MEDICINE

CONTINUING MEDICAL EDUCATION

UrosepsisEtiology, Diagnosis,
and Treatment
Nici Markus Dreger*, Stephan Degener*, Parviz Ahmad-Nejad,
Gabriele Wbker, Stephan Roth

he sepsis syndrome, a complex inflammatory host

SUMMARY
Background: Sepsis is among the most common causes of
T response to infection, carries a high mortality and
is the main cause of death of patients in non-cardiac
death in Germany. Urosepsis accounts for 931% of all intensive care. Nonetheless, early sepsis is often not
cases and has a mortality of 2040%, which is low com-
recognized in everyday clinical practice (1, 2).
pared with that of sepsis in general. As the population
Depending on geographical location, 931% of
ages, the incidence of urosepsis is likely to rise.
all cases of sepsis arise from an infection of the
Methods: Review of pertinent articles and guidelines urogenital tract and are therefore designated as
retrieved by a selective search in PubMed. urosepsis (3). As the population ages, urological
Results: Enterobacteria and Gram-positive organisms are comorbidities (e.g. such as those associated with in-
the pathogens that most commonly cause urosepsis. The dwelling bladder catheter use) can be expected to
diagnosis can and must be made early on the basis of the become more common, and the incidence of uro-
typical clinical features, altered vital signs, and laboratory sepsis is thus likely to rise.
abnormalities, so that timely treatment can be initiated.
80% of cases are due to obstructive uropathy. The diag- Learning objectives
nostic evaluation includes physical examination, blood This article is intended to inform readers about:
cultures, urinalysis, procalcitonin measurement, and ultra- The definition of urosepsis and the distinctions
sonography. In one study, each additional hour of delay in between sepsis, severe sepsis, and septic shock.
the treatment of urosepsis with antibiotics was found to Risk factors for sepsis and the most common
lower the survival rate by 7.6%. Antibiotics should be causes of urosepsis.
chosen in consideration of local resistance patterns and The crucial importance of time in the diagnosis
the expected pathogen spectrum. and treatment of urosepsis.
Conclusion: Urologists, intensive care specialists, and The pathophysiology of the sepsis syndrome.
microbiologists should all be involved in the interdisciplin- The diagnostic evaluation and the cause-directed,
ary treatment of urosepsis. Patients outcomes have im- supportive, and adjunctive treatment of urosepsis.
proved recently, probably because of the frequent use of
minimally invasive treatments to neutralize foci of infec- Methods
tion. New biomarkers and new treatments still need to be This review is based on pertinent articles published up
validated in multicenter trials. to August 2015 that were retrieved by a selective search
in PubMed, as well as on the following guidelines:
Cite this as:
Dreger NM, Degener S, Ahmad-Nejad P, Wbker G, Roth S:
The guideline of the Surviving Sepsis Campaign
(SSC) [January 2013] (4)
Urosepsisetiology, diagnosis and treatment.
Dtsch Arztebl Int 2015; 112: 83748.
The guideline of the European Association of Urol-
ogy [March 2015] (5)
DOI: 10.3238/arztebl.2015.0837

*Dr. Dreger and Dr. Degener are joint first authors.

Department of Adult and Pediatric Urology, Witten/Herdecke University, HELIOS The sepsis syndome
Klinikum Wuppertal, Center for Research in Clinical Medicine (ZFKM): Dr. med.
Dreger, Dr. med. Degener, Prof. Dr. med. Roth Sepsis is the main cause of death of patients in
Institute for Microbiology and Laboratory Medicine, Witten/Herdecke Univer- non-cardiac intensive care.
sity, Center for Research in Clinical Medicine (ZFKM), HELIOS Klinikum
Wuppertal: Prof. Dr. med. Ahmad-Nejad
Department of Intensive Care Medicine, Witten/Herdecke University, HELIOS
Klinikum Wuppertal: Dr. med. Wbker

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BOX

Diagnostic criteria for sepsis, severe sepsis, and septic schock, according to the
German Sepsis Society (Deutsche Sepsis-Gesellschaft) (2)
I. Demonstration of infection
Diagnosis of an infection by microbiological demonstration or clinical criteria

II. Systemic inflammatory response syndrome (SIRS) (at least 2 criteria) (6)
Body temperature: 38C or 36C
Tachycardia: 90/min
Tachypnea: 20/min
Respiratory alkalosis: paCO2 32 mm Hg (< 4.3 kPa)
Leukocyte count: leukocytosis 12/nL or leukopenia 4/nL or band
forms 10% (= left shift, i.e., increased percentage of immature neutrophilic granulocytes and granulocyte precursors)

III. Acute organ dysfunction (at least 1 criterion)

Acute encephalopathy: decreased wakefulness, disorientation, agitation, delirium
Relative or absolute thrombocytopenia: decline by >30% in 24 h or 100/nL
Arterial hypoxemia: paO2 75 mm Hg ( 10 kPa) on room air or paO2/FiO2 250 mm Hg ( 33 kPa)
Renal dysfunction: urine output 0.5 mL/kg/h for at least 2 hours despite fluid administration, and/or rise of the serum creatinine level
> 2 upper limit of normal
Metabolic acidosis: base excess 5 mmoL/L or lactate > 1.5 upper limit of normal*

Sepsis: criteria I and II

Severe sepsis: criteria I, II, and III

Septic shock: criteria I and II and SBP 90 mm Hg for at least 1 h or

MAP 65 mm Hg or need for vasopressors to keep SBP >90 mm Hg or
MAP >65 mm Hg. Hypotension is present despite fluid administration and is not explicable by other causes.

