Articles

Optimizing antibiotic use in Indonesia: A systematic

review and evidence synthesis to inform opportunities
for intervention
Ralalicia Limato,a,b Gilbert Lazarus,a,c Puck Dernison,a,d Manzilina Mudia,a Monik Alamanda,a Erni J. Nelwan,c,e Robert Sinto,b,c,e
Anis Karuniawati,c,f H. Rogier van Doorn,b,g and Raph L. Hamers a,b,c*
a
Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia
b
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
c
Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
d
Faculty of Health Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands
e
Department of Internal Medicine, Division of Infectious Diseases, Cipto Mangunkusumo National General Hospital, Jakarta,
Indonesia
f
Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
g
Oxford University Clinical Research Unit, Hanoi, Vietnam

Summary
Background A major driver of antimicrobial resistance (AMR) and poor clinical outcomes is suboptimal antibiotic The Lancet Regional
use, although data are lacking in low-resource settings. We reviewed studies on systemic antibiotic use (WHO ATC/ Health - Southeast Asia
2022;2: 100013
DDD category J01) for human health in Indonesia, and synthesized available evidence to identify opportunities for
https://doi.org/10.1016/j.
intervention. lansea.2022.05.002

Methods We systematically searched five international and national databases for eligible peer-reviewed articles, in
English and Indonesian, published between 1 January 2000 and 1 June 2021 including: (1) antibiotic consumption;
(2) prescribing appropriateness; (3) antimicrobial stewardship (AMS); (4) consumers’ and providers’ perceptions.
Two independent reviewers included studies and extracted data. Study-level data were summarized using random-
effects model meta-analysis for consumption and prescribing appropriateness, effect direction analysis for antimi-
crobial stewardship (AMS) interventions, and qualitative synthesis for perception surveys. (PROSPERO:
CRD42019134641)

Findings Of 9323 search hits, we included 100 reports on antibiotic consumption (20), prescribing appropriateness
(49), AMS interventions (13), and/or perception (25) (8 categorized in >1 domain). The pooled estimate of overall
antibiotic consumption was 134.8 DDD per 100 bed-days (95%CI 82.5
187.0) for inpatients and 121.1 DDD per
1000 inhabitants per day (10.4-231.8) for outpatients. Ceftriaxone, levofloxacin, and ampicillin were the most con-
sumed antibiotics in inpatients, and amoxicillin, ciprofloxacin, and cefadroxil in outpatients. Pooled estimates for
overall appropriate prescribing (according to Gyssens method) were 33.5% (18.1
53.4) in hospitals and 49.4%
(23.7
75.4) in primary care. Pooled estimates for appropriate prescribing (according to reference guidelines) were,
in hospitals, 99.7% (97.4
100) for indication, 84.9% (38.5-98.0) for drug choice, and 6.1% (0.2
63.2) for overall
appropriateness, and, in primary care, 98.9% (60.9-100) for indication, 82.6% (50.5
95.7) for drug choice and
10.5% (0.8
62.6) for overall appropriateness. Studies to date evaluating bundled AMS interventions, although
sparse and heterogeneous, suggested favourable effects on antibiotic consumption, prescribing appropriateness,
guideline compliance, and patient outcomes. Key themes identified in perception surveys were lack of community
antibiotic knowledge, and common non-prescription antibiotic self-medication.

Interpretation Context-specific intervention strategies are urgently needed to improve appropriate antibiotic use in
Indonesian hospitals and communities, with critical evidence gaps concerning the private and informal healthcare
sectors.

Funding Wellcome Africa Asia Programme Vietnam.

*Corresponding author at: Eijkman-Oxford Clinical Research Unit, Jl Salemba Raya No. 6, Jakarta, Indonesia 10430.
E-mail address: raph.hamers@ndm.ox.ac.uk (R.L. Hamers).

www.thelancet.com Vol 2 Month July, 2022 1

 Articles

Abstrak
Latar belakang Pendorong utama resistensi antimikroba/antimicrobial resistance (AMR) dan keluaran klinis yang
buruk adalah penggunaan antibiotik yang kurang optimal meskipun data tentang masalah ini masih kurang di area
yang bersumber daya rendah. Kami menelaah berbagai penelitian tentang penggunaan antibiotik sistemik (WHO
ATC/DDD kategori J01) untuk kesehatan manusia di Indonesia, dan mensintesis bukti yang ada guna melihat
peluang untuk intervensi.

Metode Kami mencari secara sistematis pada lima pangkalan data internasional dan nasional, artikel yang memen-
uhi kriteria kelayakan ditelaah mitra bestari (peer-reviewed), ditulis dalam bahasa Inggris dan Indonesia, serta diter-
bitkan antara tanggal 1 Januari 2000 sampai 1 Juni 2021, yang mencakup: 1) konsumsi antibiotik; 2) ketepatan
peresepan; 3) penatagunaan antimikroba/antimicrobial stewardship (AMS); 4) persepsi konsumen dan penyedia
layanan. Dua penelaah secara independen memilih artikel dan melakukan ekstraksi data dari artikel yang dipilih.
Analisis data dilakukan dengan menggunakan model meta-analisis efek-acak (random-effect model) untuk melihat
kesesuaian konsumsi dan peresepan, analisis arah efek (effect direction analysis) untuk intervensi AMS, serta sintesis
kualitatif untuk survei persepsi. (PROSPERO: CRD42019134641)

Hasil Dari 9323 hasil pencarian, kami memasukkan 100 laporan tentang konsumsi antibiotik (20), ketepatan pere-
sepan (49), AMS (13), dan/atau persepsi (25) (8 dikategorikan ke dalam >1 domain). Estimasi gabungan (pooled esti-
mate) konsumsi antibiotik adalah 134,8 DDD/100 pasien-hari (KI95 82,5-187,0) untuk pasien rawat inap, dan 121.1
DDD/1000 populasi per hari (KI95 10,4-231,8) untuk pasien rawat jalan. Ceftriakson, levofloksasin, dan ampisilin
merupakan antibiotik yang paling banyak dikonsumsi oleh pasien rawat inap; dan amoksisilin, siprofloksasin, and
sefadroksil oleh pasien rawat jalan. Estimasi gabungan untuk peresepan yang tepat secara keseluruhan (menurut
metode Gyssens) adalah 33,5% (KI95 18,1
53,4) di rumah sakit dan 49,4% (KI95 23,7
75,4) di fasilitas kesehatan
primer. Estimasi gabungan untuk peresepan yang tepat (menurut panduan) di rumah sakit adalah 99,7% (KI95
97,4
100) untuk indikasi, 84,9% (KI95 38,5
98,0) untuk pilihan obat, dan 6,1% (KI95 0,2
63,2) untuk kese-
suaian secara keseluruhan. Pada fasilitas kesehatan primer, estimasi gabungannya adalah 98,9% (KI95
60,9
100%) untuk indikasi, 82,6% (KI95 50,5
95,7) untuk pilihan obat, dan 10,5 (KI95 0,8
62,6) untuk kese-
suaian secara keseluruhan. Studi-studi yang mengevaluasi gabungan beberapa intervensi AMS menunjukkan efek
positif terhadap konsumsi antibiotik, ketepatan resep, kepatuhan terhadap panduan, dan keluaran pasien. Tema
utama yang diidentifikasi dalam survei persepsi adalah kurangnya pengetahuan antibiotik di antara konsumen dan
penggunaan antibiotik tanpa resep.

Interpretasi Strategi intervensi spesifik konteks sangat dibutuhkan untuk meningkatkan penggunaan antibiotik
yang tepat di rumah sakit dan masyarakat di Indonesia, dengan kesenjangan bukti kritis tentang penyedia layanan
kesehatan swasta dan informal.

