JCCA-PERDATIN JAYA

Jakarta-July 2020

The Role of PPRA in antibiotic

prescription in ICU

Rudyanto Sedono

ICU Department of Anesthesiology

Faculty of Medicine Universitas Indonesia
Cipto Mangunkusumo Hospital
Jakarta
 Competency and Qualification

Cataract Opthalmologist
Cesarian section Obstetrician

MCI Cardiologist

Stroke Neurologist
Antibiotic & Infection ?
Every one feel Competent and Qualified
in Antibiotic and Infection

Leading inappropriate of antibiotic therapy

 Appropriate antibiotic therapy

❖ Effective empirical treatment of bacterial infection at

the time of the identification of the infection
❖ The correct choice, dose and duration of therapy
❖ Use of an antibiotic to which the pathogen is sensitive

SCCM & ESICM 2009. ICU Infection in an Era of Multi-Resistance

 Inappropriate antibiotic therapy

Resistant microorganism

Unfortunately our concern is on sensitivity

and not on resistance
WHO PAYS ?

SCCM & ESICM 2009. ICU Infection in an Era of Multi-Resistance

ESICM 2007.25 Years of Progress and Innovation in Intensive Care Unit
 The vicious circle of antibiotic resistance in the ICU

High prevalence of resistant strain

(local or national)

Poor hygiene practices

Cross transmission

Clinical concern
(supra or subluminal pressure
by the pharmaceutical industry)
Selection of the most
resistance strain

Poor pharmacokinetic performance

(low dosage, poor tissue diffusion)
Excessive duration
of therapy

Broad spectrum antibiotic use

for empirical therapy

Carlet J.25 Years of Progress and Innovation in Intensive Care Unit. ESICM 2007
 Bacteria with high levels of antibiotic resistance

Gram negative bacteria : Neisseria gonorrhoeae with decreased

susceptibility to third generation cephalosporins, and
Escherichia coli, Klebsiella pneumoniae, Shigella spp, and non-
typhoidal salmonella with resistance to third generation
cephalosporins (including resistance conferred by extended
spectrum β-lactamases) and fluoroquinolones or carbapenems
Gram positive bacteria : meticillin resistant Staphylococcus
aureus and penicillin resistant Streptococcus pneumoniae

Chereau. BMJ 2017 Sep 5;358:j3393

Risk assessment for antibiotic resistance in South East Asia
 Chereau. BMJ 2017 Sep 5;358:j3393
Risk assessment for antibiotic resistance in South East Asia
Antimicrobial groups based on mechanism of action
Mechanism of action Antimirobial groups
β-Lactams
Carbapenems
Inhibit Cell Wall Synthesis Cephalosporins
Monobactams
Penicillins
Glycopeptides
Depolarize Cell Membrane Lipopeptides

Bind to 30S Ribosomal Subunit

Aminoglycosides
Tetracyclines
Bind to 50S Ribosomal Subunit
Inhibit Protein Synthesis Chloramphenicol
Lincosamides
Macrolides
Oxazolidinones
Streptogramins

Inhibit Nucleic Acid Synthesis Quinolones

Sulfonamides
Inhibit Metabolic Pathways
Trimethoprim

Reygaert. AIMS Microbiology, 2018;4(3): 482–501

An overview of the antimicrobial resistance mechanisms of bacteria
 Persistence and resistance

Natural resistance
May be intrinsic (always expressed in the species) or induced (the genes are naturally occurring in the
bacteria, but are only expressed to resistance levels after exposure to an antibiotic)

Acquired resistance
Acquisition of genetic material that confers resistance is possible through all of the main routes by which
bacteria acquire any genetic material: transformation, transposition, and conjugation (all termed horizontal
gene transfer—HGT); plus, the bacteria may experience mutations to its own chromosomal DNA. The
acquisition may be temporary or permanent
Reygaert. AIMS Microbiology, 2018;4(3): 482–501
An overview of the antimicrobial resistance mechanisms of bacteria
 Mechanisms of resistance

