Antimicrobial Resistance:

Improving Antibiotic Stewardship by Multidisciplinary Learning.

Uun Sumardi

Antimicrobial Resistance Controlling Program/Antimicrobial Stewardship Program,

Department of Internal Medicine, Infectious and Tropical Diseases Div., Intensive Care Medicine.
RSUP Dr. Hasan Sadikin, Bandung.
 Objectives
• What is antimicrobial resistance (AMR).
• Mechanisms antibiotic resistance.
• Super Bug (an infective bacterial pathogen that has become resistant to antibiotics) .
• Bacterial Pathogen Pattern in Internal Medicine Dept., RSHS, Bandung.
• Global and National initiatives on AMR
• Hospital Action Plan in RSUP Dr. Hasan Sadikin, Bandung.
• Program Penatalayanan Antimikroba (PPA)/ASP Model, RSHS, Bandung.
• Evaluation PPA/ASP Model RHS, Bandung.
• Planning PPA/ASP Model RSHS, Bandung.
• Case of optimising antibiotic treatment for CRAB.
• Summary
Antimicrobial Resistance (AMR).

- Defined as micro-organisms that are not inhibited by usually

achievable systemic concentration of an antimicrobial agent
with normal dosage schedule and/or fall in the minimum
inhibitory concentration (MIC) range.
A population-based antibiotic-resistance mechanism in bacteria.

Selective Pressure

HH Lee et al. Nature 467, 82-85 (2010) doi:10.1038/nature09354

CDC. Antimicrobial resistance threats in the United States – 2013.
 Mechanisms antibiotic resistance.

Antibiotic Resistance

Intrinsic (Natural) Acquired

Genetic Methods
[Phenotypic/Culture Result (S,R,I)]

Chromosomal Methods Extra chromosomal Methods

Mutations Plasmids

Genotypic (Bio-molecular)
 Intrinsic Resistance (Natural)
- It occurs naturally,

1. Lack target :
• No cell wall; innately resistant to penicillin
2. Innate efflux pumps:
• Drug blocked from entering cell or ↑ export of drug (does
not achieve adequate internal concentration). Eg. E. coli, P.
aeruginosa
3. Drug inactivation:
• Cephalosporinase, Betalactamase (Enzyme.) as in
Klebsiella pneumoniae ESBL, CRAB
 Acquired resistance
1. Mutations
• It refers to the change in DNA structure of the gene.
• Occurs at a frequency of one per ten million cells.
• Mycobacterium tuberculosis, Mycobacterium lepra,
MRSA.
• Often mutants have reduced susceptibility.
 Acquired resistance
2. Plasmid
• Extra chromosomal genetic elements can replicate
independently and freely in cytoplasm.
• Plasmids which carry genes resistant (r-genes) are
called R-plasmids.
• These r-genes can be readily transferred from one R-
plasmid to another plasmid or to chromosome.
• Much of the drug resistance encountered in clinical
practice is plasmid mediated
Gram Positive vs Gram Negative Bacteria

No peptidoglycan, penicillin resistant

Medical Microbiology,www.digitalproteus,com
 Bacterial Pathogen
Super Bug
Enterobacteriaceae
ESBL producer
Enterococci K pneumoniae P aeruginosa Carbamase producer

Bad Bug
MDR A baumannii

MDR P aeruginosa
S aureus A baumannii Enterobacter
spp.
MRSA

MDRSH

IDSA.2004.
 BAD BUG in Internal Medicine Dept.
Dr. Hasan Sadikin Hospital,2012 (n=1.121).
Fungal

Candida spp !&+$

103
Enterococcus spp *%$
Gram positif

Streptococcus spp !&($

257
Staphylococcus spp !&($

Salmonella spp (($

Burkholderia spp ()$

Bad Bug
Acromobacter spp ""$
Gram negatif

Klebsiella spp "'$

761

Enterobacteriaceae

Pseudomonas spp !#!$

Acinetobacter spp !%&$

Fermenters - Non Fermenters

Entrobacter spp !"#$

&$ #&$ *&$ )&$ "&$ !&&$ !#&$ !*&$ !)&$ !"&$ #&&$
Super Bug Aetiology in Sepsis Patient, Internal Med. Dept.,
MIC Room, RSUP Dr. Hasan Sadikin, 2013 (n=152)