Pendanaan Wellcome Trust Africa Asia Programme Vietnam.

Copyright Ó 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/)
Keywords: Antibiotic use; Antibiotic consumption; Antimicrobial stewardship; Indonesia; Systematic review; Meta-
analysis

Introduction quality healthcare, vaccination, safe water and sanita-

The global rise in antimicrobial resistance (AMR) is one
of the greatest public health threats, with a dispropor-
tionate impact in low- and middle-income countries
(LMICs).1 A recent global analysis estimated that AMR
was directly responsible for 1.27 million deaths and
played a part in 4.95 million deaths in 2019 worldwide,
including 97 000 and 369 000, respectively, in the
Southeast Asian region.1 One of the major drivers of
AMR is antibiotic use, including their overuse and
misuse.2,3 In low-resource settings, lack of access to
tion, leave many people vulnerable to infection and
dependent on antibiotics for treatment, with their use
largely unregulated. Globally, during the past decade
concerted efforts have been made to develop strategies
to preserve the effectiveness of existing antibiotic
agents.
Indonesia is a lower-middle-income country in
Southeast Asia with the world’s fourth largest popula-
tion (274 million), and socio-economic conditions and
health indicators vary widely across the archipelago.

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Research in context
Evidence before this study
We reviewed government resources, situation analysis
reports, websites of key global and government agen-
cies, and searched PubMed with the terms “Indonesia”,
“antibiotic use”, and “antibiotic consumption”, until
December 1st 2021, in English and Indonesian language.
Indonesia, and the Southeast Asian region, is regarded a
global hotspot for the emergence and spread of antimi-
crobial resistance (AMR) because of dense populations,
unprecedented, yet uneven, economic development,
fragile health systems with variations in access to qual-
ity health care, high infectious disease burdens, and
weakly enforced antibiotic policies. Indonesia has seen
an estimated 2.5-fold increase in nation-wide antibiotic
consumption between 2000 and 2015, based on phar-
maceutical sales data, mostly driven by broad-spectrum
penicillins, fluoroquinolones and cephalosporins. Repre-
sentative contemporary data on antibiotic use are lack-
ing, although available data suggest antibiotic overuse
in the healthcare system, widespread over-the-counter
use in communities, and high levels of AMR among
common Gram-negative bacteria. A comprehensive
review on antibiotic use in human health in Indonesia
has not been conducted to date.
Added value of this study
This review represents a first attempt at systematically
assessing the peer-reviewed literature, including English
and Indonesian language publications, on human anti-
biotic use in Indonesia spanning the past 20 years. This
evidence synthesis provides a reference document, pro-
viding important insights in the magnitude, patterns
and drivers of antibiotic use, as well as identifying areas
where critical information is lacking. Available data sug-
gested that only 34 and 49% of antibiotic prescriptions
were appropriate in hospital and primary care settings,
respectively, although the quality of the evidence was
low. Studies to date evaluating bundled AMS interven-
tions, although sparse and heterogeneous, suggested
favourable effects on antibiotic consumption, prescrib-
ing appropriateness, guideline compliance, and patient
outcomes. Perception surveys among healthcare pro-
viders and communities suggested important gaps in
community antibiotic knowledge, and that non-pre-
scription antibiotic self-medication is common practice,
although data on health system-level drivers of antibi-
otic use were lacking.
Implications of all available evidence
There are critical evidence gaps on antibiotic use in the
informal and formal private health care sector as well as
geographic areas outside of Java Island, and what are
health system drivers of antibiotic use. There is a need
to strengthen the local research base to develop con-
text-specific sustainable AMS models that consider
country-specific socio-cultural circumstances. Optimisa-
tion of antimicrobial use as a means to tackle AMR and
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Articles
improve the treatment of bacterial infections, should be
a priority of the national agenda for universal health
coverage.
More than 55% of the population is concentrated on Java
Island, which has the best developed health infrastruc-
ture.4 Indonesia has a decentralised public healthcare
system, in which provincial or district-level govern-
ments have the authority over most public hospitals,5
and a substantial private health sector.6 In 2020, Indo-
nesia had a total of 2985 hospitals, 21 550 primary
health centres, and an estimated 135 000 drug outlets in
the community selling over-the-counter drugs, of which
only 29% were officially licensed pharmacies and drug
stores.7,8 To achieve the goal of universal healthcare cov-
erage, in 2014 the Government introduced national
health insurance (Jaminan Kesehatan Nasional),4 which
had reached 84% of the population by 2021. Based on
an analysis of pharmaceutical sales data in 76 countries
between 2000 and 2015, Indonesia ranks among the
greatest risers in antibiotic consumption (29th).3 A
range of complex factors, including variable access to
quality health care, persistently high infectious disease
burdens, and weakly enforced antibiotic policies, render
Indonesia particularly vulnerable to AMR.9,10 The
implementation of the National Action Plan for AMR
since 201711,12 has been hindered due to, among other
factors, a limited evidence base of AMR epidemiology,
antibiotic utilisation and rational prescribing practices.9
To our knowledge, there has been no comprehensive
countrywide analysis to date of the magnitude and key
drivers of AMR and antibiotic use,5 which is critical to
generate evidence and highlight gaps that can help
guide priorities of the National Action Plan for AMR.13
We therefore systematically reviewed the scientific
literature on antibiotic use for human health, in both
hospital and primary care settings, in Indonesia span-
ning the past 20 years. This Review focused on four key
domains: (1) antibiotic consumption; (2) appropriate-
ness of antibiotic prescribing; (3) AMS interventions;
(4) knowledge, attitudes and perceptions among con-
sumers and providers. This Review also reflects on cur-
rent progress in the National Action Plan for AMR, and
defines evidence gaps and context-specific priorities for
action.
Methods
Search strategy and selection criteria
This systematic review was reported according to the
Preferred Reporting Items for Systematic Reviews and
Meta-analyses (PRISMA) 2020 guidelines.14 A protocol
has been prospectively registered in the PROSPERO
3
 Articles
database (CRD42019134641). We screened five interna-
tional (PubMed, EMBASE and Google Scholar) and
national (Garuda [Garba Rujukan Digital] and Neliti)
databases for peer-reviewed original articles from Indo-
nesia, published in English or Indonesian between 1
January 2000 and 1 June 2021 using search terms listed
in Table S1. Reference screening was used to identify
additional relevant papers. The review was limited to
antibacterials for systematic human use (J01 category in
WHO ATC/DDD index). We did not contact study
authors.
We categorised the included reports within one or
more of the following domains as follows:
1. Antibiotic consumption, expressed as WHO-defined
defined daily dose (DDD) per 100 bed-days (inpa-
tients) or 1000 inhabitants per day (outpatients) (or
with alternative units of measure that could be con-
verted). We decided post-hoc to exclude paediatric
studies because all studies incorrectly used DDD
instead of days of therapy (DOT), as advised by
WHO (dose recommendations may differ based on
age and weight).15
2. Audits of antibiotic prescribing appropriateness for
treatment or prophylaxis, based on either Gyssens
method or compliance with reference guideline(s).
According to the Gyssens method,16,17 an expert
panel of at least two reviewers sequentially evaluates
each prescription with related clinical and microbio-
logical data in the medical record and local guide-
lines, based on seven pre-defined indicators:
insufficient data (vi); antibiotic is not indicated (v);
alternative antibiotic is available (iv) that is more
effective (iv-a), less toxic (iv-b), less costly (iv-c), has
narrower spectrum (iv-d); inappropriate duration
(iii), either too long (iii-a), or too short (iii-b); incor-
rect dose (ii-a), interval (ii-b), route (ii-c); incorrect
timing (i); and appropriate use (0). Compliance
with specified reference guideline(s) will be
recorded as assessed by the study investigators,
based on at least one of eight pre-defined indicators:
no contra-indication or allergy label, indication,
drug choice, dose, frequency, duration, route of
administration, and overall appropriate use. Point
prevalence surveys were also included in this cate-
gory as relevant (e.g., GLOBAL-PPS, WHO-PPS).
3. AMS intervention evaluation studies, with a clearly
described pre-post or (quasi-) experimental design
and outcome measures.
4. Surveys assessing knowledge, attitudes and/or per-
ceptions on antibiotic use, including factors related
to health system, health care providers and/or con-
sumers.
We excluded non-human studies; studies exclusively
describing other (non-J01) drugs; describing or
4 www.thelancet.com Vol 2 Month July, 2022
comparing the effectiveness, cost, quality and/or molec-
ular profiles of antibiotics; exclusively targeting particu-
lar diagnoses and its treatment; non-peer-reviewed
papers, student theses, conference proceedings, and
studies with irretrievable full-text. Because the included
studies were mostly neither randomised controlled
studies nor comparative studies, traditional methods for
assessment of risk of bias were not applicable. To
ensure quality, we excluded studies that did not report
an essential set of STROBE checklist core items,18 or
did not fulfil additional criteria (Table S2). All steps in
this systematic literature search were conducted using
Mendeley reference management software. Two
reviewers (PD, MM) separately screened all titles and
abstracts, and removed duplicates. Full-text articles
were independently judged for relevance and quality by
at least two reviewers (PD, MA, MM, RL). Any disagree-
ments were resolved by a senior researcher (RLH).
Data analysis
We extracted and tabulated data on study design, loca-
tion, size, population, health care setting, year of study,
indicators, interventions, outcome measures and
effects, and emerging themes, as appropriate and rele-
vant, based on the author-reported summary estimates
(not individual patient-level data). Data were extracted
by two reviewers (PD, MM) onto a predesigned form.
Where possible, data on antibiotic consumption and
appropriateness of antibiotic prescribing were pooled
with random-effects meta-analyses. Data on antibiotic
consumption were pooled with meta-analyses of rates
using the generic inverse variance method, with DDD
per 100 bed-days for inpatients and DDD per 1000
inhabitants per day (DID) for outpatients as the rates,
and sample sizes as the denominator. Furthermore, we
also reported the top-15 antibiotics with the highest
DDDs for inpatients and outpatients, provided that the
antibiotic was reported in at least two studies, and
grouped them according to the 2021 WHO AwaRe
(Access, Watch, and Reserve) classification.19 For outpa-
tients, due to the limited number of antibiotics, we
reported all antibiotics reported in at least two studies.
Data on the appropriateness of antibiotic prescribing,
separate for Gyssens method (i.e. “appropriate use”,
indicator 0) and reference guidelines (i.e. “overall appro-
priate”), were pooled with meta-analyses of proportions
using the generalised linear mixed model with the logit
transformation.20 Heterogeneity was assessed using I2
statistic (low <25%, moderate 25
49%, substantial
50
74%, or high 75
100%) and chi-squared test
(p < 0.10). When two or more studies involved overlap-
ping populations, data synthesis was prioritised to stud-
ies with larger sample sizes. Subgroup analyses were
then performed by dichotomising the studies based on
health care setting (primary care vs hospital [including
secondary and tertiary levels]), study location, year of

