefore we continue to use the fever, pain, edema, and hyperaemia.
term “epididymorchitis”, even if only the Tuberculous epididymorchitis without
epididymis appears indurated. any other focuses of TB was diagnosed in
TB of the testis is almost always second- 21.5%. All those patients had acute onset
ary to infection of the epididymis, which mimicking acute non-specific epididymor-
in most cases is blood-borne because of chitis. All patients were operated on and
the extensive blood supply of the epidi- diagnosis was established by pathomor-
dymis, particularly the lobus minor. phological investigation [24].
Isolated tuberculous orchitis is extremally The usual presentation of tuberculous
rare [11]; we have found two cases in the epididymorchitis is a painful, inflamed
literature, and actually both had epidi- scrotal swelling. Occasionally, a discharg-
dymal lesion, too. The route of infection ing sinus may be found posteriorly, fistu-
is through the hematogenous spread of lous forms were seen in 11.9% (Figure 1).
organisms, as in infection of the kidney. In these patients only the diagnosis may
Prostate TB seems to be rare, it is usu- be made by culture of MTB from a dis-
ally asymptomatic and found after a charging sinus, in other cases by patho-
transurethral resection. Nevertheless, 77% morphology after epididymectomy. In case
men died from tuberculosis of all localiza- of a testicular mass, genital TB is difficult
tions, had prostate tuberculosis, mostly to differentiate from malignancy [25].
overlooked during life time [6]. In patients Frequency and nocturia are the most
with AIDS, large tuberculous abscesses of common symptoms of prostate TB. Other
the prostate have been reported [19–20]. urinary tract symptoms such as dysuria,
There are also unusual pathways of pri- haematuria, and haematospermia are also
mary infection. Recent data showed that present in prostate TB. Urgency is usually
TB is also a sexually transmitted disease. present if the bladder is involved [24–25].
Patients with pulmonary TB presented The physical findings suggesting genital
MBT in ejaculate in 0.08%, in case of TB are the following: an enlarged, hard,
co-morbidity of TB and hepatitis in 18.8%. and non-tender epididymis; thickened or
Patients suffering from TB, hepatitis beaded vas deferens; prostatic indura-
and syphilis simultaneously have shown tions or nodules on rectal examination; or
growth of MBT in ejaculate in 48.5% [21]. a non-tender testicular mass. As inflam-
Penile TB is very rare but can occur mation progresses, fistula formation on
after sexual coitus with infected females the scrotum or perineum may also be seen
881
(126.1/100000 in 2003 and 128.8 in 2007).

However, during the same period the inci-
dence of extrapulmonary forms decreased
from 4.3 to 3.2 in 100000 habitants. In
2003, 1078 new patients with extrapul-
monary TB were diagnosed in Siberia;
in 2007 only 854. The proportion of clini-
cal forms was identical throughout these
years: urogenital TB was the prevalent
form (46.0–33.5%); TB of bone and joints
was in the second place (20.1–32.7%),
followed by lymphonodal TB (14.7–
14.9%) [16, 28]. The clinical findings of
newly revealed extrapulmonary TB in
Russian Federation is demonstrated in
Diagram 1. There is, however, a big dif-
ference between the clinical appearance
of extrapulmonary TB in Germany and in
Russian (Diagram 2) [11].
From 514 patients with UGTB in West
Siberia, 58 (11.3%) had prostate TB and
42 (8.2%) – scrotal TB. The mean age of
Figure 1 Tuberculous orchiepididymitis with fistula,
metatuberculous dermatitis.
the patients was about 40 years. 11.9% of
the patients were 20–30 years old; there
were no patients under 20 years. Most
patients were between 30 to 50 years old
(61.9%). 33.6% of patients had a previous
history of TB; the present disease was a
relapse of TB [24].
Tuberculous epididymorchitis may be
associated with renal disease, but not
always. Nevertheless in 61.9% of cases
besides epididymorchitis, nephrotuber-
culosis was diagnosed. In 30.9% bilat-
eral lesion of the epididymis was marked.
Co-morbidity of scrotal organs and pros-
tate was diagnosed in 35.7% [24]. A case
Figure 2 TB epididymitis. In the tissue of the epididymis – of generalized UGTB with TB of kidney,
focuses of caseous necrosis, surrounded by epithelioid cells ureter, bladder, prostate, seminal vesicles
and fibrosis with different maturity. X100. van Gieson.
is demonstrated on Figure 3.
The culture of MTB in urine was posi-
in 11–50% of patients [1, 26] (Figure 2).
tive in 38.1% of patients with tuberculous
Hydrocele and inguinal lymphadenopathy
epididymorchitis. All of them had also
may be present infrequently [17, 27].
kidney TB, none had a growth of MBT in
ejaculate or prostate secretion [24].
7. MALE GENITAL TUBERCULOSIS Every fifth patient (21.4%) was diag-
IN WEST SIBIRIA nosed after orchidectomy, performed
while misdiagnosed as non-specific acute
Over the last five years the inci- epididymorchitis in general urological
dence of TB stayed constant in Siberia clinics (Figure 4) [21].
882
The mean age of patients with pros- prostatic secretions in 29.3%. MBT was
tate TB was 49 years. Half of the found only in 36.2%, but in 9.5% with
patients complained of dysuria, 39.6% drug resistance to ethambutol and strep-
had perineal pain, 58.6% had flank pain. tomycin (Diagram 3) [24].
Laboratory findings showed leucocyturia In 79.3% tuberculous prostatitis was
in 84.5%, and leucocytes in prostate secre- combined with nephrotuberculosis, in
tions or ejaculate in 77.6%. Erythrocytes 31.0% with TB of a testicle and epidi-
in urine were presented in 53.4%, and in dymis; in 17.2% with bladder TB [24].
As whole
Male Bone and joints

Urogenital
Female Lymphonadal
Eyes
Children under 17 Others
Adult
0% 20% 40% 60% 80% 100%
Diagram 1 Clinical appearance of newly diagnosed Extrapulmonary Tuberculosis in Russia in 2005 [12].
Extrapulmonary TB in Russian Extrapulmonary TB in Germany
11% 6% 6%
26%
8% 17%
Bone and joints
UGT
Lymph. nodes
17%
Eyes
Others 50%
21%
38%
Diagram 2 Clinical appearance of extrapulmonary TB in Germany and in Russian.
Figure 3 TB epididymitis. Forming cavity within epididymis, Figure 4 Generalized Urogenital Tuberculosis: Tuberculosis
different maturity fibrosis is around. X100. van Gieson. of kidney, ureter, bladder, prostate, seminal vesicles.
883
84,5
90 77,6
80
Leucocyturia
70
53,4 Erythrocyturia
60
Leucocytes in
50 36,2 secretion
40 29,8 Erythrocytes in
30 secretion
MBT
20
10
0
Diagram 3 Laboratory findings of prostate tuberculosis [19].
8. DIAGNOSIS 50% of patients. MTB can be identified in

urine in 64% of UGTB patients by urine
The main reason for late diagnosis of acid-fest bacteria (AFB) cultures, AFB
UGTB is probably poor knowledge of smears, or nucleic acid amplification tests
the doctors and the population of this (NAATs) [32], but actually bacteriologi-
disease. Also the clinical picture has cal verification is significantly lower due
changed over the last years, which makes to the widespread use of fluorquinolons.
an on-time diagnosis difficult. For a cor- Because TB is epidemic in Russia the
rect diagnosis a careful investigation of National Russian Urological Congress
the epidemiological history (contact with approved a resolution in 2007, that all
tuberculous infection, TB in history, espe- cases of infections of the urogenital
cially in childhood) and special diagnostic tract should be suspicious for TB, and
algorithms, including provocative tests, is first line therapy should exclude anti-
necessary. bacterials affecting MBT (fluorquinolons,
In patients with suspected genital TB rifampicin, streptomycin or amycacin).
the clinical investigation should aim to All patients with an infection of the uro-
detect concomitant urinary and pulmo- genital tract should be investigated for
nary TB, since most genital TB cases are TB by culture and/or microscopy. Only
combined with renal or pulmonary TB. after TB is excluded, they may be treated
The Mantoux test is positive in more than with fluorquinolons.
90% of patients, but it has no value in The detection rates of MGTB may be
regions with a severe epidemic situation lower than that of renal TB, because the
(China, Russia, India, Africa), where all quantity of mycobacteria in urine can be
adults are infected with MBT and thus all lower, the affected sites may not be in
have positive skin tuberculin test [29–31]. direct contact with urine, and the urine
Chest films reveal lung lesions in about itself may not be infected [33]. Therefore
50% of patients [29–31]. All patients with bacteriological investigations of prostate
suspected or confirmed genital TB should secretion and ejaculate are obligatory for
be screened for HIV. patients with suspected MGTB.
Abnormal urinalysis can be seen in Since tuberculous prostatitis is mostly
up to 90% of UGTB [26]. Sterile pyu- associated with renal and bladder TB,
ria was the classic finding in kidney TB, urinalysis should be performed prima-
but now up to 75% patients with UGTB rily, before digital rectal examination or
have associated non-specific pyelonephri- prostatic massage, to exclude renal and
tis. Thus, the growth of uropathogens in bladder lesions. If urinalysis shows any
urine is not uncommon in TB patients pathology, complete investigation of the
[6]. Haematuria is presented in about urinary tract is indicated.
884
The urine should be examined for red Ultrasound investigation of the uri-
blood cell and leucocytes in three con- nary system should be performed in all
sequent portions (three-glass-test) dur- patients with inflammation of the geni-
ing urine voiding without interruption. tals. Epididymal or testicular TB has
As the prostate is part of the external nonspecific findings. The presence of
sphincter of the bladder, it contracts various pathologic components, includ-
at the end of a micturition. Therefore ing caseous necrosis, granulation tissues
it is necessary, that urination into the and fibrosis, are responsible for the diver-
three glasses should be performed with- sity of findings. Tuberculous epididymitis
out interruption of the urine stream to and orchitis present as diffusely enlarged
avoid earlier contraction of the external lesions, which may be homogeneous or
sphincter including the prostate gland. heterogeneous and can also present as
Leucocyturia in the first portion means nodular enlarged heterogeneously hypoe-
an inflammation in the urethra, in the choic lesions [35–36].
second portion an inflammation in the Transrectal ultrasonogram findings
urinary bladder or upper urinary tract, of prostatic disease are irregular hypoe-
and in the third portion an inflammation choic lesions in the peripheral zone [37].
in the prostate. Leucocyturia in all three On contrast-enhanced CT scan, TB of the
portions mirrors a severe inflammation prostate or seminal vesicles can be seen
of the total urinary system. In our opin- as low density or cavitation lesions due
ion the classical four-glass test (initial to necrosis and caseation with or without
urine, midstream urine, prostatic secre- calcification. Without calcification, the
tion obtained by prostatic massage, and findings may be similar to pyogenic pros-
urine after prostatic massage) is more tatic abscess [38–39]. Reports about MRI
difficult for the physician and more both- findings of prostatic TB are relatively
ersome for the patient and also is of less rare. Diffuse radiating streaky low signal
informative value. Therefore, we consider intensity lesion in the prostate (water-
it unsuitable. Moreover, in the case of melon skin sign) on T2-weighted images
prostate TB the four-glass test may show may be specific for tuberculosis of the
false-positive results of midstream urine prostate [40].
if micturition was interrupted after the Complex radiography is indicated for
first voided portion due to contamination patients suspected on UGT: plain X-ray
of the urine with prostatic secretion. films of the urinary tract detect calcifica-
Digital rectal examination (DRE) with tion in the renal areas and in the lower
soft massage of the prostate should be urogenital tract; intravenous urography
performed only after urinalysis, because is indicated for patients with leucocy-
DRE before urinalysis may lead to false turia and/or abnormality on ultrasound
positive leucocyturia. The prostatic secre- investigations. Retrograde urethrography
tion and/or ejaculate have to be investi- should be performed in all patients with
gated microscopically and by culture for genital tuberculosis to exclude caverns
both, uropathogens and MBT, as soon as of the prostate. Some cases of cavernous
possible after DRE or ejaculation, opti- tuberculosis of the prostate are demon-
mally not later than 40 min after. At least strated on Figures 5–8.
three to five consecutive early morning The FNAC may be useful in the diag-
specimens of urine and prostatic secre- nosis of TB of external male genitals
tion or ejaculate should be cultured by [41–44]. FNAC has been helpful in pre-
two slants [34]. The antimicrobial suscep- venting aggressive and inappropriate sur-
tibility of the strain should be estimated. gical procedures by providing an accurate
Prostatic secretion and ejaculate should and rapid diagnosis. Even though FNAC
also be investigated with PCR. of epididymal nodules is not easy to
885
Figure 5 Tuberculosis of a prostate gland with fistula. Figure 7 Retrograde urethrogram: tuberculous caverns of a
Duration of disease is 17 years. prostate.
Figure 6 Tuberculosis of a prostate. Giant multinucleated Figure 8 Retrograde urethrogram: tuberculous caverns of a
cell (left) is surrounded by lymphocytic infiltration. X100. prostate.
Hematoxylin and eosin.
perform since the nodules are small and subcutaneous tuberculin provocative test
slippery, it has a reported successful rate in modification Kulchavenya [45].
of 90.3% for diagnosis of epididymal nod- The indications for the provocative test
ules [41] and a reported sensitivity and are the following:
specificity of 87% and 93%, respectively, • Epidemiological anamnesis (contact
for tuberculous epididymitis [44]. A few with people or animal, suffering from
studies have reported successful diag- tuberculosis);
nosis of tuberculous orchitis by FNAC
[42–43]. However, scrotal violation should • Recurrent pyelonephritis with simul-
be considered if the mass is malignant. taneous cystitis, chronic prostatitis,
The correct diagnosis of the urogenital chronic epididymorchitis when stand-
tuberculosis is difficult in general uro- ard medical treatment did not solve
logical clinics; it is a prerogative of the the symptoms
urologist with a special skill in phthisiol- • Suspicion of a destruction of calyxes
ogy. The diagnostic algorithm includes a seen by intravenous urography;
886
Figure 10 Small cavern of a prostate.
reaction (hyperemia, induration in place

of injection tuberculin) is to be taken into
account. After provocative subcutaneous
tuberculin test identification of MBT by
culture or PCR increased by 16% [45]. On
the whole, this test improved the diag-
nostics of UGTB, especially the hidden,
latent forms, to 63.4% [45].
Figure 9 TB of right seminal vesicle in stage of calcification.

9. TREATMENT
Contraindications are: fever, gross
haematuria. Drugs that can cure most TB patients
have been available since the 1950s,
yet TB remains the world’s second most
Technique of the provocative test is
important cause of death by infectious
as follows:
diseases [46]. Unfortunately, after half a
1. 48 hours before the test, survey of century of phthisiology there is no new
body temperature drug. In the same time resistance of
2. Initial laboratory investigation mycobacteria has increased enormously.
includes analyses of urine and blood, Mono-, poly, and multi-drug resistant
microscopy of the prostatic secretion MBT to the basic antituberculous drugs
and ejaculate, culture of urine, pros- was found in up to 52.2% of extrapulmo-
tate secretion and ejaculate, including nary TB patients and up to 78.7% in pul-
PCR investigation. monary TB patients [47].
3. Injection of 50 unit tuberculin Medical treatment of genital TB is
subcutaneously somewhat different from that of other TB,
because prostatotropic drugs have to be
4. All laboratory investigations including preferred. In countries with low incidence
body temperature are repeated 24 and of TB three antituberculous drugs with
48 hours after tuberculin injection. bactericidal activity may be sufficient for
The test is positive if leucocytosis, lym- bacterial eradication and prevention of
phocytopenia, leucocyturia, leucocytosper- resistance. In epidemic regions patients
mia and body temperature have increased with MGTB should be treated with four
by more than one degree. Also local or five antituberculous drugs: isoniazid
887
10 mg/kg + rifampicin 10 mg/kg + pyrazin- of antibiotics and antituberculous chemo-

amid 20 mg/kg + streptomycin 15 mg/kg + therapy [50].
PAS 150 mg/kg (or ofloxacin 800 mg or
levofloxacin 500 mg daily) simultaneously
for two to four months, followed by six to 10. FOLLOW-UP
eight months of chemotherapy with isoni-
azid and rifampicin only [48]. After antituberculous therapy patients
Table 1 shows WHO recommended should be observed for at least three
essential antituberculous drugs [49]. The years, because the cavities of the prostate
treatment time has been reduced from do not close earlier. Therefore the risk of
two years to nine or six months with relapse is high.
these combination therapies, in compli-
cated or combined cases the length of
the therapy may be 12–14 months. Table 11. FURTHER RESEARCH
2 summarizes a six month therapy of
uncomplicated extrapulmonary TB rec- Up to now late diagnosis of MGTB domi-
ommended from WHO [49]. In cases of nates. It is necessary to develop a screen-
re-treatment, immunosuppression and ing system for early detection of MGTB
HIV/AIDS the treatment time increases patient. Also the improvement of pharma-
to nine or 12 months. In epidemic regions cotherapy of MGTB should be improved
a scheme of chemotherapy, approved by in order to avoid unnecessary surgical
the Russian Ministry of Public Health interventions, as MGTB like other infec-
should be used (Table 3) [1]. tions should be cured without surgery.
Surgical managements of genital
tuberculosis are abscess drainage and
epididymectomy. At least four weeks of 12. CONCLUSIONS
antituberculous chemotherapy should
be performed before surgery. There are The incidence of MGTB is not high, but
two indications for epididymectomy: diagnosis is difficult because genital TB
a caseous abscess that is not respond- has no pathognomonic signs. We recom-
ing to chemotherapy, and a firm swell- mend following an algorithm to improve
ing that has remained unchanged or has the management of patients with prosta-
slowly increased in size despite the use titis or epididymitis:
Table 1 Essential antituberculosis drugs.
Recommended dosage (dosage range) in mg.kg

Essential drug (abbreviation)
Daily 3 times weekly
Isoniazide (H) 5 (4–6) 10 (8–12)
Rifampicin (R) 10 (8–12) 10 (8–12)
Pyrazinamide (Z) 25 (25–30) 35 (30–40)
Streptomycin (S) 15 (12–18) 15 (12–18)
Ethambutol (E) 15 (15–20) 30 (25–35)
Thioacetazone (T) 2.5 Not applicable
888
Table 2 Male genital TB treatment regimens.
Initial phase Continuation phase
Preferred Preferred
2 HRZE 4 HR
4 (HR)
Optional Optional
2 (HRZE) 4 (HR)
or or
2 HRZE 6 HE
Table 3 Standard schemes of a chemotherapy.
Phase
Regime
Intensive Continuation phase
I 2 H R Z E/S 6 H R / 6 H 3 R3
II-a 2HRZES+1HRZE 5 H R E / 5 H3 R3 E3
II-b 3 H R Z E [Pt] [Cap] / [K] [Fq] According to sensitivity of MBT
III 2HRZE 4 H R / 4 H 3 R3
6HE
IV Not less then 5 drugs Not less then 3 drugs

[Z E Pt Cap/K Fq] [E Pt Fq]
[Rb] [Cs] [PAS] [Rb] [Cs] [PAS]
Length not less then 6 mo. Length not less then 12 mo.
i. Careful study of the history: if the antituberculous effects (fluorquino-

patient had TB or contact with tuber- lons, streptomycin, and rifampicin)
culous infection earlier, he has a high should be restricted unless TB can be
risk of relapsing UGTB. excluded after full examination of the
ii. Complex examination is necessary: patient.
a three-glass test before digital rec-
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891
|15.4|
Genitourinary tuberculosis in a
developing country (Vietnam):
diagnosis and treatment
Chuyen Vu Le, Nguyen Phuc Cam Hoang
Corresponding Author: Chuyen Vu Le, MD, Professor of Urology, Chief of Department of Urology,
Binh Dan Hospital, 371 Dien Bien Phu Q.3, Hochi Minh City, Vietnam
Tel +84 903 840514, Fax +84 8 8391315, vulechuyen@hotmail.com
ABSTRACT 1. INTRODUCTION
In this chapter, genitourinary tuberculo- Vietnam is one among 22 countries in

sis is reviewed in its entirety. Seen in a the world who faces the most serious
single institution in a developing country tuberculosis endemic with infectious risk
where the incidence remains important, around 2% per year and incidence of 100
the disease is presented in terms of epi- per 100,000 population [1]. Genitourinary
demiology, clinical manifestations, inves- tuberculosis (GUTB) in South Vietnam
tigation, treatment and follow-up with remains relatively common with many
an emphasis on diagnosis and treatment retardative complications such as urinary
attitudes. Some outcomes of local studies tract deformation, nonfunctioning kidney
are also presented in terms of diagnos- and renal insufficiency [2–3].
tic tools, treatment modalities, and min- These days, physicians are provided with
imally-invasive surgical interventions. many modern therapeutic means includ-
The diagnostic strategy and treatment ing many novel antituberculous drugs,
attitudes are presented according to local minimally invasive endourological inter-
clinical aspects and health-care facilities. ventions and various constructive surgical
techniques, but the therapeutic point-of-
Key words: Genitourinary tuberculosis view and management strategy vary from
(GUTB); directly observed treatment, short- one physician or one centre to another. The
course (DOTS); Tuberculosis ureteric stric- diagnosis of GUTB remains a difficult one,
ture, Tuberculosis nonfunctioning kidney. the concept of medico surgical therapy and
Genitourinary tuberculosis in a developing country (Vietnam) | 15.4 |
surveillance is a complicated issue and ureteric strictures: 12.6%, contracted urinary

there is no universal consensus. The clinical bladder: 7.2%, scrotal abscess: 16.2%, mixed
diagnosis, the duration of antituberculous complications: 5.4%. (Figure 4)
therapy and the timing of surgical interven-
tions remain questions to be clarified.
3. CLINICAL MANIFESTATIONS
2. EPIDEMIOLOGY Clinical symptoms: in a more recent

series of 50 GUTB patients complicated
In our institution, on average, 35 new with ureteric strictures over seven years
cases of genitourinary tuberculosis are (1998–2005), flank pain and dysuria pre-
seen per year [4]. In our former series of dominated [4].
five years (1989–1994) with 167 new cases In this series, the mean duration of
of GUTB [21], young age (31–50 years old) onset of symptoms is 6.3 months (1–36).
predominates: 73 / 167 cases (43.7%), with Five patients had history of pulmonary TB
the male: female ratio = 1.8 (Figure 1.). (10%), one had lymph node TB (2%) and
In this series, isolated GUTB accounted one had reactivated GUTB. Forty-seven
for 77.2% (129/167 cases), GUTB con- patients had positive urine, two had nega-
comitant with pulmonary tuberculosis tive urine in which one had been previously
accounted for 19.2% (32/167 cases), GUTB
concomitant with other extra-pulmonary
tuberculosis accounted for 3.54% (6/167 77.2
80
cases) (Figure 2.).
In terms of organ involvement, in this 70
series of 167 new cases of GUTB, iso- 60

lated kidney disease accounted for 13.2% 50
(22/167 cases); kidney and ureter disease 40
accounted for 25.7% (43/167 cases); kid- 30
19.2
ney, ureter, bladder disease accounted 20
for 26.3% (44/167 cases); kidney and 3.54
10
epididymis: 6% (10/167 cases); epidi-
0
dymis: 27.5% (46/167 cases); complex GUTB+PTB GUTB+EPTB GUTB
involvements: 1.2% (2/167) (Figure 3).
The complications of GUTB in this Figure 2 Genitourinary tuberculosis (GUTB) in 167 new
cases (1989–1994)(PTB: Pulmonary tuberculosis, EPTB: other
series: renal insufficiency: 9.6%, pyonephro- extrapulmonary tuberculosis).
sis: 8.9%, TB nonfunctioning kidneys: 3%,
30 27.5
43.7 25.7 26.3
45 25
40
32.9 20
35
30 15 13.2
25 19.8 10
20 6
15 5
1.2
10 0
3.6 Kidney, Kidney, Kidney,
5 Kidney
Ureter Ureter, BL Epidydy-
Epidydy- Complex
mis mis
0
0-15 16-30 31-50 > 50 13.2 25.7 26.3 6 27.5 1.2
Figure 1 Age distribution of 167 new cases of GUTB Figure 3 Organs involment in 167 new cases of GUTB
(1989–1994). (1989–1994).
893
18
16.2
• Urine culture for non-specific
16
organisms.
14 12.6
12 • Ziehl-Neelsen stain for AFB (three
10 9.6
8.9 to six consecutive urine samples)
8 7.2
6 5.4 • Polymerase Chain Reaction (PCR):
4 2.99 for detection of M. tuberculosis
2
(reaction IS6110-PCR).
0
Renal Pyone- Atrop- Ureteric Contra- Scrotal
insuffi- phrosis hied strictu- cted abscess
Combi-
nation • Culture on Löwenstein-Jensen
ciency kidney res bladder
9.6 8.9 2.99 12.6 7.2 16.2 5.4 medium to isolate M. tuberculosis
and nontuberculous mycobacteria
Figure 4 Complications in 167 new cases of GUTB (three consecutive urine samples).
(1989–1994).
In our recent series of 50 GUTB
patients complicated with uret-
Table 1 Clinical manifestation in a series of 50 GUTB eric strictures over seven years
patients complicated with ureteric strictures. (1998–2005) [4], we had the following
results: Ziehl-Neelsen stain for AFB
Clinical symptoms Cases %
in urine: positive: 39 / 50 (78%); nega-
Flank pain 37 74 tive: 11 / 50 (22%). Urine culture on
Löwenstein-Jensen: positive with
Haematuria 10 20
M. tuberculosis: 20 / 47 (42.6%);
Frequency 22 44
positive with M. nontuberculosis:
4 / 47 (8.5%); spoiled urine sample:
Clouded urine 8 16 1 / 47 (2.1%). PCR for M. tuberculosis
Dysuria 25 50
(IS6110-PCR) in 33 patients: posi-
tive: 14 / 33 (42.4%); negative: 19 / 33
Recurrent UTIs 7 14 (57.6%) with PCR sensitivity about
45.2–73.7%. This sensitivity is consid-
Hemospermia 1/12* 8,3
ered inferior to those of the authors.
*In 12 male patients
Moussa, 2000 [5], by using two
reactions: IS6110-PCR and 16S
treated with antituberculous drugs in rRNA gene-PCR had the sensitivity
another centre (decapitated-pretreated TB). of reaction IS6110-PCR and reaction
rRNAgene-PCR being 95.59% and
87.05%, respectively.
4. INVESTIGATION Nevertheless, in this series, with
the combination of AFB, urine
Over the last 10 years, for the diagnosis culture, and PCR, 47 / 50 patients
of GUTB in our institution, these are per- (94%) had mycobacterium positive
formed routinely: urine. This makes the diagnosis of
1. Erythrocyte sedimentation rate, GUTB easier in comparison with
tuberculin test only 38% patients with AFB (+) in
our former series of 167 patients
2. Chest X-ray and acid-fast bacilli
(1989–1994) [6].
(AFB) in sputum in case of suspicious
pulmonary images. 4. Radiography: Intravenous urography
3. Urine examination, including: (IVU) remains the key investigation.
• Urinalysis, for red blood cells and • Ultrasonography and IVU are
leukocytes; urine pH and concentra- performed in all cases with suspi-
tion documented. cion of GUTB. Standard IVU was
894
performed to detect hydronephro- indicated in 9/50 patients, revealing

sis, ureteric strictures and dila- contracted bladder in 1 / 50 cases, and
tion, split renal function (Figure VUR in 9 / 50 cases
5). However, in case of poor quality • Computed tomography (CT) or multi
IVU or poor functioning kidney, sliced CT is indicated for visual-
retrograde pyelography is indicated. izing difficult intrarenal lesions
In the series of 50 GUTB patients (Figure 8). It was indicated in 4 / 50
complicated with ureteric strictures patients: one had renal abscess and
over seven years (1998–2005) [4], fistula, two had hydronephrosis.
retrograde pyelography was done in
5. Cystoscopy and/or bladder biopsy
26/50 patients (52%) (Figure 6).
is of limited diagnostic value (Figure
• Voiding cystourethrography (VCUG) 9). Cystoscopy was indicated in 34/50
was indicated for detecting deformities cases in which bladder biopsy were
of the urinary bladder and/or vesi- performed in two cases. In these two
coureteral reflux (VUR) (Figure 7). cases, the results were nonspecific
In this series, cystography was chronic inflammation.
Figure 5 IVU in GUTB patients.A. Left juxtavesical ureteric stricture. B. Bilateral hydronephrosis with deformity of
urinary bladder. C. Right nonfunctioning kidney, left hydronephrosis and contracted urinary bladder.
Figure 6 Retrograde pyelography. A. Left upper and mid-ureter strictures. B. Left distal ureteric stricture.
895
Figure 7 Voiding cystourethrography in GUTB. A. Contracted urinary bladder with bilateral