4. Active drug efflux 1. Limiting uptake

of a drug

2. Inactivating
3. Modifying of a drug
of drug target
Reygaert. AIMS Microbiology, 2018;4(3): 482–501
An overview of the antimicrobial resistance mechanisms of bacteria
Munita. Microbiol Spectr. 2016 April ; 4(2)
Mechanisms of Antibiotic Resistance
 1. Limiting uptake of a drug

There is a natural difference in the ability of bacteria to limit the uptake of

antimicrobial agents.
The structure and functions of the LPS layer in gram negative bacteria
provides a barrier to certain types of molecules

Reygaert. AIMS Microbiology, 2018;4(3): 482–501

An overview of the antimicrobial resistance mechanisms of bacteria
Munita. Microbiol Spectr. 2016 April ; 4(2)
Mechanisms of Antibiotic Resistance
 2. Inactivating of a drug

1. Degradation of the drug

The β-lactamases are a very large group of drug hydrolyzing
enzymes. Another drug that can be inactivated by hydrolyzation
is tetracycline, via the tetX gene

2. Transfer of a chemical group to the drug.

Drug inactivation by transfer of a chemical group to the drug
most commonly uses transfer of acetyl, phosphoryl, and adenyl groups.
Acetylation is the most diversely used mechanism, and is known
to be used against the aminoglycosides, chloramphenicol, the
streptogramins, and the fluoroquinolones. Phosphorylation and
adenylation are known to be used primarily against the
aminoglycosides
Reygaert. AIMS Microbiology, 2018;4(3): 482–501
An overview of the antimicrobial resistance mechanisms of bacteria
Munita. Microbiol Spectr. 2016 April ; 4(2)
Mechanisms of Antibiotic Resistance
 3. Modifying of drug target

There are multiple components in the bacterial cell that may be

targets of antimicrobial agents; and there are just as many targets that
may be modified by the bacteria to enable resistance to those drugs.
One mechanism of resistance to the β-lactam drugs used almost exclusively by gram positive
bacteria is via alterations in the structure and/or number of PBPs (penicillin-binding proteins).
PBPs are transpeptidases involved in the construction of peptidoglycan in the cell wall. A
change in the number (increase in PBPs that have a decrease in drug binding ability, or
decrease in PBPs with normal drug binding) of PBPs impacts the amount of drug that can
bind to that target

The glycopeptides (e.g. vancomycin) also work by inhibiting cell wall synthesis, and
lipopeptides (e.g. daptomycin) work by depolarizing the cell membrane. Gram negative
bacteria (thick LPS layer) have intrinsic resistance to these drugs. Resistance is mediated
through acquisition of van genes which results in changes in the structure of peptidoglycan
precursors that cause a decrease in the binding ability of vancomycin

Reygaert. AIMS Microbiology, 2018;4(3): 482–501

An overview of the antimicrobial resistance mechanisms of bacteria
Munita. Microbiol Spectr. 2016 April ; 4(2)
Mechanisms of Antibiotic Resistance
 4. Active drug efflux
Bacteria possess chromosomally encoded genes for efflux pumps.
Some are expressed constitutively, and others are induced or
overexpressed (high-level resistance is usually via a mutation that
modifies the transport channel) under certain environmental stimuli
or when a suitable substrate is present.
The efflux pumps function primarily to rid the bacterial cell of toxic
substances, and many of these pumps will transport a large variety of
compounds (multi-drug [MDR] efflux pumps).
There are five main families of efflux pumps in bacteria classified
based on structure and energy source:
1. The ATP-binding cassette (ABC) family
2. The multidrug and toxic compound extrusion (MATE) family
3. The small multidrug resistance (SMR) family
4. The major facilitator superfamily (MFS)
5. The resistance-nodulation-cell division (RND) family
Reygaert. AIMS Microbiology, 2018;4(3): 482–501
An overview of the antimicrobial resistance mechanisms of bacteria
Munita. Microbiol Spectr. 2016 April ; 4(2)
Mechanisms of Antibiotic Resistance
General structure of main efflux pump families