Super Bug Enterobacteriaceae

Fermenters (44.2%), Non Fermenters (25%)

MDRO Coccus (19.1%) and Fungal (1.97%)

Blood Cultures Result in Septic Patients at RSUP dr. Hasan Sadikin, 2015.

Staphylococcus (MRCONS, 27.27%)

Escherichia coli (ESBL)
Acinetobacter baumannii (CRAB)
Escherichia coli (WT)
Klebsiella pneumoniae (ESBL)
Staphylococcus (WT)
Klebsiella pneumonia (WT)
Pseudomonas aeruginosa (MDR)
Aeromonas hydrophila (WT)
Enterobacter cloacae (MDR)
Salmonella spp. (WT)
Lain-lain

H Nugraha, U Sumardi, R Wisaksana.Gambaran Karakteristik Pasien Sepsis dan Nilai

Kadar Hambat Minimal dari Terapi Empiris Antibiotika Golongan Sefalosporin di
Instalasi Rawat Inap Rumah Sakit Hasan Sadikin Tahun 2016.
 WHO,2017: These 12 bacteria pose greatest risk to human health.

P aeruginosa E faecalis Campylobacter N gonorrhoea Shigella

A baumanii Entertobacteriaceae MRSA Salmonella S pneumoniae

(E coli and K pneumoniae)

CRAB’s
CRPsA’s
NDM’s
KPC’s

ug
r B
up e
S
27 February 2017 | GENEVA - WHO today published its first ever list of antibiotic-resistant "priority pathogens" – a catalogue of 12 families
of bacteria that pose the greatest threat to human health.
Mechanisms for Carbapenem Resistance in Super Bug
Bacterial Pathogen

Enzymes

Pediatr Infect Dis J. 2011; 30(12):1094-5. Int J Med Microbiol 2010;300(6)371-9. N Engl J Med. 2008;20;358(12):1271-81.
Initiative Action Plan on Antimicrobial Resistance

2015 2017
Indonesia NAP on Antimicrobial Resistance

1. Improve awareness and understanding of AMR through effective

communication, education and training.

2. Strengthen knowledge and evidence base through surveillance and
research.
3. Reduce incidence of infection with sanitation, hygiene and infection
prevention.

4. Optimise use of antimicrobial medicines in human and animal health.

5. Develop economic case for sustainable investment and increase
investment in new medicines, diagnostic tools, vaccines and other
interventions.

WHO, 2017.
 add.4. Optimise use of antimicrobial

Strategic objective 4: relates to optimising use of antimicrobial

medicines to minimise precipitation of resistance in target microbes.
A robust system for regulation and surveillance of use of antimicrobial
agents for control of human and veterinary use of antimicrobial
substances is suggested with formulation of a National AMR
Containment and Use Policy with related regulatory frameworks,
- National Drug Policy,
- National Drug Regulatory Authority,
- Essential medicines list and
- Standard treatment guidelines for use of antimicrobial agents and
- Evidence based guidelines for National Antimicrobial Stewardship
Program in human and animal health care, amongst others.

WHO, 2017.
HAP in RSUP dr. Hasan Sadikin, Bandung.

PROGRAM PENATALAYANAN ANTIMIKROBA

(ANTIMICROBIAL STEWARDSHIP PROGRAME)
RSUP DR. HASAN SADIKIN BANDUNG TAHUN 2017.