study, AWaRe classification (for DDD only), and age
groups (for appropriateness only). We also performed
sensitivity analyses by sequentially excluding individual
studies (for DDD and Gyssens), and by replicating the
analysis using other transformations and without trans-
formation (for Gyssens only). All meta-analyses were
performed in R version 4.1.0. When appropriate (k
10),
publication bias assessments were performed by visu-
ally inspecting funnel plots, generated by plotting the
inverse square root of study sizes against the effect esti-
mates,21 and by Egger’s tests (p < 0.10).
Due to substantial clinical heterogeneity in studies
evaluating AMS interventions, we synthesised the find-
ings using a vote-counting method based on effect direc-
tion. The interventions were classified as structural,
enabling, persuasive, restrictive, or combined (bun-
dled).22 The perception surveys were qualitatively syn-
thesised based on the main emerging themes, stratified
by consumers (community) and healthcare providers.
Role of the funding resource
The funder of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report.
Results
Study characteristics
The search strategy collectively gave 9 323 hits. After
title and abstract screening and duplicate removal, 551
articles remained (Figure 1). After full-text screening
and quality assessment, 100 reports (covering 97 stud-
ies) were included. Study characteristics are summa-
rized in Tables 1 and S3. 86.0% (86/100) of reports had
an observational design, 13.0% (13/100) were pre-post
intervention comparisons, and 1.0% (1/100) was a ran-
domized study. Most reports were from the public sec-
tor (58.4%, 59/101). Most (53.0%, 53/100) studies were
conducted in hospital settings followed by primary care
(24.0%, 24) or in the community (17.0%, 17) (6 reports
provided no information). The study populations were
mostly patients (68.6%, 74/108), followed by communi-
ties (18.5%, 20/108) and health care providers (12.9%,
14/108). Most reports originated from Java (60.2%, 62/
103), followed by Sumatra (15.5%, 16/103), Papua and
Nusa Tenggara (7.8%, 8/103), Sulawesi (6.8%, 7/103),
Kalimantan (5.8%, 6/103) and Bali (1.9%, 2/103)
(Figure 2). 62.0% (62/100) of all reports were pub-
lished during the most recent five years (2016
2021),
29.0% (29/100) during 2011
2015, and only 9.0% (9/
100) during 2000
2010.
Antibiotic consumption
There were 20 reports (5 193 626 patients) that reported
data on antibiotic consumption, of which 1623
33 in
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Articles
inpatients and four34
37 in outpatients. Most of these
studies were conducted in hospital settings (16 reports,
76.2%), in Java (14 reports, 66.7%), and between 2016-
2021 (17 reports, 81.0%; Table S4). The pooled estimate
of overall antibiotic consumption was 134.8 DDD per
100 bed-days (95% confidence interval [CI] 82.5-187.0;
I2=100%; Figure S1) for inpatients and 121.1 DID
(95%CI 10.4-231.8; I2=100%; Figure S2) for outpatients.
Among inpatients, ceftriaxone was the most consumed
antibiotic (60.0 DDD per 100 bed-days [95%CI 22.9-
97.2]), followed by levofloxacin (21.3 DDD per 100 bed-
days [95%CI 0.0-44.0]) and ampicillin (18.7 DDD per
100 bed-days [95%CI 0.0-55.2]; Figure 3). Among outpa-
tients, amoxicillin was the most consumed antibiotic
(73.2 DID [95%CI 11.4-134.9]), followed by ciprofloxacin
(15.1 DID [95%CI 12.1-18.1]) and cefadroxil (4.3 DID
[95%CI 1.1-7.5]). Sensitivity analysis found that the
pooled estimate for antibiotic consumption in inpa-
tients was not dominated by a single report (Figure
S3), while the pooled estimate for antibiotic con-
sumption in outpatients was largely influenced by
the study by Pradipta et al,35 suggesting a non-robust
finding (Figure S4).
Among inpatients, subgroup analyses (Figure 3)
showed higher antibiotic consumption in recent years
(2016-2021: 150.8 DDD/100 bed-days [95%CI 90.3-
211.4]) than previous years (2000-2015: 65.2 DDD/100
bed-days [95%CI 17.3-113.1]), and outside of Java (193.5
DDD/100 bed-days [95%CI 0.0-413.5]) than in Java
(121.2 DDD/100 bed-days [95%CI 76.3-166.2]). Sub-
group analyses for outpatients were not performed due
to the limited number of studies in each subgroup
which precluded a reliable estimate. Due to the lack of
studies investigating outpatients (studies n < 10), publi-
cation bias assessment was only performed for inpa-
tients, which showed an asymmetrical funnel plot
(Egger’s p = 0.050; Figure S5), indicating potential
reporting bias or true heterogeneity in antibiotic con-
sumption patterns between studies, hospitals and/or
geographic areas.
Appropriateness of antibiotic prescribing
There were 49 reports that reported data on the appro-
priateness of antibiotic prescribing, of which 1827,38
54
(3167 prescriptions) used Gyssens method and 31 (7826
prescriptions)23,55
84 used reference guidelines. Most
were conducted in hospitals (37 reports, 74.0%), in Java
(33 reports, 66.0%), and in adults (29 reports, 58.0%)
and between 2016-2021 (62 reports, 62.0%) (Tables S5
and S6).
Based on the Gyssens method, the pooled estimate
for the appropriateness of antibiotic prescribing was
35.3% (95%CI 20.7-53.4%; I2=97.2%) (Figure S6). Con-
fidence analysis showed that the overall estimate was
not dominated by a single study (Figure S7) and was
similar between approximation methods (Figure S8).
5
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Figure 1. PRISMA flowchart of study selection.