*Elevated lactate levels due to inadequate perfusion can arise even if the blood pressure is within normal limits (cryptic shock); falling lactate levels seem to be at least as good an indica-
tor for successful treatment as the central venous oxygen saturation (Scv02) (e39).
DSG, German Sepsis Society (Deutsche Sepsis-Gesellschaft); MAP, mean arterial blood pressure

The S2k-guideline of the German Sepsis Society Definition

(Deutsche Sepsis-Gesellschaft, DSG) and the Ger- The DSG and the DIVI define sepsis as a complex
man Interdisciplinary Association for Intensive Care inflammatory host response to infection (the host
and Emergency Medicine (Deutsche Interdiszipli- response itself is called the systemic inflammatory
nre Vereinigung fr Intensiv- und Notfallmedizin, response syndrome [SIRS]; see Box). This definition
DIVI) [February 2010] (2), as amended up to No- is in accordance with those of analogous societies in
vember 2011. This guideline is now being updated. other countries (eBox 1) (2, 6) (recommendation grade
The evidence levels and recommendation grades re- E, evidence level V).
ported here are in accordance with the definitions of the If an infection has been demonstrated or is clinically
Oxford Centre of Evidence Based Medicine. suspected, and the SIRS criteria (Box) are met, then

Definition Severe sepsis

Sepsis is defined as a complex inflammatory host If, in the setting of sepsis, at least one organ fails
response to infection. (multi-organ dysfunction syndrome [MODS]), then
severe sepsis is present (severe sepsis = infec-
tion + SIRS + organ dysfunction).

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FIGURE 1

Uncontrolled infection/major trauma/circulatory shock

Insult
Dead tissue/apoptosis/hypersensitivity

Pathogen-associated molecular patterns Danger-associated molecular patterns

Trigger (PAMPs) (DAMPs)
LPS, etc. HMGB-1, etc.

Complex Cells in blood vessels and tissue blood and lymphatic cells
protein systems
Sensors &
effector cells
Complement Clotting Endothelial cells Epithelial cells Adipocytes Granulocytes Macrophages Lymphocytes
system system Monocytes (T & B cells)

Mediators & Massive release of mediators

biomarkers e.g., acute phase response (CRP, PCT, etc.)

Brain Lung Cardiovascular Kidney Liver Bowel Microcirculation

system
Effects on organ
function Loss of bar-
Failure of bile rier function, Capillary leak-
Confusion Dyspnea Shock Oliguria/anuria secretion ileus age, edema, DIC

Effective control of infectious foci Ineffective control of infectious foci

Result Normalization of biomarkers Persistent biomarker abnormalities
Reversal of organ dysfunction Multiple organ failure
Recovery Death

The pathophysiology of urosepsis

Infection or trauma leads to the release of pathogens and pathogen products (pathogen-associated molecular patterns, PAMPs) and/or intrinsic signaling molecules of
the body (danger-associated molecular patterns, DAMPs) that are recognized by receptors on various cells (including the complement system, endothelium, adipose
tissue), so-called pattern recognition receptors (PRRs). The latter can modulate the immune response through a variety of pro- and anti-inflammatory mediators and
biomarkers.
aPTT, activated partial thromboplastin time; CRP, C-reactive protein; DIC, disseminated intravascular coagulation; HMGB-1, high mobility group protein B1; LPS, lipo-
polysaccharide (component of Gram-negative bacterial membranes; PCT, procalcitonin.
Modified from Reinhart et al. (e43) with the kind permission of Prof. Dr. med. K. Reinhart, Department of Anesthesiology and Intensive Care Medicine, Universittsklinik
Jena, and ASM Journals

Elements of the inflammatory response Pathophysiology

Precipitating factors Infection or trauma leads to the release of patho-
Recognizing sensors gens and pathogen products that serve as PAMPs
Inflammatory mediators (pathogen-associated molecular patterns), and/or
The targets of these mediators intrinsic signaling molecules of the body, called
DAMPs (danger-asociated molecular patterns).

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Epidemiology
a) b) In 2003, a prospective cross-sectional study entitled
PRVALENZ carried out by the Sepsis Competence
Network (SepNet) yielded the first set of specific epi-
demiologic data on sepsis in Germany (8). The one-day
prevalence of sepsis in 310 hospitals and 454 intensive
care units was assessed. 1348 of 3877 patients (34.8%)
had an infection, and 30.8% of these had severe sepsis
or septic shock. The related prevalence figures were, for
sepsis, 85116/100 000 persons, and, for severe sepsis
or septic shock, 76110/100 000 persons; the mean age
of the affected persons was 67 years. The mortality of
severe sepsis varied depending on the origin of the in-
fection (9); it was 55.2% overall (8).
The prognosis of urosepsis is more favorable, with
reported mortality rates of 2040% for severe urosepsis
(5, 10). In general, sepsis is more common in men than
in women (9).
Even though the incidence of sepsis is increasing
Figure 2: Eliminating the focus of infection in obstructive pyelonephritis (for example, from 82.7 to 240.4 cases per 100 000 per-
a) A correctly placed double-J ureteric stent to treat obstruction due to distal ureterolithiasis. sons per year in the USA over the period 19792000,
The residual contrast medium in the renal pelvis and calyx already reveals markedly corresponding to an average annual increase of 8.7%),
reduced ectasia the mortality due to sepsis has markedly declined (9),
b) A correctly placed nephrostomy catheter with a contrast void representing at the site of the
partly because of the introduction of guidelines (4, 11).
blocking balloon (arrow) in a patient with obstruction by locally advanced prostate cancer
According to Martin et al., the mortality of sepsis
dropped from 27.6% in 1994 to 17.9% in 2000 (9).

