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Determinants of carriage of resistant Escherichia coli in the Indonesian population inside and outside hospitals

September 2007
Journal of Antimicrobial Chemotherapy 60(2):377-84

September 2007
60(2):377-84

DOI:10.1093/jac/dkm197

Source
PubMed

Authors:

Usman Hadi

Airlangga University

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Antibiotic resistance is a worldwide healthcare problem exacerbated by antibiotic use and transmission of resistant bacteria. Not much is known about resistance in commensal flora and about determinants for resistance in Indonesia. This study analysed recent antibiotic use as well as demographic, socioeconomic, disease-related and healthcare-related determinants of rectal carriage of resistant Escherichia coli in the community and in hospitals in Indonesia. Carriers of susceptible E. coli were compared with carriers of E. coli with resistance to any of the tested antibiotics. Logistic regression analysis was performed to determine which variables were associated with carriage of resistant E. coli. Individuals in the community with varying levels of contact with healthcare institutions and hospitalized patients were analysed as separate populations. Of 3275 individuals (community 2494, hospital 781), 54% carried resistant E. coli. Recent antibiotic use was the most important determinant of resistance in both populations [community: odds ratio (OR) 1.8, 95% confidence interval (95% CI) 1.5-2.3; hospital: OR 2.5, 95% CI 1.6-3.9]. In the community, hospitalization (OR 2.4, 95% CI 2.0-3.0), diarrhoeal symptoms (OR 1.9, 95% CI 1.3-2.7) and age under 16 years (adults: OR 0.4, 95% CI 0.3-0.5) were associated with carriage of resistant E. coli. For hospitalized patients, having no health insurance was associated with less resistance (OR 0.6, 95% CI 0.4-0.9) and differences were observed between hospitals (Semarang: OR 2.2, 95% CI 1.5-3.3) and departments (Paediatrics: OR 4.3, 95% CI 1.7-10.7). Further research is needed to investigate whether transmission is responsible for these differences.

. Demographic characteristics of community and hospital populations

…

. Resistance patterns

…

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Determinants of carriage of resistant Escherichia coli in the

Indonesian population inside and outside hospitals

D. Offra Duerink

*, Endang S. Lestari

, Usman Hadi

, Nico J. D. Nagelkerke

, Julie

tte A. Severin

Henri A. Verbrugh

, Monique Keuter

, Inge C. Gyssens

and Peterhans J. van den Broek

on behalf

of the study group ‘Antimicrobial Resistance in Indonesia: Prevalence and Prevention’ (AMRIN)†

Department of Infectious Diseases, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The

Netherlands;

Department of Clinical Microbiology, Dr Kariadi Hospital—School of Medicine, Diponegoro

University, Jalan Dr Soetomo 16-18, Semarang 50231, Indonesia;

Department of Internal Medicine, Dr Soetomo

Hospital—School of Medicine, Airlangga University, Jalan Prof. Dr Moestopo 6-8, Surabaya 60132, Indonesia;

Department of Community Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab

Emirates;

Department of Medical Microbiology and Infectious Diseases, University Medical Centre Rotterdam,

‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands;

Department of Internal Medicine, Nijmegen

University Centre for Infectious Diseases International Health (NUCI-IH), Geert Grooteplein 10, 456, 6525 GA

Nijmegen, The Netherlands

Received 19 February 2007; returned 11 March 2007; revised 1 May 2007; accepted 7 May 2007

Objectives: Antibiotic resistance is a worldwide healthcare problem exacerbated by antibiotic use and

transmission of resistant bacteria. Not much is known about resistance in commensal ﬂora and about

determinants for resistance in Indonesia. This study analysed recent antibiotic use as well as demo-

graphic, socioeconomic, disease-related and healthcare-related determinants of rectal carriage of

resistant Escherichia coli in the community and in hospitals in Indonesia.

Methods: Carriers of susceptible E. coli were compared with carriers of E. coli with resistance to any

of the tested antibiotics. Logistic regression analysis was performed to determine which variables

were associated with carriage of resistant E. coli. Individuals in the community with varying levels of

contact with healthcare institutions and hospitalized patients were analysed as separate populations.