6 www.thelancet.com Vol 2 Month July, 2022

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Total reports N %
care 49.4% [95% CI 23.7-75.4%]) vs hospitals (33.5%
100 [95%CI 18.1-53.4%]), Java (31.4% [95%CI 18.8-47.6%])
vs outside of Java (38.1% [95%CI 6.2-85.0%], and recent
Domains 107
years (2016-2021: 39.1% [95%CI 19.4-63.0%] vs previ-
Antibiotic consumption 20 18.7
ous years (2000-2015: 26.1% [95%CI 12.4-47.1%]
Appropriateness of antibiotic prescribing 49 45.8
(Figure 4A).
Gyssens method 18 16.8
Based on reference guidelines, most individual indi-
Reference guidelines 31 29.0
cators of appropriateness scored excellent (>80%),
Antibiotic stewardship 13 12.1
except for duration (65.8% [95%CI 38.6-85.5%])
Knowledge, attitude and practice survey 25 23.4
(Figure 4B) and overall appropriate antibiotic use (8.0%
Study design 100
[95%CI 1.0-43.6%]). Between-study heterogeneity was
Observational 86 86.0
substantial (75-100%) for all indicators, except for
Pre-post design 13 13.0
administration route (I2=0%, p > 0.999) and no contra-
Randomized control trial 1 1.0
indication/allergy label (I2=6.4%, p = 0.382). Possible
Study population 108
small-study effects were found for indication and dura-
Patients 74 68.6
tion (Egger’s test p=0.092 and p=0.074, respectively).
Inpatients 56 51.9
Subgroup analysis showed higher appropriateness of
Outpatients 18 16.7
duration in hospitals (80.0% [95%CI 66.0-89.2%])
Community 20 18.5
than primary care (34.5% [95%CI 4.3-86.1%]), and in
Healthcare providers a 14 12.9
adults (83.2% [95%CI 65.3-92.9%] than children
Study location 103
(17.9% [95%CI 1.2-79.4%]; Figure S10), and higher
Java 62 60.2
appropriateness of drug choice, dosing, and overall
Sumatra 16 15.5
appropriate use outside of Java (95.2% [95%CI 73.9-
Papua and Nusa Tenggara 8 7.8
99.3%], 90.0% [95%CI 71.1-97.1%], and 34.5% [95%CI
Sulawesi 7 6.8
3.1-89.8%] than in Java (70.0% [95%CI 23.2-94.7%],
Kalimantan 6 5.8
77.3% [95%CI 48.9-92.3%], and 3.3% [95%CI 0.3-
Bali 2 1.9
32.0%]; Figs. S11
S13, respectively)
although the latter
National 2 1.9
differences were not statistically significant. There were
Year of study 100
no significant differences for no contraindication/
2016-2021 62 62.0
allergy label, indication, dosing frequency, or adminis-
2011-2015 29 29.0
tration route (Figs. S14
17).
2000-2010 9 9.0
Healthcare level 100
Primary care 24 24.0
Antimicrobial stewardship interventions
Hospitalsb 53 53.0
There were 13 reports that reported data on the effect of
Not applicable c 17 17.0
AMS interventions in hospitals (11 reports),24,27,33,46,85
91
No information provided 6 6.0
primary care (1),92 and community pharmacies (1)93
Health care sector 101
(Table 2). Twelve reports used a pre-post design, and one
Public 59 58.4
was a randomized controlled trial. Five reports evaluated a
Private 19 18.8
bundled intervention and eight studies evaluated single
Not applicable (community) 19 18.8
interventions. Enabling interventions were most common
No information provided 4 4.0
(antibiotic prescribing guidelines or clinical pathway [7
Table 1: Characteristics of included reports.
reports], audit and performance feedback [3], and pharma-
Total N for some characteristics are greater than N=100 because some cist counselling [1]), followed by education interventions
reports were included in more than category, i.e. for domain (7 reports), [6], structural interventions (free blood cultures [1], inte-
population (8), location (3), and health care sector (1).
a
grated drug management [1]), and restrictive interventions
Physicians (10 reports), pharmacists (1 report), mix of physicians,
nurses, paramedics, and pharmacists (3 reports). (antibiotic restriction with pre-approval [1]). The most
b
Hospitals included secondary and tertiary levels. common reported outcome measures were changes in
c
Studies conducted in the community (11 reports) and pharmacies appropriateness of prescribing (10 reports), antibiotic con-
(6 reports).
sumption (8) and mortality (2), followed by prescribers’
scores for knowledge of and attitude towards antibiotic use,
The symmetrical funnel plot (Egger’s p = 0.108; Figure blood culture sampling, hand hygiene compliance, clinical
S9) indicated low risk of bias from small-study effects. outcomes, length of hospital stay, and antibiotic compli-
Subgroup analyses showed higher appropriateness of ance (1 each).
antibiotic prescribing in adults (43.1% [95%CI 25.9- Studies that evaluated bundled interventions
62.2%] than in children (8.4% [95%CI 0.6-57.9%]), but (5 reports) reported favourable effects on antibiotic
there were no significant differences between primary consumption, prescribing appropriateness, guideline

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8

Articles
Figure 2. Geographical map of the 100 included reports on antibiotic use in Indonesia 2000
2021.
The map includes 2 KAP surveys that were conducted nationwide, and 1 AMS study and 1 KAP survey that were conducted in multiple provinces.
Editor note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations.
www.thelancet.com Vol 2 Month July, 2022
 Articles

Figure 3. Summary forest plot of reports on antibiotic consumption in inpatients and outpatients.
The figure summarizes (A) 16 inpatient reports and (B) 4 outpatient reports in the domain antibiotic consumption, expressed as
DDD/100 bed-days (for inpatients) or DDD/1000 inhabitants per day (for outpatients) for all antibiotics that were reported in at least
two studies, listing here up to 15 antibiotics (“top-15”). The antibiotics were grouped according to the 2021 WHO AwaRe (Access,
Watch, and Reserve) classification. We noted some discrepancies between the 2021 WHO AWaRe classification and the 2021 Indone-
sian Ministry of Health AWaRe classification (Kementerian Kesehatan Republik Indonesia 2021); erythromycin and ciprofloxacin were
classified as Watch vs Access; cefoperazone-sulbactam as Not recommended vs Watch; and cefepime and meropenem as Watch vs
Reserve, respectively. Egger’s tests to assess publication bias could only be performed for the primary analysis and the individual
AWaRe antibiotics.
Abbreviations: CI, confidence interval; DDD, defined daily dose; NA, not applicable.