Reygaert. AIMS Microbiology, 2018;4(3): 482–501

An overview of the antimicrobial resistance mechanisms of bacteria
Munita. Microbiol Spectr. 2016 April ; 4(2)
Mechanisms of Antibiotic Resistance
1. Resistensi Antimikroba adalah kemampuan mikroba untuk bertahan
hidup terhadap efek antimikroba sehingga tidak efektif dalam
penggunaan klinis.
2. Pengendalian Resistensi Antimikroba adalah aktivitas yang ditujukan
untuk mencegah dan/atau menurunkan adanya kejadian mikroba
resisten.
3. Komite Pengendalian Resistensi Antimikroba yang selanjutnya
disingkat KPRA adalah komite yang dibentuk oleh Kementerian
Kesehatan dalam rangka mengendalikan penggunaan antimikroba
secara luas baik di fasilitas pelayanan kesehatan dan di masyarakat.
Penerapan penggunaan antibiotik secara bijak sebagaimana dimaksud
pada ayat (1) dilakukan melalui tahapan:

a. Meningkatkan pemahaman dan ketaatan staf medis fungsional dan

tenaga kesehatan dalam penggunaan antibiotik secara bijak;
b. Meningkatkan peranan pemangku kepentingan di bidang penanganan
penyakit infeksi dan penggunaan antibiotik;
c. Mengembangkan dan meningkatkan fungsi laboratorium
mikrobiologi klinik dan laboratorium penunjang lainnya yang
berkaitan dengan penanganan penyakit infeksi;
d. Meningkatkan pelayanan farmasi klinik dalam memantau
penggunaan antibiotik;
e. Meningkatkan pelayanan farmakologi klinik dalam memandu
penggunaan antibiotik;
f. Meningkatkan penanganan kasus infeksi secara multidisiplin dan
terpadu;
g. Melaksanakan surveilans pola penggunaan antibiotik, serta
melaporkannya secara berkala; dan
h. Melaksanakan surveilans pola mikroba penyebab infeksi dan
kepekaannya terhadap antibiotik, serta melaporkannya secara
berkala
Pelaksanaan Program Pengendalian Resistensi Antimikroba
sebagaimana dimaksud pada ayat (1) dilakukan melalui:

a. Pembentukan tim pelaksana Program Pengendalian Resistensi

Antimikroba;
b. Penyusunan kebijakan dan panduan penggunaan antibiotik;
c. Melaksanakan penggunaan antibiotik secara bijak; dan
d. Melaksanakan prinsip pencegahan pengendalian infeksi.
 Kategori antibiotik berdasarkan pembatasan peresepan

Lini 1 Lini 2 Lini 3

1. Penisilin : ampisilin, amoksisilin, benzatin 1. Kombinasi penisilin + 1. Glikopeptida : vancomisin,
penisilin, fenoksimetil penisilin, prokain p e n g h a m b a t teikoplanin
benzil penisilin G, kombinasi penisilin + betalaktamase : ampisilin + 2. Tetrasiklin : tigesiklin
penghambat betalaktamase : amoksisilin + sulbaktam 3. Oksazolidinon : linezolid
klavulanat 2. Sefalosporin 3 oral : 4. Sefalosporin 3 : seftazidim,
2. Sefalosporin 1 : sefaleksin, sefadroksil, sefiksim sefoperazon-sulbaktam
sefazolin 3. S e f a l o s p o r i n 3 I V : 5. Sefalosporin 4 : sefepim,
3. Sefalosporin 2 : sefotiam, sefuroksim sefoperazone, sefotaksim, sefpirom
4. Sefalosporin 3 : sefditoren seftizoksim, seftriakson 6. Kuinolon : moksifloksasin
5. Fenikol : kloramfenikol, tiamfenikol 4. Kuinolon : levofloksasin 7. Karbapenem : meropenem,
6. Linkosamid : linkomisin, klindamisin 5. Aminoglikosida : amikasin, imipenem + silastatin,
7. Makrolid : eritromisin, spiramisin, netilmisin doripenenm, ertapenem
klaritromisin, azitromisin 8. Kombinasi penisilin +
8. Kuinolon : siprofloksasin, ofloksasin p e n g h a m b a t
9. Tertrasiklin : tertrasiklin, doksisiklin, betalaktamase : piperasilin-
oksitetrasiklin tasobaktam
10. Aminoglikosida : gentamisin, dibekasin, 9. Lain-lain : aztreonam,
kanamisin sulfat, tobramisin fosfomisin, kolistin
11. Kotrimoksazol
12. Imidazol : metronidazol
13. Lain-lain : linkomisin
Antibiotik lini 1 : adalah antibiotik yang boleh diresepkan oleh
dokter umum, PPDS, dan DPJP.