VUR in a 59-years-old woman. B. Same condition in another woman patient.
Figure 8 CT, MSCT. A. Right perinephric abscess. B. Pseudotumoral image of a TB nonfunctioning kidney on the right side.
C. MSCT with image reconstruction which reveals contracted urinary bladder, calcifications on left nonfunctioning kidney.
5. TREATMENT urinary bladder, for patients with

destroyed organs such as nonfunctioning
All GUTB patients received directly kidneys, epididymal abscess. Extirpation
observed treatment, short course (DOTS). surgery is indicated after 2 months of
The patients are referred to local antitu- attacking chemotherapy [3, 7–9].
berculous establishments for antituber- In our former series of 167 new patients
culous drugs but they are monitored by (1989–1994) [6], chemotherapy alone
the urologists during the whole treat- accounted for 70%, chemotherapy in combi-
ment course. Patients with complications nation with surgery accounted for 30% with
of ureteric strictures are recommended over-all satisfactory outcome being 85.1%.
not to take Streptomycin for prevention Upper tract obstructions (ureteric stric-
of accelerated healing fibrosis leading to tures) are managed by staged treatment
acute upper tract obstruction. [4, 10]: antituberculous drugs are admin-
The national antituberculous program istered first, if there is deterioration or no
comprises two regimens [1]. Regimen 1: 2 improvement after three weeks, corticos-
SHRZ / 6 HE for new GUTB patients; teroids (prednisolone 20 mg tid) are added
regimen 2: 2 SHRZE / 1 HRZE / 5 H3 R3 for four to six weeks. If there is deteriora-
E3 for recurrent GUTB patients. tion or no improvement after a six-week
Surgery is indicated for patients with period, ureteral dilation is attempted,
complications of urinary tract deformi- from one to three sessions. If there is
ties, e.g. Ureteric strictures, contracted no improvement after three sessions of
896
Figure 9 A.B. Velvet bladder mucosa in TB cystitis. C. Tuberculosis golf-hole ureter.
Figure 10 A. Balloon catheter dilation. B. Catheter dilation. C. Endoincision of ureter [4].
Table 2 Treatment modalities in a series of 50 GUTB patients complicated with

ureteric strictures (59 ureters) (1998–2005) [4].
Treatment Ureters %
Chemotherapy 11 18,6
Chemotherapy + Corticoids 6 10,2
Chemotherapy + Corticoids + Ureteral dilation 10 16,9
Chemotherapy + Ureteral dilation 11 18,6
Chemotherapy, corticoids, ureteral dilation, surgery 14 23,7
Chemotherapy + Corticoids + surgery 3 5,1
Chemotherapy + ureteral dilation + surgery 1 1,7
Chemotherapy + surgery 3 5,1
Total 59 100
ureteral dilation, reconstructive surgery (1998–2005) [4], medical treatment

is indicated. brought in satisfactory outcomes only in
In a series of 50 GUTB patients compli- case of mild hydronephrosis (11/12 ure-
cated with ureteric strictures (59 ureters) ters, 91.7%) with overall satisfactory
897
Figure 11 Ureteral reimplantation [22]. A. Lich-Grégoir. B. Boari. C. Specimen of TB strictured ureter.
outcome of 26.8% (11/41 ureters). The role Table 3 Ureteric strictures: endoscopic dilation in 33
of corticosteroids was not statistically sig- patients with 36 strictured ureters.
nificant with rate of satisfactory outcomes
only 41.5% (17/41 ureters) (p=0.162). Endourological technique Ureters %
Bennani et al. [11] had a good outcome Placement of a Double-J 6 16,7
with corticosteroids in 8/16 strictured ure-
ters (50%), in 5/8 contracted urinary blad- Ureteral dilation using ureteroscope 6 16,7
der, and 2/3 contracted renal pelvis. He Balloon catheter dilation 1 2,8
advocates corticosteroids and endoscopic
Catheter dilation 7 19,4
dilation. Hamburger [12] recommends
prednisone 30–40 mg per day in no more Endoincision 6 16,7
than 2 months for fear of disseminated TB. Endoincision + balloon catheter
1 2,8
On the contrary, Le Guillou et al. [13] dilation
argued against the role of corticosteroids Endoincision + catheter dilation 3 8,3
in prevention or treatment of tuberculosis
Failure of endoscopic dilation 6 16,7
fibrosis in GUTB. He used it only in case
of acute TB cystitis. Total 36 100
In this series [4], 33 patients (66%) with
36 ureters (61%) were managed endo-
scopically (one to four sessions per ure- had good outcome in 55–79% cases. He
ter, mean of 1.47). Endoscopic procedures recommends ureteral dilations before
ranged from placement of a DJ stent (six surgical reconstruction in all patients.
ureters) to balloon or catheter dilations Similarly, Wemeau et al. [15], using the
(14 ureters) and to endo-incision of ure- molding ureteral catheter, had the suc-
ter (10 ureters) (Table 3). Failure rate cess rate of 73%.
of endoscopic dilations were 16.7% (six In this series [4], 18 patients (36%)
ureters). The role of endoscopy was sta- with 21 ureters underwent surgical
tistically significant with satisfactory out- reconstruction: one UPJ reconstruction
comes of 65.9% (27/41 ureters) (p=0.0267). (Hynes-Anderson), 17 ureteral reim-
Of the 36 ureters managed by endoscopic platations (Lich-Grégoir: 12, LeDuc:1,
dilation, 13 ureters had encouraging out- Politano:1, Boari: 3), two placements of
comes (36.1%). Six out of 10 ureters (60%) DJ stent, one augmentation ileocysto-
with the length of the stricture ≤ 1cm had plasty for contracted urinary bladder
encouraging outcomes. associated with ureteral reimplantation
Murphy et al. [14], in 25 years and in (Table 4). Surgical reconstruction had
92 patients, reported good outcomes with the rate of encouraging outcomes of 85%
endoscopic dilation of 64% (on average (17/20 ureters, one patient-ureter was lost
four sessions per patient). Other authors of follow-up).
898
Globally, with the staged regimen of or 2) the bladder is severely distorted.

management for these 50 patients with The technique is Goodwin “cup-patch”
complication of ureteric strictures, the ileocystoplasty. In recent cases, laparo-
rate of encouraging outcomes was 79.3% scopic ileocystoplasty was performed with
(46/58 ureters, one patient was lost of encouraging outcomes [16].
final follow-up IVU), failure rate was For TB nonfunctioning kidneys,
10.2% (5/49 patients), the theoretical nephrectomy is indicated because: 1) short-
nephrectomy rate was 10% (5/50 patients) course chemotherapy is administered
For TB contracted urinary bladder, aug- in all cases [17], 2) the rate of pyoneph-
mentation ileocystoplasty is indicated in rosis is quite high [3] (Figure 13), 3) the
cases where 1) bladder capacity < 100 mL necessity of removal of a potential source
Figure 12 Augmentation ileocystoplasty. A,B. Open surgery [22]. C.D.. Laparoscopy [16].
Figure 13. Specimen of TB nonfunctioning kidneys. A. Caseous necrosis and cavities. B. C. Tuberculosis
pyonephrosis [4]
Figure 14 Epididymal abscess and epididymectomy [21].
899
Table 4 Ureteric strictures: reconstructive surgery in 18 contraindication to laparoscopic nephrec-

patients with 21 strictured ureters. tomy anymore.
Technique Ureters %
Placement of a ureteral catheter 2 9,5

6. FOLLOW-UP
Hynes-Anderson 1 4,8
All patients are followed-up by urologist
Lich-Gregoir 12 57,1 during the whole treatment course. After
LeDuc 1 4,8
the initiation of antituberculous chemo-
therapy, if the patient has signs of upper
Politano 1 4,8 tract obstruction, he is seen every three
Boari 3 14,3 weeks according to the staged treatment
regimen furnished with a IVU for early
LeDuc + Aug. Cystoplasty 1 4,8
detection of acute upper tract obstruction
Total 21 100 (healing fibrosis precipitated by antitu-
berculous drugs [22]) or for early relief
of urinary tract obstruction to improve
of bacterial persistence [18], 4) the fear renal function [23–24]; if he has no sign
that renal carcinoma can develop [19]. In of upper tract obstruction, he will be
recent years, in our institution, laparo- seen every four weeks for the first three
scopic nephrectomy is indicated if preop- months, then every three months in the
erative CT reveals little or no perinephric first year, then every six months in the
inflammation and adhesions. second year. Urine negatization of AFB on
In a review of our 14 initial cases of Ziehl stain and/or M. tuberculosis on cul-
laparoscopic nephrectomy for TB non- ture are monitored during the first three
functioning kidneys from May 2003 to months of treatment course to detect
November 2006 [20], six patients under- multidrug resistance or bacterial per-
went left nephrectomy, eight underwent sistence due to excluded foci somewhere
right nephrectomy. There were four intra- in upper tract that may require surgical
peritoneal laparoscopic nephrectomies removal. IVU of control is required every
and 10 retroperitoneoscopic nephrecto- three months in the first year to detect
mies. Operative technique: extracapsular the eventual healing fibrosis and urinary
perirenal dissection: 13 cases, extracapsu- tract deformities. After the second year,
lar and subcapsular perirenal dissection: the patient is seen every year for urine
one case. Mean operating time: 163.3 min- examinations of control.
utes (140–180), estimated blood loss: 60
ml (30–150), intraoperative incident: one
small-hole peritoneal penetration (retro- 7. CONCLUSIONS
peritoneoscopic nephrectomy). There were
five conversions (35.7%): four cases with GUTB in (South) Vietnam remains a top-
dense perinephric adhesions, in which one ical issue in terms of prevalence as well
pseudotumoral TB; one case with active as severity. The diagnosis of GUTB is
hemorrhage due to perinephric inflam- currently not a too difficult one because
matory oozing. There was no preoperative the combination of AFB, PCR, urine cul-
blood transfusion. Postoperative hospital ture can make the diagnosis up to 94% of
stay was 4.3 days (1–7). cases.
Despite high conversion rate, our expe- Short-course chemotherapy is cost-
rience suggests that TB nonfunctioning effective. GUTB is a medico-surgical
kidneys should not be considered as a disease, a timely intervention and an
900
effective management could prevent seri- 10. McAleer SJ, Johnson CW, and Johnson
ous complications. Minimally invasive Jr. WD, Genitourinary Tuberculosis, in
procedures might be helpful in patients Campbell-Walsh urology : ninth edition,
who require surgical treatment. Wein AJ, Editor. 2007, Elsevier
Saunders: Philadelphia, Pa. ; Edinburgh.
p. xxviii, 528 p.
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902
|15.5|
Guidelines for the treatment of

fungal urinary tract infections
Jack D. Sobel1, John Fisher2, Carol A. Kauffman3
1
Division of Infectious Diseases, Department of Medicine, Wayne State University School of Medicine, Detroit, MI
2
Division of Infectious Diseases, Medical College of Georgia, Augusta, GA
3
Division of Infectious Diseases, University of Michigan Medical School and Veterans Affairs Ann Arbor Healthcare
System, Ann Arbor, MI
Correspondence: Jack D. Sobel, M.D., Chief, Division of Infectious Diseases, Professor of Medicine,
Harper University Hospital, 3990 John R – 5 Hudson, Detroit, MI 48201
Tel: (313) 745-7105, Fax: (313) 993-0302, E-mail: jsobel@med.wayne.edu
ABSTRACT Key words: candiduria, Candida spp.,

antifungal drugs, fluconazole, amphoteri-
Fungal infections of the urinary cin B, flucytosine
tract are extremely common espe-
cially those caused by Candida spe-
cies. Epidemiological studies reveal a
significant increase in Candida spp.
UTI’s (candiduria) predominantly the Asymptomatic candiduria
result of health care (nosocomial) asso- 1. Treatment is not recommended unless
ciated infection. Progress has followed the patient falls into a high-risk group
identifying risk factors for candiduria, for dissemination (GoR A).
however diagnostic criteria including
microbiologic remain elusive. While 2. Elimination of predisposing fac-
numerous effective antifungal agents tors often results in resolution of
are now available, widespread imple- candiduria (GoR A).
mentation of approved indications for 3. High-risk patients include neutropenic
therapy has been slow in forthcoming. patients, low birth weight infants,
This review summaries new treatment and patients who will undergo uro-
guidelines for treating funguria and logic manipulations. Neutropenic
provides a rational basis for use of anti- patients and neonates should be man-
fungal agents. aged as for invasive candidiasis. For
those undergoing urologic procedures, 5.4. For fluconazole-resistant Candida

fluconazole 400 mg daily or AmB-d isolates, especially C. glabrata,
(0.3–0.6 mg/kg daily) for several days, alternatives include AmB-d (0.8–
before and after the procedure is 0.7 mg/kd daily) +/- flucytosine 25
recommended (GoR B). mg/kg qid (GoR A), or flucytosine
4. Imaging of the kidneys and collecting alone 25 mg/kg qid (GoR B).
system to exclude abscess, fungus ball, 5.5. For fungus balls, surgical inter-
or urologic abnormality is prudent for vention is strongly recommended
persistent candiduria among asympto- (GoR A). Fluconazole 200–400
matic patients with predisposing fac- mg daily is recommended (GoR
tors (GoR B). B). AmB-d 0.5–0.7 mg/kg daily
with or without flucytosine, 25
Symptomatic candiduria mg/kg qid is an alternative (GoR
B). If access to the renal collect-
5. For candiduria with suspected dis- ing system is available, irriga-
seminated candidiasis, treatment with tion with AmB-d 50 mg/L sterile
systemic antifungals for candidemia is water is recommended as an
recommended (GoR A). adjunct to systemic therapy (GoR
5.1. For cystitis due to fluconazole- B). Treatment duration should
susceptible Candida species, oral be until symptoms have resolved
fluconazole, 200 mg daily for 2 and urine cultures no longer yield
weeks, is recommended (GoR B). Candida (GoR B).
For fluconazole-resistant organ-
isms, AmB-d 0.3–0.6 mg/kg daily
1. INTRODUCTION
for 1–7 days or oral flucytosine 25
mg/kg qid for 7–10 days are alter-
natives (GoR B). Although many fungal genera and species
can involve the urinary tract, more than
5.2. AmB bladder irrigation is gener- 95% of UTI’s due to fungi are caused by
ally not recommended, but may Candida species (see Table 1). Accordingly
be useful for fluconazole-resistant these guidelines will focus on the treat-
Candida species, especially C. gla- ment of Candida urinary tract infections
brata (GoR B). recognizing that treatment principles,
5.3. For pyelonephritis due to pharmacokinetic and pharmacodynamic
fluconazole-susceptible organisms, issues of antifungal agents used to treat
oral fluconazole 200–400 mg daily for Candida species apply equally to all gen-
2 weeks is recommended (GoR B). era of fungi.
Table 1 Urinary Tract Involvement by Invasive Mycoses.
Infection Prostate Bladder Kidney Penis/Cutaneous
Blastomycosis +++ ± + +
Histoplasmosis ++ + ++ ++
Coccidioidiomycosis + + ++ +
Aspergillosis + + +++ +
Cryptococcosis +++ + +++ +
Candidiasis +++ ++++ ++++ ++
904
Guidelines for the treatment of fungal urinary tract infections | 15.5 |
2. METHODS species [9–14]. Nosocomial candidiasis

is also common in the neonatal and pedi-
In 2008, the Infectious Diseases Society of atric ICU’s [11]. It has been estimated
America commissioned a select committee that the incidence of candiduria in the
of Infectious Diseases experts to update ICU setting to be approximately 25,000
previous guidelines for the treatment cases per year in the United States [14].
of Candida infections including those Nosocomial candiduria is by no means
involving the urinary tract [1]. These confined to ICU’s. Candiduria is often
peer reviewed guidelines form the foun- transient and most positive cultures
dation of this document and no inconsist- represent colonization rather than true
encies are expressed. Levels of evidence infection. On occasion candiduria may
and grading of guideline recommendation be associated with symptomatic UTI and
were modified by the authors of this docu- fungemia [15].
ments to be consistent with ICUD stand-
ards [2–3]. A Medline search identified 70
articles dealing with fungal urinary tract 4. MICROBIOLOGY
infections during 1979 until 2009. The
studies were rated according to the level C. albicans is the most common fungal
of evidence (LoE) and the grade of recom- species isolated from the urine and in one
mendation (GoR) using ICUD standards large study was found in 446 (52%) of 861
(for details see Preface) [2–3]. patients with funguria [16]. C. glabrata
accounts for 25–35% of infections whereas
8–28% of infections are due to C. tropi-
3. EPIDEMIOLOGY OF CANDIDA calis, C. krusei, and C. parapsilosis [12,
URINARY TRACT INFECTIONS 16]. Nevertheless, many recent epidemio-
logic microbiologic studies have reported
Candida microorganisms exist as sapro- a marked increase in infections caused
phytes on the external genitalia or ure- by non-albicans Candida species espe-
thra; however, yeast in measurable cially C. glabrata and C. tropicalis [15,
quantities are found in <1% of clean 17–18]. Unusual species are common in
voided urine specimens. Candida infec- hospitalized patients, especially diabetics
tions currently account for 5% of urine and those with chronic indwelling blad-
isolates in the general hospital and 10% der catheters. Mixed infections caused by
of positive urinary cultures in tertiary- more than one Candida species are not
care centers [4–5]. Candiduria occurs in infrequent, as is concomitant bacteriuria.
patients throughout medical centers but
is especially common in surgical ICU’s
and Candida urinary isolates are sec- 5. PATHOGENESIS AND
ond only to E. coli in combined medical- PREDISPOSING FACTORS
surgical ICU’s [6]. Twenty-two percent
of critically ill patients admitted for Candiduria is rare in the absence of pre-
more than seven days in the ICU devel- disposing factors. Most infections are
oped candiduria in a large multicenter associated with use of Foley catheters
study in Spain [7]. Moreover ICU studies (50–70%), internal stents, percutane-
have consistently reported a relationship ous nephrostomy tubes and recent sur-
between candidiasis and heavy coloniza- gery. Diabetic patients, especially when
tion, suggesting that candiduria could be their diabetes is poorly controlled, are
considered as a marker for heavy colo- particularly at risk primarily because of
nization [8]. Presently 10–15% of noso- increased instrumentation, urinary stasis,
comial UTI’s are caused by Candida and obstruction secondary to autonomic
905
neuropathy. Concomitant bacteriuria manifestations depend on the site of infec-

is common and bacterial adherence to tion. Candida cystitis may present with
bladder epithelium may play a key role frequency, dysuria, urgency, hematuria,
in pathogenesis of Candida infection. and pyuria. Ascending infection resulting
Antimicrobials (50–100%) similarly play in Candida pyelonephritis is characterized
a critical role, in that candiduria almost by fever, leukocytosis, and rigors and is
always emerges during or immediately indistinguishable from bacterial pyelone-
after antibiotic therapy. Antibiotics, espe- phritis. Excretory urography and CT
cially broad-spectrum agents, act by sup- scanning may reveal ureteropelvic fungus
pressing protective indigenous bacterial balls or papillary necrosis. Renal candi-
flora in the gastrointestinal (GI) tract and diasis is difficult to diagnose when second-
lower genital tract, facilitating Candida ary to hematogenous spread and presents
colonization of these sites and subsequent with fever and other signs of sepsis. By
access to the urinary tract. Nosocomial the time renal candidiasis is considered,
candiduria is more common among blood cultures are usually no longer posi-
women than men in an ICU setting, per- tive; however, unexplained deteriorating
haps related to the contribution of vagi- renal function is often evident.
nal Candida colonization to urinary tract
colonization [19]. The pool of critically ill,
immunosuppressed medical and surgical 7. DIAGNOSIS
patients has increased, and this increase,
together with improved technology, pro- Because isolation of Candida from a urine
vides an expanded population at risk of specimen may represent contamination,
developing Candida infection. colonization, or superficial or deep infec-
Most lower UTIs are caused by retro- tion of the lower or upper urinary tract,
grade infection associated with an ind- determining the significance of candiduria
welling catheter or genital and perineal is difficult. Management also depends on
colonization [20]. The upper urinary tract the determination of the most likely site
is uncommonly involved during ascending of infection. Contamination of the urine
retrograde infection and then only in the sample is particularly common in women
presence of urinary obstruction, reflux, or with vulvovaginal colonization and may
diabetes. Renal candidiasis is usually the be excluded by repeating urine culture
consequence of secondary hematogenous with special attention to proper collec-
seeding of the renal parenchyma; Candida tion techniques. Differentiating infection
species have a unique tropism for the kid- from colonization may be extremely dif-
ney and hematogenous renal infection ficult if not impossible in some patients,
results in anterograde candiduria. especially if they are catheterized.
Accompanying clinical features may facil-
itate identifying the source of candiduria,
6. CLINICAL ASPECTS but unfortunately these are often nonspe-
cific in critically ill patients, and accom-
Most patients with candiduria are asymp- panying fever and leukocytosis may be
tomatic, especially those with indwelling related to several different sources.
bladder catheters. Even if asymptomatic, Quantitative urine colony counts have
several studies indicate that ICU patients little value in separating infection from
with candiduria have a higher in ICU colonization and then only in the absence
and hospital mortality [15]. Candiduria of a Foley catheter. The latter negates
in this context reflects Candida coloniza- any diagnostic value even of quantita-
tion but also is a major marker of overall tive cultures in distinguishing coloniza-
sickness of the individual patient. Clinical tion from infection. In noncatheterized
906
patients, counts greater than 104 CFU/ml may be of value in localizing the source
are usually associated with infection. It is of candiduria in catheterized subjects in
rare for patients with invasive disease of that post-irrigation persistent candiduria
the kidney, pelvis, or bladder to have 103 originates from above the bladder, thus
CFU/ml or less. Most patients with uri- identifying patients with need for further
nary tract Candida infection have pyuria, studies. Unfortunately, the lengthy nature
but the value of this finding is similarly of this diagnostic test excludes its utility
diminished in the presence of a catheter in most febrile, critically ill subjects.
or concomitant bacteriuria and in neutro-
penic subjects. Serologic tests of Candida 8. PRINCIPLES OF MANAGEMENT
tissue invasion are not available however
tests such as beta-glucan titer may be use-
8.1 Drug therapy
ful. Treatment is preceded by attempts
to localize the source or anatomic level of Since the original availability of ampho-
infection. Unfortunately, no reliable tests tericin B desoxycholate (AmB-d) used
to differentiate renal candidiasis from the parenterally or for bladder catheter irri-
more frequent lower tract infections exist. gation, washout or retention, a vari-
The extremely rare finding of Candida ety of new antifungals including azoles
microorganisms and pseudohyphae and echinocandins are now available
enmeshed in renal tubular casts is useful [21]. New antifungal agents are listed
when present. Ultrasonography and com- in Table 2. None of the new agents have
puted tomography (CT) scans have a useful proved more useful than fluconazole for
but limited role in localization. A five-day the treatment of Candida urinary tract
bladder irrigation with amphotericin B infection. Critical factors by which these
Table 2
Class Achieves therapeutic urine

concentration
Polyene
Amphotericin B desoxycholate Yes (√)
Liposomal A (Ambisome®) No
(Abelcet®) No
Nystatin No
Flucytosine Yes (√) [Not in renal failure]
Azoles
Ketoconazole No
Itraconazole No
Fluconazole Yes (√)
Voriconazole No
Posaconazole No
Echinocandin
Caspofungin No
Micafungin No
Anidulafungin No
907
numerous agents are judged include: i) For symptomatic Candida cystitis, flu-
toxicity especially nephrotoxicity, ii) spec- conazole is the drug of first choice. It is
trum of activity, iii) excretion into urine highly water-soluble, primarily excreted
to achieve concentrations capable of in urine in its active form, and eas-
inhibiting fungal pathogens even in the ily achieves urine levels exceeding the
presence of renal failure. MIC for most Candida isolates [25]. No
other currently available azole is use-
ful because of minimal excretion of the
8.2 Clinical evidence supporting
active compound into urine. For patients
treatment principles
who have cystitis and who are allergic
The presence of yeast in the urine, to fluconazole or who clearly fail therapy
whether microscopically visualized or despite maximum doses and optimal
grown in culture, must be evaluated in management of urologic abnormalities,
the context of the particular clinical set- oral flucytosine, systemic AmB-d, or blad-
ting to determine its relevance and the der irrigation with AmB-d can be tried.
need for antifungal therapy. If no pre- Flucytosine demonstrates good activ-
disposing condition is uncovered as is ity against most Candida isolates and
the case in the majority of asymptomatic is concentrated in urine [26]. It is par-
patients only observation is warranted ticularly useful for C. glabrata infection.
[1]. Unfortunately unnecessary treat- Treatment with flucytosine is limited by
ment of asymptomatic candiduria is wide- toxicity and the development of resist-
spread [22]. In a multicenter U.S. study, ance when used alone; it is not recom-
43% of patients, most of whom were mended as primary therapy for patients
asymptomatic with Candida isolates in with uncomplicated Candida cystitis [1]
urine were treated [16]. Among patients and should not be used in the presence of
with predisposing conditions, manage- renal failure.
ment of that condition alone may be suf- Irrigation of the bladder with a sus-
ficient to eliminate candiduria without pension of amphotericin B, 50 mg/L ster-
specific antifungal therapy. Several pre- ile water for five to seven days resolves
disposing conditions require an aggres- candiduria in more than 90% of patients
sive approach to persistent candiduria, [27] but there is a high relapse rate. This
even among asymptomatic patients. approach is generally discouraged except
Disseminated candidiasis should be con- as a measure to treat refractory cystitis
sidered in low birth weight neonates and due to azole resistant organisms, such as
severely immunocompromised patient C. glabrata and C. krusei.
with fever and candiduria, independent Fluconazole is the drug of choice for
of urinary symptoms or anatomic geni- most patients with Candida pyelone-
tourinary abnormality. phritis. C. glabrata accounts for approxi-
The major principle underlying the mately 20% of urine isolates [15, 17] and
concept of not treating asymptomatic is frequently resistant to fluconazole.
nosocomial candiduria in patients with Amb-d has demonstrated efficacy for
indwelling bladder drainage devices is pyelonephritis, and remains the choice of
based upon the frequently documented many clinicians for upper urinary tract
observation that lower urinary tract can- candidiasis in critically ill patients [28].
didiasis rarely results in ascending infec- The reduced nephrotoxicity of lipid for-
tion (retrograde) and candidemia [15, mulations of AmB suggests that tissue
23–24]. Exceptions to this observation penetration in the renal parenchyma is
include following instrumentation of uri- reduced. There are both experimental
nary tract and when urinary obstruction animal data and clinical case report that
is present. demonstrate failure of lipid formulation
908
AmB to clear Candida from the kidneys that differentiate tissue invasion and
and lower urinary tract [29–30]. true infection from lower urinary tract
There are very limited data, includ- colonization.
ing several animal studies and a few
reports of a small number of patients, in
which echinocandins were used success- 10. CONCLUSIONS
fully for treatment of renal parenchymal
infections [31–33]. There are no data Considerable progress has been made in
regarding the use of voriconazole or posa- determining the epidemiology and risk
conazole for renal candidiasis. factors for fungal UTI`s. Although many
Candida prostatitis and epidymo-orchitis fungal genera may invade the urinary
are rare and can present as either acute or tract, Candida species continue to be
chronic infection [34–36]. Most patients responsible for the overwhelming major-
require surgical drainage of abscesses or ity. Based upon in vitro susceptibility and
other surgical debridement as well as fun- pharmacokinetics of antifungal drugs
gal therapy. Fluconazole is the agent of together with an increased number of
choice, but treatment recommendations randomised controlled studies, rational
are based on anecdotal data. guidelines for antifungal use have been
Fungus balls can occur anywhere in the developed.
urinary collecting system. Aggressive sur-
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911
|15.6|
Vulvovaginal candidosis
Werner Mendling
Corresponding author: Werner Mendling, MD, PhD, Professor and Head of Department of Gynecology and Obstetrics,
Hospital Vivantes Am Urban, Dieffenbachstr. 1, 10967 Berlin, Germany, and
Hospital Vivantes im Friedrichshain, Landsberger Allee 49, 10249 Berlin, Germany
Tel +49-30-130-23 1442, Fax +49-30-130-23 2043, werner.mendling@vivantes.de
ABSTRACT Diagnostic tools are anamnesis, clinical