PPRA
RSUP dr. Hasan Sadikin,
2017
 PPA/ASP RSUP Dr. Hasan Sadikin Model

Pemilihan Antimikroba
Optimasi Dosis
Right Diagnosis,
Perubahan Pemberian Konversi Antimikroba
Antimikroba Right Drugs, IV-PO

Right Doses,
PPA/ASP
Permintaan
Antimikroba
Right Dosing,
RSUP
Surveilans &
Umpan Balik

Right Duration,
RSHS
IT
Restriksi =“5D” in Audit (Prospektif) &
Antimicrobial
Preotorisasi
Strategi Utama Stewardship Program/
Umpan Balik
Strategi Utama

Program Penatalayanan Antimikroba

Formularium
RSUP Dr. Hasan Sadikin Edukasi
CP

PPA, , 2016
PERATURAN MENTERI KESEHATAN REPUBLIK INDONESIA NOMOR 2406/MENKES/PER/XII/2011
PERATURAN MENTERI KESEHATAN REPUBLIK INDONESIA NOMOR 8 TAHUN 2015
PPRA.SK.Direktur Utama, RSUP Dr. Hasan Sadikin, 2015
Restriksi dan Preotorisasi Antimikroba RSUP dr.Hasan Sadikin

Kategori I Kategori II Kategori III

Aminopenisilin Cepalosporin generasi 3 dan 4 Vancomisin
Penisillin Cepalosporin Antipseudomonas Teicoplanin
Cepalosporin (Gen.1 dan 2) Fluorokuinolon Antipeseudomonas Linezolid
Khlorampenikol Flukonazol Tigecycline
Asam Fusidat Fosfomycin Carbapenem
Linkosamid Acyclovir Aminoglykosida
Makrolida Pirimetamin Fluorokuinolon (Gen.4)
Metronidazole Piptazo
Fluorokuinolon (Gen.1 dan 2) Colistin
Tetrasiklin Variconazole
Trimetoprim-sulfametoksasol Mycafungin
Nitrofurantoin Anidulafungin
Albendazole Gancyclovir
Mupirosin
Sulfadiazin

Kategori III, adalah antimikroba yang membutuhkan persetujuan sebelum antimikroba tersebut boleh
diresepkan. Persejutuan diberikan oleh konsultan spesifik di SMF jika telah memenuhi kriteria.
Kategori II, adalah antimikroba yang hanya boleh diresepkan atas indikasi spesifik yang kemudian ditinjau
oleh Tim PPRA dalam kurun waktu 3 hari kerja.
PPA, , 2016
 PPRA
RSUP dr. Hasan Sadikin,
2017
Formulir Permintaan Antimikroba

Terapi Empirik Terapi Definitif

PPRA
RSUP dr. Hasan Sadikin,
2017
 First Study
Blood Cultures Result in Sepsis Patients, Pre and Post PPA
[Pra PPA Januari-Maret (n=55), Post PPA April-Juli 2016 (n=57) di 4 Ruang Intermediate dan 1 Intensive]

Pre PPA Post PPA

Bacterial Pathogen
(n=55) (n=57)
Escherichia coli (ESBL) 2(3,6) 1(1,7)
Staphylococcus haemolyticus (MRCONS) 1(1,8) 2(3,5)
Staphylococcus epidermidis (MRCONS) 0(0) 2(3,5)
Pseudomonas aeruginosa (MDR) 1(1,8) 1(1,7))
Acinetobacter baumannii (MDR) 0(0) 1(1,7)
Aerococcus viridans (MDR) 1(1,8) 0(0)
Burkholderia cepacia (MDR) 1(1,8) 0(0)
Chryseobacterium gleum (MDR) 1(1,8) 0(0)
Enterococcus faecalis (wild type) 0(0) 1(1,7)
Kocuria rosea (MDR) 1(1,8) 0(0)
Sphingomonas paucimobilis (MDR) 1(1,8) 0(0)
Staphylococcus Iugdunensis (wild type) 1(1,8) 0(0)
Staphylococcus hominis (MRCONS) 0(0) 1(1,7)

Blood Cultures Result 10(18) 9(15,5)