Economic aspects
Sepsis carries high treatment costs (e3). The estimated
sepsis is present (sepsis = infection + SIRS) (2, e1). total cost of treatment in intensive care in Germany is
If, in the setting of sepsis, at least one organ fails 1.77 billion per year, and the estimated direct treat-
(multi-organ dysfunction syndrome, [MODS]), then ment cost of all septic diseases is 5 billion per year
severe sepsis is present (severe sepsis = infection + (12, e4). Moerer et al. estimated the average cost of
SIRS + organ dysfunction) (Box) (2, e1). In particular, treating sepsis at 25 695 per patient (1454 per day)
acute renal failure is defined by international consensus (13).
as acute oliguria (<0.5 mL/kg/h or 45 mmol/L for The indirect cost of sepsis in Germany, resulting
2 h) and a rise of the serum creatinine level by at least from work absences, rehabilitation, and early retire-
0.5 mg/dL (e2). ment, is estimated at 2.53.5 billion per year (e5).
Septic shock is defined as sepsis with treatment-
resistant hypotension or hypoperfusion despite ad- Pathogenesis and pathophysiology
equate fluid administration, resulting in the need for Urosepsis is a consequence of urinary tract infection.
vasopressor drugs (Box) (2, e1). Enterobacteria are the most common pathogens:
The SIRS criteria were newly defined in an inter- E. coli (52%)
national consensus conference in 2003. The general, in- Proteus spp.
flammatory, and hemodynamic variables incorporated Enterobacter spp.
in these criteria indicate early organ dysfunction and Klebsiella spp.
are interpreted as warning signs (eBox 1) (7). There is P. aeruginosa
no minimum requirement for the number of criteria that and Gram-positive bacteria, such as enterococci
must be met for SIRS to be diagnosed. (5%) (e6).

Prevalence Common pathogens

Despite increasing incidence, the mortality due to E. coli, Proteus spp., Enterobacter spp., Klebsiella
sepsis has markedly declined, partly because of spp., P. aeruginosa, and Gram-positive bacteria
the introduction of guidelines. such as enterococci.

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FIGURE 3

6hrs 1hr
Clinical suspicion of sepsis Observation
no
yes General ward
SIRS criteria positive Observation
no
yes
Initial O2 administration
ICU or stepdown unit
and fluid replacement

Microbiology (urine/blood)

Symptoms and signs 1. Early goal-directed therapy (EGDT) & Transfer

indicate urosepsis empirical antibiotic therapy to alternative
no 2. Imaging department
yes
1. Early goal-directed therapy (EGDT) &
empirical antibiotic therapy
2. Imaging

Supportive & adjunctive treatment,

Urogenital: complicating factor
no if necessary
yes
Source control (focus, entry portal)

Supportive & adjunctive treatment,

as needed

Diagnostic and therapeutic algorithm for urosepsis

ICU, intensive care unit. Modified from Grabe et al., Guidelines on urological infections. In: EAU-Guidelines 2015 (5)

Patients at risk of sepsis are more likely to develop components of the bacterial cell wall act as pathogen-
bacteremia as a consequence of a urinary tract infection associated molecular patterns (PAMP) that bind to
(eBox 2). Obstructive uropathy causes 78% of cases of pattern-recognition receptors (PRR) on the surface of
urosepsis (e7). In one study involving 205 cases of uro- macrophages, neutrophils, and endothelial or urothelial
sepsis, 43% were due to urolithiasis, 25% to prostatic cells (Figure 1) (10, e10). The transcription factor
adenoma, 18% to urologic cancers, and 14% to other NF-B mediates the production of pro-inflammatory
urologic diseases (e8). cytokines such as IL-6, IL-12, and TNF (e11e14).
The course and severity of sepsis depend both on the The production of further mediators (chemokines, pros-
pathogenicity of the organism and on the nature and ex- taglandins, thromboxans, and leukotrienes) adds to the
tent of the patients immune response (Figure 1) (e9). mediator storm (e6). High-mobility group protein B1
When an infection is present, bacteria or (HMGB-1), which is released during cell death as a

The role of bacteria Effects on the immune system

In infection, bacteria or bacterial cell wall com- Infection activates the complement system
ponents act as pathogen-associated molecular and the native immune system, leading to a
patterns (PAMP) that bind to pattern-recognition massive initial pro-inflammatory response.
receptors (PRR) on the surface of macrophages,
neutrophils, and endothelial or urothelial cells.

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a) b)

Figure 4: Ultrasonographic findings in

urosepsis
a) Widening of the renal pelvis and calyx
with tubular dilatation of the ureter due to
distal ureterolithiasis (not shown).
b) Inhomogeneous renal parenchyma at the
upper pole (arrow) due to abscess
formation

danger-associated molecular pattern (DAMP) or Effects on hemostasis

produced by macrophages in the late stage of sepsis, The over-activated complement system is closely linked
also binds to PRR (14). Wagenlehner et al. propose that to the clotting system. Surface receptors on endothelial
the higher survival rate of urosepsis compared to sepsis cells and neutrophils are up-regulated, causing increased
from other causes may be due, in part, to the lesser de- mutual adhesiveness. Moreover, the clotting system is
gree of tissue damage associated with urologic surgical activated by endothelially synthesized plasminogen-
procedures to eliminate infectious foci. Helpful minim- activator inhibitor; this predisposes to thrombosis and to
ally invasive procedures include the internal stenting of disseminated intravascular coagulation (DIC). A low
ureteral stenoses (Figure 2a) and percutaneous antithrombin III level, Quick value, and platelet count
nephrostomy (Figure 2b) (e15). may be the first signs of DIC. At the same time, antico-
agulant substances such as protein C are inhibited,
Effects on the immune system promoting systemic coagulation and leading to microcir-
Infection activates the complement system and the culatory insufficiency and tissue hypoxia (4, 10, 14).
native immune system (Figure 1), leading to a These recently elaborated scientific facts are
massive initial pro-inflammatory response. Hemato- inadequately reflected in the sepsis criteria. Thus, the
poietic growth factors stimulate the generation of PIRO (predisposition, infection, response, and organ
neutrophilic granulocytes, which release bactericidal dysfunction) staging system has been developed.
substances such as proteases and oxygen radicals. Although the PIRO system has not yet entered into
Lymphocytes, too, are stimulated to produce wide clinical use, a study in more than 680 patients
antibodies and to mount a cell-mediated immune has demonstrated its superiority to both the well-
response. Endothelial cells are induced to make established MEDS score and the APACHE-II score
nitric oxide (NO), which, in turn, lowers vascular with respect to both stratification and prognosis (area
tone, causing hypotension. Damaged endothelium is under the curve [AUC] = 0.889 for need of treatment in
abnormally permeable, and edema ensues (10, 14). an intensive care unit, 0.817 for organ failure, and
This initial phase is followed by an opposing anti- 0.744 for 28-day mortality; p<0.05) (e16).
inflammatory (immune-suppressive) phase that is
responsible for the high mortality of sepsis in its Clinical features and diagnostic evaluation
later course. Macrophages and neutrophils may suc- Rapid diagnosis is essential for early goal-directed ther-
cumb to immune paralysis, and lymphocytes and apy (EGDT) (1). In the evaluation of urosepsis, attention
dendritic cells display high rates of apoptosis (15). must be paid both to the defining criteria for sepsis (Box 1)

Predisposition to thrombosis The PIRO staging system

Surface receptors on endothelial cells and neutro- PIRO stands for predisposition, infection,
phils are up-regulated, causing increased mutual response, and organ dysfunction.
adhesiveness. Moreover, the clotting system is acti-
vated by endothelially synthesized plasminogen-
activator inhibitor.