signs, microscopic investigation of the
The estrogenized vagina is colonized vaginal fluid by phase contrast (400 ´),
by Candida (C.) species, mostly by vaginal ph-value, and in clinically and
C. albicans, in at least 20% of women microscopically uncertain or in recur-
in late pregnancy and at least 30% of rent cases, a yeast culture with species
immunosuppressed patients. The risk determination. In sporadic acute cases,
of Candida vulvovaginitis is influ- therapy is easy and successful in about
enced by host factors, especially local 80% of patients. Vaginal preparations of
defence deficiencies, gene polymor- polyenes, imidazoles, ciclopyroxolamine
phisms, allergic factors, serum glu- or oral triazoles (which are not allowed
cose levels, antibiotics, psychosocial during pregnancy) are equally success-
stress and estrogen induced vaginal ful. C. glabrata is resistant to the usual
factors. In less than 10% of cases, with dosages of all local antimycotics and
regional differences, non-albicans spe- so vaginal boric acid suppositories or
cies (especially C. glabrata, but in rare vaginal flucytosine are recommended.
cases also Saccharomyces cerevisiae,) As these are not allowed or not avail-
cause vulvovaginitis, often with fewer able in some countries, a high dose of
clinical signs and symptoms. Typical 800 mg fluconazole per day for two to
symptoms are premenstrual itching, three weeks is also recommended, and
burning, redness and non-odorous dis- nowadays also oral posaconazole 800
charge. Although pruritus and inflam- mg for 15 days is discussed. C. kru-
mation of the vaginal introitus are sei is resistant against triazoles. Side
typical symptoms, fewer than 50% of effects, toxicity, embryotoxicity and
women with genital pruritus are suf- allergy are of no clinical importance.
fering from Candida vulvovaginitis. In two studies, vaginal clotrimazole
Vulvovaginal candidosis | 15.6 |
treatment during the first trimester 2. Therapy for acute vulvovaginal can-
of pregnancy was shown to reduce the didosis is possible with: polyenes,
rate of preterm births. The resistance imidazoles or ciclopyroxolamine in
of C. albicans does not play a clinically the form of vaginal tablets; ovules
important role in vulvovaginal candi- or creams for a one day to one week
dosis. Although it is not necessary to treatment duration; skin cream for
treat vaginal Candida colonization in the vulva; or with one day oral tria-
healthy women, in Germany it is rec- zole treatment. The results of all
ommended during the third trimester of clinical and mycological therapies
pregnancy, because it reduces the rate are similar. Asymptomatic coloni-
of oral thrush and napkin dermatitis zation must not be treated unless
induced by colonization during vaginal there is immunosuppression, it is a
delivery in mature healthy newborns. complicated case or there is chronic
Until immunological therapies become recurrent vulvovaginal candidosis
available, chronic recurrent vulvovagi- (LoE 1a, GoR A). For treatment of
nal candidosis requires “chronic recur- vaginal colonization duringpregnancy
rent” suppression therapy. Weekly to see 3.5.
monthly oral fluconazole regimes sup-
press relapses well, but cessation of 3. Treatment for chronic recurrent C.
therapy after 6 or 12 months leads to albicans vulvovaginitis is (due to the
relapse in 50% of patients. The decreas- lack of immunological therapy) sup-
ing-dose maintenance regime of 200 mg pressive intermittent antimycotic
fluconazole three times a week initially, therapy over a period of months with
decreasing to once monthly [1] leads to an oral triazole. The best results are
more acceptable results. Future studies obtained with the fluconazole regime
should include candida autovaccination, described by Donders et al. (table 4)
antibodies against candida virulence (LoE 2a, GoR B).
factors and other immunological trials. 4. C. glabrata vaginitis is resistant to
Probiotics should also be considered in the common vaginal or oral treat-
further studies. Over-the-counter ther- ments. Therefore the recommenda-
apy needs to be reduced. tions are: vaginal boric acid 600 mg
Key words: guideline, vulvovaginal capsules for 14 days; amphotericin
candidosis, candida, pregnancy, diagno- B ovules; vaginal 17% flucytosine; or
sis, therapy, immunology. 800 mg oral fluconazole per day for
2–3 weeks (LoE 2a, GoR B) or posa-
conazole 800 mg orally for 15 days
(LoE 4, GoR C). C. krusei vaginitis is
SUMMARY OF RECOMMENDATIONS resistant to oral triazoles and should
therefore be treated with local clot-
rimazole, imidazoles or boric acid
1. A diagnosis of vulvovaginal candidosis (LoE 2b, GoR B).
is made from a combination of clinical
signs and symptoms and the presence 5. In Germany, antimycotic local treat-
of yeasts, usually proven by microscopic ment for vaginal C. colonization
investigation (400 fold phase contrast) is recommended during the last 6
of the vaginal fluid. A yeast culture weeks of pregnancy to inhibit ver-
with species determination is necessary tical transmission during vaginal
in doubtful, recurrent or complicated delivery. Thus, neonatal C. infection
cases. Serological blood tests are not rates are significantly reduced (LoE
recommended (LoE 1b, GoR B). 2a, GoR B).
913
1. INTRODUCTION recommendation (GoR) using ICUD stand-

Vulvovaginal candidosis is an infection
of the estrogenized vagina and the vesti-
bulum, which can extend to the outside 3. MICROBIOLOGY
of the labia minora, the labia majora and
the intercrural region. Candidosis of the Candida albicans is able to form blast-
cervix or the endometrium is unknown. ospores, pseudomycelia, true mycelia and
Connatal foetal candidosis and Candida chlamydospores. Candia glabrata forms
amnionitis are rare events. The terms only blastospores. Blastospores are usu-
“vulvovaginal candidosis” or “Candida albi- ally formed in colonized women together
cans vulvovaginitis” are recommended [2]. with (pseudo)mycelia in vaginitis patients
The ending “-iasis” should be used for par- [17–18]. In premenopausal, pregnant,
asitic infections (e.g. trichomoniasis) [3–4]. asymptomatic and healthy women, and
women with acute Candida vaginitis,
Candida albicans constitutes 85–95% of
2. METHODS the colonizing vaginal candida species,
whereas non-albicans species (especially
A MedLine/PubMed search with the Candida glabrata) are more frequent in
keywords “vulvovaginal candidosis” postmenopausal, diabetic and immuno-
resulted in 2812 titles and a search suppressed women [19–25]. There are
with the keywords “vulvovaginal can- regional differences in the distribution of
didosis therapy studies” resulted in 286 candida species (Tables 1 and 2 contain
titles. All were screened for title and examples for Berlin, Germany). Candida
abstract, but only very few recent stud- krusei, Candida guilliermondii, Candida
ies were randomized and/or prospective tropicalis, Candida parapsilosis and oth-
controlled trials [1, 5–10]. Only three ers can cause vulvovaginitis with typical
metanalyses or Cochrane analyses were symptoms [17, 25–28]. Saccharomyces
found [11–13] and only two guidelines cerevisiae rarely causes vaginal symp-
[4, 14]. toms [18, 29], but is identified in about
The studies were rated according to the 1–2% of cultures.[23, 25] (Table 3).
level of evidence (LoE) and the grade of Candida albicans is found in 80–95% of
Table 1 Candida colonization of the vagina in healthy HIV-positive and HIV-negative women [25].
Species HIV-neg. HIV-pos.

n = 383 100% n = 66 100%
Candida positive 88 22.9 p = 0.02 24 36.4
all 88 100 24 100
C. albicans 77 87.5 14 58.3
C. glabrata 6 6.8 8 33.3

¯˘˙
C. krusei 2 2.3 0 0
C. dubliniensis 1 1.1 p = 0.001 0 0
C parapsilosis 1 1.1 1 4.2
C. famata 1 1.1 0 0
C. magnoliae 1 4.2
914
Table 2 Distribution of vaginal Candida species in HIV-negative colonized women [25].
Patients premenopausal postmenopausal pregnant not pregnant
all patients n = 338 n = 45 n = 192 n = 146
with positive culture n = 92 (23.3%) n = 6 (13.3%) n = 52 (27.1%) n = 30 (20.5%)
p = 0.003 p = 0.02
n % n % n % n %
C. albicans 75 91.5 2 33.3 48 92.3 27 90.0
C. glabrata 4 4.9 2 33.3 2 3.8 2 6.7
C. krusei 1 1.2 1 16.7 1 1.9 0 –
C. dubliniensis 1 1.2 0 – 1 1.9 0 –
C. famata 0 – 1 16.7 0 – 0 –
C. parapsilosis 1 1.2 0 – 0 – 1 3.3
vagina[32] and the estrogen receptors of

Table 3 Distribution of Candida species in 472 cases of
acute vaginal candidosis in Poland and Germany [101]. C. albicans [33–34], and therefore do not
usually not suffer from candida vaginitis.
acute Candida vulvovaginitis
n % 20–30% of healthy, non pregnant and
472 100 premenopausal women are vaginally col-
C. albicans 450 95.3 onized, compared to at least 30% of preg-
C. glabrata 10 2.1 nant women in the third trimester and
C. krusei 4 0.9 30% of women with immunodeficiences
2.3
[19, 25] (Tables 1–2). However, vaginal
Others (C. tropicalis, C. kefyr, 11
C. africana, S. cereviciae) colonization can alter in individuals from
time to time: in a longitudinal cohort
study with 1248 asymptomatic healthy
chronically recurrent vulvovaginal candi- young women over one year, 70% were
dosis cases (with small differences region- colonized once, but only 4% at all three-
ally), making it the most frequent yeast monthly visits. Recent sexual intercourse,
in these cases [1, 17–18]. There is no evi- injection of medroxyprogesteronacetate
dence (although proven in intensive care and concurrent colonization with lacto-
and hematooncology and thus often men- bacilli and B-streptococci were identified
tioned in gynaecology) for an increase of as risk factors [35]. The sexual partner’s
non-albicans species either in acute or sperm can also be colonized by the identi-
recurrent vaginal candidosis [1, 5, 30]. cal Candida strain as in the vagina [36],
There is evidence for different genotypes despite the partner being free of symp-
of Candida albicans strains in asymp- toms. However, Candida prostatits is a
tomatic women and in those with acute very rare event found only in immuno-
Candida vaginitis [31]. suppressed men [37]. However, the role
of the partner’s genital colonization, or
the orointestinal colonization of both
4. GENITAL COLONISATION partners, as the source of recurrence of
Candida vaginitis is unclear [17]. The
Premenstrual girls and postmenopausal progression from colonization to vagin-
women are less frequently vaginally colitis is not well understood and seems
onized due to the estrogenization of the to underline host factors [38]. Because
915
infection is colonization plus disposition not increase vaginal Candida coloniza-

(“candidosis is illness of the ill”), immu- tion [57] or infection rates [58], but some
nosuppressed people are especially prone results are contradictory [59]. Vaginal
to developing candidosis. However, 75% colonization rates are higher in women
of healthy women develop vaginal candi- with a well estrogenized vagina, espe-
dosis at least once during their lives, and cially in pregnancy. There is up to a 33%
up to 10% suffer more than 4 episodes risk of women who already have vaginal
per year (chronic recurrent vulvovaginal Candida colonization developing Candida
candidosis/CRVVD) [17, 22]. vaginitis after antibiotic treatment
[60–63]. Although vaginal candidosis
often occurs in women with normal lacto-
5. CANDIDA VIRULENCE FACTORS bacillus flora, lower numbers of lacto-
bacilli have been found in women with
The first step from colonization to infec- vaginal candidosis [64]. The possibly
tion is the adherence of a Candida cell to protective role of lactobacilli (or special
the vaginal wall using mannoproteins strains of them) against yeasts is not yet
[39–41]. Aspartate proteinases (SAP 1–10) understood. Sobel stresses the potentially
and proteases mainly secreted from the top underestimated role of sexual behaviour
of germinating pseudomycelia [42–44] are in the recurrence of vaginal candidosis
probably the most important virulence fac- [17], based on repeated infections follow-
tors and these correlate with pathogenic- ing sexual intercourse [60, 65]. Last but
ity [45–46]. Other important virulence not least, genetic factors are responsible
factors are: iron binding from host cells for recurrences, as both mannose-binding
by siderophores [47–48]; the immunosup- lectin gene polymorphisms [66–67] and
pressive mykotoxin gliotoxin of C. albicans the blood group ABO-Lewis non-secre-
[49]; a strong pH-tolerance from 2–11 [50]; tor phenotype [68] have been identified
and enzymes which enable C. albicans to as risk factors. Women with atopy and
survive in macrophages [51]. allergies develop vaginal candidosis more
frequently than others [69] and allergic
phenomena are found to be important in
6. PREDISPOSING HOST FACTORS development of clinical signs, especially
redness and itching [17, 70]. Women with
Candida strains and species differ in a history of recurrent Candida vagin-
pathogenicity and thus candidosis devel- itis express immunologically important
ops due to a combination of Candida vaginal heat shock proteins during the
strain and weak local defence mecha- symptom-free interval [71]. Psychosocial
nisms [52]. Impaired glucose tolerance stress is also an important risk factor for
was found in approximately 25% or more Candida vulvovaginitis [6, 72], as this
of women with CRVVC than in controls may potentially cause immunosuppres-
[53]. Although C. glabrata is less “viru- sion. Conversely, recurrent vaginal can-
lent”, more women with type 2 diabetes didosis may cause psychosocial stress
are colonized than healthy women [21, and have a negative impact on both work
54], which underlines the importance and social life [28, 73].
of host factors. Diabetic patients suffer
from both vaginal candidosis and therapy
failure more frequently, if serum glucose 7. CLINICAL SIGNS
levels are not normalized [55]. Modern
oral contraceptives with low estrogen Due to the estrogen-induced conditions,
levels, which do not significantly influ- premenopausal women usually suffer pri-
ence carbohydrate metabolism [56], do marily from vaginal candidosis (which can
916
extend to the vulva) and postmenopausal 8.1 Necessary/obligate

women only from vulval and/or intercru- Anamnestic questions, a gynaecologi-
ral candidosis. Clinical symptoms typical inspection, pH measurement and
cally occur premenstrually due to higher either 10% potassium hydroxid investi-
sugar levels in the vagina after ovulation gation or saline solution of the vaginal
[18, 60]. In about 90% of patients, pruri- fluid (400fold phase contrast) are essen-
tus is the most typical symptom, but not tial. Budding cells or (pseudo)hyphae
reliable as only 35–40% of women with can only be detected in approximately
itching have Candida vaginitis [25, 74]. 50–80% of patients with vaginal can-
Discharge can vary from thinly-fluent didosis [17, 79]. Unfortunately there is
(often at the beginning of acute vaginal a lack of practice and teaching in many
candidosis), to cottage-cheese-like, to no hospitals and practices around the world
discharge at all [75]. From the clinical [18, 80–81]. However, if no blastospores or
and therapeutical perspective, classifi- (pseudo)hyphae are seen microscopically
cation of vulvovaginal candidosis [17] is or in chronic recurrent or complicated
useful, although in uncomplicated can- cases, then cultural species determination
didosis (pseudo)hyphae are not found is necessary [18, 60, 82–83]. Routine cul-
microscopically in all cases. Symptoms tures are usually not necessary, if yeasts
include vaginal redness, soreness, burn- are found microscopically. The typical
ing, dyspareunia and dysuria. Symptoms culture medium is Sabouraud agar, but
alone do not allow patients or clinicians there are equally sensitive media com-
to confidently distinguish the cause mercially available, e.g. CHROMagar®,
of vaginitis, but a lack of itching and Microstix®-Candida and others. It is pos-
inflammation makes vaginal candido- sible for two different Candida species
sis less likely [74]. In contrast to bacte- to be cultured in one Candida vagin-
rial vaginosis there is no unusual odour. itis, for example C. albicans and C.
The labia minora can be swollen, and glabrata. In such as case, the patient
in recurrent cases burning fissures can is suffering from C. albicans vaginitis.
occur. Dermatologically, vulval candido- After treatment, resistant C. glabrata
sis is divided into three forms: vesiculo- remains in situ, mostly only colonizing
pustulous, eczematoid and follicular [4]. the vagina.
In heavy cases an adherent white layer
of discharge can be seen on the vagi-
8.2 Not effective
nal wall, which can cause bleeding if
removed. C. glabrata vaginitis (usu- Serological tests are not useful for the
ally occuring during the late pre- and diagnosis of vulvovaginal candidosis
perimenopausal decades) [26, 76–78], because low antibody levels are found in
C. parapsilosis vaginitis [28], and (rare) most people with or without vaginal can-
Saccharomyces cerevisiae vaginitis didosis due to intestinal colonization, and
[18, 29] are associated with mild clinical because this superficial vaginal disease
symptoms and complaints. The cervix is does not affect antibody levels.
not infected. (LoE 1b)
9. THERAPY
8. DIAGNOSIS
There are many conventional and alter-
A diagnosis of vaginal candidosis is native therapies [84]. Polyenes form com-
made from a combination of clinical plexes with the ergosterole of the yeast
signs and symptoms and the presence of cell wall and thus alter permeability
yeasts. [85]. Azoles inhibit the transformation of
917
lanosterole to the ergosterole of the yeast itraconazole, or others, is also possible.

cell wall [86]. Ciclopyroxolamine inhibits Vaginal suppositories or vaginal creams
potentially important iron-needing are also available with varying dosages,
enzymes via chelate formation [87]. formulations and treatment durations
Patients prefer oral treatment if they are varying from 1, 3, 6 or 7 days without
asked to choose [88]. toxicity [99]. All mycological and clinical
cure results are equal and range between
9.1 Colonisation approximately 85% after 1–2 weeks and
75% after 4–6 weeks [11, 17, 100–102].
Asymptomatic, vaginally colonized
Cure rates during pregnancy are signifi-
women do not require treatment if they
cantly better with imidazoles than with
are immunocompetent and if there is no
polyenes [12]. If the candidosis involves
chronically recurrent candidosis.
the region of the vulva outside the introi-
tus or inguinal region, a twice daily
9.2 Colonisation during pregnancy antimycotic skin cream for up to 6 days is
Nearly all healthy, mature neonates who recommended. Treatment of the asympto-
have been colonized by Candida during matic sexual partner is of no benefit for
vaginal delivery develop oral thrush and the patient [103–104].
napkin dermatitis within their first year,
with a peak of 10–13% during 2–4 weeks
of life [89–90]. In Germany, prophylac- 9.4 Side effects
tic treatment of asymptomatic vaginal
Candida colonization is recommended All local antimycotics are well tolerated,
during the last weeks of pregnancy in but topical azoles and ciclopyroxolamine
order to protect the baby during vaginal can cause local burning in 1–10% [97,
delivery. This significantly reduces the 101]. Allergic reactions are rare, but
risk of neonatal candidosis to approxi- possible. The oral imidazole ketocona-
mately 2% during the 4th week of life [89, zole can cause side effects in about 5%
91–92]. of patients, e.g. headache and non-viral
A retrospective randomized [93–95] and hepatitis in 1:500000–1000000 gynae-
a prospective randomized [96] study sur- cological patients [105]. The hydrophile
prisingly showed a decrease of preterm fluconazole and the lipophile itraconazole
deliveries after vaginal treatment with cause far fewer side effects due to yeast-
clotrimazole in the first trimester; this selective cytochrome P450-depending
needs further investigation. There are no ergosterole-inhibition, but like ketocon-
teratogenic effects after vaginal clotrimazole they are not recommended during
zole therapy during pregnancy [93]. pregnancy. However, as yet, no neonatal
teratogenecity after therapy during the
first trimester of pregnancy has been
9.3 Acute Candida vulvovaginitis detected [106].
Acute vulvovaginal candidosis can be
treated locally with polyenes (Nystatin,
9.5 Resistance of Candida albicans?
Amphotericin B or Pimaricin), imida-
zoles (clotrimazole, miconazol-nitrate, Although vaginal C. albicans strains
econazole-nitrate, fenticonazole-nitrate, with higher minimum inhibitory con-
sertaconazole-nitrate, tioconazole-nitrate, centrations (MIC) to fluconazole can be
terconazole-nitrate and others,) [17, 97] found[107], cases of azole resistance are
or with ciclopyroxolamine [98]. Oral rare in gynecology [107–108]. Clinical
treatment with the imidazole ketocona- resistance does not correlate to labora-
zole, or better the triazole fluconazole or tory MIC tests and vice versa, a well
918
known problem in medical mycology. dose of 3 ´ 200 mg fluconazole in the first

Therefore, MIC tests are usually not week followed by a decreasing dose main-
recommended [109]. tenance regime (Table 4). They found that
90% of patients were disease-free after 6
months and 77 % disease-free after one
9.6 Non-albicans vaginitis year.
The common vaginal or oral treatments

usually fail in C. glabrata vaginitis. Sobel Table 4 Individualized decreasing – dose maintenance
et al. [109] therefore recommend vaginal fluconazole regime for recurrent vulvovaginal
candidosis [1].
boric acid 600 mg capsules for 14 days,
and Philips [110] recommends ampho-
tericin B ovules. In refractory cases a 2
week course of topical 17% flucytosine is Fluconazole
3 × 200 mg
90% successful [109]. In some countries
boric acid is not allowed and vaginal flu- during
one week
cytosine is not available. In this case, a
daily high dose of 800 mg fluconazole for
2–3 weeks is recommended depending Microscopy
on resistance tests [4, 111]. Recently oral
Culture if not okay
posaconazole 2 ´ 400 mg for 15 days was
recommended due to resistance against Symptoms
fluconazole [112]. C. krusei vaginitis is
resistant to fluconazole and flucytosine,
200 mg once/week
but local clotrimazole, other imidazoles × 8 weeks
or boric acid are mostly successful [27].
As cases are rare, systematic studies are
missing.
Microscopy
Culture if not okay
9.7 Chronically recurrent Candida Symptoms
albicans vulvovaginitis
Since infection is colonization plus dis- 200 mg once/2 weeks
position and no therapy against disposi- × 4 months
tion (immunological local incompetence)
exists, local or oral maintenance thera-
pies to prevent relapse are recommended Microscopy
[5, 113–115]. The results for local clot-
Culture if not okay
rimazole 500 mg, oral ketozonazole 100
mg or fluconazole 150 mg are comparably Symptoms
effective, but recurrence occurs in 50%
of patients shortly after therapy cessa-
200 mg once/month
tion [5, 114]. In a placebo-controlled trial × 6 months
with 387 women randomly assigned 150
mg fluconazole weekly for 6 months, the
proportions of disease-free women after
Microscopy
12 months were 42.9% in the fluconazole
group and 21.9% in the placebo group [5]. Culture if not okay
Donders et al. [1] gave 117 women (with- Symptoms
out a placebo control group) an initial
919
10. DISCUSSION non-conventional management of recur-

rent vulvovaginal candidosis.
There are many questions. Many healthy
women are colonized without complaint:
10.3 Over-the-counter (OTC)
why is the immunological system of the
therapy?
vagina in some women with Candida
prone to recurrent infection or inflamma- Over 80% of treatment for vulvovaginal
tion? Antimycotics are not the solution candidosis with clotrimazole or (in some
and provide only acute relief. countries) fluconazole is in the form of
OTC therapy. However, the hopeful expec-
10.1 Immunological therapies? tation in the early 1990s that patients
would be able to correctly diagnose cand-
There is currently no satisfactory ida vaginitis, is obviously not correct [30,
proven immunotherapy for (chronic 35, 83], as only about 33% of 95 women
recurrent) vaginal candidosis, although who buy vaginal antimycotics are indeed
30 years ago Rosedale and Brown [116] suffering from Candida vaginitis [131].
reported encouraging first results It is therefore only appropriate to treat
with hypersensitation. In vitro stud- after a correct diagnosis.
ies using both the autologous mem-
brane bound C. albicans antigen and
T-Lymphozytes of a chronic recurrent C. 11. FURTHER RESEARCH
albicans vaginitis patient, showed bet-
ter immunological reactions than with
There are a lot of holes in our knowledge
commercially available Candida anti-
of Candida host interactions which need
gens [117]. Meanwhile, Rigg et al. [118]
further research. How can Candida viru-
has reported on Candida allergen ther-
lence factors (aspartate proteases and oth-
apy and Moraes et al. [119] and Rusch
ers) be weakened? How can adhesion to
and Schwiertz [120] have reported first
vaginal epithelial cells be inhibited? How
clinical results with Candida autovac-
can host resistance be improved? (T-cell-
cination. Antibodies against aspartyl-
stimulation? Humoral factors? Allergy?) Is
proteases, adhesins or allergen therapy
a vaccination against Candida possible?
could potentially play a role in future
Which new antimycotics are able to
[121]. However, a therapeutical break-
treat C. glabrata or C. krusei vaginitis?
through does not currently exist despite
multiple efforts to understand the
immunopathogenesis of Candida vagin-
itis [38, 43, 67, 69, 73, 121–125]. 12. CONCLUSIONS
Vulvovaginal candidosis is, in the major-

10.2 Lactobacilli? Alternatives?
ity of cases, an acute and uncomplicated
Intramuscular injections of non-H2O2- local infection of the estrogenized vagina,
producing lactobacilli to induce antibodies and in over 80% of cases is caused by cC.
[73] and probiotics [126–129] have shown albicans. Non albicans species arise in
encouraging but controversial results, higher frequency (especially C. glabrata)
which need further investigation. in postmenopausal women and in women
Watson and Calabretto [130] have com- with immunosuppression or diabetes
plained about the lack of randomized con- mellitus. Whilst yeast-host interactions
trolled trials for both conventional and remain unclear, the cure for chronically
920
recurrent vaginal candidosis will con- vaginal candidiasis. Genitourin Med,

tinue to be a challenge. 1992. 68(6): 374–7.
8. Quereux C, Gelas B, Chevallier T, Petit F,
and Micheletti MC, [Evaluation of the effi-
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927
|15.7|
Viral genitourinary infections