Cultures (-) 45(81,8) 48(84,2)

A Felani, U Sumardi, I Parwati. The Difference of Defined Daily Doses and Cost of Ceftriaxone Therapy Before and After Antimicrobial Stewardship Programmed In
Critically Ill Patients. Thesis 2016.
Capaian Kinerja Tim PPRA Tahun 2017
A. Penggunaan Antimikroba
No KPI Target Capaian

1 % Penggunaan Antimikroba di 4 bagian 60% 59.9 %

besar RSHS (Ilmu Penyakit Dalam, - IKA = 43.5%
Obgyn, Bedah, Anak)
- OBGYN = 70.5 %

- BEDAH = 78 %

- IPD = 47.75 %

2 Evaluasi penggunaan antimikroba Dilakukan Tercapai

kuantitatif DDD minimal setiap 6 Evaluasi DDD semester I
bulan dan II

PPRA, RSHS, Jan. 2018.

 Penggunaan Cefriaxon 1 Gr. Injeksi.
Jumlah Vial Cefriaxon (CFX), LASA 1 Gr. Injeksi, 2018.

8.000 100.334.000 IDR 7.718

6.000

4.000
- 68.263.000 IDR
2.467
2.000
32.071.000 IDR
0
Januari Februari Maret April Mei Juni Juli Agustus September Oktober

PPRA, RSHS, Jan. 2018.

Penggunaan Antibiotik Profolaktik, Cefazolin 1 Gr.

270.800.000 IDR
14.000 13.540
41.13%

10.572
10.500
159.400.000 IDR
7.970
11.832 5.219
7.000 1.464
1.694
1.427
3.500
238 4.812
RAWAT INAP 3.926
ODS
COT
1.470
-
2015 2016 2017

PPRA, RSHS, Jan. 2018.

 PPRA
RSUP dr. Hasan Sadikin,
2017
B. Peningkatan Mutu Penanganan Kasus Infeksi secara
Multidisiplin

No KPI Target Capaian

1 Terlaksananya audit Dilakukan minimal Tidak Tercapai
prospektif penggunaan 1 minggu 1 kali
antimikroba

PPRA, RSHS, Jan. 2018.

 There are 2 core strategies, both proactive, that provide the
foundation for an antimicrobial stewardship program.
These strategies are not mutually exclusive.
A. Formulary restriction and preauthorisation. Formulary restriction
and preauthorization requirements can lead to immediate and significant
reductions in antimicrobial use and cost (A-II) and may be beneficial as part
of a multifaceted response to a nosocomial outbreak of infection (B-II). The
use of preauthorisation requirements as a means of controlling antimicrobial
resistance is less clear, because a long-term beneficial impact on resistance
has not been established, and in some circumstances, use may simply shift
to an alternative agent with resulting increased resistance (B-II). In
institutions that use preauthorisation to limit the use of selected
antimicrobials, monitoring overall trends in antimicrobial use is necessary to
assess and respond to such shifts in use (B-III).

B. Prospective audit with intervention and feedback. Prospective audit

of antimicrobial use with direct interaction and feedback to the prescriber,
performed by either an infectious diseases physician or a clinical pharmacist
with infectious diseases training, can result in reduced inappropriate use of
antimicrobials (A-I).
Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional
Program to Enhance Antimicrobial Stewardship. Dellit TH et al, Clin Infect Dis 2007; 44:159–77
 Two core ASP strategies have emerged

“Front–end strategies” where antimicrobials are made

available through an approval process (formulary
restrictions and preauthorization).

“Back-end“strategies are where antimicrobials are

reviewed after antimicrobial therapy has been initiated
(prospective audit with intervention and feedback).

Chung GW et al. Virulence 2013; 4:1-7

Planning PPA/ASP Model RSUP Dr. Hasan Sadikin, Bandung in
2018.