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 Articles

Figure 4. Summary forest plot on prescribing appropriateness.

The figure summarizes 49 reports in the domain prescribing appropriateness based on Gyssens method (A) or references guide-
lines (B). The pooled proportions were weighted using a random-effects model. Indicators (B) were reported by different numbers
of studies. Egger’s tests to assess publication bias in Gyssens method (A) could only be performed for the primary analysis.
Abbreviations: CI, confidence interval; NA, not applicable.

compliance, blood culture sampling, HAI rates, hand
hygiene compliance, and mortality, although the
authors of one study concluded that the multifaceted
intervention had limited success, with an important
drawback being the absence of adequate microbiological
diagnostics.24,87
89,92
Studies that evaluated the implementation of anti-
biotic prescribing guidelines or clinical pathway
(7 reports) reported mixed effects on antibiotic con-
sumption and favourable effects on prescribing
appropriateness.24,46,85,86,88,90,91 Studies that evaluated
education interventions (6 reports) reported mixed
effects on antibiotic consumption and prescribing
appropriateness.24,27,87
89,92
The one study that evaluated antibiotic restriction
with pre-approval found that consumption of
restricted antibiotics decreased and of unrestricted
narrow-spectrum antibiotics increased.33 The one
randomised study that evaluated the effect of a phar-
macist counselling session of outpatient antibiotic
users in community pharmacies found that self-
reported antibiotic adherence was significantly
higher in the intervention group compared to the
control group.93

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 Author Year of study Location (city, Health care setting Study population Study design Intervention Outcome Summary of study Effect Favourability Comments
province) description measures findings direction of effect

Hadi et al 2003-2004 Surabaya (East Tertiary hospital Residents and specialists in Pre-post design Combined Antibiotic Antibiotic consumption ! (+) The multifaceted
(2008)24 Java) the internal medicine (enabling, consumption decreased from 99.8 to intervention
department education, and 73 (-26.9%) DDD/100 had limited
structural): compris- patient-days. success, with a
ing guideline devel- Appropriate anti- Appropriate antibiotic pre- ᐃ (+) very important
opment, distribu- biotic prescrib- scribing improved insig- drawback
tion of a guideline ing (Gyssens) nificantly from 16% to being the
pocketbook, free-of- 25% overall (+9%, 95%CI absence of
charge blood cul- -6% to 24%). Prescribing adequate
tures, teaching ses- without indication insig- microbiolog-
sions and refresher nificantly decreased from ical
courses 53% to 40% (-13%, 95%CI diagnostics.
4% to -32%).

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Guideline Guideline compliance did GF (+/-)
compliance not change overall (from
87% to 88%), except for a
significant increase for
sepsis (from 49% to 72%;
+23% [95%CI 4-41%])
and dengue fever (from
58% to 88%; +30%
[95%CI 12-48%]).
Blood culture Taking blood cultures ~ (+/-)
sample taken increased from 3% to
81%. However, only 3%
of the blood cultures
post-intervention were
taken before starting
antibiotic treatment.
Mortality within 6 Mortality in pre-post-period GF (+/-)
days of were similar (from 6.6%
admission to 6.2%).
Murni et al 2011-2013 Yogyakarta Tertiary hospital All doctors, nurses, and Pre-post design Combined (education Primary: Propor- Proportion of patients with ! (+) Multifaceted
(2014)89 (Daerah Isti- allied workers in the pae- and enabling): com- tion of patients HAI decreased from intervention
mewa diatric wards and PICU prising educational with an HAI 22.6% (277/1227 reduced HAI
Yogyakarta) seminars, audit and patients) to 8.6% (123/ rates,
performance feed- 1419 patients) (RR 0.38 improved
back [95% CI 0.31 to 0.46]). rational use of
Secondary: inap- Inappropriate antibiotic use ! (+) antibiotics,
propriate anti- decreased from 43% to increased
biotic use 20.6% (RR 0.46 [95%CI hand hygiene
(reference 0.40 to 0.55]). compliance,
guideline), Hand hygiene compliance ~ (+) and reduced
hand hygiene improved from 18.9% mortality in
compliance (319/1690) to 62.9% children
and mortality (1125/1789) (RR 3.33
rates [95%CI 2.99 to 3.70]).
In-hospital mortality ! (+)
decreased from 10.4%
(127/1227) to 8% (114/
1419) (RR 0.78 [95%CI
0.61 to 0.9]7).

Table 2 (Continued)
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11
12
Articles

Author Year of study Location (city, Health care setting Study population Study design Intervention Outcome Summary of study Effect Favourability Comments
province) description measures findings direction of effect

Hapsari et al 2003-2004 Semarang (Cen- Tertiary hospital Doctors in the paediatric Pre-post design Combined (education Antibiotic Antibiotic consumption ! (+)
(2006)88 tral Java) ward and enabling): com- consumption decreased from 0.48 to
prising develop- 0.38 DDD/100 patient-
ment of antibiotic days (p=0.01).
prescribing guide- Appropriate anti- Appropriate antibiotic pre- ~ (+)
line, prescriber biotic prescrib- scribing improved from
training, and two ing (Gyssens) 37% to 70.4% (p < 0.01).
rounds of feedback Prescribing without indi-
during a 6 months’ cation did not change
period (from 43% to 42.7%).
Dwiprahasto 1997-1998 West Kalimantan, Primary care Doctors, nurses, and para- Pre-post design Combined (education Proportion of Significant decrease from ! (+)
(2004)92 West Sumatra, medics at 118 PHCs and with control and enabling): (1) patients with 92.7-93.4% of patients to
West Nusa provincial health office group Interactive problem- ARI who 64.6-72.4% after 6
Tenggara, East staff in 18 districts' based pharmaco- received an months (p < 0.05) and
Java warehouses therapy training; (2) antibiotic 35.4-37.4% after 12
integrated drug months (p < 0.01) post-
management and intervention, compared
use for provincial to no decline in the con-
health office staff; trol group (89.9-92.2%)
followed by (3) self- The use of injec- Significant decrease from ! (+)
monitoring of drug tion medica- 82.4-89.2% of patients to
use at PHCs post- tion (analgesic 76.2-72.5% after 6
intervention, and or antibiotic months (p < 0.05) and
monthly reporting combined with 32.8-41.2% after 12
to health office. antihistamine) months (p < 0.01) post-
for myalgia intervention, compared
to no significant decline
in the control group
(86.2-87.2%)
King & Ciptaning- 2015 Semarang (Cen- Tertiary hospital Prescribers In the digestive Pre-post design Enabling: Implementa- Proportion of Proportion of patients who GF (+/-)
tyas (2015)90 tral Java) surgery ward tion of a revised patients who received an antibiotic
antibiotic prescrib- received an insignificantly decreased
ing guideline antibiotic from 50% to 40.7% for
therapeutic use, and
from 32.5% to 29.6% for
surgical prophylaxis
(overall p-value = 0.410).
Antibiotic Antibiotic consumption ᐃ (-)
consumption increased from 35.4 to
51.1 DDD/100 patient-
days, mostly ceftriaxone
and ciprofloxacin

Table 2 (Continued)

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 Author Year of study Location (city, Health care setting Study population Study design Intervention Outcome Summary of study Effect Favourability Comments
province) description measures findings direction of effect