Laurent Vaucher1,2,3, Darius A. Paduch1,2
1
Department of Urology, Weill Cornell Medical College, New York, NY 10021, USA
2
The Population Council, Center for Biomedical Research, New York, NY 10021, USA
3
Department of Urology, CHUV, Lausanne CH-1011, Switzerland
Corresponding author’s address: Darius A. Paduch, MD, PhD, Assistant Professor of Urology, Assistant Professor of
Reproductive Medicine, Staff Scientist, CBR, Department of Urology, Weill Cornell Medical College,
525 East 68th St.ST-924A, New York, NY 10021
Tel: 212-746-5309, Fax: 212-746-7287, E-mail: darius.paduch@mac.com
ABSTRACT 18 is modifying the prevention and the

approach of this viral infection. Herpes
In immunocompetent hosts, viruses are simplex is also a common cause for geni-
an uncommon cause of urinary tract tal ulcers; treatment depends on host age,
infections (UTI’s). However, in immuno- as well as immune and serological status.
compromised patients, they are increas- Key words: urinary tract infection, gen-
ingly recognized as the cause of UTI’s, ital infection, virus, human polyomavi-
especially hemorrhagic cystitis (HC). rus, adenovirus, CMV, hantavirus, herpes
The diagnosis of viral lower UTI, based virus, HPV.
on molecular techniques and real time
PCR, is often the method of choice since it
allows for quantification of viral load. BK SUMMARY OF RECOMMENDATIONS
virus, adenovirus, and CMV are the pre-
dominant pathogens involved in HC after Urinary tract infections
stem cell and solid organ transplantation,
and their early diagnosis and treatment 1. Human polyomavirus (BKV) and
may prevent significant morbidity of HC. Adenoviruses: Treatment of BKV
Viruses are also responsible for geni- infection and its urological complica-
tal cutaneous or mucosal lesions and tions focus on supportive measures
ulcerations. HPV is the most commonly and reduction in immunosuppression
diagnosed sexually transmitted infec- (GoR A). Presently, no controlled tri-
tion. The recent availability of vaccine als have demonstrated any benefits of
preparations against HPV 6, 11, 16, and antiviral agents in these infections.
Viral genitourinary infections | 15.7 |
2. Cytomegalovirus (CMV): Universal case of HPV or HSV presence of infection

prophylaxis and preemptive strategies in sexual partner. For didactic purposes,
are beneficial in preventing CMV infec- we will divide all GU-related viral infec-
tions and related complications in solid tions into two major categories based on
organ transplant recipients (GoR A). predominant presentation: urinary tract
3. Hantaviruses: There are no accepted infections and dermatological lesions.
antiviral therapies for Hantavirus
infections. Because of high mortal- 2. METHODS
ity, prevention of transmission from
rodents to humans, and increased
As viral infections in the genitourinary
awarness will be critical in controling
tract also include HIV and immunosup-
this emerging viral infection.
pression related infections, which are
treated in a different section of this book,
Dermatological lesions the authors selected the six major viral
4. Herpes simplex viruses (HSV): Among pathogens (Human polyoma virus [BKV],
patients with a primary episode of Adenovirus, CMV, Hantaviruses, Herpes
genital HSV, antiviral therapy is rec- simplex virus and Human Papilloma
ommended (GoR A). Suppressive treat- virus) responsible for urogenital infec-
ment with oral Famciclovir extends tions, based on a PubMed search using
the time between symptomatic out- the terms: virus, viral and urinary infec-
breaks in patients with frequent tion. A systematic review of published
recurrences of genital herpes (GoR A). literature, beginning in 1980, using
PubMed and Scopus was performed,
5. Human papiloma virus (HPV): using as key words urinary tract infection
Quadrivalent and bivalent HPV vac- and genital infection associated with each
cines demonstrate efficacy in pre- of the pathogens. Limitations used were
venting incident and persistent HPV English language, human and abstract
infection (GoR A). Indications, and available. 211 Publications were found.
risk to benefits ratio of systematic The publications were screened by title
immunization with HPV vaccine and abstract and 48 were included into
for women and men is still under this review.
investigation. The studies were rated according to the
1. INTRODUCTION recommendation (GoR) using ICUD
Viral infections of the genito-urinary (GU)
system can manifest as a GU tract infec- 3. URINARY TRACT INFECTIONS
tion (fever, dysuria, pain, hematuria),
and/or genital cutaneous/mucosal lesions
3.1 Introduction
and ulcerations. Depending on most
likely infectious organism, predominant Urinary tract infections (UTI) due to bac-
presentation (localized v. generalized teria are commonly seen in urological
infection), age of patient, involvment of practices, but viral pathogens, which can
other than GU systemts (like pulmonary also cause UTI, are less often encountered.
system in hemorrhagic fever), and hosts One of the main differences between bac-
immune defense status, initial diagnos- terial and viral pathogens affecting the
tic and therapeutic approaches may be urinary tract is that no bacteria should
quite different and have to be individu- be found in the urine of healthy persons,
alized based on clinical picture and as in especially in men; the same cannot be
929
assumed with viruses. Some of them, like quick demise of the patient. This scenario
the BK virus, can be found in healthy indi- is almost never seen in healthy patients
viduals. The other difference is the ability with a normal immune system.
of some viruses to integrate into the host
genome, often indefinitely, leading to reac-
3.2 Symptoms and signs
tivation and delayed symptomatology;
although some bacteria, like tuberculosis, The typical symptomatology of lower UTI
can persist in the host in dormant state (dysuria, frequency, urgency, and lack of
for a long time; this is rather an excep- high-grade fever) may be altered by the
tion. Hence viral infection is defined as immune status of the host. Gross hematu-
the presence of an identifiable viral organ- ria, fever and malaise are seen more com-
ism and of symptoms due to an inflamma- monly in immunocompromised patients.
tory response. The presentation, as well as The symptom most commonly presented
the natural history of viral UTI, depends with viral UTI is hemorrhagic cystitis
on existing anatomical abnormalities, and (HC). Less commonly seen are irritative
most importantly on the immune status of bladder symptoms such as frequency of
the host. urination and pelvic pain. In the recent
With the emergence of new chemothera- past, HC was considered a direct result of
peutic agents, immune modulators, and chemotherapy. However, with improved
immunosuppressants to treat systemic methods of viral detection, it became
diseases or prevent graft rejection, the clear that viruses are commonly identi-
number of immunocompromised patients is fied in urine and most likely are respon-
increasing accordingly, and may be responsible for HC. In a prospective study of
sible for the increased prevalence of viral- over 100 children who underwent bone
related disorders of the GU tract (Table 1). marrow transplant, hemorrhagic cystitis
Dissemeninated viral UTI in immunocom- occurred in 25.5% of patients, and a viral
promised patients, often associated with cause was identified in over 95% of them
viremia, can quickly lead to multiorgan [3]. As bacteria still causes the majority
viral infections, multiorgan failure, and the of UTI’s, bacteriological cultures have to
Table 1 Syndromes and conditions associated with increased risk of viral urinary tract infection.
Condition Mechanism of increased risk to viral infections
Bone marrow transplantation immunosuppression and chemical bladder irritation
Solid organ transplantation immunosuppression
Hematopoietic malignancies abnormal function of immune system, immunosuppression
Chemotherapy for malignancies myelosuppression, chemical bladder damage
HIV infection; immunosuppression abnormal function of immune system
Congenital immunodeficiency abnormal function of immune system
Wiskott-Aldrich syndrome abnormal function of immune system
Wegener’s granulomatosis abnormal function of immune system
Rheumatologic diseases and their treatment immunosuppression
Pregnancy abnormal function of immune system, changed hormonal status
Diabetes, alcoholism, malnutrition, liver cirrhosis abnormal function of immune system
930
be obtained in every patient. However, in under a fluorescent microscope by second-

patients not improving clinically despite ary antibodies coupled with fluorochrome
antibiotic treatment, or in patients with a [5]. This method is relatively simple and
compromised immunity, viral UTI has to fast, but is not quantitative and cannot be
be strongly considered. used for viruses with genomic instability
and rapidly changing antigens.
3.3 Diagnosis of Viral UTI
3.3.2 ELISA – enzyme linked
Diagnosis of viral UTI is challenging since
immunosorbent assay – and
viruses cannot be visualized with even
competitive ELISA
the best optical microscope, and viral cul-
tures may take up to 14 to 28 days, delay- The enzyme-linked immunosorbent assay
ing the treatment accordingly. Molecular (ELISA) and competitive ELISA are used
and immunofluorescence techniques are to detect viral antigens and antibodies
therefore frequently used nowadays. The against the viruses in a specimen. The
reliability of diagnosis depends on an ade- sample is set on a styrene plate with an
quate technique obtaining and transport- antibody against a specific antigen, and
ing the specimen, as well as on method of a fluorochrome-coupled secondary anti-
detection. These methods include: body is applied with chemiluminescence
or colorimetric detection reagents. In
Culture competitive ELISA, a “tracer” antigen of
Viruses live in the host cells, and the pres- known concentration competes with the
ence of some viruses (CMV, BKV) may be specimen antigen for a set number of
suspected by characteristic changes on binding sites, which allows quantitative
urine cytology [4]. Otherwise, the virus detection. ELISA is a relatively simple
has to be grown in a culture, determining and fast technique, and is often used in
the type of virus based on characteristic automatic assays; however, small changes
cytopathological changes of the cell culture in the volumes of reagents affecting the
inoculated with the specimen. This diag- results (pipetting error) and contamina-
nostic method is cumbersome and prone to tion between different runs of the assay
false negative results, and not all viruses are known problems. The ELISA method
can be cultured (hepatitis viruses, parvo- can also detect changes in titers of anti-
virus, human papillomavirus, etc.). Since bodies against a known pathogen. Since
each of these viruses require a specific the development of antibodies against a
cell line, media and method of detection, virus takes time, and the use of an immu-
it is important to provide adequate clini- nosuppressant may modulate immune
cal information and to be specific about response, the lack or presence of anti-
the type of virus to be detected. However, bodies may not exclude or confirm cur-
due to the cost and time required for diag- rent infection. This is especially true in
nosis using cultures, most laboratories viruses with a high prevalence among
have shifted to other techniques, which the immunocompetent population such
can be divided into methods which detect as HSV (17% in USA), CMV (>60%), and
the presence of a pathogen (antigen), and BKV (>90%) [6].
methods which detect the genetic material
(DNA or RNA) of the virus. 3.3.3 Genomic amplification;
quantitative or qualitative
3.3.1 Direct immunofluorescence Due to problems with the detection of anti-
of organism bodies, and the fact that many viruses are
In bodily fluid or cells, antibodies against a present in immunocompetent hosts, the
specific antigen is used, and then detected current state-of-the-art detection methods
931
are based on molecular techniques [7]. 3.4.1 Human polyoma virus (BKV)
Those techniques use PCR, which allows BKV, a double strand DNA virus, is ubiqui-
specific and fast amplification of small tous in the human population, and approx-
regions of the viral genome. Since the imately 97% of adults have antibodies
genome of most clinically important against BKV [6]. Infection with BKV prob-
viruses are known, it is relatively easy to ably occurs early in life, and is asympto-
amplify viral DNA or RNA, and to detect matic or is associated with fever and mild
amplicon by gel electrophoresis, chroma- upper respiratory symptoms. It is hypoth-
tography or real time PCR. Although PCR esized that primary infection viremia
is a very sensitive diagnostic method, its results in seeding in uroepithelial cells [9].
sensitivity is also one of its drawbacks. Viral infection is reactivated during peri-
First of all, the genomes of viruses are not ods of immunosuppression, causing hem-
stable, and even a single change in the orrhagic cystitis, interstitial nephritis or
nucleotide sequence can affect the bind- urethral stenosis. Polyomavirus-associated
ing of primers, resulting in a false nega- nephropathy (PVAN) is an emerging cause
tive result. Furthermore, viruses occur in of kidney transplant failure, effecting
multiple genotypes (i.e. HPV or adenovi- 1–10% of patients [10]. Late-onset hemor-
rus) and a single assay is often not able rhagic cystitis of long duration (> 7 days)
to detect them all. Since the PCR reaction after hematopoietic stem-cell transplanta-
produces millions of copies of viral DNA tion (HSCT) is associated with BKV infec-
“amplicon”, it is very easy to obtain false tion in 55% cases [11].
positive results from airborne amplicon
contamination. The real time PCR, which 3.4.1.1 Diagnosis
eliminates the transfer of amplified prod- BKV infection should be suspected in
uct to the gel, avoids many of the contam- immunodeficient patients who present
ination problems, and therefore became a with haematuria (micro- to gross hae-
method of choice for molecular detection maturia), hydronephrosis and increased
of clinically important viruses. Real time creatinemia. Urine cytology can be indic-
PCR also allows relative or absolute quan- ative of BKV infection by identifying so
tification of viral load, which is especially called “decoy” cells; however, the sensi-
usefull in monitoring response to therapy. tivity of this method is low. High grade
TCC can be difficult to distinguish from
BKV on cytology, and cytology follow-up
3.4 Most common viral pathogens may be considered in patients with risk
causing UTI factors for TCC [12]. Because of the high
Since viruses with extremely different prevalence of positive antibodies in the
genomes and biology may cause simi- serum, and a lack of reliable viral cell
lar diseases, the classification of clini- cultures, the diagnosis of BKV infection
cally important viruses becomes difficult. requires molecular techniques. Real time
The most commonly used classification PCR quantification of viral loads has a
is called Baltimore classification, and significant prognostic value in predicting
divides viruses into seven groups based clinical outcomes [13], and can be used to
on the nucleic acid of their genome (DNA monitor response to therapy. Recipients
or RNA) and subsequently based on bio- of a renal transplant may also have BKV-
chemical properties (single or double associated graft dysfunction, however
strand, etc.) (Table 2). Basic knowledge because of high prevalence of BKV sero-
of viral classification is useful since the conversion in general population, 2005
majority of antiviral drugs are active Consensus conference stated that allo-
against viruses with similar biochemical graft biopsy is mandatory to confirm BKV
and molecular properties [8]. nephropathy [10].
932
Table 2 Baltimore classification of viruses.
Group I: double-stranded DNA: Adenoviruses, Herpesviruses, Human Papilloma Virus, Polyoma viruses
(BKV), smallpox, molluscum contagiosum virus
Group II: single-stranded DNA: Parvoviruses (parvovirus B19)
Group III: double-stranded RNA: Reoviruses, Birnaviruses (rotaviruses)
Group IV: positive-sense single-stranded RNA: Picornaviruses; Togaviruses (coronavirus, SARS, West Nile virus, hepatitis
A, E, and C, rubella virus, polio virus)
Group V: negative-sense single-stranded RNA: Orthomyxoviruses, Rhabdoviruses (influenza, mumps, measles viruses,
rabies virus)
Group VI: reverse-transcribing RNA: Retroviruses (HIV-1, AMV, M-MLV)
Group VII: reverse-transcribing DNA: Hepadnaviruses (hepatitis B virus)
AMV – avian myeloblastosis virus; BKV – BK virus; HIV-1 – human immunodeficiency virus type 1; JCV – JC virus; M-MLV – Moloney murine leukemia
virus; SARS – Severe Acute Respirtory Syndrome.
Baltimore classification is based on genomic methods of replication and has been created by Dr. David Baltimore.
3.4.1.2 Treatment there are no reports on treatment of

Until recently, the treatment of BKV BKV-associated HC in HSCT.
infection, and its urological complications, The standard use of these treatments
focused primarily on supportive meas- needs, however, to be further addressed
ures (i.e. hydration, analgesia, correction in randomized, multicentre trials. One
of coagulopathy, bladder irrigation) and non-randomized clinical trial showed that
reduction in immunosuppression [14] ciprofloxacin prophylaxis decreased the
(LoE 1b). More recently, antiviral therapy viral load of BKV viruria in adult patients
has been considered, especially in those with HSCT, as compared to cephalosporin
with renal allograft dysfunction, despite (LoE 2b). The mechanism of this finding
immunosuppressive therapy decrease. is unclear [19]. It is important to remem-
Antiviral agents include: ber that BKV may be associated with
• Intravenous Immune Globulin (IVIG), increased risk of bladder cancer, and follow
which has immunomodulatory proper- up with cytological studies once hematuria
ties and contains polyomavirus-reactive resolves may be indicated [20] (LoE 3).
antibodies. Favorable treatment out-
come was reported in 88% of patients 3.4.2 Adenoviruses
with BKV nephropathy [15].
Adenoviruses (AdV) are double strand
• Cidofovir, despite moderate in-vitro DNA viruses with at least 51 serological
activity against polyomaviruses, has subtypes, and are known to cause upper
shown efficiency in treating hemat- respiratory, GI and conjunctival infections
opoietic stem-cell transplantation- in healthy people and children. However,
related HC [16]. Due to nephrotoxicity, a variety of clinical symptoms, including
intravesical instillation represents genito-urinary tract infection, can occur in
an acceptable alternative [17]. Use of immunocompromised patients with AdV
Cidofovir in BKV-related nephropa- infection; among these, hemorrhagic cys-
thy is not FDA approved and consid- titis is the most common clinical presen-
ered an off label use and still under tation. The adenoviral infections are more
investigation. common in stem-cell transplantation and
• Leflunomide has shown efficacy in solid organ transplants [21]. Children,
treating BKV nephropathy [18], but recipients of allogeneic versus autogeneic
933
stem-cell graft, and patients with graft ver- • Ribavirin and Vidarabine have rela-
sus host disease (GVHD) are much more tively poor activity against AdV in-
prone to adenoviral diseases, which is a vitro [25], but have been successfully
reflection of the more pronounced immuno- used in the treatment of hemorrhagic
suppression used in the above conditions. cystitis and may be a viable alterna-
tive to Cidofovir (LoE 3).
3.4.2.1 Diagnosis • Ganciclovir is mostly used for the pre-
Infection with adenovirus is defined as vention of CMV infection, however, it
the presence of the virus in culture, the has also been used in the treatment
presence of viral antigens by immunoflu- of hemorrhagic cystitis in transplant
orescence, or the presence of AdV DNA patients [26].
by PCR, irrespective of symptoms. The
diagnosis using molecular techniques is
3.4.3 CMV
faster since the culture can take up to 21
days. AdV is never present in the urine of Cytomagalovirus (CMV) infection is com-
healthy individuals, and the detection of mon (>60 % adults are seropositive) and
AdV in the urine of patients with HC is like other members of the Herpes virus
pathognomic of adenoviral cystitis [22]. family, CMV establishes latent infection
Since adenoviral infection can coexist after the resolution of acute infection.
with Aspergillosis and CMV in immuno- CMV reactivation, or new infection, is one
compromised patients, multiviral cultures of the most important infections in renal
should be obtained. transplant [27] patients; it is a rare cause
of lower UTI’s, however, evidence sup-
3.4.2.2 Treatment ports association between CMV and HC
Adenoviral infections are associated with [28]. Although very rare, CMV cystitis
significant mortality and morbidity, and can occur in immunocompetent patients
some have advocated preemptive treat- [29]. CMV is also believed to cause uret-
ment in immunocompromised patients if eritis and ureteral stenosis [30].
AdV can be detected in the blood by PCR
[23] (LoE 3). However, at this time, no 3.4.3.1 Diagnosis
consensus exists regarding the treatment CMV can be detected by seroconversion
of asymptomatic patients with detectable in negative hosts, and by an increase in
adenoviremia. Adenoviral HC is usually IgM and IgG antibody titers in previ-
self-limiting. As for other serious infec- ously seropositive patients [31], however,
tions in immunocompromised patients, molecular amplification of CM antigen
supportive measures and reduced immu- (pp65), RNA or DNA is now more com-
notherapy are the cornerstone of treat- monly used [32]. As the comparison of
ment. Presently, no controlled trials have quantitative results obtained using dif-
demonstrated any benefits of antiviral ferent techniques is not possible, it is
agents in human adenoviral disease. important to use the same test method
• Cidofovir is the most commonly used when monitoring changes of viral load in
treatment of adenoviral infections. A patients over time.
lower dose (1 mg/kg three times a week
for three weeks) is used in renal trans- 3.4.3.2 Treatment
plant patients because of concerns of Prophylaxis and preemptive strategies
nephrotoxicity, but this regiment fails are beneficial in preventing CMV organ
to prevent HSV or CMV infections and disease in solid organ transplant recipi-
a higher dose (iv or intravesical) may ents (LoE 1a). Most patients receive
be a better choice [24]. prophylaxis with gancyclovir, however, in
934
active disease, other agents like Foscarnet rheumatologic disorders [38]. Recurrent
can be used [33]. Cidofovir is active episodes are usually shorter and less
against both BKV and CMV and may severe.
become the drug of choice in patients who
present with hemorrhagic cystitis after 4.1.1 Diagnosis
solid organ or bone marrow transplant. Diagnosis is relatively easy since HSV
can be detected by cell culture (active
3.4.4 Hantavirus
lesion) or by serology (non-active lesion).
Hantavirus causes two major forms of Direct immunofluorescence and PCR are
disease, depending on virus subtype: alternative methods [39].
hemorrhagic fever with renal syndrome
(HFRS) and hantavirus cardiopulmonary 4.1.2 Treatment
syndrome [34]. Infections occur in sea-
HSV infection treatment depends on
sonal outbreaks; Hantavirus is carried by
host age, immune and serological status.
rodents and transmitted to humans via
Among patients with a primary episode
inhalation of aerosolized excreta. Renal
of general HSV, antiviral therapy is rec-
manifestations vary depending on the
ommended (LoE 1a). Acyclovir or valacy-
type of hantavirus; the European form
clovir are commonly used in symptomatic
causes fever and mild renal failure [35],
subjects with primary infection (Table 3).
whereas manifestations due to the Asian
Suppressive treatment with oral famciclo-
strain are more severe, potentially lead-
vir extends the time between symptomatic
ing to renal failure and requiring dialysis.
outbreaks in patients with frequent recur-
Diagnosis is made with a serologic test.
rences of genital herpes [40] (LoE 1b).
There are no accepted antiviral thera-
Routine screening for HSV-1 or HSV-2
pies, and therapy is therefore restricted
infection by serologic testing is not recom-
to supportive care.
mended [41].
4. DERMATOLOGICAL LESIONS 4.2 HPV

HPV has a worldwide prevalence of
4.1 Herpes simplex
approximately 10% [42] and it is the most
Herpes simplex virus (HSV) infection is commonly diagnosed sexually transmitted
a common cause of genital ulcers world- infection (STI). It is associated with con-
wide. Although HSV-2 remains the main dyloma acuminatum, squamous intraepi-
causative agent, HSV-1 is associated with thelial lesions and anogenital malignancy,
an increasing proportion of cases of geni- including cervical, vaginal, vulvar, penile,
tal herpes [36]. Infection, resulting in and anal carcinoma, as well as some
varying clinical manifestations, can be of oropharyngeal squamous cell cancers.
primary, non-primary (infection with HSV Risk factors for acquiring HPV include
in a patient seropositive for the alternate multiple sexual partners, early age of
type) or of recurrent type. Primary infec- onset of sexual intercourse, and having a
tions are usually the most severe, with sexual partner with HPV.
multiple painful ulcerating vesicular Human papillomaviruses are small,
lesions, inguinal adenopathia and consti- non-enveloped DNA viruses infecting
tutional symptoms, resolving in a mean of basal epithelial cells by entering the
19 days [37]; urinary retention and HSV nucleus. Their life cycle is integrally
cystitis can occur in immunocompetent linked to keratinocyte maturation. Most
patients who have some other predispos- people who are infected with HPV have
ing factors such as diabetes mellitus or no signs or symptoms and approximately
935
936
Chapter
Table 3 Common antivirals in urologic practice: spectrum, use, and therapeutic implications.
| 15 |
Name, function Viral activity FDA-approved use Typical dose Comments
Acyclovir, inhibits viral DNA HSV-1, HSV-2 herpes simiae, Genital HSV: primary, acute 200 mg PO 5x/d 10 d Adjust for renal and liver function;
polymerase and incorporates VZV; acyclovir is more contraindicated with cidofovir
Genital HSV, recurrent 400 mg PO 3x/d 5 d
into viral DNA active against HSV-1 than HSV-2 (increased risk of nephrotoxicity);
than VZV, respectively; potential Genital HSV, suppression 400 mg PO 2x/d 12 mo* avoid aminoglycosides,
activity against EBV clofarabine, and gallium nitrate
Herpes zoster 800 mg PO 5x/d 10 d
HSV encephalitis 10 mg/kg IV 3x/d 10 d
Varicella, primary 800 mg PO 4x/d 5 d
Famcilovir, inhibits DNA HSV-1 and HSV-2, VZV; limited Herpes zoster 500 mg PO 3x/d 7 d Adjust for renal function; monitor
polymerase activity against EBV and HBV digoxin levels if used together;
Genital HSV primary 250 mg PO 3x/d 10 d
may increase digoxin level
Special urogenital infections
Genital HSV recurrent 125 mg PO 2x/d 5 d

Genital HSV suppression 125 mg PO 2x/d 12 mo*
Valacyclovir, inhibits DNA HSV-1 and HSV-2, VZV Genital herpes, primary 1000 mg PO 2x/dx10 d Adjust for renal function;
polymerase adequate hydration; avoid
Genital herpes, recurrent 500 mg PO 2x/d 3 d
carboplatin, cimetidine, entecavir,
Genital herpes, suppression 500-1000 mg 1x/d 12 mo* and phenytoins
Reducing transmission in 500 mg PO QD together with safe

discordant couples sex practices
Herpes zoster 1000 mg PO 3x/d 7 d
Ganciclovir, inhibits DNA CMV, HSV-1, HSV-2, EBV, VZV; CMV: prophylaxis, transplantation 5 mg/kg IV Q12 h x7–14 d then Granulocytopenia; anemia;
polymerase very active against CMV and HSV; 5 mg/kg IV Q24 h thrombocytopenia; carcinogenic
requires intracellular conversion to and teratogenic in animal studies;
1000 mg PO 3x/d
triphosphate causes azoospermia; adjust
CMV prophylaxis, HIV-related 1000 mg PO 3x/d” for renal function; do not
use with cidofovir; multiple drug
CMV retinitis 5 mg/kg IV Q12h 14–21 d interactions and adverse effects
Foscarnet, selectively inhibits viral CMV, HSV-1, HSV-2, EBV, VZV, CMV retinitis in AIDS 90 mg/kg IV Q12h 3 wk then Renal toxicity: severe seizures (cip-
DNA polymerase, reverse tran- herpes virus-6; limited data on Q24h rofloxacin [contraindicated]); exac-
scriptase inhibitor activity for hepatitis B and HIV erbates electrolyte abnormalities;
HSV and VZV infections mucocu- 40 mg/kg IV Q12h 3 wk multiple drug interactions; adjust
taneous, resistant to other agents for renal function
Cidofovir, active intracellular CMV, adenovirus, HSV-1 and CMV 5 mg/kg IV Q7d for 14 d then Acute renal failure; death; highly
metabolite – cidofovir diphos- HSV-2, VZV, EBV, BKV 5 mg/kg IV Q14 d, nephrotoxic and concomitant
phate – inhibits viral polymerase use probenecid before injection use of nephrotoxic drugs to be
1–2 gm avoided; hydrate well; probenecid
prevents nephrotoxicity
Imiquimod (Aldara®)Immune HPV, pox virus HPV 1x/d bedtime 3d/we intil lesion is non specific inflammation,
modulator, Enhance T-cell activity gone, max 16 we dermatitis
Podophyllotoxin antimitotic action HPV (anogenital wart) HPV (anogenital wart) 10–25% solution during 1–4 transient burning, erythema,
hours/d 3x/we tenderness, abdominal pain and
cerebral toxicity reported
Gardasil® vaccine HPV 16, 18, 6, 11 Female 9–26 years to prevent HPV 3 IM injections (month 0, 1, 6) local reaction at injection site
16, 18, 6, 11
Cervarix® vaccine HPV 16, 18 (31, 45) not approved yet (approved in 3 IM injections (month 0, 1, 6) local reaction at injection site
Europe Union)
CMV – cytomegalovirus; HSV-1 – herpes simplex virus type-1; HSV-2 – herpes simplex virus type-2; IM – intramuscular; IV – intravenous; PO – by mouth; Q – every; VZV – herpes varicella-zoster virus; we – week.
*suppressive treatment should be discontineud for one or two month after one year, to reassess the frequency of recurrence.
The treating physician should be familiar with multiple drug interactions and labeling for each drug because many of the antiviral drugs have well-proven teratogenic and reproductive side effects in animals.
Viral genitourinary infections
937
| 15.7 |
75% to 90% of HPV infections will clear prevention of HPV infection. Two vac-
up within two years of the initial infec- cines are now available: the bivalent HPV
tion [43–44]. In 10% to 20% of patients, 16/18 VLP vaccine (Cervarix®), and the
however, the infection persists. quadrivalent HPV 6/11/16/18 VLP vac-
There are more than 100 types of HPV; cine (Gardasil®). Both demonstrate effi-
over 30 types can infect the genital area. cacy against incident and persistent HPV
Genital or anal warts (condyloma acu- infection and abnormal histology (LoE
minata) are the most recognized sign of 1a). It is estimated that HPV protection
genital HPV infection, mostly caused by with the bivalent or quadrivalent vaccine
types 6 and 11. Infection with high-risk would prevent as much as 70% of all cer-
types, including HPV 16 and 18, may vical cancers. The quadrivalent vaccine
lead to high-grade lesions and eventually would also prevent most genital warts
anogenital malignancies. [43]. With both vaccines, it is important
to be vaccinated before becoming sexu-
4.2.1 Diagnosis ally active, since the vaccine most likely
Diagnosis of HPV infection is made by does not eliminate HPV infection after
clinical examination. After application it has occurred. Immunization for men
of acetic acid 3%-5%, lesions develop a is still under investigation. Female vac-
characteristic acetowhite appearance, cination has proven to be cost effective
resulting from cytokeratins coagulation. as compared to Pap smear screening, at
Biopsy is recommended in atypical cases, least in the 46 richest countries [47]. It
or when the benign nature of the lesion will, however, not replace the need for
is unclear. Molecular detection meth- preventive strategies, such as cervical
ods (PCR, Hybrid capture assay) allows screening. Since HPV infection in men
HPV detection; it has been suggested in contributes to cervical disease in women,
optimal follow-up of women with atypical vaccinating both men and women is pre-
squamous cells of undetermined signifi- dicted to be more beneficial than vacci-
cance (ASCUS) [45]. No indications have nating women only [48]. Whether boys
been yet described for men. and men routinely receive the HPV vac-
cine will depend primarily on efficacy and
4.2.2 Treatment cost effectiveness [49]. Because a quanti-
fiable clinical endpoint is more difficult to
Podophyllotoxin is a mitotic poison define in males than in females (i.e. geni-
applied on an every-other-day basis for tal HPV infection), it will be difficult in
three weeks. Imiquimod (Aldara®) is an the near future to define efficacy of vac-
immune modulator, applied three times cination in males.
a week; treatment is continued until the
lesions clear, or for a maximum of 16
weeks. A number of surgical options exist 5. FURTHER RESEARCH
for the treatment of anogenital warts
including cryotherapy, laser therapy, elec- As described previously, Polyomavirus
trosurgery, and surgical excision BK-associated nephropathy (PVAN) is an
emerging cause of early renal transplant
4.2.3 Prevention failure. To date, no antiviral agent has
While the efficacy of condoms in prevent- demonstrated any proven benefits. Further
ing HPV infection is unknown, condom research is needed to learn more about
use has been associated with a lower the cellular response to BK virus in graft
rate of HPV infection [46]. The recent recipients. This will help to develop new
availability of a vaccine preparation has strategies for the treatment of graft rejec-
dramatically altered the approach to tion due to viral infections. New antiviral
938
therapies with proven efficacy and safety main steps for developing and grading
are also under investigation for patients guideline recommendations. Prog Urol,
with progressive allograft dysfunction, 2007. 17(3): 681–4.
despite decreased immunosuppressive 3. Gorczynska E, Turkiewicz D, Rybka K,
therapy. Research in HPV will focus on a Toporski J, Kalwak K, Dyla A, Szczyra Z,
better understanding of disease transmis- and Chybicka A, Incidence, clinical out-
come, and management of virus-induced
sion, and on the efficacy and cost-effective-
hemorrhagic cystitis in children and
ness of male and female immunization. adolescents after allogeneic hematopoietic
The effect of circumcision in disease trans- cell transplantation. Biol Blood Marrow
mission is currently under investigation. Transplant, 2005. 11(10): 797–804.
One can’t forget that viruses are able to 4. Boldorini R, Brustia M, Veggiani C, Barco
adapt and change not only their nucleic D, Andorno S, and Monga G, Periodic
sequence making detetion more compli- assessment of urine and serum by cytology
cated, but they can overcome differences and molecular biology as a diagnostic tool
in host biology much better than any for BK virus nephropathy in renal trans-
other microorganism. As most of us stud- plant patients. Acta Cytol, 2005. 49(3):
ing virology two decades ago would teach 235–43.
that that certain viral disorders never 5. Hogan TF, Padgett BL, Walker DL,
occur in humans, same can’t be assumed Borden EC, and McBain JA, Rapid detec-
today, as each year a new virus believed tion and identification of JC virus and BK
virus in human urine by using immun-
to infect only rodents, is discovered to
ofluorescence microscopy. J Clin Microbiol,
cause clinically signicant and very often
1980. 11(2): 178–83.
letal infection in humans (for example
6. Zhong S, Randhawa PS, Ikegaya H,
Lujo virus was identified in 2009). Thus Chen Q, Zheng HY, Suzuki M, Takeuchi
only through increase in research and T, Shibuya A, Kitamura T, and Yogo Y,
awarness of microbiology and pathology Distribution patterns of BK polyomavirus
of GU important viruses, will be be able (BKV) subtypes and subgroups in American,
to serve our patients the best. European and Asian populations suggest
co-migration of BKV and the human race.
J Gen Virol, 2009. 90(Pt 1): 144–52.
6. CONCLUSIONS 7. Schmutzhard J, Merete Riedel H,
Zweygberg Wirgart B, and Grillner L,
As urologists, we need to include the Detection of herpes simplex virus type 1,
most recent developments in GU virology herpes simplex virus type 2 and varicella-
zoster virus in skin lesions. Comparison
in our practices, since knowledge of viral
of real-time PCR, nested PCR and virus
biology and clinical pathology may pre- isolation. J Clin Virol, 2004. 29(2): 120–6.
vent viral transmission (HSV and HPV),
8. Paduch DA, Viral lower urinary tract
and early management of viral infections infections. Curr Urol Rep, 2007. 8(4):
may decrease mortality in immunocom- 324–35.
promised patients. 9. Arthur RR and Shah KV, Occurrence and
significance of papovaviruses BK and JC
in the urine. Prog Med Virol, 1989. 36:
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942
|15.8|
Genitourinary schistosomiasis
Ismail M. Khalaf1, Ahmed A. Shokeir2
1
Professor of Urology, Al-Azhar Faculty of Medicine, Cairo Egypt
2
Professor of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
Correspondence: Ismail Khalaf, MD, PhD, Professor of Urology, Al Azhar Faculty of Medicine, Cairo
Mailing address: P O Box 2477, Elhorria, Heliopolis, Cairo 11361, Egypt
Tel: +20 12 2137100, Fax: +20 2 26709709, E-mail: ismkhalaf@yahoo.com
ABSTRACT neck obstruction, contracted bladder and