Chung GW et al. Virulence 2013; 4:1-7

Antimicrobial Stewardship Team RSUP dr Hasan Sadikin Model
(Multidisciplinary Team Approach in ASP to Optimizing Clinical Outcomes)*

Director/Chief
Medical Officer P&T

Information (CMO)
 Committee
Technology (TFT)
Infection
 Medical

Prevention Information

(PPI) ASP
ARCP Systems
Coordinators Leader
RSUP dr Hasan Sadikin
(Qualitative,Quantitative,
Infectious
 Resistance,Education)
Diseases 
 Nursing Care

Microbiology
 Clinical

Laboratory Partners in Optimizing
Pharmacy
 ASP~Dept./SMF
Specialists

Decentralized

Pharmacy

Specialist
Modified from : Dellit TH et al. Clin lnfect Dis. 2007;44:159-177.
PPA/ASP. RSUP dr Hasan Sadikin Bandung. 2016
Indikator Mutu PPA/ASP Model RSUP Dr. Hasan Sadikin, Bandung,
2018.
No Indikator Target

1 % Penggunaan Antibiotik di 4 bagian besar RSHS 0,5

(Ilmu Penyakit Dalam, Obgyn, Bedah, Anak)

2 Evaluasi penggunaan antibiotik kuantitatif DDD Dilakukan minimal setiap 6 bulan

3 Evaluasi penggunaan antibiotik secara kualitatif Dilakukan minimal setiap 6 bulan

4 Evaluasi Penggunaan Antibiotik Profilaksis Dilakukan setiap bulan

5 Terlaksananya audit prospektif, intervenes dan Dilakukan minimal 1 minggu 1

umpan balik penggunaan antimikroba kali

6 % Pengisian Formulir PPRA untuk antibiotik yang 0,9

masuk dalam dalam restriksi dan preotorisasi

7 Terlaksananya edukasi penggunaan antimikroba Dilakukan minimal setiap 6 bulan

untuk dokter, farmasi dan perawat

PPRA, RSHS, Jan. 2018.

 PPA plan of action as quality indicators, 2018-2020.

2020 Improved antibiotic

sensitivity patterns
and decreased levels
of AMR
2019

Decreased incidence of multi-resistant

bacterial infections (80%)
2018

Improved appropriateness of bacterial infection

treatment by multidiscipline team (80%) with
Prospective audit, Intervention & Feed back
2016-2017

Antibiotic Use:
- Restriction/Preauthorisation
- Quantitatives
- Qualitatives

PPRA, RSHS, Jan. 2018.