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(recommendation grade C, evidence level V) and to the TABLE 1

symptoms and signs pointing to the underlying cause of
the infection: flank pain and tenderness (perhaps with Early-goal-directed therapy (EGDT) (1)
radiation), dysuria/pollakisuria, urinary retention, and Variable Target
scrotal and/or prostatic pain. In men, the physical exam-
Central venous pressure (CVP) 812 mm Hg *
ination must include a digital rectal examination (tender-
ness indicates prostatitis, a fluctuating mass indicates a Mean arterial pressure (MAP) 6590 mm Hg
prostate abscess) and palpation of the testes (tenderness, Central venous oxygen saturation (ScvO2) 70%
warmth, and swelling indicate epididymorchitis). The Mixed venous oxygen saturation (SvO2) 65%
presence of an indwelling catheter should be noted as a
Hematocrit (Hct) >30%
possible cause of infection. The diagnostic and
therapeutic algorithm recommended by the European Urine output >40 mL/h
Association of Urology (EAU) is shown in Figure 3.
* CVP >12 mm Hg for intubated patients

Blood cultures
Empirical antibiotic treatment should be begun only
after blood cultures have been drawn (at least 23
pairs), preferably by aseptic peripheral venous puncture
(recommendation grade C, evidence level IIb). Only
about 30% of blood cultures in patients with suspected
urosepsis are positive (e17). The culture bottles should
be filled to the greatest extent possible, as the rate of bacteremia in patients with febrile urinary-tract
positivity also depends on the volume of blood in the infections with 95% sensitivity (95% confidence
bottle (3% more false-negative findings for each ml of interval [0.890.98]) and 50% specificity (95% confi-
decreasing volume [e18]). dence interval [0.460.55]) (20).
More than one study (ProHOSP, PRORATA) has re-
Urine testing vealed that the use of PCT-guided causally directed
Urinalysis and urine culture must be performed in all treatement to shorten the duration of antibiotic adminis-
patients with urosepsis before antibiotic treatment is tration in patients with sepsis (recommendation grade
begun (recommendation grade B, evidence level Ic). C, evidence level IIb) does not elevate mortality (21,
The findings of midstream urine culture are of limited 22). Heyland et al. (2011), in a meta-analysis, con-
utility in obstructive pyelonephritis, because the urine firmed that this strategy lessens antibiotic use but could
with the highest infectious load is often above the ob- not definitively rule out an increase in mortality by up
struction (sensitivity 30.2%, specificity 73%) (16). to 7% (23). More light will be shed on this issue by the
SISPCT study of the SepNet (NCT00832039), which is
Biomarkers currently in progress. The purpose of the SISPCT study
Urosepsis cannot be diagnosed from biomarkers is to investigate the effect of adjunctive intravenous
alone. Among all available inflammatory markers, therapy with sodium selenite, and that of PCT-guided
procalcitonin (PCT) is the best studied, and its use to antibiotic treatment, on the survival of patients with
confirm or rule out severe sepsis is therefore recom- severe sepsis and septic shock.
mended (2). PCT is more reliable than the acute-phase The cytokine IL-6 is also a marker of sepsis; its con-
protein CRP (17, 18) and enables the differentiation of centration is elevated in febrile urinary tract infections
bacterial infection from other types of infection (e19). (e20). Unlike PCT and CRP, however, the measurement
PCT levels below 0.5 ng/mL practically rule out of IL-6 (or, indeed, of entire cytokine panels) has not
severe sepsis or septic shock; levels above 2 ng/mL yet been incorporated into clinical standards (e21).
make severe sepsis or septic schock highly likely (rec- The detection of specific, sepsis-associated RNAs and
ommendation grade C, evidence level IIb) (2, 19). In a the direct demonstration of specific bacterial DNA by am-
prospective, multicenter cohort study, the use of a plification techniques such as PCR may soon become
PCT cutoff value of 0.25 ng/mL was found to identify clinically relevant, but further studies are needed (e22).

Urinalysis Biomarkers
Urinalysis and urine culture must be performed in Urosepsis cannot be diagnosed from biomarkers
all patients with urosepsis before antibiotic treat- alone. Among all available inflammatory mark-
ment is begun. The findings of midstream urine ers, procalcitonin (PCT) is the best studied.
culture are of limited utility in obstructive pyelo-
nephritis.