bladder carcinoma. The lower ureters are
Schistosomiasis is a parasitic infesta- the second most favorable site for the bil-
tion; ≈200 million people are infested and harzial worms after the urinary bladder.
1,000 million are at risk of the disease Ureteric lesions include simple epithelial
worldwide. Humans infected through hyperplasia, sandy patches, ureteritis
skin contact with cercariae and any per- cystica, calcinosa and glandularis, ureteral
son complaining of skin itching after con- polyps, muscular atrophy, obliterated ure-
tact with contaminated water must be teritis, ureteral strictures and carcinoma.
considered infected. Bilharzial lesions The prostate, seminal vesicles, spermatic
in the urinary tract result from variable cord and epididymis are affected in cases
tissue reactions to bilharzial eggs with with severe bilharzial infestation while the
subsequent healing or progression and testis has a remarkable immunity against
complications. Subsequent changes may bilharzial invasion. Immunoblast assay
assume an atrophic, proliferative, meta- has the highest sensitivity and specificity
plastic or neoplastic pattern. Although of detection of adult worm antigens in the
the pathology is usually extensive in the urine or serum and tissue diagnosis is the
submucosa, all layers from the mucous most precise method for diagnosis of uri-
membrane through the musculosa and nary tract schistosomiasis. Praziquantil is
up to the perivesical or periureteral tis- the drug of choice and metrifonate can be
sue may be implicated. Bladder lesions used after failure of praziquantil. Proper
are the most common and vary between sanitation and avoidance of contaminated
active bilharzial cystitis, chronic bilharzial water would minimize the prevalence of
cystitis, bilharzial bladder ulcer, bladder human infestation with schistosomiasis.
Key words: epidemiology of schistoso- while chronic deep type needs open
miasis, pathology and pathogenesis of surgery (GoR B).
schistosomiasis, genitourinary bilhar- 10. Chronic bilharzial ureteric stric-
ziasis, genitourinary schistosomiasis, ture mostly affects its lower third.
ureteric bilharzial strictures, bladder car- Endourological treatment can give
cinoma, squamous cell carcinoma success in < 50% of cases while open
surgery gives better satisfactory
results (GoR C).
1. Use of sanitation and avoidance 1. INTRODUCTION

of contaminated water would
minimize the prevalence of human Genitourinary schistosomiasis (bilharzia-
infestation with schistosomiasis) is a communicable parasitic disease
sis (GoR A), because humans are caused by Schistosoma haematobium
infected through skin contact with (S.haematobium). It affects a high propor-
cercariae. tion of the population in developing coun-
tries especially children under 14 years,
2. Any person complaining of skin itch- causing major socioeconomic and pub-
ing after contact with contaminated lic health consequences. An estimated
water must be considered infected 100 million people in developing countries
(GoR B). are currently infected; more than 80% of
3. Immunoblast assay has the highest them live in Africa [1] (LoE 1b). Being a
sensitivity and specificity of detec- worldwide communicable disease, the
tion of adult worm antigens in the purpose of this guideline is to update the
urine or serum (GoR B). disease risks, transmission, epidemiology,
4. Tissue diagnosis is the most precise pathologic lesions, and prophylaxis.
method for diagnosis of urinary tract
schistosomiasis (GoR A).
2. METHODS
5. Praziquantel is the drug of choice of
all forms of schistosomiasis with a For the period 1998–2009 a system-
65–90% cure rate after a single oral atic literature search was performed in
dose (GoR A). Medline, Cochrane, PubMed, etc with
6. Metrifonate can be used after failure the following key words: epidemiology of
of praziquantel (GoR B). schistosomiasis, pathology and pathogen-
7. Bilharzial bladder carcinoma is esis of schistosomiasis, genitourinary bil-
mostly locally advanced and radio- harziasis, genitourinary schistosomiasis,
resistant. Radical cystectomy with and the following limitations; English
some form of urinary diversion is the language abstracts available, double
optimum treatment option (GoR A). blind studies, large clinical studies and
multi-institutions collective data.
8. Bilharzial contracted bladder (store A total of 90 publications were identi-
<100 cc urine) might need augmenta- fied, which were screened by title and
tion cystoplasty (GoR B). abstract. After exclusion of duplicates, a
9. Chronic superficial Bilharzial blad- total of 61 were included into the review
der ulcer is mostly treated endo- analysis, supplemented by citations
scopically by transurethral resection known to the authors.
944
Genitourinary schistosomiasis | 15.8 |
The studies were rated according to access to the mesenteric arteries survive
the level of evidence and the strength of [6] (LoE 3).These migrate into the infe-
recommendations as given by the Oxford rior mesenteric veins, proceeding further
Centre for Evidence Based Medicine [2]. to reside in the pelvic plexus of veins.
The ICUD consultations use a modified There, the worms become sexually mature
version of the Oxford system [3]. and the fertilized females lay eggs. From
this venous plexus the worms proceed to
different urinary and genital organs [7]
3. EPIDEMIOLOGY (LoE 3). The worms can remain active and
discharge ova for five to 18 years, but peri-
S. haematobium is found in 53 countries ods of 27 to 40 years have been reported [8]
in the Middle East and Africa. Human (LoE 3). Each female worm produces and
infection is caused by skin contact, dur- deposits approximately 200 to 500 eggs per
ing swimming or bathing, with fresh day. Thus, during its estimated mean life
water that harbors infected snails. In span of three to six years, a single worm
Europe and United states, schistosomia- pair spawns 250,000 to 600,000 eggs; in
sis is always an imported disease mainly nature, the ova hatch if they fall into fresh
present in travelers or immigrants from water where the ciliated larva or miracid-
endemic areas [4] (LoE 3). The preva- ium emerges. The miracidium can remain
lence of infection is linked to the economic alive in water for 16–32 hours looking for
level, adequacy of sanitation and contact the snail of the genus Bulinus. Within the
to contaminated water. Survey in 2000 of snail the miracidium develops into cer-
disease specific mortality reported 70 mil- cariae. From a single miracidium 100–250
lion of 682 millions in Africa had experi- thousand cercariae are produced by a proc-
enced haematuria and 32 million suffered ess of asexual multiplication and are subse-
dysuria with S. haematobium infection. quently discharged from the snail into fresh
Moreover, 18 million suffered bladder wall water to infect human host [9] (LoE 3).
pathology, and 10 million suffered hydrone-
phrosis [1] (LoE 1b). Schistosomiasis is
directly responsible for an annual death of 5. PATHOGENESIS AND PATHOLOGY
20,000 patients [5] (LoE 1b).
5.1 Initial tissue reaction and repair
4. LIFE CYCLE OF SCHISTOSOMA Bilharzial lesions in the urinary tract
HAEMATOBIUM AND MODE OF result from variable tissue reactions to
TRANSMISSION bilharzial eggs with subsequent heal-
ing or progression and complications.
Schistosomes are digenetic, which means Ova entrapped in the tissues of the
that their life cycle involves a definitive genitourinary tract will induce delayed
human host, in which sexual maturity of hypersensitivity cell-mediated TH1 and
the worms occur, and an intermediate snail TH2 responses with local cytokine pro-
host in which processes of asexual multi- duction. Granulomata form in the lam-
plication of larval forms occur. Humans ina propria by accumulation of plasma
are infected by skin contact with cer- cells, lymphocytes, and eosinophils [6]
cariae which can reach the subepider- (LoE 3) (Figure 1). Subsequently, wide-
mis and start the sexual part of the life spread collagen deposition occurs and the
cycle passing through peripheral venules whole cellular reaction is replaced by a
or lymphatic vessels to reach the sys- laminated fibrotic nodule. Blood vessels
temic circulation. Only cercariae that gain undergo thromboangitis and endarteritis
945
hyperemic polypoid masses projecting

into the lumen (bilharzial granuloma)
(Figure 2).
Specific bilharzial pathologic lesions
in the genitourinary tract can occur with
variable degrees of severity according to
the organ affected, severity and frequency
of egg deposition, reinfection, and second-
ary microbial infection [8, 11] (LoE 3).
5.3 Bilharziasis of the bladder

Figure 1 Histopathological picture of active bilharzial cystitis 5.3.1 Active bilharzial cystitis
showing multiple active schistosomal ova containing mera-
cidia inside with moderate to dense inflammatory infiltrate Active bilharzial cystitis commonly occurs
composed of lymphocytes, plasma cells and eosinophils. at school age of five to 15 years represent-
ing the period of ovideposition in the blad-
obliterans [7] (LoE 3). Degeneration of der wall, the immediate tissue reaction to
muscle fibers and dense interstitial fibro- deposited ova, and the release of ova in
sis often occur. Following the granuloma- the urine. Presenting symptoms include
tous bilharzial reaction in the submucosa, painful micturition, frequency and ter-
subsequent epithelial changes ensue. minal haematuria. On cystoscopy, the
mucous membrane shows multiple hyper-
5.2 Subsequent pathology emic patches, with pinpoint yellowish bil-
harzial tubercles [7] (LoE 3) (Figure 3).
Subsequent changes may assume an
atrophic, proliferative or metaplastic
pattern. Although the pathology is usu- 5.3.2 Chronic bilharzial cystitis
ally extensive in the submucosa, all lay- Chronic bilharzial cystitis may assume an
ers from the mucous membrane through atrophic or hyperplastic pattern. All blad-
the musculosa and up to the perivesical der layers from the mucous membrane
or periureteral tissues may be implicated through the musculosa and up to the
[10] (LoE 2b). As ovideposition ceases, perivesical tissue may be implicated [10]
entrapped eggs are destroyed or calcified (LoE 2b): Mucosal lesions include simple
and inflammation wanes, being replaced atrophy, sandy patches, cystitis cystica,
by fibrous tissue. In sites of recent bladder ulcers and mucosal transforma-
ovideposition, perioval granulomatous tions. Bilharzial infiltrations in the sub-
inflammation results in large, bulky and mucosa diminish the vascularity of the
Figure 2 Cystoscopic view showing polypoid lesion Figure 3 Cystoscopic view of active bilharzial cystitis showing
covered by intact mucosa (bilharzial granuloma). yellowish tubercles and confluent mucosal hyperaemia.
946
Figure 4 Cystoscopic view of chronic bilharzial cystitis

showing diminished vascularity and pale mucosa.
Figure 5 Plain radiograph of the pelvis showing dense
bladder calcification pathognomic of bilharzial infestation.
overlying mucous membrane leading to
its atrophy (Figure 4). Submucosal lesions appearance lined by one layer of cuboi-
include bilharzial fibrosis, nodules, pol- dal epithelial cells. Cystitis glandularis
yps, and calcification. Muscular lesions appears as rounded or oval gland-like
include muscular degeneration and fibro- structures filled with mucoid secretion
sis, bladder-neck fibrosis and contracted and lined with a single layer of cuboidal
bladder. Perivesical lesions appear as bil- cells with strictly basal nuclei. It is fre-
harzial pericystitis. quently met with in chronic bilharzial
bladders and is regarded by some as pre-
5.3.2.1 Bilharzial nodules cancerous as it is found in 32–50% of bil-
Heavy egg deposits excite massive reac- harzial bladder carcinoma [12] (LoE 2a).
tion around aggregations of bilharzial On cystoscopy, they appear as velvety red
tubercles and develop spheroid grayish elevations of the mucosa.
nodules, covered by pale anemic intact
mucosa. These occur mainly in children 5.3.2.4 Squamous metaplasia and
through their early teens. Polyps may leukoplakia
obstruct ureters or, rarely, the bladder Squamous metaplasia and leukopla-
outlet. Nodules can reach large dimen- kia may be encountered in long stand-
sions mimicking bladder carcinoma on ing chronic bilharzial cystitis but mostly
cystoscopy and urography. in association with squamous cell blad-
der carcinoma [12] (LoE 2a) (Figure 6).
5.3.2.2 Bilharzial fibrosis and calcification
They result from chronic irritation of the
This results from healing of mild bilhar- mucous membrane by the bilharzial ova.
zial infiltrations of the submucosa reduc- On cystoscopy, they appear as well-defined,
ing the pliability of the overlying mucosa. white, slightly raised patches surrounded
When calcification of dead ova in the sub- by inflamed mucosa. Follow up is man-
mucosa occurs, the bladder wall becomes datory as it is considered a precancerous
dull pale yellow in color. Calcification will lesion [13] (LoE 2b).
cast a linear or circumferential shadow on
a plain radiogram [7] (LoE 3) (Figure 5).
5.3.3 Bladder ulcer
5.3.2.3 Cystitis cystica and glandularis Bilharzial bladder ulcer is most com-
Cystitis cystica appears as tiny rounded monly met with in patients between 20
translucent yellowish cysts of uniform and 40 years of age. Microscopically, there
947
Figure 6 Keratinizing squamous metaplasia of bladder

mucosa with bilharzial ova laid in the submucosa.
Figure 7 Cystoscopic view showing chronic deep bilharzial
bladder ulcer.
is complete loss of the surface epithelium.
In active ulcers, the surface layer is com-
posed of necrotic tissue with foci of meta- suggestive history is difficulty in initiat-
plasia at the margins of the ulcer. The ing voiding, straining and weak inter-
underlying layers show bilharzial cellular rupted stream in a young-aged male [15]
reaction, with little ova, oedema, hemor- (LoE 2b). The diagnosis can only be set-
rhages and degeneration of muscle fib- tled by urodynamic pressure flow study
ers. In other cicatricial types of ulcers, with simultaneous imaging.
the predominant feature is the presence
of dense fibrous tissue and endarteritis
obliterans causing relative avascularity 5.5 Contracted bladder
[13] (LoE 2b). A bilharzial bladder ulcer This results from heavy infestation with
rarely heal spontaneously due to the severe body reaction affecting submucosa,
presence of calcific or fibrotic plaque in its musulosa and perivesical tissues, sparing
floor and associated secondary infection. the trigone resulting in marked decrease
Diagnosis is settled by cystoscopy, in the size and capacity of the bladder. In
where ulcers appear as; 1) Active ulcers severe forms the reduced bladder capac-
with a bleeding surface from the base ity will lead to ureteric reflux and renal
of active bilharzial granuloma, and 2) impairment [16] (LoE 3) (Figure 8).
Cicatricial ulcers characterized by dense
fibrosis and appear as stellate or linear 5.6 Carcinoma of the bladder
ulcers [14] (LoE 2a) (Figure 7). The ulcers associated with bilharziasis
are usually single, situated in the poste-
rior wall or the dome of the bladder. The Bladder carcinoma is common in countries
trigone and anterior walls are almost where schistosomiasis is endemic such as
exempt from ulceration [13] (LoE 2b). Egypt, Sudan, Iraq, Mozambique, Gold
Coast and Nigeria. No such increased
incidence is found in South Africa or in
5.4 Bilharzial bladder neck West Africa for unknown cause.
obstruction (BNO) The association between urinary schis-
This could be encountered as a signifi- tosomiasis and vesical carcinoma can be
cant entity in 7.5% of patients with com- explained by many etiologic factors that
plicated cystitis [14] (LoE 2a). Bilharzial work together including chronic mucosal
infiltration of the bladder neck results irritation by bilharzial ova, recurrent bac-
in fibrous scarring of the submucosa and terial infection, carcinogenic toxins pro-
destruction of the muscle bundles. The duced by the miracidium or worms and
948
Figure 8 Ascending cystography showing contracted bladder Figure 9 Dilated ureter at operation showing group of large
with dilated refluxing ureters with marked hydronephrosis. ureteritis cystica in its opened lumen.
a raised level of carcinogenic tryptophan The tumor histology in bilharzial cases

metabolites, nitrates, serotonin and uri- is squamous cell type in 54% to 77%.
nary beta-glucuronidase enzyme in bil- 80% of these are low-grade tumor [21]
harzial patients [7, 12, 17–18] (LoE 2b, (LoE 2a). Transitional cell tumors consti-
GoR B). Immunohistochemical studies tute 21% to 39% in bilharzial bladders,
showed P53 protein over-accumulation in and the majority are grade II or III [17]
71% of cases of squamous cell carcinoma (LoE 2b). Adenocarcinoma constitutes 4%
of bilharzial bladder. Moreover, molecular to 9.6% of bilharzial bladder cases [21]
genetic studies showed P53 mutations in (LoE 2b). The pathologic stage is mostly
33% of tumors [19–20] (LoE 2b). advanced; P3 (64%) and P4 (23%). Lymph
Bilharzial bladder carcinoma arises node spread is encountered in 18–24% of
from any wall of the bladder except the cases [22–24] (LoE 2a, GoR B).
trigone (only in 2% of cases) [17] (LoE
2b). The tumor is usually single and
bulky one. Its gross appearance is most 5.7 Bilharziasis of the ureter
commonly the nodular fungating type The lower ureters are the second most
(85%); less common types are the ulcera- favorable site for the bilharzial worms
tive (8%), the diffuse infiltrative (4%) after the urinary bladder. The intramu-
papillary (1.5–3%) and Verrucus carci- ral part is affected almost as frequently
noma (3.6%). The latter is a rare pecu- as the bladder. Other common sites are
liar type to bilharzial squamous cell the juxtavesical part, pelvic segment and
carcinoma (SCC). It presents as a hyper- lumbar spindle opposite the third lumbar
keratotic exophytic growth with filamen- vertebra [7, 25] (LoE 3). In the chronic
tous white projections locally malignant stage, ureteric lesions include simple
without any tendency to spread to epithelial hyperplasia, sandy patches,
regional lymph nodes or distant organs ureteritis cystica, calcinosa and glandu-
[21] (LoE 2a, GoR B). laris, ureteral polyps, muscular atrophy,
949
obliterated ureteritis, ureteral strictures 5.8 Bilharziasis of the prostate,

and carcinoma [25] (LoE 2b, GoR B). seminal vesicles, spermatic cord
Calcification of the ureter may appear as and epididymis
pseudocalculus on plain UT [26] (LoE 2a). In severe and repeated bilharzial infesta-
Ureteritis cystica may reach large size tion the worms navigate to other organs
mimicking stones (Figure 9). such as the prostate, seminal vesicles,
The bilharzial ureter takes one of and the intrascrotal structures. Notably,
three forms: thick ureter, stricture ure- the testis has a remarkable immunity
ter, dilated ureter or any combination of against bilharzial invasion [29] (LoE 3).
them. The thick ureter is rigid like a pipe- Subsequent bilharzial infiltrations in
stem. The lumen is slightly narrowed these structures will progress to severe
and the mucosa is degenerated. The wall fibrosis. In the seminal vesicles, fibro-
cuts with a gritty sensation and minimal sis invited marked calcification and the
bleeding. The peri-ureteric fascia forms organs become firm, nodular and smaller
a thick scaffold adherent to the ureter. in size [29]
Sometimes a fibrolipomatous mass is (LoE 3, GoR C). Prostatic and semi-
formed around the ureter, especially its nal calcifications should alert physicians
pelvic segment. The ureter can prima- to the possibility of schistosoma infection
rily form or traps migrating stones from when they are found in young patients
the kidney allowing these to enlarge and who have been in endemic areas [30–31]
reach giant dimensions [25] (LoE 2a). (LoE 2b).
In the stricture ureter, stenosis or The concomitant presence of adeno-
almost complete obliteration of the lumen carcinoma of the prostate and schisto-
is the end result of contraction of the somiasis is very rare. Up to the present
dense fibrosis involving all the layers of time, only eight cases of prostatic schis-
the ureteral wall. In a study on 804 bil- tosomiasis associated with adenocarci-
harzial strictures of the ureter, involve- noma of the prostate have been reported,
ment of the lower third was found in three of which were associated with
91.7% [25] (LoE 2a). In the lower ureter, S.heamatobium, three with S. mansoni
45% of the strictures were juxtavesical, and in two cases the species of parasite
37.5% intramural, 8.9% combined jux- was not specified [32–33] (LoE 3).
tavesical and intramural 7.7% pelvic, In epididymal affection a solitary mass
and 0.9% meatal strictures. Bilateral is commonly found in the globus major.
involvement was noted in 63.7% of cases Bilharziasis of the spermatic cord may be
[27–28] (LoE 2b). Gradual lengthening manifested as firm mass in its lower part
and widening of the ureter result in tor- or as one big irregular mass along the
tuosity and kinking. Dilatation of the intrascrotal cord. Ironically, the lumen
renal pelvis and calyces will necessarily of the tubules of the epididymis and the
follow, and migratory stones proximal to lumen of the vas remain patent and
the stricture are a common complication unobstructed.
[28] (LoE 3).
Dilatation without a distal stricture
5.9 Urinary stones in relation to
(dilated ureter) may result from bilhar-
bilharziasis
zial degeneration of the muscles and neu-
ral elements in the wall of the ureter or Comparison of the incidence rate of uri-
due to vesico-ureteral reflux. It is usually nary stones in bilharzial and non-bilhar-
restricted to the pelvic segment, but may zial patients suggests that bilharziasis
involve the whole ureter. Only one-quar- does not contribute to the high incidence
ter of dilated bilharzial ureters are truly of urinary stones in Egypt [34] (LoE 3),
obstructive [28] (LoE 3). nor in Sudan [35] (LoE 3, GoR C). Other
950
Figure 10 Plain urinary tract showing giant stones in the bladder (left figure), lower part of the right ureter with calcified left
ureter (middle figure) and left renoureteral stone (right figure).
predisposing factors of stone formation end-stage renal failure [5] (LoE 1b).
may be considered. However, Bilharziasis Hydroureteronephrosis and renal func-
may re-distribute the stone location along tion deterioration gradually occur as a
the urinary tract with a relative increase sequel of lower ureteric obstruction.
in the number of ureteral calculi in bil-
harzial ureters. Giant forms of stones 6. DIAGNOSIS OF SCHISTOSOMIASIS
may form at the bladder and ureteric lev-
els [34] (LoE 3, GoR C) (Figure 10). 6.1 Clinical manifestations
Following a localised itching caused
5.10 Nephropathy and renal failure by skin penetration by the cercaria, a
Nephrotic syndrome occasionally develops rash and fever may occur. Symptomatic
in patients with S. haematobium. Severe disease starts few months later by
renal changes are seen in up to 25% of active stage of acute cystitis symptoms
patients with bilharzial infections [36] associated with fever and haematu-
(LoE 2b). Clinical features include pro- ria. After some years, egg deposition
tienuria and oedema. Immune complexes and excretion continue at a lower rate
formed in response to Schistosoma infec- and symptoms cease. Over 30% of light
tion may be deposited on glomerular cap- infections “resolve” spontaneously in
illaries and renal basement membrane, some endemic areas. Although symp-
leading to 5 classes of glomerulonephritis: toms are absent, silent obstructive
mesangioproliferative, exudative, mesan- uropathy can develop as fibrosis ensue
giocapillary, focal segmental sclerosis and and the bladder and ureters undergo
amyloidosis [5, 37] (LoE 1b). Although the irreversible pathology. Patients finally
acute and early chronic lesions regress enter a chronic inactive phase, in which
under antiparasitic treatment, chronic viable eggs are no longer detected in
sequelae are irreversible and may cause urine or tissues. Signs and symptoms at
951
this stage are caused by complications 6.2.5 Semen analysis

rather than by the schistosoma infection Semen analysis is used for cases of
itself. Vesical, ureteral, renal and geni- haemospermia to look for bilharzial
tal lesions develop [38–39] (LoE 2a). ova to diagnose genital schistosomiasis
[43] (LoE 3).
6.2 Laboratory tests
6.2.1 Egg detection, diagnosis and 6.3 Imaging studies
quantitation of infection Vesical or ureteric bilharzial calcification
The presence of terminally- spiked eggs and honey-combed calcification of the
in urinary sediment is diagnostic of seminal vesicles on plain UT are stigma
active S . haematobium infection. S. hae- of infestation and are not necessarily an
matobium egg excretion peaks between evidence of active disease. Other imaging
10 AM and 2 PM; the extent of egg shed- studies as ultrasonography and CT of the
ding may fluctuate widely, and as many abdomen and pelvis can diagnose disease
as three specimens may be required in complications.
some patients. The test may be performed
after the incubation period of last known 6.4 Tissue biopsy
contact to fresh water; usually after three
Being a very sensitive test is done for
months. Urinary egg excretion measure-
histological diagnosis from bladder, pros-
ment accurately estimates infection and
tate and seminal vesicle lesions and in
its intensity during the early stages but
patients with typical clinical picture and
is imprecise in late stages and inactive
negative urine specimens.
cases [40–41] (LoE 2a).
6.2.2 Serologic tests 7. TREATMENT OF SCHISTOSOMIASIS