Results and conclusions: Of 3275 individuals (community 2494, hospital 781), 54% carried resistant

E. coli. Recent antibiotic use was the most important determinant of resistance in both populations

[community: odds ratio (OR) 1.8, 95% conﬁdence interval (95% CI) 1.5 –2.3; hospital: OR 2.5, 95% CI

1.6–3.9]. In the community, hospitalization (OR 2.4, 95% CI 2.0 –3.0), diarrhoeal symptoms (OR 1.9,

95% CI 1.3 –2.7) and age under 16 years (adults: OR 0.4, 95% CI 0.3–0.5) were associated with carriage

of resistant E. coli. For hospitalized patients, having no health insurance was associated with less

resistance (OR 0.6, 95% CI 0.4– 0.9) and differences were observed between hospitals (Semarang: OR

2.2, 95% CI 1.5–3.3) and departments (Paediatrics: OR 4.3, 95% CI 1.7– 10.7). Further research is

needed to investigate whether transmission is responsible for these differences.

Keywords: antibacterial agents, drug resistance, risk factors

Introduction

Antibiotic resistance is a worldwide healthcare problem that

threatens the progress in healthcare in developing countries.

1,2

Limited published data are available on antibiotic resistance in

Escherichia coli in the Far East and these primarily concern

clinical isolates.

3–14

Resistance data from Indonesia are mostly

limited to pathogens of diarrhoeal disease.

10,12,13,15 – 19

The use

.....................................................................................................................................................................................................................................................................................................................................................................................................................................

*Corresponding author. Tel: þ31-71-5262613; Fax: þ31-71-5266758; E-mail: d.o.duerink@lumc.nl

†Members of the AMRIN study group are listed in the Acknowledgements section.

Journal of Antimicrobial Chemotherapy (2007) 60, 377–384

doi:10.1093/jac/dkm197

Advance Access publication 26 June 2007

377

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of antibiotics is the most important determinant for emergence

of resistant micro-organisms.

20,21

Little is known about other

determinants for carriage of resistant bacteria, such as demo-

graphic

and socioeconomic

23,24

factors.

The study group ‘Antimicrobial Resistance in Indonesia:

Prevalence and Prevention’ (AMRIN) investigated rectal car-

riage of resistant bacteria among inhabitants of the island of

Java. Rectal swabs of individuals in the community and the hos-

pital were cultured for the presence of E. coli, a commensal

intestinal bacterium frequently used as an indicator of antibiotic

resistance in populations.

Antibiotic susceptibility testing of

the E. coli isolates was conducted for six antibiotics commonly

used in Indonesia: ampicillin, ciproﬂoxacin, cefotaxime, genta-

micin, chloramphenicol, and trimethoprim/sulfamethoxazole.

The aim of the present study is to investigate whether recent

antibiotic use as well as demographic, socioeconomic, health-

care-related and disease-related variables are risk factors for car-

riage of resistant E. coli. We hypothesized that recent antibiotic

use would be associated with carriage of resistant E. coli, and

that due to transmission of resistant bacteria differences would

be found between nursing wards, departments and hospitals.

Materials and methods

Two government hospitals, the Dr Soetomo hospital in Surabaya,

East Java, and the Dr Kariadi hospital in Semarang, Central

Java, Indonesia, as well as three primary healthcentres (PHC,

two in Surabaya and one in Semarang) were selected for this

study. The hospital in Surabaya has ~60 000 and that in

Semarang 26 000 admissions per year. The Medical Ethics

Committees of the hospitals approved of the study protocol

[ethical clearance No/Panke.KKE/2001 (Surabaya) and 11/EC/FK/

RSDK/2001 (Semarang)]. Patients upon admission to hospital

(group A), healthy family members accompanying them (group

B), people visiting a primary healthcentre for consultation or

vaccination (group C) and patients upon discharge after hospital-

ization for 5 days or more (group D) were enrolled after giving

informed consent. The aim was to include 4000 individuals; 500

individuals per group per city, whereby each department was

equally represented.

For the purpose of analysis, individuals who had not been hospi-

talized (groups A, B and C) were combined into a community popu-

lation, whereas patients upon discharge from hospital (group D)

formed the hospital population.

Group A patients were included within the ﬁrst 24 h of admis-

sion. Persons in group B were included on admission of group A

patients at a rate of one contact per patient. Patients in group C were

included on speciﬁc study days twice weekly in Surabaya and once

weekly in Semarang. Individuals were excluded from the study if

they had been transferred from another hospital, if they were not

accompanied by a family member (group A), or if they had been

admitted to a hospital during the previous three months (groups A,

B and C).