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TABLE 2 Imaging studies

Ultrasonography is the imaging method of first
Cause-directed treatment choice because of its rapidity and wide availability
(recommendation grade B, evidence level Ic). It
Empirical initial parenteral therapy as recommended by the Paul Ehrlich
Society for Chemotherapy (Paul-Ehrlich-Gesellschaft fr Chemotherapie e. V.) enables the rapid detection of, for example,
hydronephrosis (Figure 4a), renal abscesses (Figure
Common pathogens Nosocomially acquired Community-acquired
4b), and prostatic abscesses. Abscesses should be
1
E. coli * Fluoroquinolone group 2/3 + Aminopenicillin/(BLI) punctured under ultrasonographic (or other radiological)
Proteus mirabilis cephalosporin group Fluoroquinolone group 2/3 guidance, and the removed fluid should be studied
Pseudomonas spp. 3a/3b/4 Cephalosporin group 3a
Enterobacteriaceae Aminopenicillin / beta- Carbapenem group 2 microbiologically (recommendation grade D,
lactamase inhibitor (BLI)*2 evidence level V) (e23). If it is unclear whether
Carbapenem group 1 obstructive pyelonephritis or merely a fixed, ectatic
Targeted antibiotic therapy for known pathogens as recommended calyx system of the renal pelvis is present, a diagnostic
by the Paul Ehrlich Society for Chemotherapy puncture of the renal pelvis can be considered: low
pressure and a negative urine dipstick test rule out
Pathogen Monotherapy Combination therapy
infection, so that a nephrostomy can be avoided (e24).
E. coli Aminopenicillin/BLI If the ultrasonographic findings are equivocal, ab-
Klebsiella pneumoniae Acylaminopenicillin/BLI
Proteus mirabilis Cephalosporin group dominal computed tomography (CT) is recommended,
3a/3b/4 so that any anatomical abnormalities that have caused
Fluoroquinolone group 2/3 or exacerbated urosepsis can be identified with high
Carbapenem sensitivity (e25, e26).
ESBL-forming E. coli Carbapenem Carbapenem + fosfomycin
Klebsiella pneumoniae Carbapenem + tigecycline Treatment
Proteus mirabilis Colistin + fosfomycin In an oft-cited trial involving 260 patients, Rivers et al.
P. aeruginosa Cephalosporin group 3b/4 + (2001) showed that EGDT (mentioned above) lowers
fluoroquinolone group 2/3 or the mortality of severe sepsis and septic shock. In com-
fosfomycin or
aminoglycoside
bination with the rapid correction of target variables
(Table 1), EGDT lowered mortality from 46.5% to
Acylaminopenicillin/BLI + 30.5%, with a number needed to treat (NNT) of 68 (1).
fluoroquinolone group 2/3 or Kumar et al. confirmed the importance of timing as a
fosfomycin or
prognostic factor (24, 25): the initiation of empirical
aminoglycoside
antibiotic treatment within one hour of the diagnosis of
Carbapenem group 1 + hypotension was associated with an 80% survival rate.
fluoroquinolone group 2/3 or Delays in starting antibiotics were associated with an
fosfomycin + aminoglycoside
average 7.6% decline in survival rate for each hour of
Citrobacter freundii Carbapenem delay (79.9% versus 70.5% at 12 hours, 42.0% at 56
Enterobacter spp. Cephalosporin group 4 hours, and 25.4% at 912 hours) (25).
Serratia marcescens Fluoroquinolone group 2/3
Early goal-directed therapy (EGDT) is now contro-
Acinetobacter baumanii Carbapenem group 1 Carbapenem group 1 + versial, as the ProMISe, ARISE, and ProCESS trials
fluoroquinolone group 2/3 or showed no significant survival benefit from strict ad-
tigecycline
herence to the EGDT protocol. It should be pointed out,
Colistin + tigecycline however, that the septic patients central venous oxygen
Enterococcus faecalis Aminopenicillin Aminopenicillin +
saturation levels (ScvO2) on first contact were not below
(high-dosed) aminoglycoside 70% in any of these three trials (2628), whereas
Acylaminopenicillin Rivers et al. identified ScvO2 < 70% as an indicator of
(high-dosed) Acylaminopenicillin + the need for hemodynamic treatment (Table 1) (1).
aminoglycoside
Therefore, in the absence of subgroup analyses of such
In penicillin allergy: glyco- high-risk patients, and in the absence of further trials,
peptide + aminoglycoside these findings cannot be considered conclusive (e27).
Enterococcus faecium Glycopeptide Glycopeptide + aminoglyco-
Daptomycin side
Linezolid
Vancomycin-resistant en- Linezolid Imaging studies
terococci, usually Entero- Daptomycin Ultrasonography is the imaging method of first
coccus faecium (VRE) Tigecycline
choice. It enables the rapid detection of, for
*1Adjust depending on local E. coli resistance pattern. + As a result of increasing fluoroquinolone resistance, example, hydronephrosis, renal abscesses, and
fluoroquinolones are now inferior to a combination of cephalosporin + BLI (40). In areas with a high rate of prostatic abscesses.
ESBL-forming enterobacteria (>10%), carbapenem is recommended for initial treatment (e42).
*2 Recommended for catheter-associated infections, which are usually mixed infections with enterococci
(because of the enterococcal gap of cephalosporins, fluoroquinolones, and aminoglycosides)

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In general, there are three categories of treatment for inserted for urinary drainage at low pressure. Abscesses or
urosepsis: infected lymphoceles requiring treatment can be drained
Cause-directed (antibiotic treatment and elimin- with a pigtail catheter inserted under ultrasonographic (or
ation of foci of infection) other radiological) guidance (e23). Clinical decision-
Supportive (hemodynamic and pulmonary making in such situations should be based not only on the
stabilization) anatomical particulars (e.g., ureteral strictures), but also on
Adjunctive (glucocorticoid and insulin treatment) the patients clotting status (possibly affected by therapeutic
(Figure 3) (2, 5). anticoagulation).