Antibiotik lini 2 : adalah antibiotik yang boleh diresepkan oleh

dokter umum, PPDS, dan DPJP, tetapi hanya untuk indikasi
tertentu sesuai dengan PPAB atau PPK departemen.

Antibiotik lini 3 : adalah antibiotik yang hanya boleh diresepkan

atas persetujuan konsulen PRA yang ditunjuk oleh Direktur
Utama atau dokter spesialis penyakit tropik infeksi.
Overview of the WHO AWaRe groups and essential
antibiotics on the WHO EML
 Peresepan antibiotik di ICU

Indikasi pemakaian antibiotik

1. Profilaksis
2. Empirik
3. Definitif
4. Preemptif
 Empirik

DPJP ICU dapat meresepkan antibiotik sesuai dengan

antibiogram atau pengalaman klinis DPJP ICU
Bila diperlukan antibiotik lini 3 untuk empirik DPJP ICU bisa
melakukan komunikasi langsung (telp) kepada tim PPRA untuk
mendapat persetujuan. PPRA akan memberikan persetujuan ke
unit farmasi.
Pengambilan sampel untuk kultur dan resistensi
Evaluasi pemberian antibiotik setelah 2-3 hari secara klinis
 Definitif

DPJP ICU dapat mengubah atau mengganti antibiotik sesuai dengan

hasil kultur mikrobiologi
Bila terdapat perbedaan pendapat, dilakukan kominukasi antara DPJP
ICU dengan tim PPRA
PPRA akan memberikan persetujuan kepada unit farmasi
Evaluasi pemberian antibiotik

Evaluasi pemakaian antibiotik oleh PPRA

melalui ronde PPRA
 Riwayat Antimikroba
imipenem 3x500 mg

polymixin B
2x1 jt U
ceftazidim 2x1 gr

levofloksasin
1x750 mg

3/4 7/4 14/4 17/4 19/4 23/4 29/4 4/5 5/5 6/5 10/5 14/5 15/5

tygecyclin 2 x 100 mg
amikasin
1 x 1 gr

polymixin B 1x1 jt U

IGD ICU
Ruang
Rawat
 AB alternatif: Efektifitas
cefotaksim broad spectrum
cefoperazone broad spectrum
Empiric: broad
spectrum AB alternatif: Harga (Per hari)
cefotaksim Rp 13306,-
cefoperazone Rp 163680,-
ceftazidim Rp 55786,-

3x1 g

Setiap 24 jam
intravena
Sesuai klinis
ceftazidim 3x1 gr
Kategori IV b, IVc dan I
Tgl 6 - 17 April
definitive gram -, +, AB alternatif: -
anaerob, MRSA,
multi drug resistent
strain of
acinetobacter
baumannii

2x200 mg

Setiap 24jam

intravena

sesuai hasil kultur

tigecyclin 2 x 200 mg
Kategori I
Tgl 4 mei-saat ini
Evaluasi antibiotik dengan ronde PPRA
Teng kyu