Rosdiana et al 2016 Pekanbaru Secondary hospital Doctors in internal medicine Pre-post design Enabling: Develop- Appropriate anti- Appropriate antibiotic pre- ~ (+)
(2017)46 ward ment and imple- biotic prescrib- scribing increased from
mentation of ing (Gyssens) 33.7% to 48.8% (p=0.020)
antibiotic prescrib- Prescribing without indica- ! (+)
ing guideline tion decreased from
27.2% to 16.3%
(p=0.038).
Narulita et al 2018-2019 Pamekasan Secondary hospital Prescribers in surgery wards Pre-post design Enabling: Implementa- Antibiotic Antibiotic consumption 5 (+)
(2020)86 tion of an antibiotic consumption decreased from 197.3 to
prescribing 102.4 DDD/100 patient-
guideline days (p=0.065)
Lizikri et al 2017-2018 No city men- Secondary hospital Pediatricians at pediatric Pre-post design Enabling: Develop- Length of hospi- Proportion of patients dis- 5 (-) The intervention

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(2020)91 tioned wards ment and imple- tal stay (days) charged <3 days could not
(West Java) mentation of a decreased from 51.7% to achieve the
pneumonia clinical 31.1% (p=0.065) targeted goals
pathway, with a Clinical outcomes No discernible change in GF (+/-) to reduce the
patient manage- (recovered, clinical outcomes as length of hos-
ment algorithm ICU/referred) nearly all study patients pitalization
had good clinical out- and improve
comes (p=1.00) antibiotic pre-
Appropriate anti- Appropriate antibiotic use GF (+/-) scribing. Con-
biotic prescrib- did not change from sumption
ing (Gyssens) 3.3% to 3.3% (p=1.00) almost
Antibiotic Antibiotic consumption ᐃ (-) doubled.
consumption increased from 222.4 to
408.4 DDD/100 patient-
days (p=0.408)
Widowati et al 2018 Denpasar (Bali) Community pharmacy Pharmacy clients purchas- Randomized con- Enabling: Intervention Antibiotic compli- The proportion of compli- ~ (+)
(2018)93 ing antibiotics trolled trial group: counseling ance was mea- ance in the intervention
by a pharmacist; sured using group was 65.3% and the
Control group: drug the Morisky control group was 18.4%
information accord- Medication (proportion ratio 3.56,
ing to the pharmacy Adherence 95% CI: 1.90- 6.64).
service standard. Scale-8 ques-
tionnaire
within 3-5
days after pur-
chasing the
medication

Table 2 (Continued)
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13
14
Articles

Author Year of study Location (city, Health care setting Study population Study design Intervention Outcome Summary of study Effect Favourability Comments
province) description measures findings direction of effect

Karuniawati et al 2016-2018 Surakarta (Central Secondary hospital Hospital-wide prescribers Pre-post design Enabling: Implementa- Antibiotic Antibiotic consumption ! (+) Shift from pre-
(2021)85 Java) tion of clinical prac- consumption decreased from 90.8 to dominantly
tice guidelines 61.4 DDD/100 patient- “red” antibiot-
days ics (mostly cef-
Appropriate anti- Appropriate antibiotic pre- ~ (+) triaxone) to
biotic prescrib- scribing improved from “green” antibi-
ing (Gyssens) 31.3% to 62.5% otics (mostly
Prescribing without indica- GF (+/-) ampicillin
tion did not change sulbactam)
(from 0% to 0%)
Length of hospi- Length of stay did not GF (+/-)
tal stay (days) change significantly from
9.9 days to 10.0 days
Farida et al 2003-2004 Semarang (Cen- Tertiary hospital Doctors in the pediatric Pre-post design Combined (education Prescribers' Scores for knowledge of and ~ (+)
(2008)87 tral Java) ward and enabling): Pre- scores for attitude significantly
scriber training on knowledge of increased from 59 to
appropriate antibi- and attitude 77.5, and from 56 to 59,
otic use (two-day towards antibi- respectively.
training seminar) otic use
with feedback after Appropriate anti- Appropriate antibiotic pre- ~ (+)
one month biotic prescrib- scribing improved signifi-
ing (Gyssens) cantly from 36.3% to
58.2% (p < 0.01) overall,
except for pneumonia
(decreased) and typhoid
fever (no change). Pre-
scribing without indica-
tion significantly
decreased from 42.7% to
23.3% (p < 0.05).
Kartika et al 2018 Semarang (Cen- Secondary hospital Doctors, nurses, and phar- Pre-post design Education: Antimicro- Antibiotic Antibiotic consumption 5 (+)
(2019)27 tral Java) macists in internal medi- bial resistance & consumption decreased insignificantly
cine wards stewardship from 103.7 to 99.6 DDD/
training 100 patient-days
(p=0.092)

Table 2 (Continued)

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www.thelancet.com Vol 2 Month July, 2022

Author Year of study Location (city, Health care setting Study population Study design Intervention Outcome Summary of study Effect Favourability Comments
province) description measures findings direction of effect

Susanto et al 2017-2018 Pekanbaru Secondary hospital Hospital-wide prescribers Pre-post design Restrictive: Implemen- Antibiotic con- Consumption decreased of ! (+)
(2019)33 tation of a hospital- sumption for restricted antibiotics mer-
wide antibiotic restricted and openem (from 3.39 to
restriction pro- unrestricted 2.71; p=0.04); doripenem
gramme. Pre- antibiotics (from 0.42 to 0.08;
approval was p=0.003); imipenem
required from the (from 0.29 to 0.04;
antibiotic steward- p=0.02); cefepime (from
ship team for third- 1.53 to 0.28; p=0.001),
line antibiotics whereas consumption of
amikacin, tigecycline,
vancomycin remained
unchanged.
Consumption decreased of GF (+/-)
the unrestricted antibiot-
ics ceftriaxone (from 14.8
to 9.4; p=0.03) and levo-
floxacin (from 13.6 to 9.0;
p=0.02). Consumption
increased of the narrow-
spectrum antibiotics
ampicillin/sulbactam
(from 1.82 to 3.66;
p=0.003) and cefazoline
(from 1.38 to 4.38;
p=0.001)

Table 2: Summary of reports on antimicrobial stewardship interventions.

The table summarizes 13 reports in the domain antimicrobial stewardship interventions. Findings are synthesized based on direction and favourability of effects. Antibiotic consumption is expressed as DDD/100 patient-days.
Abbreviations: ARI, acute respiratory infection; CI, confidence interval; DDD, defined daily dose; HAI, hospital-associated infection; ICU, intensive care unit; PHCs, primary health care centres; PICU, paediatric intensive care unit;
RR, relative risk.

