Choosing & Using Antibiotic

Wisely in Critically Ill Patients

Bambang Pujo Semedi
Dept. of Anesthesiology and Intensive Therapy
Faculty of Medicine Universitas Airlangga Dr Soetomo Hospital
SURABAYA
One of the most important discoveries of the 20 th century

1928
Sir Alexander Fleming discovered

ANTIBIOTICS
Transformation of Life and Livelihoods
THE INTRODUCTION OF ANTIBIOTICS RAPIDLY
EXTENDED LIFE EXPECTANCY

1945 = 50 years
Today = 80 years
(developed countries)
Increase of 30 years
within 50 years
PRODUKSI PENDAPATAN SEJAHTERA
There is the danger, that the
ignorant man may easily
under dose himself and by
exposing his microbes to
non-lethal quantities of the
drug make them RESISTANT.

Alexander Fleming
7
It is anticipated to be only a
matter of time before
gonococci with full
resistance to the third-
generation extended
spectrum cephalosporins
emerge and spread
internationally.
Consequently, gonorrhoea
may become untreatable
unless new drugs become
available.
WHO AMR surveillance report 2014
8
 Sepsis in newborns in five countries in South Asia
(India, Pakistan, Afghanistan, Nepal, Bangladesh)
Sepsis in newborns in five countries in South Asia
(India, Pakistan, Afghanistan, Nepal, Bangladesh)
One child dies every five minutes because the
antibiotics given are not effective due to
bacterial resistance
One child dies every five minutes because the
antibiotics given are not effective due to
bacterial resistance

Zulfiqar Bhutta presentation at ReAct

conference Sep. 2010 9
 Rational Multi problem.
overuse
misuse
underuse

Mikroba Resisten

KOMITE PENGENDALIAN RESISTENSI ANTIMIKROBA

Indonesia bagaimana ??
MENGAPA RESISTENSI MENJADI MASALAH GLOBAL ?
1. Kasus infeksi akibat bakteri resisten meluas di seluruh
negara
2. Kegagalan pengobatan infeksi akibat bekteri resisten
menimbulkan masalah : mortalitas, morbiditas dan
masalah sosial
3. Mengatasi infeksi bakteri resisten perlu biaya tinggi
4. Penemuan antibiotik baru sangat lambat
(WHO-2015)

12
Selective Pressure

Microbiology : A Clinical Approach ( Garland Science

14
 The use of broad-spectrum antibiotics rather than
narrow-spectrum drugs is known to favor the
emergence of resistance by broadly eliminating
competing susceptible flora, leading to the rise in
resistance.
It permits the SUPER INFECTION effect.

15
 Antibiotics Milestones

The war against infectious

1944 Streptomycin
1945 Bacitracin, diseases has been won
Chloramfenikol Dr. William Stuart,1969
1947 polymyxin
Alexander 1948 Tetracyclin BUT
Flemming (1928) 1949 Neomycin
Penicilin was 1950 Oxytetracyclin The pipeline is drying up!
found 1952 Eritromycin
US FDA approval of new antibacterials
down 56% from 1983 to 2002
Infectious diseases are still the most
common cause of death worldwide
EVOLUSI..RESISTENSI ANTIBIOTIK

17
 Kecepatan
penemuan
antibiotik

Timbulnya
resistensi
kuman

Post antibiotic era

- Kembali ke zaman
pra antibiotik
- Peningkatan kematian
Bagan akibat penyakit infeksi
Spekulatif Waktu
Bagan Spekulatif. Prof.dr. Karjadi W, SpAnK.IC 19
 Antibiotic resistance will not go away
AMR will not go away.