Demographic and socioeconomic data and, for community

patients, data on health complaints and consumption of antibiotics

in the month preceding the study were collected by semi-structured

interviews, performed by pairs of trained Indonesian and Dutch data

collectors (researchers, residents and medical students). For group

A, diagnosis on admission, and for group D, data on antibiotic con-

sumption during hospitalization and diagnosis on discharge were

collected from medical records. Subjects for whom susceptibility

testing and data on antibiotic consumption were available were

included in the analyses.

Variables

Recent antibiotic use was deﬁned in accordance with the nomencla-

ture and subcategory deﬁnitions of the WHO ATC Classiﬁcation

code, subgroup antibacterials for systemic use.

We analysed any

antibiotic use, i.e. whether or not a patient took any antibiotic in the

preceding month or during hospitalization; use of an antibiotic from

a speciﬁc ATC class, combined or not combined with an antibiotic

from a different class; and single antibiotic use, i.e. use of an anti-

biotic from a speciﬁc ATC class not combined with an antibiotic

from a different class. Combined use was deﬁned as either simul-

taneous or successive use of antibiotics from different ATC classes.

Origin (Surabaya or Semarang), sex, age (newborn to 16 years of

age versus over 16 years of age in accordance with the age limit for

the Departments of Paediatrics, and children of less than two years

old versus people of more than two years of age in accordance with

approximate pre- and post-weaning periods), ethnicity and living

area (urban or rural) were the selected demographic variables.

Health insurance, income (below or above poverty line),

education

(primary school not completed versus primary school education and

higher), employment and crowding (one through eight versus nine

or more individuals sharing a household) were the chosen socioeco-

nomic variables. Group, Department (Internal Medicine, Surgery,

Obstetrics and Gynaecology or Paediatrics), nursing ward (sub-

department), nursing class (I, II or III, with class I being the most

expensive class) and length of stay in hospital (5 through 8 versus

9 days or more) were studied as healthcare-related variables. Only

the last ward of admission was recorded; transfers were not

recorded. For community patients, clinical signs and symptoms in

the month preceding the study (fever, diarrhoea, respiratory symp-

toms, other symptoms or no symptoms) were the disease-related

variables and for patients upon admission and discharge whether or

not an infection was diagnosed.

Selection of strains and susceptibility testing

Rectal samples were taken with sterile cotton-tipped swabs, which

were transported to the laboratory in Amies transport medium (Copan,

Brescia, Italy) in closed boxes at ambient temperature. They were

cultured within 24 h on CHROMagar Orientation (Becton–Dickinson,

Heidelberg, Germany) for the isolation of E. coli.

From each

culture, two colonies representing the dominantly growing bacterium

were further analysed. Pink colonies were assumed to be E. coli and

used for susceptibility testing without additional determination. From

the original 3995 isolates, almost 400 were conﬁrmed by Vitek 2

(bioMe

rieux, Marcy-l’Etoile, France).

Previously published vali-

dation of identiﬁcation of E. coli by CHROMagar yielded a positive

predictive value of 0.93, which is comparable to our results.

Susceptibility testing was performed by the CLSI (formerly the

NCCLS)-based disc diffusion method on Mueller –Hinton agar

using discs containing ampicillin (10 mg), chloramphenicol (30 mg),

gentamicin (10 mg), cefotaxime (30 mg), ciproﬂoxacin (5 mg) and

trimethoprim/sulfamethoxazole (1.25/23.75 mg).

The performance

of the susceptibility testing was monitored twice weekly with the

quality control strain E. coli ATCC 25922. Isolates that were suscep-

tible or intermediately susceptible according to the CLSI criteria

were categorized as susceptible.

For the purpose of analysis, a maximum of one E. coli isolate

per enrolled individual, namely the ﬁrst E. coli isolate in the study

database, was included in the analysis.

Duerink et al.

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Analysis

Individuals carrying resistant strains were compared with individuals

carrying bacteria susceptible to all tested antibiotics. Resistance as

an outcome variable for each of the different antibiotics was

explored in two different ways:

(i) Resistance of E. coli to any of the tested antibiotics, irrespective

of whether this was resistance to the speciﬁc antibiotic con-

sidered, or whether the resistance to the antibiotic of interest

was part of a pattern of resistance to multiple antibiotics, was

taken as the outcome (dependent) variable, and possible deter-

minants for this variable identiﬁed.

(ii) Carriage of E. coli resistant to the speciﬁc antibiotic of interest

was taken as the outcome variable, and determinants for this

outcome variable identiﬁed. This approach was only pursued

when at least 100 isolates with the relevant resistance pattern

were available.