Cause-directed treatment Supportive treatment

Antibiotic treatment should be begun as soon as possible According to the concept of early goal-directed therapy
(within an hour) after diagnosis, but only after blood and (EGDT), hemodynamic stabilization promotes the
urine cultures have been obtained (recommendation grade delivery of an adequate oxygen supply to the tissues.
B, evidence level Ic). The antibiotic(s) should be chosen in As soon as the diagnosis of urosepsis is suspected, the
the light of local resistance rates and the expected pathogen intravenous administration of isotonic crystalloid solution
spectrum. The recommendations of the Paul Ehrlich Society should be begun within 15 minutes, with the goal of
are reproduced in Table 2. adminstering at least 30 mL/kg of body weight in the first
In view of the presence of capillary leakage leading to hour (proceed with caution in case of congestive heart
edema formation and lower volumes of distribution, as well failure) (recommendation grade A, evidence level Ic).
as increased clearance because of the hyperdynamic circula- On the basis of the findings of the VISEP,
tory situation or low clearance rates because of multiple CRYSTMAS, 6S, and CHEST trials (recommendation
organ dysfunction, antibiotics should generally be given grade A, evidence level Ia), colloid HAES solutions are
initially at high doses, which are reduced later on in the no longer recommended in the treatment of severe sepsis
course of treatment. This consideration applies above all and septic shock (3033). The results of the CRYSTAL
to hydrophilic, renally eliminated antibiotics (-lactam trial (NCT00318942) are now pending. The findings of
antibiotics and aminoglycosides) (e26, e28). In contrast, the SAFE trial imply that the additional administration of
fluoroquinolones are concentration-dependent and are human albumin can be considered (recommendation
barely influenced by altered volumes of distribution; their grade E, evidence level V) (18).
doses should only be adjusted in the setting of elevated renal Low mean arterial pressure (MAP < 65 mm Hg)
retention values (e26, e28). The MAXSEP trial revealed no despite volume substitution is an indication for
additional benefit from dual empirical antibiotic treatment vasopressor administration (recommendation grade B,
(meropenem in 298 patients vs. meropenem/moxifloxacin evidence level Ic); norepinephrine is the vasopressor
in 302 patients) (e29). The antibiotic regimen should be drug of first choice (recommendation grade E, evidence
re-evaluated daily with a view toward potential de-escalation, level IIb) (34). If the cardiac output is low despite
to avoid both drug resistance and unnecessary costs (recom- volume therapy, the positive inotrope dobutamine
mendation grade E, evidence level V). (20 g/kg/min) is the catecholamine of first choice
The elimination of foci of infection and the early control (recommendation grade E, evidence level V) (2). Once
of complicating factors are important components of tissue perfusion is normal, and in the absence of
causally directed treatment (recommendation grade A, coronary heart disease, anemia with hemoglobin values
evidence level Ic). In the case of an infected kidney above under 7 g/dL should be treated with erythrocyte
an obstruction, this is accomplished by internal ureteral concentrate transfusion (e30). Low-dose dopamine
stenting (Figure 2a) or percutaneous nephrostomy (Figure (5 g/kg/min) for nephroprotection is not recommended
2b). A meta-analysis did not show either of these methods to (recommendation grade A, evidence level Ia) (33).
be superior to the other (29); the choice between them can Pulmonary stabilization to achieve an arterial oxygen
be made individually. saturation above 93% and a central venous oxygen
Urosepsis due to a high residual urine volume or acute saturation of at least 70% should be an early goal, with
urinary retention (even without pyuria) is best treated with controlled, lung-sparing ventilation at low tidal volumes
a transurethral bladder catheter; in the setting of acute (6 mL/kg of body weight) and peak pressures no higher
prostatitis or epididymitis, a suprapubic catheter should be than 30 mbar, whenever adequate oxygenation (>90% by

The three categories of treatment Supportive treatment

Cause-directed (antibiotic treatment and elimi- According to the concept of early goal-directed
nation of foci of infection), therapy (EGDT), hemodynamic stabilization pro-
Supportive (hemodynamic and pulmonary motes the delivery of an adequate oxygen supply
stabilization), to the tissues.
Adjunctive (glucocorticoid/insulin treatment)

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MEDICINE

pulse oximetry) cannot be achieved by hemodynamic initially high concentrations of IL-6, IL-1, and TNF- and
stabilization and mask oxygen administration alone lessened the need for vasopressor drugs (e37, e38). This
(recommendation grade B, evidence level Ic). method of treatment cannot yet be recommended, pending
further evaluation in randomized, multicenter trials.
Adjunctive treatment
Adjunctive treatment is given simultaneously with, and in Conclusion
addition to, supportive treatment. Urosepsis can usually be identified early in its course,
Glucocorticoid treatment is contoversial. Early and distinguished from sepsis of other causes, by a basic
randomized trials showed a benefit from high-dose diagnostic evaluation consisting of physical examination,
treatment in septic shock (e31e33), but the CORTICUS urinalysis, laboratory blood tests, and ultrasonography.
trial revealed elevated mortality (albeit without statistical Once urosepsis has been diagnosed, the treatment should be
significance) and a higher risk of superinfection with begun at once. Rapid diagnosis and the (usually) minimally
low-dose steroid treatment (36, e34). Only in septic shock invasive elimination of infectious foci have led to improved
with treatment-resistant hypotension despite vasopressor outcomes in patients with urosepsis. Nonetheless, compet-
administration and volume substitution can the admini- ence networks, standardized treatment recommendations,
stration of hydrocortisone (200 mg/d) be considered as a and interdisciplinary collaboration during the acute illness
last resort (recommendation grade E, evidence level V). and beyond will be indispensable prerequisites for further
Conventional insulin treatment is superior to intensified improvement.
insulin treatment for sepsis patients: in the VISEP trial,
17% of patients receiving intensified treatment developed Conflict of interest statement
The authors state that they have no conflict of interest.
severe hypoglycemia (blood glucose <40 mg/dL), as
opposed to 4.1% of those receiving conventional Manuscript submitted on 19 June 2015, revised version accepted on
2 November 2015.
treatment (30). Moreover, the NICE-SUGAR trial showed
a 2.6% increase in mortality (27.5% vs. 24.9%, p = 0.02) Translated from the original German by Ethan Taub, M.D.
attributable to intensified insulin treatment (37). Strict
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Adjunctive treatment Overview

Adjunctive treatment is given simultaneously Urosepsis can usually be identified early in its
with, and in addition to, supportive treatment. course, and distinguished from sepsis of other
causes, by a basic diagnostic evaluation con-
sisting of physical examination, urinalysis,
laboratory blood tests, and ultrasonography.