Restoring
balance

20
 Kecepatan
Tujuan PRA
penemuan
antibiotik

Timbulnya
resistensi
kuman

prevalensi
AMR

Peran komunitas,
Bagan dokter, farmasi
Spekulatif
Waktu
21
 Bagaimana
Menggunakan Antibiotik
Secara Bijak ?
 The Principle of Antibiotic Use
Therapeutic Prophylaxis
Antibiotic use in the presence of
clinical manifestations with
suspected infection or infection
There are Preventing
no signs of infections in
Empiric Definitive high risk
infection
patients or
occurrence of
postoperative
Burke A, Cunha. Antibiotic Essentials, 2010
infection
 Dilemma in deciding on empirical antibiotic
therapy in critically ill patients
Using antibiotics may improve individual
patient outcome, but will induce selection
pressure and potential harm to future
patients or to the same patient in the future,
whereas withholding antibiotics will avoid
selection pressure but may put the individual
patient at increased risk of harm caused by an
untreated infection.
Reducing Antibiotic Use in the ICU: A Time-Based Approach to Rational Antimicrobial Use
P. O. Depuydt, L. De Bus, and J. J. De Waele
 Dilemma in deciding on empirical antibiotic therapy in critically ill patients

Clinical presentation of HAI in critically ill patients

may be subtle or atypical at the time when the
decision of whether or not to start antibiotics has to
be made.

Moreover, at that time, the causative pathogen is

usually not identified but assumed to be potentially
resistant to multiple antibiotics.
Reducing Antibiotic Use in the ICU: A Time-Based Approach to Rational Antimicrobial Use
P. O. Depuydt, L. De Bus, and J. J. De Waele
 An Art in Medicine..
Keep in balance

An Evidence-Based Problem: A Theoretical Dilemma :

Mortality with Concern of Resistance with
Inadequate Therapy Broad-Spectrum Therapy

Evans RS et al. N Engl J Med 1998;338:232-238.

Gruson D et al. Am J Respir Crit Care Med 2000;162:837-843.
Raymond DP et al. Crit Care Med 2001;29:1101-1108.
 Tingginya mortalitas terkait dengan kurang adekuatnya
terapi awal dan tampaknya BUKAN akibat tingginya virulensi
bakteri.
Pemberian antibiotik yang EFEKTIF sejak awal berkaitan dengan
perbaikan outcome klinis, khususnya pada pasien kritis

Penggunaan antibiotik spektrum luas secara berlebihan akan

mengarah pada resistensi yang lebih berat dan paparan
terhadap toksisitas yang tidak perlu.
Perlu seleksi lebih cermat untuk menentukan pasien yang akan
memperoleh terapi empiris yang mencakup bakteri ESBL
sangatlah penting
Kapan sebaiknya
diberikan?

Kumar A, et al. Crit Care Med 2006; 34:1589-1596

 Reducing Antibiotic Use in the ICU: A Time-Based Approach to Rational
Antimicrobial Use
P. O. Depuydt, L. De Bus, and J. J. De Waele

The Surviving Sepsis Campaign (SSC) recommendation

is largely based on a retrospective cohort study of
septic shock patients in which mortality increased per
hour delay in administration of adequate antibiotic
therapy (1), and should not be lightly extrapolated to
patients without septic shock
1. Kumar A, Roberts D, Wood KE et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the
critical determinant of survival in human septic shock. Crit Care Med 34:15891596
 Reducing Antibiotic Use in the ICU: A Time-Based Approach to Rational
Antimicrobial Use
P. O. Depuydt, L. De Bus, and J. J. De Waele

A recent meta-analysis that included 11,017 patients with

severe sepsis or septic shock could not confirm the mortality
benefit of starting antibiotics within 1 h of shock recognition
and CHALLENGES THE CURRENT SSC RECOMMENDATION(1).
A multicenter RCT suggested that the exact timing of
antibiotics may be less important when EARLY AGGRESSIVE
RESUSCITATION IS ACHIEVED(2)
1. Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE (2015) The impact of timing of antibiotics on outcomes in severe
sepsis and septic shock: A systematic review and meta- analysis. Crit Care Med 43:19071915
2. Puskarich MA, Trzeciak S, Shapiro NI et al (2011) Association between timing of antibiotic administration and mortality from
septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med 39:20662071
The Puzzle of Antimicrobial Therapy
Memahami PK, PD, and PK/PD
Dose

