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 20th 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
ADANYA ANTIBIOTIK DENGAN
MENINGKATKAN
KESEJAHTERAAN HIDUP...

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.
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
 Ration
Multi
al
problem.
overuse
misuse
underus
e

Mikroba Resisten

KOMITE PENGENDALIAN RESISTENSI ANTIMIKROBA

blem di peternakan & pertanian...

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 15
 Antibiotics Milestones
1944
Streptomycin
1945 Bacitracin, The war against
infectious diseases
has been won
Chloramfenikol
1947 polymyxin
Dr. William
Alexander 1948 Tetracyclin BUT
Stuart,1969
Flemming
(1928)
1949 Neomycin The pipeline is drying up!
1950
Penicilin was Oxytetracyclin
found 1952
US FDA approval of new
Eritromycin antibacterials down 56% from
1983 to 2002
Infectious diseases are still the
EVOLUSI..RESISTENSI
ANTIBIOTIK

17
 Kecepatan
penemuan
antibiotik

Timbulnya
resistensi
kuman

Post antibiotic era

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

Restoring
balance

20
 Kecepatan
Tujuan PRA
penemuan
antibiotik

Timbulnya
resistensi
kuman

prevalen
si
AMR

Peran
Bagan komunitas,
Spekulatif dokter, farmasi
Waktu
21
 Bagaimana
Menggunakan
Antibiotik Secara
Bijak ?
 The Principle of Antibiotic
Use
Therapeutic
Antibiotic use in the Prophylaxis
presence of clinical
manifestations with
suspected infection or Preventing
infection infections
Definitiv There in high risk
Empiric e are no patients or
signs of occurrence
infection of
postoperat
Burke A, Cunha. Antibiotic Essentials, 2010
ive
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
Reducing Antibiotic Use in the ICU: increased risk toofRational
A Time-Based Approach harm caused
Antimicrobial Use by an
P. O. Depuydt, L. De Bus, and J. J. De Waele
untreated infection.
 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

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

ruson D et al. Am J Respir Crit Care Med 2000;162:837-843.
aymond 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
Kapan
sebaiknya
diberikan?

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

 d ak
i nt i
n g k
m u
io t i k 2
t i b ma n
l a n k u
a w a : b a t
o ve r
a pi b i l a terla m g c a n g
Ter w at y a
a m e n
A B y
d e k r i a n n
k b i s
fe k si
a d a p
a mb
e t id a
ab i
n ter h
Pe tibiotik enyeb esisten w at
n p r d ek
A togen togen ak a
p a p a tid
a n s is
K um n , d o
ri ka ing
dib e se r
l in g
P a
 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
1. Kumar A, Roberts D, Wood KE et al (2006) Duration of hypotension before initiation of effective
without septic shock
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
1. Sterling SA, Millerof antibiotics
WR, Pryor may
J, Puskarich MA, Jones be The
AE (2015) less important
impact of timing of antibiotics on

when EARLY AGGRESSIVE RESUSCITATION

outcomes in severe sepsis and septic shock: A systematic review and meta- analysis. Crit Care Med
43:19071915

IS ACHIEVED
2. Puskarich MA, Trzeciak S, Shapiro
(2)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 Sistim pernafasan
kardiovaskuler kapasitas penetrasi dari
curah jantung beberapa antibiotik
permeabilitas vaskuler
fungsi kardiovaskuler

Sistim ginjal Sistim hepatik

renal function metabolisme dan klirens
renal function Renal obat-obatan yang melalui
Clearance (ARC) metabolisme hepar
Hipoalbuminemia
Robert, J.A. Current Pharmaceutical Biotechnology, 2011, 12, 2037-2043
Physiological Changes Induced
Altered PKparameters which is affected are C and V
The principle L d
Inisial
phase of
sepsis or
septic
shock
vascular
Endothelial
CO due to fluid permeability and
damage and
resuscition & use transcapillary loss of
capillary leak
of vasopressors albumin
Extravascular
renal perfusion Severe
fluid shift
hypoalbuminemia

CL &
Vd
CL Vd M.O. Cotta et al.
MEDIN-827;Pages 1
 Pieralli F, Mancini A,
Crociani A. Appropriate
Antibiotic Therapy in Critically
Ill Patients. Italian Journal of
Medicine 2016; 10:792

Early Sepsis Late Sepsis

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 Wells,Diana L et al. Surviving Sepsis Campaign
time
Hy Lip
d ro
ph op
i li hi
c l ic
 Post-antibiotic effect
Antibiotics (PAE)Gram Pseudomon
Gram
Positive Negative as
bacteri bacteria aeruginosa
a
Penicillins 1-2 0 0
Cephalospori 1-2 0 0
ns
Carbapenems 1-2 (1) 1-2
Quinolones 1-3 1-3 1-2
Protein 3-5 3-8
synthesis
inhibitors
 Concentration-dependent
bactericidal activity with
prolonged PAE
Goal of dosing
Aminoglycoside regimen :
s Maximize concentrations
Fluoroquinolon Parameters of efficacy
es 1. AUC/MIC > 125 (gram
negatif) & 30 (gram positif)
Metronidazole 2. C /MIC > 8-10
max
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 15.tepat pengkajian
orang/pasien
16.tepat peracik
6. tepat rute
17.waspada efek
7. tepat lama samping
pemberian
8. tepat interval
9. tepat 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