To identify determinants for any of these outcome variables, logistic

regression analysis with backward selection of variables (statistical

package SPSS, version 12.0, SPSS Inc., Chicago, IL, USA) was

used.

In view of the large number of inter-related candidate determi-

nants, some of which were sparse (i.e. most individuals had the

same value for this variable), each of the analyses was performed

using a two-step procedure. First, candidate variables were selected

by performing logistic regression on four partially overlapping sets

of co-variables [Table S1, available as Supplementary data at JAC

Online (http://jac.oxfordjournals.org/)]:

(i) any antibiotic use, combined with all demographic, socioeco-

nomic, disease-related and healthcare-related determinants,

(ii) demographic determinants,

(iii) socioeconomic determinants,

(iv) disease-related and healthcare-related determinants (without

nursing wards).

Then, a ‘ﬁnal’ logistic regression analysis was performed with all

variables that were signiﬁcantly associated with antibiotic resistance

in any of these four analyses. The variables that were signiﬁcantly

associated with resistance in this ﬁnal analysis were presumed to be

independently associated (in the sense that the association was not

caused by confounding) with resistance. This approach of selecting

candidate variables was preferred over the usual strategy of picking

variables univariately signiﬁcantly associated with the outcome vari-

able, as in our experience that strategy sometimes misses variables

that are only signiﬁcantly associated with the outcome variable in

conjunction with other variables. Use of antibiotics from speciﬁc

antibiotic classes and single use of speciﬁc antibiotic classes were

analysed as separate sets of variables. When logistic regression

could not be performed because of sparse data, variables with very

small dispersion were excluded from the analyses.

Possible clustering of susceptibility patterns between groups A

and B was investigated by comparing whether included pairs of

individuals had similar susceptibility patterns and calculating

Pearson’s correlation coefﬁcient.

Results

Between July and October 2001 in Surabaya and January and

May 2002 in Semarang, 3995 subjects were included. In 3275

individuals, culture and susceptibility data on E. coli and anti-

biotic use data were complete. In 720 patients, data were not

suitable for analysis: 180 because there was no growth on the

agar plate, 385 because no pink colonies were present in the

culture and 155 because of missing susceptibility data

(Figure 1). No growth was observed signiﬁcantly more fre-

quently in Semarang (8%) than in Surabaya (1%, P , 0.001). In

Surabaya, no signiﬁcant differences were observed between the

groups, whereas in Semarang, the proportion with no growth

varied from 5% in group B to 13% in group D (P , 0.001). The

proportion of pink colonies did not differ signiﬁcantly between

Surabaya and Semarang, or between the groups in Surabaya, but

varied between 80% in group D and 92% in group B (P , 0.001)

in Semarang. Missing or incomplete susceptibility data occurred

more frequently in Surabaya (8%) than in Semarang (1%,

P , 0.001). In Semarang, no signiﬁcant differences were

observed between the groups, whereas in Surabaya, the pro-

portion with missing susceptibility data varied from 1% in group

B to 11% in group C (P , 0.001).

No signiﬁcant differences in demographic, socioeconomic,

disease-related and healthcare-related variables were observed

between the community and hospital populations, with the

exception of age (Table 1). Additional information regarding

population characteristics can be found in Table S2 [available as

Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]

for the community and in Table S3 [available as Supplementary

data at JAC Online (http://jac.oxfordjournals.org/)] for the

hospital.

Antimicrobial resistance

Of the 3275 E. coli strains, 1552 (47%) were susceptible to all

tested antibiotics, 585 (18%) to a single antibiotic and 1138

(35%) to two or more antibiotics (Table 2). In 69 strains (data

not shown in Table 2), resistance patterns were observed that

occurred less than eight times.

In the community, ampicillin resistance was observed most

frequently (851 isolates, 34%), followed by trimethoprim/sulfa-

methoxazole resistance in 716 isolates (29%) and chlorampheni-

col resistance in 369 isolates (15%). Resistance to ciproﬂoxacin,

gentamicin and cefotaxime occurred less than 100 times. Single

ampicillin resistance was observed in 236 isolates (9%) and

single trimethoprim/sulfamethoxazole resistance in 162 isolates

(6%), whereas single chloramphenicol, gentamicin and cipro-

ﬂoxacin resistance were observed less than 100 times. Single

cefotaxime resistance was not present in any of the isolates.