Articles
15
 Articles
Knowledge, attitudes, and perceptions on antibiotic
use
There were 25 reports that reported data on knowl-
edge, attitudes, and perceptions among communities
(consumers) (22)94
115 and healthcare providers
(3)116
118 (Tables S7 and S8). Interpretation was chal-
lenged by the considerable between-study clinical (e.
g., study populations) and methodological (e.g., sur-
vey questionnaires) heterogeneity. The main themes
that emerged were AMR awareness and antibiotic
use knowledge, and antibiotic self-medication
(including source of antibiotics, associated factors,
and drivers) in the community reports and antibiotic
dispensing without prescription in reports on health-
care providers.
Among community respondents, there was a sub-
stantial lack of AMR awareness (10 reports) and knowl-
edge about antibiotics (16), with wide variations
between communities; overall, 23
26% did not know
that antibiotics treated bacterial infections and 58-74%
stated that antibiotics can cure viral
infections.96,105,110,115 Antibiotic knowledge was found
to be associated with higher education and higher
income (2).105,111 Further, antibiotic self-medication
without prescription was reportedly common (20-
100%) (9 reports). Community respondents reported
they purchased antibiotics for self-medication at the
pharmacy (46-90%),94
96,99,104,106,109,112 at the kiosk
(20-44%),96,104 or received them from family and
friends (9
12%), 95,109 20
100% reported that they
had ever self-medicated with an antibiotic
(11),94
96,99,102,104,106,109,112
114 and 87
100% had ever
purchased an antibiotic without a prescription
(3).104,109,112 One study found that people without health
insurance were more likely to self-medicate than those
with health insurance,111 whereas another study
reported the opposite.104 The main reported reasons for
self-medication included positive previous experience
(54
82%),102,104,109,112 self-medication being practical
(61
83%),94 easy access from the pharmacy (71%),102
and doctor visit being expensive (44
72%)102,109 or
unpractical (56%).96 The main advisors to self-medicate
included health care providers (51
83%),100,103,104,109
family, relatives or friends (21
45%),96,102,112 internet
(71%),115 or reliance on their own knowledge (71%).96
Antibiotic adherence levels were not associated with
education level or employment status (2).98,101
Among health care providers, antibiotic dispens-
ing without prescription was the most important
theme reported with conflicting findings. A survey
among 250 community pharmacists in Yogyakarta
(Java), 68% reported that they would dispense antibi-
otics without prescription,116 whereas a survey
among 110 health providers in community health
centres in Padang (Sumatera) found that 98.8% did
not prescribe antibiotics without a prescription,
despite patient request.117
16
Discussion
This systematic review represents a first attempt of an
evidence synthesis of human antibiotic use in Indone-
sia, spanning the past 20 years. The evidence collected
in this Review comes from a range of health care and
community settings, including hospitals, primary care,
pharmacies and communities, and includes a range of
interventions targeting different types of health pro-
viders and consumers. The rising number of scientific
reports published in the most recent years reflects the
increasing momentum of AMR on the national health
agenda. Nonetheless, the evidence base is uneven with
hospital and urban contexts over-represented, and infor-
mal and formal private health providers, who play a
major role in antibiotic distribution, particularly under-
represented.
Based on our review, most of the antibiotics listed in
the top-15 most consumed antibiotics were beta-lactams,
especially cephalosporins and penicillins. Among adult
hospital inpatients (overall consumption 134.8 DDD per
100 bed-days [95%CI 82.5-187.0]), ceftriaxone and levo-
floxacin (both Watch) and ampicillin (Access) were the
most consumed, and consumption was highest in the
recent five years, and outside of Java. Available data
among primary care outpatients were limited (overall
consumption 121.1 DDD per 1000 inhabitants per day
[10.4-231.8]), with amoxicillin, cefadroxil (both Access),
and ciprofloxacin (Watch) being the most consumed
antibiotics. According to national pharmaceutical sales
data (2000-2015), antibiotic consumption increases
were largely driven by the major classes broad-spectrum
penicillins (2.6-fold), fluoroquinolones (7.1-fold), and
cephalosporins (5.1-fold).3 In 2015, the antibiotic con-
sumption rate per capita in Indonesia (3022 DDDs per
1000 inhabitants per year) fell in the same range as, for
instance, China (3060) and Philippines (2600), but was
still lower than, for instance, Vietnam (11 480) and Thai-
land (6682).3 About 69% of antibiotic consumption in
Indonesia were Access antibiotics, which was above the
WHO target of >60% Access antibiotics in total con-
sumption.3 Our findings are consistent with the wide-
spread use of broad-spectrum antibiotics,
predominantly third-generation cephalosporins and flu-
oroquinolones, in other Asian countries119
123 and glob-
ally, and with the disproportionate rise in Watch
antibiotic consumption in LMICs compared with high-
income countries.3 Barring policy changes, antibiotic
consumption is projected to increase worldwide by
200% between 2015 and 2030.3 The above concerning
developments underscore the urgent need for regula-
tion of antibiotic use in Indonesia, and other LMICs.
By comparison, the WHO Report on Surveillance of
Antibiotic Consumption 2016-2018, representing 2015
data from 65 countries, including mostly high-income
countries and no countries in Southeast Asia, found
wide intra- and interregional variation in the total
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amount of antibiotics and the choice of antibiotics con-
sumed,124 with overall consumption ranging from 4.4
to 64.4 DDD per 1 000 inhabitants per day. In the Euro-
pean Union, the average antibiotic consumption during
2010-2019 was 18.0 DDD per 1 000 inhabitants per day
in the primary care sector, ranging from 8.7 in the Neth-
erlands to 32.4 in Greece, and 1.8 DDD per 1 000 inhab-
itants per day in the hospital sector, ranging from 0.8 in
the Netherlands to 2.5 in the UK.125 The wide variation
in antibiotic consumption, both in inpatients and outpa-
tients, is explained by differences in infectious disease
burdens, health system and sector, antibiotic accessibil-
ity and regulatory policies, among many others.126,127
In Indonesia, among the studied populations, appro-
priateness of antibiotic prescribing was found to be
poor overall (35.3%), 49.4% in primary care versus
33.5% in hospitals, despite nationwide implementation
of hospital AMS programmes during the past five
years.9 Several studies in primary healthcare settings in
both developed and developing countries have also
reported considerable rates of inappropriate antibiotic
use, with a wide reported range of between 8 to
100%.126 In a global survey, guideline compliance of
antimicrobial drug choice in hospitals in Latin America,
Africa and Asia, was estimated <70% for each
region.128 Inappropriate prescribing of antibiotics has
been attributed to a range of complex factors, with varia-
tions across settings and countries, including phys-
icians’ nonadherence to antibiotic guidelines, lack of
diagnostic facilities or, where available, lack of utiliza-
tion and quality, diagnostic uncertainty, pressure from
pharmaceutical industry or patients.129,130 Around 60%
of total health care spending in Indonesia is in the pri-
vate sector, where financial incentives potentially pro-
mote prescribing practices that deviate from guidelines.
The scale and consequences of non-prescription and
private sector antibiotic consumption in Indonesia are
an urgent priority for further study and action. Addi-
tionally, the local implementation of universally applica-
ble quality indicators for antibiotic prescribing will be
essential to identify targets for AMS interventions and
measure their effectiveness.131 Point prevalence surveys
to assess antibiotic use in hospitals have proven to be
useful tools for identifying targets for improvement and
evaluating the effect of interventions.128,132
Reports from high-income settings have shown that
AMS can optimise the use of antimicrobials, improve
patient outcomes, reduce AMR and health-care-associ-
ated infections, and save health-care costs amongst
others.22,133 In Indonesia, AMS programmes are typi-
cally in an early stage of implementation,134,135 with
many hospitals lacking the basic infrastructure to ade-
quately measure process, outcome and structural indi-
cators, e.g., access to microbiology services, hospital
antibiotic guidelines, AMS staff training and education,
human resources (including infectious disease special-
ist or clinical microbiologist), and information and
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Articles
communication technology support.136,137 Whereas to
date government policy has focused on assessing hospi-
tal antibiotic use as an AMS outcome indicator (using
DDD and Gyssens method),137 a recently launched
national guideline incorporated additional outcome
measures, such as cost-effectiveness, mortality, and
AMR rates.138
The few AMS intervention studies conducted to date
reported clear benefits from implementing bundled
interventions combining antibiotic prescribing guide-
lines, trainings, review and feedback, restriction with
pre-approval, among others. These findings demon-
strate that AMS interventions are feasible in the local
context and that there is considerable potential for
reducing antibiotic consumption, particularly of
restricted antibiotics, improving prescribing appropri-
ateness, and reducing prescriptions without indication.
However, the interventions evaluated to date were
mostly single-centre and short-term (<1 year), and data
are lacking about the sustained benefits of AMS pro-
grammes in the Indonesian context.
Previous evidence has shown that given the varying
priorities and contextual issues in LMICs, such as
health system processes, patient demands, varying cul-
tures of care, availability of universal access to quality
antimicrobials, laboratory infrastructure and surveil-
lance systems, multipronged interventions combining
different restrictive and enabling strategies are most
likely to be effective.139,140 Indeed, the available Indone-
sian data confirm that a stand-alone guideline distribu-
tion approach may not work.141 Further enhancement
of post-prescription review and feedback efforts holds
potential to decrease antibiotic consumption and antibi-
otic duration.142 For pre-prescription approval, local
data suggested that the decreased use of last-resort anti-
biotics might cause a “squeezing the balloon” phenome-
non
the increased use of non-restricted antibiotics due
to restrictions of the restricted antibiotics.143 The chal-
lenge for stewardship teams lies in selecting locally tai-
lored change interventions based on a careful
assessment of context-specific barriers and facilita-
tors.144 Limited progress will be made with imple-
menting AMS in Indonesian hospitals, and in
settings with similar structural features, without
addressing a considerable spectrum of challenges
and constraints, such as lack of sustainable manage-
ment-level support, competing interests and profit
generation in the private sector, limited national
insurance reimbursements, and limited functionality
of enabling AMS infrastructures.145
147
Key themes identified from perception surveys were
a substantial lack of AMR awareness and knowledge
about antibiotics, particularly among the poor and lower
educated, widespread antibiotic self-medication without
prescription, and over-the-counter non-prescription
antibiotic dispensing in community pharmacies