846 Deutsches rzteblatt International | Dtsch Arztebl Int 2015; 112: 83748
 MEDICINE

8. Engel C, Brunkhorst FM, Bone HG, et al.: Epidemiology of sepsis in Germany: re- 34. Martin C, Viviand X, Leone M, Thirion X: Effect of norepinephrine on the outcome
sults from a national prospective multicenter study. Intensive Care Med 2007; of septic shock. Crit Care Med 2000; 28: 275865.
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study on prevalence by the competence network sepsis (SepNet)]. Anasthesiol outcome of adult sepsis. Crit Care Med 2006; 34: 1521.
Intensivmed Notfallmed Schmerzther 2006; 41: 434. 39. Bjerklund Johansen TE, Cek M, Naber K, et al.: Prevalence of hospital-acquired
13. Moerer O, Schmid A, Hofmann M, et al.: Direct costs of severe sepsis in three urinary tract infections in urology departments. Eur Urol 2007; 51: 110011;
German intensive care units based on retrospective electronic patient record discussion 12.
analysis of resource use. Intensive Care Med 2002; 28: 14406. 40. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO: Ceftolozane-
14. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J tazobactam compared with levofloxacin in the treatment of complicated urinary-
Med 2003; 348: 13850. tract infections, including pyelonephritis: a randomised, double-blind, phase 3
trial (ASPECT-cUTI). Lancet 2015; 385: 194956.
15. Astiz ME, Rackow EC: Septic shock. Lancet 1998; 351: 15015.
16. Mariappan P, Loong CW: Midstream urine culture and sensitivity test is a poor
predictor of infected urine proximal to the obstructing ureteral stone or infected Corresponding author
Dr. med. Nici Markus Dreger
stones: a prospective clinical study. J Urol 2004; 171: 21425.
Klinik fr Urologie und Kinderurologie
17. Luzzani A, Polati E, Dorizzi R, Rungatscher A, Pavan R, Merlini A: Comparison of HELIOS Klinikum Wuppertal
procalcitonin and C-reactive protein as markers of sepsis. Crit Care Med 2003; Lehrstuhl der Universitt Witten/Herdecke
31: 173741. Heusnerstr. 40
D-42283 Wuppertal, Germany
18. Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J: Serum procalcitonin and nici-markus.dreger@helios-kliniken.de
C-reactive protein levels as markers of bacterial infection: a systematic review
and meta-analysis. Clin Infect Dis 2004; 39: 20617.
19. Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R: Procalcitonin for early
diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock.
Intensive Care Med 2000; 26 (Suppl 2): 14852.
@ Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref4915

20. van Nieuwkoop C, Bonten TN, van't Wout JW, et al.: Procalcitonin reflects bac- eBoxes:
teremia and bacterial load in urosepsis syndrome: a prospective observational www.aerzteblatt-international.de/15m837
study. Crit Care 2010; 14: R206.
21. Schuetz P, Christ-Crain M, Thomann R, et al.: Effect of procalcitonin-based
guidelines vs standard guidelines on antibiotic use in lower respiratory tract in-
fections: the ProHOSP randomized controlled trial. JAMA 2009; 302: 105966. Further information on CME
22. Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J: Use of procalcitonin to shorten
antibiotic treatment duration in septic patients: a randomized trial. Am J Respir This article has been certified by the North Rhine Academy for Post-
Crit Care Med 2008; 177: 498505. graduate and Continuing Medical Education. Deutsches rzteblatt
23. Heyland DK, Johnson AP, Reynolds SC, Muscedere J: Procalcitonin for reduced provides certified continuing medical education (CME) in accordance
antibiotic exposure in the critical care setting: a systematic review and an econ- with the requirements of the Medical Associations of the German
omic evaluation. Crit Care Med 2011; 39: 17929. federal states (Lnder). CME points of the Medical Associations can
24. Kumar A, Ellis P, Arabi Y, et al.: Initiation of inappropriate antimicrobial therapy be acquired only through the Internet, not by mail or fax, by the use of
results in a fivefold reduction of survival in human septic shock. Chest 2009;
136: 123748. the German version of the CME questionnaire. See the following
25. Kumar A, Roberts D, Wood KE, et al.: Duration of hypotension before initiation of
website: cme.aerzteblatt.de
effective antimicrobial therapy is the critical determinant of survival in human
septic shock. Crit Care Med 2006; 34: 158996. Participants in the CME program can manage their CME points with
26. Mouncey PR, Osborn TM, Power GS, et al.: Trial of early, goal-directed resusci- their 15-digit uniform CME number (einheitliche Fortbildungsnummer,
tation for septic shock. N Engl J Med 2015; 372: 130111. EFN). The EFN must be entered in the appropriate field in the
27. Pro CI, Yealy DM, Kellum JA, et al.: A randomized trial of protocol-based care for cme.aerzteblatt.de website under meine Daten (my data), or upon
early septic shock. N Engl J Med 2014; 370: 168393. registration. The EFN appears on each participants CME certificate.
28. Investigators A, Group ACT, Peake SL, et al.: Goal-directed resuscitation for pa-
tients with early septic shock. N Engl J Med 2014; 371: 1496506.
This CME unit can be accessed until 28 February 2016, and earlier
29. Ramsey S, Robertson A, Ablett MJ, Meddings RN, Hollins GW, Little B: Evidence-
based drainage of infected hydronephrosis secondary to ureteric calculi. J
CME units until the dates indicated:
Endourol 2010; 24: 1859.
30. Brunkhorst FM, Engel C, Bloos F, et al.: Intensive insulin therapy and pentas- The diagnosis and treatment of optic neuritis (issue 37/2015)
tarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 12539. until 6 December 2015,
31. Guidet B, Martinet O, Boulain T, et al.: Assessment of hemodynamic efficacy and The diagnosis and treatment of ectopic pregnancy (issue 41/2015)
safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in pa-
tients with severe sepsis: the CRYSTMAS study. Crit Care 2012; 16: R94. until 3 January 2016,
32. Myburgh JA, Finfer S, Bellomo R, et al.: Hydroxyethyl starch or saline for fluid The interdisciplinary management of acute chest pain
resuscitation in intensive care. N Engl J Med 2012; 367: 190111. (issue 45/2015) until 31 January 2016.
33. Perner A, Haase N, Guttormsen AB, et al.: Hydroxyethyl starch 130/0.42 versus
Ringer's acetate in severe sepsis. N Engl J Med 2012; 367: 12434.