Serologic tests are valuable diagnostic and AND ITS COMPLICATIONS
epidemiologic tool, but cannot distinguish
active from past infections. Antibody 7.1 Medical treatment
detection has a limited use because anti- Praziquantel is the drug of choice for all
bodies persist after parasitological cure. types of schistosomiasis giving a cure
Immunoblast assay is used to detect adult rate of 65–90% after single treatment
worm antigens in urine or serum. It has [44] (LoE 1a, GoR A). It is given as one
95% sensitivity and 99% specificity for S. oral dose of 40 mg/ kg BW. By inhibit-
haematobium. Antigen tests may become
ing egg release, praziquantel reduces
negative as early as 10 days after therapy.
prevalence and parasitic burden [45]
These tests may also be negative in light
(LoE 1b). Praziquantel resistance to
infections [37, 42] (LoE 2a).
treatment of S. haematobium infections
has been reported in Egypt and Kenya
6.2.3 CBC count and coagulation profile 20 years after multiple courses of treat-
Eosinophilia is prominent in acute schis- ment [46] (LoE 2b). Other drug which
tosomiasis while thromocytopenia, anemia is effective against S. haematobium is
an organophosphate called Metrifonate
and prolonged prothrombin time are
administered in a dose of 5 mg/kg, orally
present in severe chronic Schistosomiasis. in three biweekly administrations [47]
(LoE 3, GoR C) Because of multiple
6.2.4 Urine cytology administrations, Metrifonate is opera-
Urine cytology is used for suspected tionally less convenient in community-
malignant epithelial cells. based control programmes [48] (LoE 1a,
952
GoR A). Evidence on the artemisinin Radical cystectomy and some form of
derivatives is currently inconclusive, and urinary diversion is the optimum treat-
further research is warranted on combi- ment option to most cases of organ-con-
nation therapies [48] (LoE 1a, GoR A). fined invasive bladder tumors [39–40].
Several orthotopic continent reservoirs
7.2 Surgical treatment are applicable in nearly half of cases.
The reported overall five-year disease-
7.2.1 Bilharzial ulcer
free survival after radical cystectomy is
Conservative treatment in the form of 48–55.5% [46] and the 10 year survival is
antibilharzial and antibacterial drugs 50% and node positivity has an independ-
may be tried in small active ulcers. ent negative impact on disease-free sur-
Transurethral coagulation of the floor vival [49] (LoE 2a, GoR A).
and edges of the ulcer may give relief of
symptoms for few months, but recurrence 7.2.6 Stricture ureter
is the rule. Transurethral resection (TUR) Bilharzial ureteric strictures represent
of localized superficial ulcers may give a real surgical challenge. Endourological
good results. An alternative treatment for treatment is indicated for early cases,
a chronic deep bilharzial bladder ulcer is non-tight short-segment strictures. High-
open excision or partial cystectomy [13] pressure balloon dilatation and endour-
(LoE 2b, GoR B). eterotomy have been reported to have a
success rate of 40–87% [50–52] (LoE 2b,
7.2.2 Leukoplakia GoR B). Open surgery is usually needed
Treatment is TU Resection [16] (LoE 3, for the more established cases associ-
GoR C) ated with periuretritis [53] (LoE 2b, GoR
B). The type of reconstructive surgery
7.2.3 Bilharzial BNO depends on the site of the stricture, its
Treatment is by TUR incision or resection length, bilaterality, extent of periureteral
of the fibrous scar. This will give only a fibrosis, condition of the proximal ureter,
temporary relief but further formation of and bladder capacity. Excision and spat-
fibrous tissue and re-contracture usually ulated end-to-end anastomosis affords
occurs (LoE 4, GoR D) the best result in properly selected
cases. Most strictures of the lower part
7.2.4 Contracted bladder of the ureter need ureterovesical re-
implantation [53] (LoE 2b). However,
Treatment in established cases with blad- tailoring of the markedly dilated ureter
der capacity < 100 ml under anaesthesia provides better results [53] (LoE 3, GoR
by augmentation entero-cystoplasty [16] C). For more proximal strictures of the
(LoE 3, GoR B) pelvic ureter, the bladder flap opera-
tion (Boari’s) is recommended [54] (LoE
7.2.5 Bilharzial bladder carcinoma 2b, GoR B). In very extensive strictures
The tumor is usually low-grade deeply involving a long segment, ileal loop
invasive, consequently transurethral replacement is the only available option,
resection and chemotherapy have little although its long-term effects of reflux
place in the management [20] (LoE 1b, and urinary tract infection can compro-
GoR A). mise the kidney [53] (LoE 2b, GoR B).
Radiotherapy results are generally dis- Tailoring of the ileal ureter with crea-
appointing as the tumor is mostly a low- tion of an intussuscepted nipple valve
grade SCC, of a considerable bulk and at its distal end may prevent reflux and
very frequently associated with fibrosis provide better functional results [55–56]
and infection. (LoE 4, GoR D) (LoE 1a and 2b).
953
8. DISEASE CONTROL end-stage renal failure are debilitating

diseases which are considered as national
Satisfactory disease control can be health problems in the endemic areas
attained by large-scale population-based consuming a great percentage of the
antibilharzial treatment, adequate sani- human resources and increasing the cost
tation for the proper disposal of urine of the health services. Therefore, preven-
and stools, mass eradication of snails and tion and early treatment of schistosomia-
proper health education. This large scale sis should be one of the most important
prevention strategy is difficult to attain in health care targets in endemic areas..
many countries for cultural and economic The majority of bilharzial-associated
reasons. Moreover, chemical eradication of bladder cancers are SCC, whereas the
snails cannot be implemented because of majority of non-bilharzial cases in the
its serious environmental consequences. Western world are transitional cell cancers
The World Health Organization strategy in (TCC), suggesting different carcinogenetic
schistosomiasis control in Africa is a mor- mechanisms. Squamous cell carcinoma of
bidity control package. This includes pro- the bladder is a distinct clinico-pathological
viding praziquantel at an affordable price, entity different from SCC encountered in
a proper case management and an effec- the Western World and also different from
tive health education, especially in school the conventional TCC. Most of the SCC
health programs [57] (LoE 2b, GoR B). tumors are detected at an advanced stage
Few countries like Puerto Rico, Saudi and superficial papillary tumors are very
Arabia and Morocco have eradicated rare. Therefore, the prediction of prognosis
the disease. Others like Brazil, China in this cohort of patients depending upon
and Egypt have attained partial control, the presence of superficial type does not
largely as a result of mass treatment of exist because the vast majority of patients
all school children by Praziquantel [1]. present in muscle-invasive stage which
Travellers to endemic areas should requires cystectomy.
be strictly advised to avoid any contact Numerous individual molecular mark-
to canal water in rivers or lakes [58] ers have been identified in the tissue,
(LoE 1a, GoR A). They should boil any serum, and urinary specimens that corre-
possibly contaminated water to destroy late to some extent with tumor stage and
the parasite. Glycosaminoglycans is given possibly with its prognosis. However, the
as bladder instillations or orally for uro- power of many of these individual mark-
protection in patients suffering chronic ers in predicting recurrence, progres-
cystitis [58] (LoE 1a). sion or the clinical outcome of individual
tumors is still limited. It is conceivable
that the development of biomarkers that
9. DISCUSSION identify patients, whose tumors are likely
to recur or progress, so that they can
Schistosomiasis is an endemic disease in be treated more aggressively, would be
many regions of the Middle East, Africa, beneficial for patients presenting at all
South East Asia and South America; ≈ stages. Patients with superficial disease
200 million people are infested and 1000 represent a group who would greatly
million are at risk of the disease world- benefit from predictive markers of recur-
wide [20] (LoE 2b). The most serious rence and progression into invasive dis-
complications of genitourinary schisto- ease. This can be attributed to their high
somiasis are the predisposition to SCC of chance of relapse within the first 5 years
the bladder and development of obstruc- after surgery and the poorer clinical out-
tive uropathy that my lead to end-stage come once muscle invasion is present.
renal failure. Both bladder cancer and For patients with invasive tumors, tumor
954
markers are needed to predict response to b. EAU guidelines for the manage-
chemotherapy and development of meta- ment of Urogenital Schistosomiasis,
static disease [59] (LoE 2a). European Urology 2006, 49: 898–1003.
The Food and Drug Administration c. WHO search,www.who.int.
(FDA) has already accepted urinary tests Schistosomiasis: Burden and trends.
for the monitoring of patients with non- Update 25 Jan, 2008.
muscle invasive bladder cancer, including
bladder tumor antigen (BTA) test, the BTA d. Khalaf I and Koritim M.
stat test, the fibrinogen-fibrin degradation Genitourinary Schistosomiasis. In
products test, fluorescent in situ hydridi- Textbook of Tropical Surgery by
zation cell assay and the nuclear matrix Kamel R and Lumely J, Westminser
protein 22. In general, each of these mark- Publishing Ltd; 2004:673–680.
ers has better sensitivities but lower spe-
cificities than cytology, and must still be
used as adjuncts with cystoscopy [60] (LoE 11. CONCLUSIONS
2b). The use of these markers was applied
to TCC of the bladder in the vast majority Schistosomiasis is a parasitic infestation;
of studies. The role of these biomarkers 200 million people are infested and 1000
in the early detection of SCC of bilharzial million are at risk of the disease world-
bladder is a subject of further research. wide. The bladder and lower ureters are
Genetic and ultimately protein altera- the most common sites of bilharzial infes-
tion are primary determinants controlling tation. The bladder lesions are precancer-
neoplastic transformation and protein ous while the ureteric lesions may cause
changes ultimately determine a tumor’s obstructive uropathy with subsequent
phenotype and subsequent clinical behav- end-stage renal failure
ior. The advent of high-throughput DNA The best treatment option of geni-
microarrays is accelerating the identifi- tourinary Schistosomiasis is prevention
cation process of these molecular events through disease control. The disease can
characteristics of bladder cancer [61]. The be controlled through mass eradication of
information provided by these analyses snails, adequate sanitation and popula-
is resulting not only in the identification tion-based antibilarzial treatment (GoR
of novel therapeutic targets for bladder A). Travellers to the endemic regions
cancer, but also in the development of would be advised to avoid contact to the
diagnostic tools [61] (LoE 2a). Most of the contaminated water in the canals, lakes
genomic and proteomic studies were con- and rivers (GoR A).
fined to TCC of the bladder. Identification
of genetic and protein alterations in bil-
harzial SCC is a virgin area which needs
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|15.9|
Brucellosis: genitourinary
involvement
Ziad A. Memish1, Georgios Pappas2
1
Director Gulf Cooperation Council (states) Center for Infection Control,
Executive Director Infection Prevention & Control Program, King Abdulaziz Medical City, Riyadh, KSA
Adjunct Professor Department of Medicine, Division of Infectious Diseases, University of Ottawa, Canada
E-mail: zmemish@yahoo.com
2
Institute of Continuing Medical Education of Ioannina, H. Trikoupi 10, 45333, Ioannina, Greece,
E-mail: gpele@otenet.gr
ABSTRACT applying in the latter (recently summa-

rized as expert guidelines, termed the
Genitourinary involvement in brucello- “Ioannina Recommendations”), also apply
sis is common and may be the presenting to genitourinary localization.
symptom of the disease. The most typical Treatment should be based on a com-
presentation is that of testicular involve- bined regimen of doxycycline, adminis-
ment, in the form of orchitis/epididymo-or- tered for 6 weeks, with streptomycin, for
chitis, which can be readily attributed to 2–3 weeks, or rifampicin, administered for
brucellosis when the epidemiological back- 6 weeks. For alternative regimens, see the
ground indicates towards this common following summary of recommendations.
zoonotic infection. In endemic areas in Clinicians should be aware of the poten-
particular, any testicular pathology should tial for development of abscess or necrotic
predominantly orientate towards brucello- testicular forms that may necessitate sur-
sis, and diagnosis (or exclusion) through gical excision. Relapses, as in brucellosis
appropriate cultures or serology should in general, can be observed in a minority
be rapid. The available literature on geni- of patients, but can be treated with the
tourinary brucellosis does not contain any initial regimens or minor modifications.
data from randomized trials, and mainly The effect of brucellosis in male fertility
consists of few large historical series of has not been adequately estimated.
patients. Yet, since genitourinary brucello- Key words: Brucellosis, orchitis,
sis is treated as uncomplicated brucellosis epididymo-orchitis, genitourinary, doxy-
in general, the rules and recommendations cycline, rifampicin, aminoglycosides
SUMMARY OF RECOMMENDATIONS genitourinary infections, guidelines

applying to the optimal recognition and
Principles for choosing antibiotics: treatment of genitourinary brucellosis are
needed in order to minimize inadequately
1. Regimens are chosen according to treated cases.
expert guidelines existing for brucello-
sis in general: a combination regimen
is needed, one that should always con- 2. METHODS
tain doxycycline, and one that should
be administered in total for at least A review of the published literature on
6 weeks. The principles of the sug- genitourinary involvement in brucel-
gested combinations are efficacy and losis, using PubMed and Scopus, was
patient compliance. Cost issues are not performed by the authors using the
raised, since expensive combinations keywords “Brucellosis/brucella” AND
are less efficacious in the first place. “genitourinary/orchitis/epididymits/
epididymo-orchitis/testicular/pelvic”. We
Orchitis/epididymo-orchitis also evaluated large brucellosis series
available in the literature that contained
2. Antibiotic therapy is recommended, adequate information on genito-urinary
as follows: Doxycycline for 6 weeks complications of the disease. Of the ini-
together with streptomycin for 2–3 tially retrieved 272 articles which were
weeks (GoR A), or doxycycline with then screened by title and abstract,
rifampicin for 6 weeks (GoR A), or 154 were excluded as being single-case
doxycycline with gentamicin for at reports or reports of unusual localizations
least a week (GoR A). There is ade- of the disease (not comprising a sum of
quate evidence (GoR A) against the cases to be statistically evaluated). Of the
regular use of fluoroquinolone-contain- remainder articles evaluated through full
ing regimens. text, only six articles (as summarized in
3. Surgical therapy: Warranted in non- the relevant table) offered adequate data
responding abscess formation or in for extraction of any valuable conclusions.
cases of necrotic testicular lesions It should be stated that there are no ran-
(GoR C). domized control trials or meta-analyses
for genitourinary brucellosis published
in the literature. Genitourinary brucello-
1. INTRODUCTION sis is a complication that does not need
alteration of the therapeutic regimen,
Brucellosis is a zoonotic infection still compared to uncomplicated brucellosis,
endemic in certain parts of Europe and as will be subsequently analyzed. Thus,
often imported to non-endemic European level of evidence and strength of recom-
countries also. Genitourinary involve- mendation in the case of genitourinary
ment is common and may be the present- brucellosis are indirectly applied, accord-
ing symptom of the disease; thus urology ing to general brucellosis treatment
specialists may be the first clinicians guidelines.
to encounter the disease and need to be The studies were rated according
aware of its presentation, and diagnostic to the level of evidence (LoE) and the
and therapeutic principles. Since the lat- grade of recommendation (GoR) using
ter principles are significantly different ICUD standards (for details see Preface)
compared to the commonly encountered [1–2].
960
Brucellosis: genitourinary involvement | 15.9 |
3. DEFINITION OF THE DISEASE direct inoculation through skin and mucosal

abrasions, or through inhalation, since the
3.1 Overview pathogen is volatile and environmentally
resistant. The latter mode of transmission is
Brucellosis is the commonest zoonotic
implicated in brucellosis being the common-
infection worldwide, and a significant vet-
est laboratory acquired infection [7], and its
erinarian, medical, and public health issue
potential for use as biological warfare [8].
with socioeconomic and political param-
Human brucellosis is characterized by a
eters [3]. Being prevalent in a series of
variable clinical presentation [9–10] and a
animal species, it can be encountered even
propensity for relapses and chronicity.
in non-endemic areas, imported through
contaminated products or through world-
wide travel [4]. Brucellosis is still endemic 3.3 Classifications
in certain European countries, includ- Genitourinary involvement in brucellosis
ing Greece, Italy, Spain, and Albania and is considered as the presence of confirmed
has furthermore re-emerged in numerous Brucella infection that is accompanied by
countries of the Balkans, including Bosnia, symptoms or signs related to the geni-
Bulgaria, and the Former Yugoslav tourinary tract. The clinical characteristics
Republic of Macedonia. Imported cases, can be, in descending order of frequency,
acquired through international travel com- orchitis, epididymo-orchitis, epididymi-
prise the majority of cases encountered in tis, testicular abscesses, and prostatitis in
non-endemic countries as Germany [5]. males, various forms of abscesses, pelvic
Worldwide, brucellosis is endemic in the inflammatory disease, pyelonephritis in
Middle East [6], Central Asia, parts of females, or pure dysuria in both genders.
Latin America, the whole Mediterranean
basin, and probably in sub-Saharan 3.4 Characterizations
Africa as well [3]. Brucella is comprised
of numerous species with specific animal 3.4.1 Orchitis/epididymo-orchitis
host predilection: of these, B. melitensis is By far the most frequent form of genitouri-
the commonest cause of human disease, nary involvement in brucellosis, it has
encountered typically in sheep and goats, been reported in 1.6–20% of male patients
while B. abortus (bovine species), B. suis with the disease. Typically presents with
(pigs but also wildlife animals), B. canis scrotal swelling and pain. It may be accom-
(canine species), and possibly the provi- panied by fever and may be complicated by
sionally called B. ceti and B. pinnipedialis evolution to necrotizing orchitis or abscess
(marine species) may also induce human formation. It may be related to oligosper-
disease, particularly B. abortus. mia or aspermia, transient or protracted,
according to one study [11]. Usually
presents in young adults who are occupa-
3.2 Epidemiology tionally exposed to the disease. It is often
Human disease is caused either by direct reported as presenting a more indolent
contact with contaminated animals, course compared to epididymo-orchitis of
aborted placenta being a particularly infec- other causes. It is typically unilateral.
tious source for domestic animal caretakers
and slaughterhouse workers, or through 3.4.2 Prostatitis
contaminated animal products, especially Brucellosis is possibly a frequent cause
non-pasteurized milk and fresh cheese. of prostatitis in endemic areas, but
Transmission though can be attributed to understudied.
961
Table 1 Selected recent series of patients with Brucella epididymo-orchitis reporting therapeutic regimens and outcome.
962
Chapter
Country of origin/ Number of Overall incidence

Year [Reference] patients (in brucellosis) Therapeutic regimens used Outcome
Saudi Arabia 2001 [19] 26 1.6% DOX/TET-STR or RIF (numbers of patients Duration of treatment 6 weeks
| 15 |
not specified) No failures

1 relapse (regimen not specified)
Spain 2001 [14] 59 Not available DOX-STR (31 patients) Treatment duration 45 days or more in 85% of the patients
DOX-GENT (6) Failure in 13% of DOX-STR, 37% of DOX-GENT/NET, 0% of
DOX-NET (2) DOX-RIF and TMP-SMX-RIF, 29% of TMP-SMX
DOX-RIF (10) Relapse in 19% of DOX-STR, 25% of DOX-GENT/NET, 40%
TMP-SMX (7) of DOX-RIF, 43% of TMP-SMX, and 0% of TMP-SMX-RIF
TMP-SMX- RIF (3)
Greece 2002 [22] 17 11% DOX-RIF 9all patients) Treatment duration 6 weeks
No failures
No relapses
Turkey 2005 [23] 17 9.1% DOX-STR (5 patients) Treatment duration 6–12 weeks (the latter in cases with other
Special urogenital infections
DOX-RIF (6) complications needing protracted therapy)

DOX-CIP (1) No failures
DOX-STR-RIF (2) No relapses
DOX-STR-TMP-SMX (1)
DOX-CIP-STR (1)
DOX-CIP-CTX (1-neurobrucellosis also)
Turkey 2006 [11] 17 12.7% DOX-STR (4 patients) Treatment duration 6–8 weeks
DOX-RIF (10) 2 failures (regimen not specified)
STR-RIF (1) 1 relapse (DOX-STR)
TMP-SMX-STR (1)
CIP-RIF (1)
Spain 2007 [24] 48 7.6% DOX-STR (32 patients) Treatment duration 2 months
TET-STR (1) 1 failure (DOX-RIF, abscess)
DOX-RIF (13) 3 relapses (2 DOX-STR, 1 DOX-RIF)
TMP-SMX-STR or RIF (2)
4. CLINICAL EVALUATION/RISK other etiologies in vases of orchitis-

ASSESSMENT epididymo-orchitis. Characteristics that
orientate towards brucellosis include the
4.1 Diagnostic and staging presence of heterogenicity, focal echo-
procedures genicity variation, the presence of gran-
ular pattern or septations in hydrocele
The diagnosis of orchitis/epididymo-or-
fluid, and specific patterns of maximal
chitis attributed to brucellosis is based
and minimal flow velocity in Doppler
on clinical grounds (presence of scrotal
ultrasonography [17]. Laboratory testing
swelling and/ or pain) and specific bru-
is of limited use: the presence of leucocy-
cellosis diagnostic procedures. The latter
tosis has been suggested as both a posi-
include isolation of the microorganism
tive and a negative prognostic factor for
in blood cultures, serology (agglutina-
brucellosis in numerous studies; urine
tion tests or ELISA) that is evolving or is
sediment is usually benign in cases of
accompanied by other compatible clinical
brucellosis, with non-specific changes
findings, or molecular techniques (PCR).
(hematuria, aseptic pyuria, proteinuria)
Urine cultures have an extremely low
reported in a limited number of patients,
specificity for Brucella. Semen cultures
in contrast to non-brucellar cases, where
have rarely been reported as positive
the urine sediment typically exhibits
[12], as have vaginal exudates cultures
abnormalities.
in females [13]. Isolation of Brucella from
epididymal aspirate has been reported
in one of the large brucellar epididymo- 4.4 Discussion
orchitis series [14]. Urine real time PCR Essentially the diagnosis is clinical and
has been recently shown as a rapid, requires a high index of clinical suspicion.
extremely reliable method of diagnosing This is typical in endemic areas, where
brucellar involvement of the genitouri- clinicians are aware of this complica-
nary tract [15]. tion of brucellosis. In non-endemic areas
though, one has to orientate through a
4.2 Diagnostic criteria (testing thorough patient history towards predis-
procedures) posing factors for the disease, particu-
larly international travel.
Bacteremia is present in a significant
percentage of genitourinary brucellosis
patients, according to most large patient 5. PRINCIPLES OF MANAGEMENT
series. A negative blood culture does not
rule out the diagnosis though, and appro- 5.1 Therapy
priate serologic tests should always be
performed. Real time PCR, if available, Series of patients with genitourinary
should allow for rapid diagnosis, although complications of brucellosis are limited
cost-effectiveness is an issue. Urine cul- in the medical literature and practi-
tures are optional: specific processing for cally refer only to epididymo-orchitis.
Brucella is needed, and often other path- Other complications are present as case
ogens co-exist, depending on the regional reports or isolated patient series, for
flora [16]. example prostatitis [18], or as a minority
of patients with genitourinary complica-
tions in general, for example pyelonephri-
4.3 Other issues related to clinical
tis [19]. Furthermore, in the case of
assessment
epididymo-orchitis, there are no compar-
Ultrasonography may prove useful in ative therapeutic trials in the literature.
discriminating between brucellar and Data extraction from series of patients
963
with brucellar epididymo-orchitis is dif- to the reference hospitals participat-

ficult due to the retrospective nature of ing in the study. Thus, severe disease
the majority of these studies, the hetero- resulted in the need for surgical inter-
genicity of the population included, the ventions in roughly 9% of the patients.
heterogenicity of the therapeutic regi- On the other hand, reports from endemic
mens used, the differences in the dura- areas in Greece and Turkey show excel-
tion of administration of the therapeutic lent results with various regimens,
regimens, and the differences in patient preferably doxycycline with rifampicin,
recruitment. Table 1 summarizes the with no relapses or failures mentioned.
therapeutic regimens used, their dura- Nevertheless, the drawbacks of this
tion, and the outcome, in selected recent combination, compared to the combi-
patient series with epididymo-orchitis nation of doxycycline with streptomy-
due to brucellosis. cin, as outlined in Table 2, should also
apply to genitourinary involvement in
brucellosis.
5.1.1 Medication/drug therapy Duration of treatment is not analyti-
The therapeutic principles for uncom- cally reported in some of the relevant
plicated brucellosis include the admin- patient series: Most of the patients
istration of a combination regimen were cumulatively treated for six weeks,
(monotherapy is historically associated similarly to duration recommended
to an increased percentage of relapses for uncomplicated brucellosis. A sin-
or treatment failures) and the pro- gle study refers to treatment duration
tracted administration of antibiotics, of two months and suggests it as opti-
that reaches 6 weeks in uncomplicated mal. The presented data in this spe-
brucellosis, but may extend to more than cific study do not allow for further
3 months in severe complications as clarification of the rationale behind such
spondylitis. A panel of most of the world a suggestion. Alternative regimens are
experts on the subject recently reviewed included in the evidence-based guide-
the available therapeutic data and con- lines, and include the administration of
cluded in a form of evidence-based trimethoprim-sulfamethoxazole as a third
guidelines for uncomplicated brucellosis, component, and the use of fluoroquinolo-
termed the “Ioannina recommendations” nes as an alternative regimen when other
[20]. These recommendations apply to combinations cannot be used. Regarding
most complicated cases of brucellosis, fluoroquinolones in patients with epidi-
with the exception of abscesses, spondyli- dymo-orchitis, such compounds may be
tis, central nervous system involvement, used as an empirical monotherapy before
and endocarditis. Thus, theoretically they the suspicion or confirmation of brucel-
also apply to genitourinary complications losis: in that case, a transient but inad-
such as epididymo-orchitis (Table 2). The equate response may be observed, and
available literature on specific treatment the patient may be at risk of develop-
of epididymo-orchitis patients contains ment of necrotizing orchitis or abscess,
data too scarce and diverse to be ana- unless the proper therapeutic regimen
lyzed in any possible way. The diversity is administered. Whether the addition of
of the population studied and the ways it doxycycline to the already administered
was recruited plays an important role in fluoroquinolone is adequate therapeuti-
this: For example, in the 2001 Spanish cally in such cases cannot be answered,
study, the included patients may have due to the absence of published data on
been the patients with the most seri- the efficacy of fluoroquinolone-containing
ous cases of epididymo-orchitis, or bru- regimens in brucellar epididymo-orchitis
cellosis in general, that were referred in general.
964
Table 2 Therapeutic recommendation for epididymo-orchitis attributed to brucellosis.
Treatment Level of Grade of

regimen Dose evidence* recommendation* Comments
DOX-STR DOX: 100 mg twice 1a A Considered the “gold standard.”

daily orally for
6 weeks; STR:
15 mg/kg daily
intramuscularly for
2–3 weeks
DOX-RIF RIF: 600–900 mg 1a A Convenience of the regimen overco-

daily for 6 weeks, mes slight drawbacks concerning the
one morning dose pharmacokinetics of the combination
and the overall outcome.
DOX-GENT GENT: 5 mg/kg 1b A May be considered the preferred

daily parenterally in alternative regimen. Duration of GENT
1 dose for 7 days administration may need modification
for optimal result (different studies
suggest that it may be shortened to
5 days or extended to 14 days).
TMP-SMX- TMP-SMX: 800 + 2a C Recommendation referring to three-

containing 160 mg twice daily drug regimens containing DOX.
regimens for 6 weeks
Quinolone- Ofloxacin: 400 mg 2b A Ofloxacin or ciprofloxacin may be

containing twice daily for 6 used alternatively as second or third
combination weeks; ciprofloxa- agents in combination regimens con-
regimens cin: 500 mg twice taining DOX.
daily for 6 weeks
*level of evidence and grade of guideline recommendation refer to the treatment of uncomplicated brucellosis in general, and are applied to
epididymo-orchitis treatment, based on level of evidence 4 (expert committee reports or opinions or clinical experience of respected authorities).
Adapted from Ariza J, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations.
PLoS Med. 2007;4:e317[20]
Abbreviations: DOX-doxycycline, GENT-gentamicin, RIF-rifampicin, STR-streptomycin, TMP-SMX-trimethoprim-sulfamethoxazole.
5.1.2 Interventions 5.1.3 Follow-up – monitoring –