although representative data are lacking to quantify
17
 Articles
these issues. A recent mixed-method study in drug out-
lets in urban (West Java) and rural (South Kalimantan)
settings in Indonesia reported antibiotic dispensing
without prescription in 69% of simulated-patient visits,
with non-prescription antibiotic sales being driven by
strong patient demand, unqualified drug sellers dis-
pensing medicines, business interests, and weak
enforcement of regulations.148 The available data cor-
roborate findings of a global review in community phar-
macies that over-the-counter non-prescription
antibiotics comprised 62% of all dispensed antibiotics,
most commonly for urinary and upper respiratory tract
infections.149 A review in Southeast Asia reported a
prevalence of self-medication with antibiotics ranging
from 7.3 to 85.6% (median 42.6%), highest among
men, health students and professionals, with the most
common illnesses or symptoms being common cold,
sore throat, fever, gastrointestinal and respiratory dis-
eases.150 In our review, the main reasons for self-medi-
cation included positive previous experience, easy
access from the pharmacy, doctor visit being expensive
or unpractical, and the main advisors to self-medicate
included health care providers, family, relatives or
friends, which largely concurred with findings in other
Southeast Asian countries.150
The data included in this Review highlighted several
critical evidence gaps. First, there were important limi-
tations in data heterogeneity and study methodology,
study-level confounding, and publications were predom-
inantly from Java Island, which limited our ability to
draw firm conclusions on the contemporary nationwide
antibiotic use situation in Indonesia. This is especially
relevant given the substantial within-country variations
in access to quality health care4, and therefore, the data
should be interpreted cautiously. Representative, high-
quality data will be essential for benchmarking between
healthcare facilities, districts, provinces, and interna-
tionally. Second, the exclusion of non-peer-reviewed,
grey literature meant that we might not have included
evidence on successful interventions implemented by
government and/or non-government institutions. How-
ever, their exclusion likely improved the quality of the
evidence as grey literature may not always follow gold-
standard or recommended guidelines for evaluation.151
Third, apart from the key themes from perception sur-
veys among antibiotic prescribers and consumers, there
was a gap in the literature analysing the broader health
system drivers of antibiotic use, especially concerning
the effects of the national health insurance roll-out since
2014, enforcement of antibiotic regulations in informal
and private health sectors, as well as on models of com-
munity antibiotic stewardship.
Progress in implementing Indonesia’s National
Action Plan on AMR to date includes strengthened
national capacities for microbiological laboratories and
surveillance,13 supported by the government and inter-
national funding agencies. Indonesia enrolled in the
18
WHO Global Antimicrobial Resistance and Use Surveil-
lance System (GLASS) and submitted first batches of
AMR and antibiotic consumption data in 2020.152 In
2021, the Ministry of Health launched new guidelines
for antibiotic prescribing and AMS programmes,138
which have also adopted the AWaRe classification.
Despite this progress, however, the National Action
Plan for AMR has not yet generated the required sus-
tainable capacity to contain AMR. A recent cross-coun-
try analysis of the current national action plans for
AMR in Southeast Asia, including Indonesia and 9
other ASEAN countries (The Association of Southeast
Asian Nations), listed Indonesia’s priorities towards
optimising antibiotic usage as the development of stron-
ger regulatory frameworks, evidence-based AMS pro-
grammes in ambulatory and community settings and as
part of hospital accreditation qualifying criteria, and
standard antibiotic treatment guidelines, including an
essential antibiotics list.13 Interventions to optimise anti-
microbial use need to be based on a health systems
approach, beyond AMS, informed by a broad research
base, including addressing the wider drivers of antibi-
otic use
such as inequitable burdens of ill health and
fractured care cascades. Both universal health coverage
and AMR require strong human-centered care with
accessible health care facilities, medicines and diagnos-
tics, with a focus on quality and equity.4,153,154 This
requires further investments in health care infrastruc-
ture, training of health workers, community participa-
tion and health literacy, at the country, province and
district levels. Modifiable factors related to the patient
(e.g., awareness, knowledge) and the health system (e.
g., strict policies, medicine quality, financial incentives,
infrastructure gaps) need to be further identified and
addressed when designing context-specific interven-
tions aimed at curtailing inappropriate antibiotic use.
In conclusion, this Review can be a guiding tool for
policy-makers and academics as it summarizes the state
of antibiotic use in humans in Indonesia over the past
20 years, and highlights important areas where critical
information is lacking. There are critical evidence gaps
on antibiotic use in the informal and formal private
health care sectors as well as geographic areas outside
of Java Island, and what are health system drivers of
antibiotic use. There is a need to strengthen the local
research base to develop context-specific sustainable
AMS models that consider country-specific socio-cul-
tural circumstances. Optimisation of antimicrobial use,
based on robust surveillance data and feasible interven-
tions, should be a priority of the national agenda for uni-
versal health coverage.
Contributors
RLH conceptualised the study. RLH and RL obtained
the funding. RL, PD and RLH designed the study proto-
col and data extraction instrument. PD, GL, MM, and
www.thelancet.com Vol 2 Month July, 2022

MA collected and verified the data, overseen by RL and
RLH. RL, GL and RLH performed the data analysis and
had full access to all study data. RL, GL, PD, and RLH
drafted the paper, with critical inputs from EJN, RS, AK
and HRvD. All authors had full access to all the data in
the study, critically revised the manuscript, accept
responsibility to submit for publication, and gave
approval for the final version to be published.
Data sharing statement
No additional data are available.
Declaration of interests
AK serves as the current Chair of the National AMR
Committee (KPRA). HRVD serves as an Executive
Board Member of The Surveillance and Epidemiology
of Drug-resistant Infections Consortium (SEDRIC).
The other authors declare no competing interests.
Acknowledgements
EXPLAIN study group: Erni J. Nelwan, Ralalicia Limato,
Manzilina Mudia, Helio Guterres, Enty Enty, Ifael Y.
Mauleti, Maria Mayasari, Iman Firmansyah, May Hiz-
rani, Anis Karuniawati, Prof Taralan Tambunan, Prof
Amin Soebandrio, Decy Subekti, Iqbal Elyazar, Mutia
Rahardjani, Fitria Wulandari, Prof Reinout van Crevel,
Rogier van Doorn, Vu Thi Lan Huong, Nga Do Ti Thuy,
Sonia Lewycka, Prof Alex Broom, Raph L. Hamers.
Supplementary materials
Supplementary material associated with this article can
be found, in the online version, at doi:10.1016/j.lan
sea.2022.05.002.
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