PK

PK/PD
Conc. Relationship

PD

Effect
Perubahan fisiologi pada pasien sakit kritis
Sistim kardiovaskuler Sistim pernafasan
curah jantung kapasitas penetrasi dari
permeabilitas vaskuler beberapa antibiotik
fungsi kardiovaskuler

Sistim ginjal Sistim hepatik

renal function metabolisme dan klirens obat-
renal function Renal obatan yang melalui metabolisme
Clearance (ARC) hepar
Hipoalbuminemia
Robert, J.A. Current Pharmaceutical Biotechnology, 2011, 12, 2037-2043
Physiological Changes Induced Altered PK
The principle parameters which is affected are CL and Vd

Inisial phase
of sepsis or
septic shock

Endothelial damage CO due to fluid vascular permeability

and capillary leak resuscition & use of and transcapillary loss of
Extravascular fluid vasopressors albumin
shift renal perfusion Severe hypoalbuminemia

Vd CL CL & Vd
M.O. Cotta et al.
MEDIN-827;Pages 10
 m
Pieralli F, Mancini A, Crociani A.
Appropriate Antibiotic Therapy in

om
Critically Ill Patients. Italian Journal of
Medicine 2016; 10:792

-c
Early Sepsis Late Sepsis

on
N
Pharmakokinetic
Volume of distribution (Vd)
Hydrophilic medications generally stay in the plasma volume
(Vd < 0.7 L/kg)
Influenced by fluid administration and capillary leak
Lipophilic medications distribute into intracellular & adipose
tissue (Vd > 1 L/kg)
Not generally affected by fluid administration and 3rd spacing

Cp = D/Vd
Vd is the apparent volume of distribution
Cp = [drug] in plasma at some time
D = total [drug] in system Wells,Diana L et al. Surviving Sepsis Campaign
 Post-antibiotic effect (PAE)
Antibiotics Gram Gram Pseudomonas
Positive Negative aeruginosa
bacteria bacteria
Penicillins 1-2 0 0
Cephalosporins 1-2 0 0
Carbapenems 1-2 (1) 1-2
Quinolones 1-3 1-3 1-2
Protein synthesis 3-5 3-8
inhibitors
Aminoglycosides 2-4 2-3
Concentration-dependent bactericidal
activity with prolonged PAE
Goal of dosing regimen :
Aminoglycosides Maximize concentrations
Parameters of efficacy
Fluoroquinolones 1. AUC/MIC > 125 (gram negatif) & 30
Metronidazole (gram positif)
2. Cmax/MIC > 8-10
3. In vivo : T > MIC
Tempat infeksi
Sangat penting untuk dipertimbangkan dalam
menentukan dosis AB yang tepat pada pasien kritis
Mengetahui atau menduga tempat infeksi sangat
penting untuk menentukan target konsentrasi
plasma konsentrasi terapeutik di tempat infeksi
bisa dicapai.
penetration ratio plasma : paru untuk piperacillin
adalah 0,4 - 0,5
Robert, J.A. Current Pharmaceutical Biotechnology, 2011, 12, 2037-2043
ANTIBIOTIK TEPAT
1. tepat diagnosis 11. tepat penyerahan
2. tepat indikasi 12. tepat follow up
3. tepat obat 13. tepat penulisan resep
4. tepat dosis 14. tepat pemberi
5. tepat orang/pasien 15. tepat pengkajian
6. tepat rute 16. tepat peracik
7. tepat lama pemberian 17. waspada efek samping
8. tepat interval
9. tepat informasi
10. tepat pemberi informasi
48
How to Choose & Use Antibiotic Wisely in
Critically Ill Patients
DO ADEQUATE RESUSCITATION
Establish definitive diagnosis before initiating
antimicrobials
Initiate appropriate empirical antimicrobial therapy
Change to appropriate definitive drug therapy when
possible
Understand PK, PD, and PK/PD
Avoid RESISTANCE
TERIMA KASIH