Surgical treatment is warranted in quality-of-life aspects
the absence of response to antibacte- As with all uncomplicated brucellosis, a
rial therapy, or when there is clinical clinical follow-up is advised, extending to
suspicion of an alternative diagnosis, 6 months, or one year, according to others.
including testicular tumors. Abscess for- The risk of relapse exists during this
mation can be treated with drainage or period, and can take the form of recurrent
orchiectomy. The latter is warranted in epididymo-orchitis, sometimes affecting
the case of testicular necrosis or if tes- the other testis [21]. Relapses should be
ticular tumor is a significant diagnostic treated identically to the initial infection.
possibility. It should be stressed though As already mentioned, a single study has
that, in the best interest of the patient, evaluated the impact of genitourinary
such an invasive procedure, with brucellosis on male fertility, showing the
major physical and psychological con- development of oligospermia or azoosper-
sequences, should be undertaken only mia in a subset of patients with brucel-
when appropriate antibacterial therapy lar epididymo-orchitis. In the majority of
has failed to cover an established diag- patients in this study, the phenomenon
nosis of brucellosis. reversed upon completion of treatment; it
965
did persist though in a few cases. Thus, should be elucidated, since its combina-
brucellosis can be included in the differ- tion with doxycycline may emerge as the
ential diagnosis of male infertility. There most efficacious and convenient one in
are practically no data on pediatric geni- the near future. Further validation of
tourinary brucellosis, thus one cannot real time PCR of urine samples as a diag-
speculate whether orchitis in this age nostic tool is also warranted. There is
group may be correlated to subsequent finally a need for evaluation of the effect
infertility issues in adult life. The theo- of genitourinary brucellosis in males in
retically sound, and isolatedly reported, semen production and quality; such a
possibility of bacterial presence in the study is strangely missing from medical
semen, allows for suggestion of avoidance literature.
of intercourse, until treatment comple-
tion: there have only been isolated reports
of possible sexual transmission of bru- 7. CONCLUSIONS
cellosis [13], but the theoretic potential
makes this recommendation reasonable. Although brucellar orchitis/epididymo-
The data on treatment of other geni- orchitis can raise suspicions of more
tourinary complications of brucellosis severe testicular pathology, the rapid rec-
are inadequate. In the case of prostatitis ognition of its infectious origin is feasible,
or abscess formation, it seems reason- particularly when taking into account the
able to propose a protracted therapeutic assorted epidemiological background of
regimen, or suitable invasive procedures each patient. Specific recommendations
(drainage, excision). Other complications for the optimal treatment of brucello-
should be treated according to the princi- sis, including genitourinary disease, are
ples of uncomplicated brucellosis. available, and clinicians should adhere
to them in order to minimize therapeutic
5.2 Special populations/exceptions failures, relapses, or more serious local-
ized complications.
5.2.1 Concomitant disorders
In the case of co-existent brucellosis
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967
|15.10|
Echinococcus/hydatid disease:
genitourinary involvement
Georgios Pappas, MD1, Ziad A Memish, MD, CIC, FRCPC, FACP, FIDSA2
1
Institute of Continuing Medical Education of Ioannina, H. Trikoupi 10, 45333, Ioannina, Greece
E-mail: gpele@otenet.gr
2
Director Gulf Cooperation Council (states) Center for Infection Control,
Executive Director Infection Prevention & Control Program, King Abdulaziz Medical City, Riyadh, KSA
Adjunct Professor Department of medicine, Division of Infectious Diseases
University of Ottawa, Canada,
E-mail: zmemish@yahoo.com
ABSTRACT be recognized due to it exerting space-

occupying pathology, and more rarely
Genitourinary hydatid disease equals through the, pathognomonic, hydatiduria.
renal infection by Echinococcus granu- The available therapeutically oriented
losus, since other localizations are lim- series on renal echinococcosis are old
ited to isolated case reporting. Although and only surgically oriented. Experience
there exist certain series of patients with with medical intervention through the
renal echinococcosis published in the lit- use of albendazole in renal hydatid dis-
erature, many of them are of historical ease is absent, and conclusions can only
value and not catching up with recent be extrapolated through what is known
advance in the treatment of hydatid dis- for hepatic hydatid disease. Depending
ease in general. Renal echinococcal dis- on the cyst size and the assorted array of
ease comprises 0.4 to 4% of the total symptoms, a surgical approach with cys-
hydatid disease burden. Renal hydatid tectomy/pericystectomy or, in larger cysts,
disease refers to a, typically unilateral, with partial or total nephrectomy, is advo-
renal cyst with unique characteristics cated. Smaller asymptomatic cysts can
that usually allow its rapid and safe rec- simply be followed-up. Pre-operative defi-
ognition with novel radiologic diagnostic nite diagnosis is important, in order for
approaches. Confirmation of the diagno- the surgeon to avoid rupture of the cyst,
sis can be achieved through numerous which may lead to anaphylactic shock
serologic approaches. Renal echinococco- and peritoneal seeding. There are no data
sis can be an accidental finding or it can on the use of percutaneous approaches as
Echinococcus/hydatid disease: genitourinary involvement | 15.10 |
PAIR in renal echinococcosis, so its use in genitourinary disease in the available

cannot be advocated at present. literature: A Turkish series reported a
case with concomitant hepatic and renal
Key words: hydatid disease, echinococ-
alveolar echinococcosis [1], (and also a case
cus granulosus, surgical, albendazole,
of ovarian involvement), while isolated
PAIR, renal echinococcosis
reports also exist in non-English medical
literature [2]. Indirect renal involvement
in alveolar echinococcosis, in the form of
amyloidosis [3], is beyond the scope of this
review.
Principles for avoiding surgical
The importance of renal hydatid dis-
therapy
ease may seem diminished, compared
1. Small, asymptomatic cysts can be to past decades, since the nature of a
adequately followed up through renal cystic mass can nowadays be read-
sequential ultrasonography. ily differentiated through sophisticated
imaging techniques, and the diagnosis
2. If ultrasonographic characteristics of hydatid disease can be outlined pre-
show a viable cyst that is expanding, operatively in most cases. Furthermore,
there is theoretical ground for use of the progress made in surgical interven-
albendazole (GoR C). tions has allowed for minimally amputa-
tion procedures to evolve, augmented by
Surgical approaches the appropriate use of chemoprophylaxis.
3. Cystectomy/pericystectomy is advo- Nevertheless, eradication of E. granu-
cated for smaller cysts (GoR C). losus remains futile, and international
travel allows for the disease (more pre-
4. Larger cysts or cases which have cisely, the patients) to circulate world-
affected the involved kidney’s viability wide: thus the disease, and its potential
should be treated with partial or total mis-diagnosis for tumor-like lesions, is
nephrectomy (GoR C). still relevant today.
5. The use of percutaneous approaches
such as PAIR, with or without adju-
vant albendazole, in spite of the rel- 2. METHODS
evant experience in hepatic hydatid
disease, cannot be advocated at A review of the published literature on
present in renal echinococcosis due to genitourinary involvement in echinococ-
the absence of available data (GoR D). cal disease, using PubMed and Scopus,
was performed by the authors. Keywords
used were “echinococcus or echinococ-
1. INTRODUCTION cal or hydatid or hydatidosis” and “geni-
tourinary or urinary or kidney or renal”.
Genitourinary hydatid disease practically All retrieved articles were evaluated,
refers to renal echinococcal involvement, although case reports, articles without
since all other localizations of Echinococcus abstracts, and articles not describing
in the genitourinary tract are limited to explicitly the therapeutic process fol-
random case reports. Echinococcus granu- lowed, were excluded. Of the 352 articles
losus accounts for practically all the cases screened by abstract, 74 were further
of renal echinococcosis; Echinococcus mul- evaluated through their full text, but only
tilocularis, the etiological agent of, the the ones subsequently referenced (seven
graver in prognosis, alveolar echinococ- in total summarized in the relevant Table)
cosis, has only isolatedly been implicated were considered eligible and inclusive of
969
relevant information. Additional reviews the cysts grow at diameter rate <15 mm/
on the subject of hydatid disease were year, needing 3–6 years on average to
evaluated for further information. Data on reach egg-size [6]. The internal layer is
treatment were sought in these articles. the germinal one, from which daughter
It should be stated that there are no ran- cysts emerge, and it is surrounded by an
domized control trials or meta-analyses acellular laminated membrane, which
for renal hydatid disease, the most com- in turn is surrounded by a fibrous layer
mon form of genitourinary echinococcal derived by the host, the pericyst, that can
involvement, published in the literature. be partly, or totally, when the cyst is no
It should also be stated that the majority longer viable, calcified. The hydatid cyst is
of the patient series with renal hydatid filled with scoleces and a hyaline fluid [6].
disease include patients that data as back
as the 1960s, when modern imaging and
3.2 Epidemiology
serologic diagnosis, as well as invasive
therapeutic procedures were not available. Human is an accidental intermediate dead-
Level of evidence and strength of rec- end host in the life cycle of E. granularis.
ommendation: The studies were rated Direct contact with infected hosts (defi-
according to the level of evidence and the nite, such as dogs, or intermediate, such as
strength of recommendations. The Oxford sheep) or ingestion of food contaminated
Centre for Evidence Based Medicine with shed eggs (for example non-washed
have produced a widely accepted adapta- vegetables) is incriminated for transmis-
tion of the work of the Agency for Health sion to humans. Thus, it is not surpris-
Care Policy and Research [4].The ICUD ing that the disease is more prevalent
consultations use a modified version of in rural regions and communities heav-
the Oxford system which can be directly ily involved in sheep raising. The disease
“mapped” onto the Oxford system [5]. remains a public health problem in the
Mediterranean, North and Northeastern
Africa, Central Asia including China, the
Middle East, Latin America, and Oceania
3. DEFINITION OF THE DISEASE
[7]. The slow growth of the hydatid cysts
though, which may need years to develop
3.1 Overview
any significant symptoms and be subse-
Cystic echinococcosis is caused by the quently recognized, means that, in case
tapeworm E. granulosus. Larvae of the of immigrants from areas endemic to the
parasite give rise to the hydatid cysts that pathogen, the disease may pose a differ-
are characteristics of the disease, multi- ential diagnostic problem for clinicians not
layered cysts that grow slowly, predomi- familiar with the disease.
nantly in the liver or the lungs. Canines,
such as dogs and wolves are the definite
3.3 Classifications
hosts: environmentally stable eggs are
shed after development and maturation in Genitourinary involvement in cystic
the canine intestine, and are subsequently echinococcosis is considered as the pres-
ingested by domestic ungulates, such as ence of a hydatid cyst in any part of the
sheep and cattle or camels (or human). genitourinary tract. The vast majority of
After ingestion, a larva is released by the cases refer to renal hydatidosis, which
egg, enters through the intestinal wall can develop in any part of the kidney.
into the circulation, and is usually cap- Isolated reports of hydatid cysts of the
tured by hepatic or pulmonary filters. prostate, bladder [8], testis, seminal vesi-
Subsequently a multilayered cyst devel- cles, and the female genitals also exist,
ops and gradually grows. The majority of but are too rare for appropriate guidelines
970
on recognition and treatment to develop. or can cause symptoms related to their

Renal echinococcal disease comprises 0.4 growth (mass effect): Lumbar pain or a
to 4% of the total hydatid disease burden. visible abdominal mass are the two most
The lowest percentage has been reported common presenting symptoms reported.
in a Chinese study [9], and the highest in Renal colic, usually accompanied by
a Tunisian one [10]. The median percent- hydatiduria, is also reported in varying
age is around 2% in most studies. frequency. More rare symptoms include
digestive complaints, gross hematuria, or
3.4 Characterisations fever, in the case of secondary infection of
the cyst. Hydatiduria: Upon rupture of a
3.4.1 Renal hydatid cyst hydatid cyst in the collecting system, pas-
It can be the solitary manifestation of sage of the cyst content, including scoleces
hydatid disease, or accompanied by other and cystic debris into the urine, gives rise
hydatid cysts in the liver or the lungs. It to a pathognomonic for renal echinococco-
almost always presents unilaterally. It sis state of passage in the urine of a grape-
is usually solitary and less often multi- like material.
ple cysts can be detected intrarenally. It
can be located everywhere in the kidney,
although most series report a slight pre- 4. CLINICAL EVALUATION/RISK
dominance for the superior pole. It can ASSESSMENT
grow in size giving the false positive radio-
logical view that it extends extrarenally, 4.1 Diagnostic and staging
but in most cases remains subcapsular. procedures
Accumulated pressure inside the cyst can The differential diagnosis of a renal cystic
result in rupture, most often into the col- mass is complex. Whether an incidental
lecting system, or more rarely retroperi- finding or causative of space-occupying
toneally or into the peritoneal cavity. If symptoms, imaging studies allow for
undetected, progressive growth can lead to the characterization of the cystic lesion
eventual destruction of the involved kidney and, modern techniques at least, allow
due to mechanical pressure. A slight pre- for orientation towards the diagnosis of
dominance of male patients can be traced hydatid disease in the proper settings.
in the available patient series, although The role of imaging techniques is para-
this may simply reflect the greater per- mount in diagnosis: Clinical symptoms
centage of males occupationally exposed are typically non specific, apart from
to the pathogen. In most series, median the presence of hydatiduria which is
patient age lies in the fourth decade of pathognomonic for renal echinococcosis.
life; taking into account that the growth Serologic diagnosis has significantly pro-
of the hydatid cyst to a symptom-causing gressed in recent years; in the case of
size requires years, one could specify the renal echinococcal disease, most serologic
median period of infection in late child- studies offer limited information due to
hood or early adulthood: this though can- inclusion of patients of previous decades.
not be ascertained, since growth rates of Extrapolation of the available experi-
each individual cyst do not follow a specific ence for hepatic hydatidosis in this case
pattern, but are rather decided by indig- though is theoretically sound.
enous characteristics of the parasite, as
well as anatomical details of the infected
4.2 Diagnostic criteria (testing
area. Renal hydatidosis in childhood is
procedures)
rarely reported [11–12]. Hydatid cysts
can be asymptomatic, detected inciden- Of the clinical symptoms, as already
tally during imaging for other indications, mentioned hydatiduria is pathognomonic
971
of the disease. The Casoni skin test has is non-specific. Most patients series report
been the mainstay of diagnostic orien- on the use of intravenous and retrograde
tation in the past, an experience also pyelography, as well as arteriography;
reflected in the renal echinococcosis lit- these methods though are of no use in the
erature. It is, or should be, abandoned era of modern imaging: Ultrasonography
nowadays. Inspection of urine samples can provide a rapid broad description of
for the presence of scoleces, hooklets or the lesion, and orientate toward hydatid
fragments of the parasitic membrane has disease in specific situations [19]: for
been performed in a few cases of some of example the “waterlily sign”, subsequent
the relevant studies; the presence of such to the detachment of the laminated mem-
elements is obviously pathognomonic brane, is pathognomonic. On experienced
and implies rupture of the cyst into, or hands, the disease cannot only be con-
at least communication with the collect- firmed but also classified according to the
ing duct [13–14]. Peripheral blood eosi- scheme proposed by WHO/OIE (World
nophilia is present in roughly half the Health Organization/ Office International
patients: in endemic areas it may be a des Epizooties) for hepatic cystic echino-
strong indicator of the parasitic nature of coccosis: Activity and fertility of the cyst
a renal cyst, but parasitic disease may be can thus be evaluated [20]. The most
attributed to a wide array of pathogens. important diagnostic advance though is
Positive serology is a strong indicator the ability of computerized tomography
for the presence of echinococcal disease. (CT) to accurately depict details of the
Various diagnostic serologic techniques cyst and its surroundings. The increased
have been developed, none though can density of the hydatid membrane which
be considered as the gold-standard [7]. enhances after intravenous administra-
ELISA and immunobloting, indirect flu- tion of contrast agent is also considered
orescence, and indirect hemagglutina- pathognomonic for hydatidosis. The den-
tion tests have been used with varying sity of the daughter cysts is also charac-
sensitivity and specificity. False positive teristically lower than that of the original
results can occur in cases of other para- cyst [21]. Magnetic resonance imaging
sitic infections, particularly cysticerco- has only been isolatedly evaluated and
sis. Most tests target antigens derived by any particular imaging advantages com-
the hydatid cyst fluid. Numerous candi- pared to CT have not been shown.
date antigens, aiming at improving spe-
cificity, are currently under investigation
4.3 Discussion
[15–16]. It should be noted that data on
the specificity and sensitivity of these Overall, the diagnostic possibility of renal
assays are practically based on the expe- hydatid disease should be taken into
rience with hepatic echinococcosis; the account when a cystic lesion of the kidney
use of these tests in series of renal echi- is present, particularly in endemic areas.
nococcosis patients, as reported in the Ultrasonographic and CT characteristics
literature, is scarce. For example, the can subsequently orientate towards such
utility of counter immunoelectrophoresis a diagnosis, and serology, preferably by
in a large patient series was evaluated two of the available methods in order to
in only 7 patients in a 34-patients series, increase specificity, can further confirm
and only in 2 out of 20 in another [13, the diagnosis without the need for inva-
17]. Similarly, indirect hemagglutination sive procedures. Diagnostic percutaneous
was tested in 18/23 and 19/178 patients paracentesis of a renal echinococcal cyst
in other series [10, 18]. has only been performed in rare cases
Plain abdominal x-rays can show calci- when the diagnosis had not been consid-
fications in the renal area, but this finding ered in the first place. It should always be
972
avoided upon suspicion of hydatid disease, months, and has been suggested as an opti-
due to the risk of severe anaphylactic mal treatment for inoperable disease or in
reactions that may lead do death in case of cases of systemic involvement (presence of
spillage of hydatid fluid in the peritoneal cysts in two or more organs). It is reported
cavity, and the risk for seeding of echinoc- as inducing 10–30% cure (disappearance
occal disease in other sites. of the lesion) and 50–70% improvement
(smaller size of the cyst or degeneration-
non-viable cyst). The relapses, reported in
5. PRINCIPLES OF MANAGEMENT 14–25% of the cases, can be retreated. A
recent review of the published experience
5.1 Therapy with albendazole in cystic echinococcosis
Table 1 reviews selected patient series [22] concluded that: i. albendazole is supe-
with renal echinococcal involvement and rior to placebo (or for that matter “wait and
the therapeutic approach applied, as well observe” approach) in inoperable cases, ii.
as potential consequences, when reported. is successful as a pre-adjuvant medication
It should be once more noted that most of in degenerating hydatid cysts prior to sur-
these series include patients diagnosed gery (miminizing thus operational risks),
prior to the increased differential diagnos- and iii. when used in conjunction with
tic opportunities offered by modern imag- the PAIR (Puncture, Aspiration, Injection
ing and serology, and thus their results of scolicidal agent, and Re-aspiration,
may be biased, regarding the invasive- see later) approach it is superior to PAIR
ness of the procedures used. alone or albendazole alone. What is not
It should also be noted that the natural know though, according to this review, is
history of renal echinococcal disease has whether albendazole is clearly superior to
been inadequately studied. The majority mebendazole, whether the combination of
of the patients included in these series albendazole and PAIR is superior to that
was symptomatic and was thus subject of albendazole and surgery, and whether
to a therapeutic approach. On the other the combination of albendazole and prazi-
hand, a “wait and observe” approach, quantel is superior to albendazole alone
with imaging follow-up could be advo- (when efficacy and toxicity are taken into
cated in cases where the disease is dis- account). Praziquantel increases by four-
covered accidentally. fold the concentrations of albendazole sul-
Finally, regarding medical treatment, it foxide, which is the scolicidal metabolite.
should be noted that experience with the A recent study compared the co-adminis-
use of benzimidazole derivatives in renal tration of albendazole and praziquantel
disease is limited to absent. Whether alone with their use in conjunction with
their use can replace invasive interven- surgery and concluded that no significant
tions or the “wait and observe” approach differences existed between the two groups
is further discussed on purely theoretical [23]. The major side effects of albendazole
grounds. include nausea, hepatotoxicity, potentially
non-reversible neutropenia, and alopecia.
The suggested dose for mebendazole
5.1.1 Medication/drug therapy is 40–50 mg/kg of body weight, in three
Albendazole and mebendazole are the divided doses.
two benzimidazole derivatives that have
been used in cystic echinococcal disease in
general. Of these, the former is the most 5.1.2 Interventions
extensively studied. It is administered Surgical interventions are the thera-
orally, 10–15 mg.kg of body weight in two peutic mainstay in all renal hydatidosis
divided doses, for a period extending to 3–6 series reviewed in Table 1. Conservative
973
Table 1 Selected patient series on renal hydatid disease and therapeutic interventions.
Country/Year Number of
[reference] patients Therapeutic interventions Comments
Morocco 1993 [31] 45 Nephrectomy (7 patients)

Partial cystopericystectomy (38)
Spain 1994 [32] 22 Nephrectomy (10 patients) Co-administration of mebendazole in 2

patients
Partial nephrectomy (5)
Cyst excision (4)
No intervention (3)
Spain 1997 [13] 34 Nephrectomy (21 patients) Pectunaeous approach for diagnostic
purposes in 4 patients
1 episode of anaphylaxis
Cyst excision/pericystectomy (7)
2 episodes of seeding
2 secondary nephrectomies (due to
urinary fistula)
Tunisia 2001 [10] 178 Nephrectomy (44 patients) 12 episodes of urinary fistula,
and 5 episodes of infection of
Cyst excision/pericystectomy (134)
remnant cavity, requiring in total
2 secondary nephrectomies
2 episodes of recurrence
Tunisia 2001 [33] 147 Nephrectomy (20 patients) 2 episodes of urinary fistula,
and 1 episode of suppuration of
remnant cavity
Abstention (5)
Morocco 2002 [34] 34 Nephrectomy (6 patients)

Pericystectomy (5)
Turkey 2003 [17] 20 Nephrectomy (13 patients)

Cystectomy and marsupialization (6)
Nothing (1)
Jordan 2004 [14] 8 Nephrectomy (5 patients)

Cyst excision (2)
approaches include cystectomy and peri- Echinococcus into the peritoneal cavity is
cystectomy, and require a preoperative def- also a major concern. Even in large cysts
inite diagnosis of the hydatid nature of the exerting significant pressure in the kidney,
cyst, through specific imaging and serology. these procedures have been related to sub-
This is important in order for the surgeon sequent kidney re-expansion and absence
to undertake all measures in order to avoid of sequelae in the future. Partial and total
spillage of the cyst content during surgery: nephrectomy were the procedures of choice
Serious anaphylactic reactions, resulting in most patients from past decades in renal
even to death, have been reported in renal hydatidosis series, mainly due to the diag-
hydatidosis, while the risk of seeding of nostic uncertainty regarding the nature of
974
the cyst, due to the more primitive imag- from the experience with liver echinoc-
ing techniques available. Nowadays, total occosis. Thus, upon discovery of a renal
nephrectomy should be the optimal thera- cyst with the imaging characteristics of
peutic approach in cysts too large to be hydatid disease, and upon serological con-
handled otherwise, or when the involved firmation of the diagnosis, preferably with
kidney is considered non-viable. The avail- two of the available methods, the subse-
able data for a percutaneous approach in quent approach depends on the viability
echinococcal disease of the kidney are lim- of the involved kidney and the severity
ited [24–26]: In one of these series, focus- of symptoms. Interventional procedures,
ing on univesicular cysts, an approach either cystectomy/pericystectomy or total/
similar to PAIR was used. In general, the partial nephrectomy should be advocated
risks of percutaneous aspiration are simi- in large cysts exerting significant pathol-
lar to these of cyst rupture during open ogy. At present, experience with PAIR in
surgery, i.e. spillage and anaphylaxis renal hydatidosis is limited to advocate
or secondary seeding. PAIR (Puncture, it in an evidence-based manner in renal
Aspiration, Injection of scolicidal agent, hydatidosis; centers with experience on
and Re-aspiration) has emerged as the the subject though should further experi-
optimal therapeutic approach in many mentally explore its utility. Renal hydatid
cases of hepatic hydatidosis, offering clini- cysts that are accidentally discovered and
cal efficacy and fewer complications, as exert no effect on kidney viability and no
well as minimizing the hospitalization or minor symptoms, can be followed-up by
duration and patient sequelae compared ultrasound for evaluation of activity and
with more invasive procedures. Typically fertility and the need for potential inter-
PAIR is accompanied by pre- and post- vention. These cases can also be treated
intervention use of albendazole, starting with albendazole, particularly when other
usually 24 hours prior to PAIR and con- localizations are also present, expecting
tinuing for 15–30 days. A meta-analysis disappearance, shrinkage, or degeneration
showed that the combination of PAIR and of the cyst in a considerable percentage of
albendazole or mebendazole was superior patients. The addition of praziquantel to
and associated with less morbidity, mor- enhance albendazole scolicidal effect can-
tality, and hospitalization duration than not be definitely advocated at present. An
surgical intervention in liver hydatid cysts albendazole course can be tried in patients
[27]. A significant risk with PAIR in liver who are candidate for surgery also, if there
hydatidosis is the existence of communica- is no indication of immediate surgery and
tion between the biliary tree and the cyst, if the kidney is viable, aiming at minimiz-
which may lead to sclerosing cholangiitis ing cyst size and achieving a less extensive
after instillation of the scolicidal agent. surgical procedure in the future.
There is no information on the potential The therapeutic options in renal hydati-
effect of the scolicidal agent in the collect- dosis are summarized in Table 2.
ing duct in cases of communicating renal
cysts.
In conclusion, there is insufficient evi- 5.1.3 Follow-up – monitoring –
dence regarding the optimal treatment of quality-of-life aspects
renal hydatid disease, due to the relative Although immunological follow-up has
rarity of the disorder and the fact that a been useful after cyst removal [28],
significant percentage of literature data is the mainstay of follow-up for detection
derived from past decades, when sophis- of residual disease, seeding of the dis-
ticated diagnostic and interventional ease during surgery, recurrence, or re-
procedures were limited. The current appearance of hydatid cysts in other
available evidence is mainly extrapolated organs, is imaging, and particularly
975
Table 2 Therapeutic options in renal hydatidosis and level of evidence/strength of recommendation.
Therapeutic module Level of evidence Grade of recommendation
Nephrectomy 3 C
Cystectomy/Pericystectomy and 3 C
modifications
PAIR (Puncture, Aspiration, Injection of – D

scolicidal agent, and Re-aspiration)
Albendazole 3 C
PAIR and albendazole – D
ultrasonography in the case of renal 7. CONCLUSIONS

hydatidosis. Preservation of renal anatom-
ical integrity is the major pre-requisite in Prompt recognition of renal hydatid
treatment planning in cases of renal echi- disease is feasible due to advances in
nococcal disease, and should be the major imaging, and of paramount importance
concern in therapeutic planning. prior to any therapeutic intervention in
order to avoid intra-operative rupture.
5.2 Special populations/exceptions Although experience in renal echinococ-
5.2.1 Concomitant disorders cosis is mainly historical or extrapolated
from hepatic echinococcosis, an experi-
Albendazole is potentially teratogenic enced surgeon can guarantee an optimal
and thus its use in pregnancy should be outcome, even with preservation of the
preferably avoided. Echinococcosis in involved kidney’s function, if surgical
pregnancy is an even rarer entity requir- intervention is needed.
ing critical decisions applying to mother
and fetal health [29]. A single case of
renal hydatidosis in pregnancy has been
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Renal echinococcosis: clinical study of 34 Percutaneous drainage of renal hydatid
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978
Chapter |16|
Classification of urinary
tract infections
Chair: Truls E. Bjerklund Johansen
CHAPTER OUTLINE
16.1 Critical review of current definitions of urinary
tract infections and proposal of an EAU/ESIU
classification system 980
|16.1|
Critical review of current

definitions of urinary tract
infections and proposal of an
EAU/ESIU classification system
Truls E. Bjerklund Johansen1, Henry Botto2, Mete Cek3, Magnus Grabe4, Peter Tenke5,
Florian M.E. Wagenlehner6, Kurt G. Naber7
1
Urology Department of Urology, Århus University Hospital, Skejby, Århus University, Århus, Denmark
2
Department of Urology, Hopital Foch, Suresnes Cedex, France
3
Department of Urology, Taksim Teaching Hospital Istanbul, Istanbul, Turkey
4
Department of Urology, Malmö General Hospital, University of Lund, Malmö, Sweden
5
6
Department of Urology, University of Giessen, Giessen, Germany
7
Corresponding Author: Truls E. Bjerklund Johansen, MD, PhD
Chairman and Professor, Urology Department, Århus University Hospital, Skejby, Aarhus University
Brendstrupgårdvej 100, DK-8200 Århus N, Denmark
ABSTRACT the EAU/ESIU classification system

ORENUC based on the clinical presen-
Classification of urinary tract infec- tation of the UTI, categorisation of risk
tions (UTI) is important for clinical deci- factors and availability of appropriate
sions, research, quality measurement antimicrobial therapy, which finally may
and teaching. Current definitions of UTI result in the definition of UTI severity
are above all based on the concept of the groups.
two main categories, complicated and
uncomplicated UTI. The category “com- Key words: classification, urinary tract
plicated UTI” especially is very heteroge- infection, cystitis, pyelonephritis, urosep-
neous and not always clear. We propose sis, risk factors
Critical review of current definitions of urinary tract infections | 16.1 |
1. INTRODUCTION Development of a new classification of urinary tract infections
The objectives of classification of diseases Clarifying the purposes
are Evaluation of current classifications of UTI (CDC, IDSA, ESCMID)

• to organise current knowledge
• to provide a basis for guidelines on Defining key features for a good classification system
diagnosis and treatment