Deutsches rzteblatt International | Dtsch Arztebl Int 2015; 112: 83748 847
MEDICINE

Please answer the following questions to participate in our certified Continuing Medical Education program.
Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1 Question 6
Which of these findings meets the criteria for SIRS? What type of urinary diversion is preferred for a patient
a) Respiratory frequency 18/min with urosepsis due to prostatitis?
b) Leukocyte count 11/nL ( = 11 000/L) a) Nephrostomy
c) paCO2 30 mm Hg b) A suprapubic catheter
d) Core body temperature 36.6C c) A transurethral catheter
e) Pulse 80/min d) A ureteral stent
e) A condom urinal

Question 2
Low antithrombin III level, Quick value, and platelet Question 7
count in a patient with urosepsis arouses suspicion of What percentage of blood cultures are positive in
what condition? patients with suspected urosepsis?
a) Thrombotic thrombocytopenic purpura a) 15%
b) Disseminated intravascular coagulation (DIC) b) 30%
c) Hemolytic-uremic sydrome (HUS) c) 60%
d) Von Willebrand-Jrgens syndrome d) 75%
e) Primary hyperfibrinolysis e) 90%

Question 3 Question 8
What marker is used to assess tissue perfusion? What is the imaging method of choice for patients with
a) Lactate suspected urosepsis?
b) Erythrocyte sedimentation rate (ESR) a) Ultrasonography
c) Procalcitonin (PCT) b) Computed tomography
d) D-dimers c) Magnetic resonance imaging
e) IL-1 d) Plain x-rays of the abdomen
e) Cystoscopy

Question 4
What is the supportive drug of first choice in a patient Question 9
with urosepsis and low mean arterial pressure What antibiotic is given as monotherapy to treat
(< 65 mm Hg) despite fluid replacement? vancomycin-resistant enterococci?
a) Colloid solution a) Fluoroquinolone
b) Norepinephrine b) Acylaminopenicillin
c) Insulin c) Aminopenicillin
d) Erythrocyte concentrate d) Tigecycline
e) Low-dosed dopamine e) Carbapenem

Question 5 Question 10
By what percentage does the survival rate of a sepsis What is the most common underlying cause of urosepsis
patient decline for every hour of delay in starting anti- in patients with obstructive uropathy, according to a
biotic treatment? recent study?
a) 3.1% a) Carcinoma
b) 5.2% b) Prostatic hyperplasia
c) 7.6% c) Prior surgery
d) 9.8% d) Ureterolithiasis
e) 12.3% e) Pregnancy

848 Deutsches rzteblatt International | Dtsch Arztebl Int 2015; 112: 83748
 MEDICINE

Supplementary material to:

UrosepsisEtiology, Diagnosis, and Treatment
by Nici Markus Dreger*, Stephan Degener*, Parviz Ahmad-Nejad,
Gabriele Wbker, and Stephan Roth
Dtsch Arztebl Int 2015; 112: 83748. DOI: 10.3238/arztebl.2015.0837

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eBOX 1 eBOX 2

Diagnostic criteria for sepsis according to the Risk factors for urosepsis
SCCM/ESICM/ACCP/ATS/SIS consensus conference Age 65 years (38)
(7) Diabetes mellitus
Demonstration of an infection, or clinical suspicion of infection in the Immune suppression*1 (organ transplantation,
presence of some of the following criteria: chemotherapy, corticosteroid treatment, AIDS)
General signs Nosocomial urinary tract infection acquired on a urology
Fever >38.3C ward*2 (39)
Hypothermia <36C Prior urological interventions
Tachycardia >90/min or >2 SD above age-specific normal value
*1 Candida spp., Pseudomonas spp., and coagulase-negative staphylo-
Tachypnea >30/min cocci are more common pathogens than in non-immunosuppressed
Impaired neurologic status patients (e6, e40).
Edema or positive fluid balance (>20 mL/kg/d) *2 Among patients with nosocomial urinary tract infections (UTIs)
acquired on urology wards, the prevalence of urosepsis is 12% (39).
Hyperglycemia (blood sugar >120 mg/dL or 7.7 mmoL/L) in the absence of In contrast, patients with nosocomial UTIs acquired on non-urological
previously diagnosed diabetes mellitus wards have a 2% prevalence of severe sepsis and a 0.3% prevalence
Signs of inflammation of septic shock (e41).

Leukocytosis >12/nL
Leukopenia <4/nL
Normal leukocyte count with >10% immature forms
C-reaktive protein >2 SD above normal
Procalcitonin >2 SD above normal
Hemodynamic signs
Hypotension (SBP <90 mm Hg, MAP <70 mm Hg or SBP drop by
>40 mm Hg or to <2 SD below the age-specific normal value)
Cardiac index (CI) >35 L/min/m2
Organ dysfunction
Arterial hypoxemia (paO2 / FiO2 <300)
Acute oliguria <0.5 mL/kg/h or 45 mmoL/L for 2h
Creatinine rise by 0.5 mg/dL
Coagulopathy (INR >1.5 or aPTT > 60 s)
Thrombocytopenia <100/nL
Hyperbilirubinemia (total bilirubin >4 mg/dL or >70 mmoL/L)
Ileus
Markers of tissue perfusion
Hyperlactatemia > 1 mmoL/L *
Reduced capillary filling or marbling
* Elevated lactate levels due to inadequate perfusion can arise even when the blood pressure is
normal (cryptic shock); a falling lactate level seems to be at least as good an indicator of successful
treatment as the central venous oxygen saturation (Scv02) (e39).
ATS, American Thoracic Society; aPTT, activated partial thromboplastin time; CCP, American
College of Chest Physicians; ESICM, European Society of Intensive Care Medicine; INR, interna-
tional normalized ratio; MAP, mean arterial blood pressure; SCCM, Society of Critical Care Medici-
ne; SD, standard deviation; SIS, Surgical Infection Society

II Deutsches rzteblatt International | Dtsch Arztebl Int 2015; 112: 83748 | Supplementary material