Case:
An Old Man Post Laparotomy in admission to Medical Critical Unit (MCU),
Internal Medicine Dept., RSUP dr. Hasan Sadikin.
Tanggal Kultur Patogen Leukosit Neutrofil Limfosit ANC TLC NLCR Kreatinin Antibiotik Tindakan Keterangan
20/1/17 darah E faecalis 38.500 94 2 36.190 770 47 2,06 Sepsis Bundle BSI (Sepsis)
21-1 23.000 94 2 21.620 460 47 3,46 Moxifloxacin (Int. AB)
22-1 19.300 91 3 17.563 579 30,33 4,1 1x400mg (PO)
23-1 15.600 86 4 13.416 624 21,5 4,69 (Definitif, Periop.Care
24-1 13.200 80 4 10.560 528 20 4,67 14 hari) (Inot, Diuretic)
25-1 14.400 88 5 12.672 720 15,6 4,42
26-1 urine steril 14.800 76 6 11.248 888 12,67 3,72
27-1 14.700 69 7 10143 1029 9,8 3,14
28-1 14.900 69 10 10281 1490 6,9 2,8
29-1 15.300 70 10 10710 1530 7 2,27
30-1 16.100 85 6 13685 966 14,1 1,89 ERCP
31-1 16.400 86 6 14104 984 14,3 1,76 (Laparos./
1-2 13.100 81 8 10611 1048 10,12 1,56 Lapar)
2-2 12.900 80 8 10320 1032 10 1,32
3-2 11.100 78 10 8658 1110 7,8 1,19
4-2 10.000 73 13 7300 1300 5,6 1,14
5-2 8.800 73 12 6424 1056 6,08 1,14
6-2 9.500 70 14 6650 1330 5 1,07
7/2/17 pus E faecalis 9.800 71 15 6958 1470 4,73 1,06 Laparotomy
8-2 12.700 86 7 10922 889 12,2
9-2 12.400 84 7 10416 868 12 0,96 Moxifloxacin
10/2/22 darah A baumannii 12.800 88 5 11264 640 17,4 0,96
stop BSI (HAI's)
11-2 (CRAB) 16.900 76 10 12844 1690 7,6 1,19
+ Tygecyclin
12-2 13.600 77 11 10472 1496 7 1,06
Loading,100mg
13-2 13.200 77 10 10164 1320 7,7 1,02
& maintenace
14-2 18.100 84 9 15204 1629 9,3
15-2 21.400 77 10 16478 2140 7,7 0,95 2x50mg
16/2/28 pus E.cloaceae 22.800 79 9 18.012 2.052 8,7 0,74 Tygecyclin SSI (HAI's)
17-2 (drain) (CRE) 26.000 81 8 21.060 2.080 10,12 0,78 2x100mg
18-2 26.000 82 9 21.320 2.340 9,1 + Amikacin
19-2 24.100 82 9 19.762 2.169 9,1 0,76 1x1200mg
20-2 21.500 82 8 17.630 1.720 10,25 0,73
(Definitif)
21-2 23.800 81 10 19.278 2.380 8,1 0,73
22-2 20.000 81 9 16.200 1.800 9
23-2 19.600 79 11 15484 2156 7,18 0,66 Tigecyclin stop
Amikacin
24-2 18.700 80 9 14960 1683 8,89 1x1200mg Deeskalasi
sp.7 hari.
 CRAB MIC Profile

Blood Stream Infection (IADP) not CSEP

 Antibiotic Optimizing in PKPD Principles
Amikacin

Cmax/MIC
40
Concentration (mg/L)

30 Tigecycline

20 AUC/MIC

10 MIC

PAE
0

0 0.5 8 12 16 24

Tigecycline has a half-life of 37 to 38 hours.

Its PD properties appears to have both time-dependent and concentration-
independent characteristics.
N J Onufrak, A Forrest, D Gonzalez. Clini.Ther. 2016;38(9):1930-1947.
L S. Lehman. Which Antibiotics Are Time- or Concentration-Dependent?. medscape.2007.
Drusano GL. NATURE REVIEWS / MICROBIOLOGY 2004 (April);2:289-300;
 Treatment Options for Carbapenem-Resistant
Enterobacteriaceae (CRE) Infections
Principal Characteristics of Currently Available Drugs With Activity Against Carbapenem-Resistant Enterobacteriaceae

H J Morrill, J M Pogue, K S Kaye, K L LaPlante. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. OFID, 2015.
Algorithm for antibiotic choice in patient with bacteriaemia of
carbapenem resistant Enterobacteriaceae (CRE).

F Alhashem, N L Tiren-Verbeet, E Alp, M Doganay.Treatment of sepsis: What is the antibiotic choice in bacteremia due to carbapenem
resistant Enterobacteriaceae? .World J Clin Cases. 2017; 5(8): 324-332.
 Summary
•
AMR is the main problem for antibiotic treatment.
•
ASP can improve cost effectively in antibiotic treatment.
•
ASP continuing with Prospective audit, Intervention and Feedback.
•
ASP is the solution for Combating Resistant Antibiotic Bacterial.
•
ASP with Pharmacies can do better.
Singapore Antimicrobial Stewardship Training Course,
at Tan Tock Seng Hospital August 2017.
Anti-Microbial Resistance (AMR)
Algemeene Bandoengsche Ziekenhuis, 1923.
Gemeente Ziekenhuis Juliana, 1927.

Thank You