Good Bad
• to provide a framework for design of
research projects Defining key criteria for assessment of patients with UTI
• to provide a framework for registration
of clinical activity Organising criteria into categories of risk factors
A classification must be consistent with Phenotyping risk factors

prevailing medical rationality and fit
with other frequently used classifications. Identifying clinical types of UTI
Classification categories must be clini-

Defining UTI severity grades
cally relevant. The number of categories
and grades has to be limited, so that it is
Figure 1. Development of a new classification of urinary
easy to learn and remember. A classifica- tract infections.
tion has to be tested in studies and prac-
tice. As knowledge increases and clinical
practice changes, classification systems categories of primary tumour exten-
must be revised. sion, nodal status and metastases. Each
category is staged according to a simple
2. MATERIALS AND METHODS numerical scale. In the UPOINT classi-
fication of chronic pelvic pain syndrome,
This paper presents a review of the prin- phenotypes are registered as present
ciples for disease classification, a critical or absent [1]. Results of a primary cat-
evaluation of current definitions of UTI egorisation and staging may be further
and a discussion of key criteria for clas- organised on a secondary level like the
sification of UTI. Based on this work we American four letter (A-D) [2] or stage
suggest modifying the classification of (I-IV) system [3] and the D`Amico three
UTI. The method used can be described figures risk stratification in prostate
as a consensus process involving experts cancer [4].
with clinical, scientific and organisational
experience on a high level (Figure 1).
3.2 CLASSIFICATION OF UTI
3. RESULTS 3.2.1 Evaluation of current

classifications
3.1 Principles for disease The most widely used classification of
classification urinary tract infections (UTI) are those
Diseases are usually characterised by a developed by the Centers for Disease
set of categories and described in more Control and Prevention in USA (CDC) in
detail by a grading system. For example, 1988 [5] and updated in 2008 [6], IDSA in
malignant diseases are classified with 1992 [7] and ESCMID in 1993 [8].
981
Chapter | 16 | Classification of urinary tract infections
The purpose of the CDC definitions is urinary tract like obstruction, stones,
to define and report health care-associ- diversion and catheters. Other factors
ated (nosocomial) UTI. In the 1988 edi- relate to kidney diseases or co-morbid-
tion UTI comprised symptomatic UTI, ities like diabetes mellitus, malignan-
asymptomatic bacteriuria (ASB) and cies or immune competence (e.g. immune
other infections of the urinary tract. compromised patients). In these guide-
Diagnosis of symptomatic UTI is based lines “complicated” also means a higher
on symptoms and evidence for the pres- risk for clinical complications if the UTI
ence of a pathogen. The definition pro- is not properly treated as in pregnancy
vides several possible types of evidence and childhood. The investigations needed
such as culture, dipstick, microscopy, to diagnose or exclude all the risk fac-
physician’s diagnosis or appropriate anti- tors are not clearly described. IDSA
biotic therapy. Repeated cultures are also introduced graded criteria for the
needed when the urinary culture reveals amount of bacteria as expressed by col-
colony forming units (CFU) < 102/ml. Two ony forming units (CFU) in the diagnosis
cultures are needed for diagnosing ASB of UTI in different groups of patients and
in patients without an indwelling cathe- situations.
ter for the last seven days before culture Most current UTI guidelines and
is taken. In the 2008 update the concept study protocols are based on the IDSA
of health care associated UTI (HA-UTI) [7] and ESCMID [8] guidelines using
is broadened and nosocomially acquired the concept of uncomplicated and com-
UTI (NA-UTI) has become a subtype plicated UTI with some modifications.
of HA-UTI [6]. In both editions it is not However, the term “complicated” some-
made quite clear, however, whether ASB times means an increased risk of getting
is considered an infection or probably UTI, sometimes it refers to an increased
only a risk factor under certain circum- risk of treatment failure, and sometimes
stances. The CDC definitions of HA-UTI an increased risk of loosing nephrons or
appear complex to read and to be applied even the patient’s life. In complicated
in clinical practice, but may be useful UTI other pathogens than E coli, other
for prevalence or incidence studies if antimicrobials and longer treatment
adapted to specific urological needs (see duration have to be considered. This
Chapter 12). mixed understanding of “complicated”
The IDSA [7] and ESCMID [8] guide- makes the group of complicated UTI
lines were mainly developed for the very heterogeneous and results of a clin-
evaluation of new anti-infective drugs in ical study on patients with one criterion
clinical studies. IDSA introduced the con- defining “complicated” cannot be trans-
cept of complicated and uncomplicated ferred to other patients with complicated
UTI in order to obtain more homogene- UTI where the diagnosis is based on dif-
ous study groups. In “uncomplicated” ferent criteria. Therefore, more than two
UTI mainly UTI due to Escherichia categories are needed for a comprehen-
coli and in “complicated” UTI also UTI sive description of patients’ risk factors
caused by other pathogens than E.coli related to UTI.
can be studied. The term “uncompli-
cated” means that the patient has no
known factors that will render him or 3.2.2 Criteria for classification of UTI
her more susceptible to develop UTI. The information needed for assessment
Complicated is defined as the presence of a patient suspected of having a UTI
of these factors, but the understanding is presented in Table 1. The criteria are
of “complicating factors” is not always organised into five main categories.
clear. Some factors are related to the Categories I-III and V are important for
982
Table 1 The most important criteria for patient assessment in UTI.
I. Clinical criteria
1. Clinical presentation
a. Urethritis* (UR)
b. Cystitis (CY)
c. Pyelonephritis (PY)
d. Urosepsis (US)
e. Male accessory gland infection (“male adnexitis”)* (MA) (prostatitis, vesiculitis, epididymitis, orchitis)
*need to be considered separately, because the clinical presentations show great diversity (see chapters #13 and #14)
2. Specificity of symptoms
a. UTI specific
i. For lower UTI (cystitis): dysuria, frequency, urgency, suprapubic pain
ii. For upper UTI (pyelonephritis): fever, flank pain, CVA tenderness
b. UTI non-specific symptoms, but relevant in specific clinical situations
i. For catheter associated UTI, e.g. bladder spasm, fever not explained otherwise
ii. For newborn and young children (see chapter #6 on UTI in children)
iii. For elderly patients, e.g. fever not explained otherwise, confusion (see also #10.4)
iv. For patients with neurogenic disorders, e.g. vegetative disorders (see section #8)
3. Severity of symptoms (there is no validated scoring system)
a. Mild
b. Moderate
c. Severe
d. Septic (see definitions of severity of sepsis)
4. Pattern of infection
a. Isolated or sporadic
b. Recurrent
i. Relapse
ii. Reinfection
c. Unresolved or chronic
II. Possible risk factors
1. Patient’s characteristics
a. Gender (male, female)
b. Prematuity, newborn, young child, adolescent
c. Premenopause
d. Pregnancy
e. Postmenopause
f. Elderly (geriatric: physically and/or mentally handicapped)
2. Relevant* diseases outside the urinary tract (*needs to be verified in clinical studies)
a. Immunosupression (not clear at which state it is relevant for which kind of UTI)
i. Innate
ii. Acquired, e.g. AIDS
b. Diabetes mellitus (not clear at which state it is relevant for which kind of UTI)
c. Other diseases (not clear which ones are relevant and for which kind of UTI)
(Continued)
983
Table 1 (Continued)
II. Possible risk factors (Continued)

3. Nephrological risk factors – status of the kidneys
a. Impaired kidney function (not clear which degree of renal insufficiency is relevant for which kind of UTI)
b. Kidney abscess
c. Polycystic renal disease
4. Urological risk factors (functional or morphological disorders (impaired urodynamics) within the urinary tract. (The
degree of impairment is not well defined)
a. Functional disorders e.g. reflux, neurogenic bladder disturbances
b. Obstruction without infectious nidus e.g. tumour, non-infected stone
c. Obstruction with infectious nidus e.g. infective stones, necrotising tumour, stent
5. External catheter
a. Urethral
b. Suprapubic
c. Nephrostomy
d. Others
6. Asymptomatic bacteriuria (ASB): ASB is not considered an infection and is usually not relevant, but in some
situations ASB is a risk factor, e.g in pregnancy and before traumatazing interventions of the urinary tract. In some
situations differentiation between asymptomatic and symptomatic bacteriuria is difficult, e.g. young children,
elderly patients, patients with spinal cord injury
III. Pathogen/etiological agent
1. Bacterial load (colony counts)

2. Pathogens (type, species)
3. Antimicrobial susceptibility/resistance
4. Virulence etc.
IV. Situation – circumstances under which UTI was acquired
1. Community
2. Outpatient service
a. Hospital setting
b. Private practice
3. Inpatient service (Hospital)
4. Long term residential accommodation, nursing home
5. Health care associated (2–4)
V. Therapeutic options
1. Pathogen(s) is (are) susceptible against commonly used antimicrobials,

a. which are available
b. which are not easily available
2. Pathogen(s) has (have) limited susceptibility against commonly used antimicrobials,
a. but alternative antimicrobials are available
b. but alternative antimicrobials are not easily available
3. Pathogen(s) is (are) multiresistant and appropriate antimicrobials are not (or not easily) available
984
diagnosis and treatment, while category hospitalization may be recommended. For

IV is important for surveillance of treat- urosepsis the severity grading of sepsis in
ment quality and the environment. Not general use can be adapted: sepsis, severe
all criteria are equally relevant for clas- sepsis, septic shock [9–10].
sification of UTI. In a clinical situation,
however, all criteria have to be consid- 3.2.3.3 Risk factors
ered. This shows the complexity of clini- Ideally all five main categories as out-
cal decision making in the treatment of lined in Table 1 should be weighted and
UTI. A more detailed assessment of cer- graded according to their impact on
tain criteria may be relevant in research prognosis. Unfortunately, our knowledge
projects. about their relative impact is scarce,
and therefore they cannot be just added
3.2.3 Presentation of symptomatic UTI together. Furthermore, some criteria are
numerical and continuous i.e. number of
3.2.3.1 Definition of symptomatic UTI
CFU. Some are dichotomous variables
A patient has a symptomatic UTI if there like gender. Others are categorical, like
are clinical symptoms indicative of UTI names of pathogens, and types of accom-
and if presence of pathogens can be veri- modation. We therefore recommend
fied or suspected by culture, microscopy, that the principle of phenotyping [1]
dipstick or PCR-techniques, or if the is applied on risk factors and that they
diagnosis or an appropriate therapy of are organised into groups as suggested
symptomatic UTI is made by a physician earlier [11].
upon clinical evaluation. This is consist- Risk factors may affect the patient
ent with the CDC definitions [6]. in different ways and may be grouped
according to knowledge on impact on out-
3.2.3.2 Clinical presentation come and prognosis. Some risk factors e.g.
The clinical situation is classified as cys- pregnancy, prematurity, newborn, and
titis (CY), pyelonephritis (PY) and uro- immune deficiency mean an increased
sepsis (US) as in the CDC definitions risk of a serious outcome like abortion,
[6]. Asymptomatic bacteriuria (ASB) is loss of nephrons, or even the patient’s life.
considered not as infection but as a risk Others mean that a more elaborate treat-
factor for UTI in certain circumstances. ment regimen is needed e.g. obstruction
Urethritis (UR) and male accessory gland of the urinary tract and kidney abscess.
infections (“male adnexitis”) (MA, e.g. Some risk factors increase the risk that
prostatitis) need to be discussed sepa- a UTI will recur, e.g. incomplete blad-
rately, because the clinical presentations der emptying and indwelling catheter.
show great diversity. The clinical pres- In recognition of the characteristics of
entation of the three UTI entities dis- risk factors relevant for the three infec-
cussed here (CY, PN, US) are presented tions (CY, PN, US) discussed here, we
in Table 2 with the attempt to create have re-organised the risk factors into six
severity grades considering that a PN is groups and propose the ORENUC sys-
always more severe than a CY and a US tem for phenotyping (Table 3): O – NO
always more severe than the two former known risk factor; R – risk for Recurrent
ones. In addition, PN can present as a UTI, but without risk of more severe out-
mild and moderate infection, which usu- come; E – Extraurogenital risk factors;
ally can be treated by oral antimicrobi- N – relevant Nephropathic diseases; U
als in an outpatient setting, and as a – Urological resolvable (transient) risk
severe infection with systemic reactions factors; C – permanent external urinary
like nausea and vomiting, which usu- Cathether and non resolved urological
ally needs initial parenteral therapy and risk factors.
985
Table 2 Clinical presentation of cystitis (CY), pyelonephritis (PN) and urosepsis (US) and grading of severity.
Clinical Grade of
Acronym diagnosis Clinical symptoms severity
CY-1 Cystitis dysuria, frequency, urgency, suprapubic pain; sometimes 1

unspecific symptoms (see table 1)
PN-2 Mild and moderate fever, flank pain, CVA tenderness; 2

pyelonephritis sometimes unspecific symptoms (see table 1)
with or without symptoms of CY
PN-3 Severe pyelonephritis As PN-2, but in addition nausea and vomiting 3

with or without symptoms of CY
US-4 Urosepsis (simple)* Temperature > 38°C or < 36°C 4

Heart rate > 90 beats min
Respiratory rate > 20 breaths/min or
PaCO2 < 32mmHg (< 4.3kPa)
WBC > 12,000 cells/mm3 or < 4,000 cells/mm3 or
≥10% immature (band) forms
With or without symptoms of CY or PN
US-5 Severe urosepsis* As US-4, but in addition associated with organ dysfunction, 5
hypoperfusion or hypotension.
Hypoperfusion and perfusion abnormalities may include but
are not limited to lactic acidosis, oliguria or an acute altera-
tion of mental status
US-6 Uroseptic shock* AS US-4 or US-5, but in addition with hypotension despite 6
adequate fluid resuscitation along with the
presence of perfusion abnormalities that may include, but are
not limited to lactic acidosis, oliguria, or an acute alteration
in mental status. Patients who are on inotropic or vasopressor
agents may not be hypotensive at the time that perfusion
abnormalities are measured.
X – severity category of the corresponding infection: CY, PN or US.

Note: Hypotension due to urosepsis is defined as a systolic blood pressure of < 90mmHg or a reduction of > 40mmHg from baseline in the
absence of other causes of hypotension.
*Urosepsis is defined as sepsis originating from the urogenital tract. Definition of severity is modified according to [9–10].
3.2.3.4 Antimicrobial treatment options of effective antimicrobials (Table 4).

Antimicrobial treatment is a cornerstone Updating is always needed with time and
in the treatment of UTI. Without anti- as knowledge increases.
biotics (as in developing countries) or
without effective antibiotics (as already 3.2.3.5 Severity assessment
in some countries to-day) the prognosis When assessing a patient the severity
may be very serious. For assessment of of the situation always has to be con-
prognosis and severity of UTI we suggest sidered. As mentioned earlier the clini-
that the chance of effective antimicro- cal presentation outweighs all other
bial treatment is included in the overall categories of information for diagnos-
assessment of severity in a patient with tic workup and treatment, because PN
UTI. We suggest a grading with small let- is always more severe than CY and
ters a-c based on the susceptibility of the US always more severe than the two
causative pathogen(s) and the availability former ones. Therefore assessment of
986
Table 3 Host risk factors in urinary tract infections categorized according to the ORENUC system.
Phenotype Category of risk factor Examples of risk factors
O NO known risk factor Otherwise healthy premenopausal women
R Risk factors for Recurrent UTI, but no risk of Sexual behaviour (frequency, spermicide),
more severe outcome
Hormonal deficiency in postmenopause
Secretor type of certain blood groups
Well controlled diabetes mellitus
E Extra-urogenital risk factors with risk of more Prematurity, newborn

severe outcome
Pregnancy
Male gender
Badly controlled diabetes mellitus
Relevant immunosuppression (not well defined)
N Nephropathic dieseases with risk of more Relevant renal insufficiency (not well defined)
severe outcome
Polycystic nephropathy
Interstitial nephritis, e.g. due to analgetics
U Urological risk factors with risk of more Ureteral obstruction due to a ureteral stone
severe outcome, which can be resolved
Well controlled neurogenic bladder disturbances
during therapy
Transient short-term external urinary catheter
Asymptomatic bacteriuria*
C Permanent urinary Catheter and non resolv- Long-term external urinary catheter
able urological risk factors with risk of more
Non resolvable urinary obstruction
severe outcome
Badly controlled neurogenic bladder disturbances
*only under certain circumstances in combination with other risk factors, e.g. pregnancy, urological intervention.
X – severity category of the corresponding infection: CY, PN or US.
Table 4 Therapeutic option.
Grade a b c
Situation Pathogen(s) is (are) susceptible Pathogen(s) has (have) reduced Pathogen(s) is (are)
against commonly used susceptibility against commonly multiresistant and/or
antibiotics, which are available used antibiotics, but alternative appropriate antimicrobials
antimicrobials are available are not available
severity always starts with the clinical (Table 3). For example: a cystitis (CY)
presentation and the treatment needed. combined with a risk factor of cate-
The assessment of underlying risk fac- gory “E” or “U” is usually more severe
tors is descriptive and may modify the than of category “O” or “R”. Therefore
severity of each clinical presentation the severity category for CY could be
987
modified accordingly. The same applies The handling of the proposed EAU/
for pyelonephritis (PN) and urosepsis ESIU classification is illustrated by some
(US). However, it is difficult to quan- examples in Table 5.
tify the modification by a certain risk
factor without validation. Therefore,
at this stage it is suggested to add the 4. DISCUSSION
category of the risk factor in a descrip-
tive manner only. In addition, the avail- Good and well known definitions make
ability of an appropriate antimicrobial treatment decisions easier and facilitate
therapy modifies also the risk of a more teaching and research in the field of UTI.
severe outcome in any of the clinical No clear definition of the term “com-
presentations. plicated” has ever existed, and current
Although not explicitly included, ure- definitions of complicated UTI caused
thritis (UR) could probably be handled as many controversies. According to the
cystitis, whereas acute prostatitis, epidi- IDSA [7] and ESCMID [8] guidelines
dymitis or orchitis (MA) could be handled uncomplicated UTI only occurs in oth-
like pyelonephritis, which also is an acute erwise healthy premenopausal (young)
parenchymal infection. The severity of an non pregnant women with susceptible
acute infection of these male accessory pathogens and without recurrent UTI.
glands (MA) could probably be subclas- For drug studies it was even suggested
sified in mild and moderate (MA-2) and to include only those women with acute
severe with systemic reactions (MA-3) cystitis who have ”significant” bacteriuria
similar to acute pyelonephritis. Sepsis (cfu >105/ml) [12], although it is known
originating from such infections may also since decades that also lower counts of
be classified as urosepsis with the three uropathogens can be relevant for an acute
grades of severity (US-4, US-5, US-6). episode of uncomplicated cystitis [13].
The risk factors mentioned in Table 3 In all other situations, e.g. in man
could be used as modifiers in the same by definition, a UTI had to be classi-
way as for CY, PN or US. Chronic bacte- fied as complicated, but uncomplicated
rial prostatitis and chronic pelvic pain cystitis although rarely also exists in
syndrome is better described with the men, especially in young men [14–15].
UPOINT system [1]. This has lead to the strange situation,
that many different patients have been
lumped into studies on complicated UTI.
3.2.4 Description of a UTI episode Unfortunately the results of these stud-
A given episode of UTI should be ies were then extrapolated to all patients
described with a short sentence indi- with complicated UTI with the conse-
cating the clinical diagnosis, the pres- quence that these treatment modalities
ence of risk categories as phenotypes, failed in patients with severely compli-
the pathogen(s), and the availability of cated UTI. This situation underlines that
appropriate antimicrobial therapy (see the concept of complicated and uncompli-
Table 4). The following parameters are cated may cause confusion rather than
described separately: Pattern of infection, good treatment decisions. The classifica-
the situation under which the UTI occurs tion in complicated and uncomplicated
and the source of culture sample. The UTI was intended to be a guide whether
“Situation” has to be described at least a UTI in a specific patient means an
for surveillance or research purposes. If increased risk for a more seriously out-
a pathogen was not identified, the name come unless additional precautions or
of the pathogen is replaced by the word treatment modalities are applied. This
“anonymous”. intention will be easier met with the new
988
Table 5 Examples of clinical diagnosis, severity grading, risk factors, uropathogen and antibiotic treatment option according
to the ORENUC classification system (Tables 2–4).
CY-1R: E coli (a)

Premenopausal otherwise healthy women with recurrent cystitis (CY) (severity grade 1, risk factor: R), causative agent
Escherichia coli susceptible to common antimicrobials (a), which are also available in the country. Former: uncomplicated
recurrent cystitis.
CY-1E,U: P. aeruginosa (c)

Cystitis (CY) in a pregnant kidney transplant patient (severity grade 1, risk factor: E) with nephrological (risk factor: E) and
urological risk factors (JJ-stent) (risk factor: U) and no effective antibiotics due to a multiresistant P. aeruginosa (c). Former:
complicated cystitis.
PY-3O: E. coli (b)

Severe febrile acute uncomplicated pyelonephritis (PY) with nausea and vomiting in an otherwise healthy premenopausal
woman with no known risk factors (severity grade 3, risk factor: O), due to E coli with reduced susceptibility
(fluoroquinolone resistance) (b). Former: uncomplicated (severe) pyelonephritis
PY-2E,U: K. pneumoniae (b)

Moderate acute pyelonephritis in a man with urinary obstruction due to ureteral stone and relief of obstruction by
JJ-stent (severity grade 2, risk factor: E and U), causative agent Klebsiella pneumoniae with reduced susceptibility (ESBL)
(b), Former: complicated (moderate) pyelonephritis.
US-4E,C: P. mirabilis (a)

Urosepsis in a diabetic geriatric woman in a nursing home with permanent indwelling urinary catheter due to
incontinence, but without organ failure or shock (severity grade 4, risk factor: E). Uropathogen susceptible to ciprofloxacin
(a), which is available.
MA-3U: E. coli (b)

Acute prostatitis with fever, nausea and vomiting after transrectal prostate biopsy (severity grade 3, risk factor: U) due to a
ciprofloxacin resistant E. coli (b) in a 65 year old man.
classification where each patient will be UTI. It should be replaced by UTI

assessed according to UTI severity grade grades with similar risk factors which
and specific risk phenotypes. finally may lead to the concept of sever-
Asymptomatic bacteriuria is a key ity groups, like in prostate cancer [2, 4].
issue. Since ASB can now longer be con- We are, however, aware that there is
sidered as infection, it may better be limited scientific evidence to support the
described as “colonisation”. In some selection of categories and grades at the
situations ASB may even be protective present time point. As the first step this
for recurrent symptomatic UTI [16]. kind of classification needs to be tested
However, under certain circumstances with data from already published stud-
ASB is recognised as a risk factor to ies and then it has to be evaluated in
develop (symptomatic) UTI as seems to be specifically designed prospective stud-
the fact in pregnancy, early childhood and ies. Categories and grades should then
during interventions in the urinary tract be adjusted as more knowledge is gath-
[17], and ASB has to be treated appropri- ered about the relative importance of risk
ately. This double role of ASB has to be factors. For example, the concept of vir-
recognised and handled carefully accord- ulence may one day outweigh the impor-
ing to the clinical situation. tance of colony-forming units. There has
A key ambition of the definitions of UTI to be a continuous development process
presented here is to abolish the current with consensus meetings of thought lead-
concept based on only two UTI classes, ers. This new classification can easily
“uncomplicated” versus “complicated” adopt changes. Severity grades in specific
989
infections of the urinary tract have to be Beard CJ, and Wein A, Biochemical out-
dealt with in future meetings. come after radical prostatectomy, external
beam radiation therapy, or interstitial radi-
ation therapy for clinically localized pros-
5. CONCLUSIONS tate cancer. Jama, 1998. 280(11): 969–74.
5. Garner JS, Jarvis WR, Emori TG, Horan
The new classification of UTI presented TC, and Hughes JM, CDC definitions for
nosocomial infections, 1988. Am J Infect
in this chapter are based on the best fea-
Control, 1988. 16(3): 128–40.
tures of current definitions and classifica-
6. Horan TC, Andrus M, and Dudeck MA,
tions. In addition, we introduce classical
CDC/NHSN surveillance definition of
principles of categories and grades. More health care-associated infection and cri-
attention is given to urine cultures, the teria for specific types of infections in the
susceptibility of the pathogen(s) and the acute care setting. Am J Infect Control,
availability of appropriate antimicrobials. 2008. 36(5): 309–32.
No changes are suggested for the defini- 7. Rubin USE, Andriole VT, Davis RJ,
tion and classification of urosepsis. Stamm WE, Evaluation of new anti-infec-
The new classification enables us tive drugs for the treatment of UTI. Clin
to describe more precisely when fur- Infect Dis, 1992. 15: 216.
ther evaluation and treatment shall be 8. Rubin UH SE, Andriole VT, Davis RJ,
started and when patients shall be hos- Stamm WE, with a modification by a
pitalised. Defining groups of patients for European Working Party (Norrby SR),
research studies should become easier. General Guidelines for the evaluation
Classification of UTI will become more of new anti-infective drugs for the treat-
ment of urinary tract infection. The
consistent with other fields of urology
European Society of Clinical Microbiology
and make teaching easier about UTI.
and Infectious diseases, Taukirchen,
However, we recognize that further dis- Germany, 1993: 240–310.
cussion is still needed and welcome all 9. Bone RC, Balk RA, Cerra FB, Dellinger
comments. RP, Fein AM, Knaus WA, Schein RM, and
Sibbald WJ, Definitions for sepsis and
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Urogenital Infections

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First edition 2010

Copyright © 2010 European Association of Urology – International Consultation on Urological Diseases.

Printed by Grafos, Spain

Cover illustration with thanks to:

for all of her editorial help and support in

producing this book

Foreword ................................................xiii 2. Aetiology, antimicrobial resistance

Stephanie Chu 5. Asymptomatic bacteriuria .................... 299

7.2 Emphysematous 9.3 Urinary catheters and drainage

8. Urinary tract infections in patients 10. Healthcare associated urinary tract

9. Device associated urinary tract

11.3 Urosepsis – from the view 13.3 Treatment of chronic

15.5 Guidelines for the treatment 16. Classification of urinary tract

The International Consultation on Urological Diseases (ICUD) was formed as a non-

INTERNATIONAL CONSULTATION ON UROGENITAL INFECTIONS

The International Consultation on Urogenital Infections was initiated by the

International Society of Chemotherapy for Infection and Cancer (ISC), represented by

The numerous aspects of urogenital infections were structured in 16 sections, cover-

Table 1 Levels of evidence and grades of recommendations, according to [7].

Level Type of evidence

1b Evidence obtained from at least one randomized trial

2a Evidence obtained from one well-designed controlled study without randomisation

Grade Nature of recommendation

B Based on well-conducted clinical studies, but without randomized clinical trials

LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATION

Grade A recommendation (highly recommended) usually depends on consistent

Kurt G. Naber (Chair) Anthony J. Schaeffer Chris F. Heyns

Tetsuro Matsumoto Daniel A. Shoskes Truls E. Bjerklund

1. Foxman B, Epidemiology of urinary tract infections: incidence, morbidity, and economic

Robert Koch-Institut, Nordufer 20, 13353 Berlin, Germany

ABSTRACT as well as signaling between the patho-

1. INTRODUCTION Other Gram-negative uropathogens,

Table 1 Spectrum and prevalence of uropathogenic microorganisms

Escherichia coli 80% 40% Most frequently occurring uropathogen

Proteus mirabilis 6% 11% Frequently associated with stone formation and

Staphylococcus saprophyticus 7% < 5% Frequently associated with UTI in sexually active

Staphylococcus aureus < 5% 16% Often in immuno-compromized patients

Staphylococcus epidermidis Important catheter-associated uropathogen

Enterococcus spp. Frequently associated with transplantations, up to

Candida spp. < 1% 5% Frequently associated with antibiotic treatment

Table 2 Virulence factors of microbial uropathogens

Organism Virulence factor

Toxins (α-Hemolysin, CNF1)

Autotransporter serine proteases (Sat, Vat)

Autotransporter adhesins (Ag43, UpaG)

Iron acquisition systems (enterobactin, aerobactin, yersiniabactin, salmochelin, Iha, haem

Extracellular poylsaccharides (cellulose, PGA)

Proteus mirabilis Fimbriae/adhesins (MR/P, PMF, ATF, NAF, UCA, MR/K)

Toxin (HpmA hemolysin)

Autotransporter agglutinin and cytotoxin (Pta)

Iron acquisition (Amino acid deaminases)

Klebsiella pneumoniae Fimbriae/adhesins (Type 1, Type 3 (MR/K))

Iron acquisition systems (enterochelin, aerobactin)

Organism Virulence factor

Exotoxins (e.g., hemolysin)

Enterococcus spp. Adhesins (aggregation substance, D-mannose and D-glucose-containing carbohydrates)

Staphylococcus aureus Biofilm formation (PIA, Aap)