In hospitalized patients, ampicillin resistance was also

observed most frequently (570 isolates, 73%), followed by tri-

methoprim/sulfamethoxazole resistance in 434 isolates (56%),

chloramphenicol resistance in 334 isolates (43%), ciproﬂoxacin

resistance in 173 isolates (22%) and gentamicin resistance in

141 isolates (18%). Cefotaxime resistance was observed less

than 100 times. In hospitalized patients, single resistance was

observed for less than 100 subjects for all tested antibiotics and

single cefotaxime resistance was not present in any of the

isolates.

Antibiotic use

Antibiotic use results are summarized in Table 3. In the commu-

nity (2494 individuals), 367 antibiotic courses were prescribed

in the month preceding the study, while for 781 hospitalized

individuals, 1084 antibiotic courses were prescribed. Penicillins

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ranked ﬁrst and accounted for 71% of antibiotic use in the commu-

nity and 40% in hospitals. In the community tetracyclines (10%),

sulphonamides (7%) and amphenicols (7%) were the other fre-

quently used antibiotics. In the community 93% of antibiotic use

concerned the use of a single antibiotic. In the 2125 individuals in

the community who received no antibiotic treatment, the carriage

rate of multiple resistances (resistance to more than one antibiotic)

was 24%, in the 347 patients receiving one antibiotic 38% and in

the 22 patients receiving more than one antibiotic 46%.

In hospitalized patients, cephalosporins (22%) and quino-

lones (10%) ranked second and third, respectively. Single anti-

biotic use was observed in 33% of cases. In the 127 hospitalized

patients who received no antibiotic treatment, the carriage rate

of multiple resistances was 33%, in the 159 patients receiving

one antibiotic 64% and in the 495 patients receiving more than

one antibiotic 71%.

Determinants of resistance in the community

(groups A, B and C)

Analysis of determinants for resistance in the community was

performed with resistance to any of the tested antibiotics, single

ampicillin resistance and single trimethoprim/sulfamethoxazole

resistance, because more than 100 cases were available for these

resistance groups.

Any antibiotic use was associated with carriage of E. coli

with resistance to any of the tested antibiotics [odds ratio (OR)

1.8, 95% conﬁdence interval (95% CI) 1.5–2.3], single ampicil-

lin resistance (OR 1.6, 95% CI 1.1 –2.3) and single trimetho-

prim/sulfamethoxazole resistance (OR 1.8, 95% CI 1.2–2.8).

Prior use of penicillins was associated with carriage of E. coli

resistant to any of the tested antibiotics (OR 1.8, 95% CI 1.4 –

2.4) and single ampicillin resistance (OR 1.8, 95% CI 1.2–2.7).

Prior use of amphenicols was associated with carriage of E. coli

resistant to any of the tested antibiotics (OR 3.1, 95% CI 1.3 –

7.5). Prior use of sulphonamides was associated with carriage of

E. coli resistant to any of the tested antibiotics (OR 5.5, 95% CI

2.1–14.8) and single trimethoprim/sulfamethoxazole resistance

(OR 7.5, 95% CI 2.0– 28.0).

Logistic regression analysis performed with only single anti-

biotic use did not change the ﬁndings signiﬁcantly; in most

cases, the same antibiotics were associated with resistance when

used as a single antibiotic drug or combined with other anti-

biotics (data not shown).

Socioeconomic variables were not associated with carriage of

resistant E. coli in the community. Neither were demographic

variables, except for age: adults were less likely to be carriers of

E. coli with resistance to any of the tested antibiotics (OR 0.4,

95% CI 0.3–0.5) and single ampicillin resistance (OR 0.6, 95%

CI 0.4 –0.9) than children. The same analysis with children of

Figure 1. Flow chart with numbers of enrolled and analysed subjects. Reasons for exclusion of enrolled subjects from analysis: NG, no growth on agar plate;

NP, no pink colonies on agar plate; NS, no complete susceptibility data.

Duerink et al.

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less than 2 years old versus people of more than 2 years of age

yielded similar results (data not shown). Admission to hospital

(group A) was associated with carriage of E. coli resistant to

any of the tested antibiotics (OR 2.4, 95% CI 2.0 –3.0) and

single ampicillin resistance (OR 2.7, 95% CI 1.9–4.0, group

B ¼ reference category). Susceptibility patterns of groups A and

B did not correlate, although individuals from these groups were

included as pairs (Pearson’s correlation coefﬁcient ¼ 0.014).

Diarrhoea was associated with carriage of E. coli resistanttoany

of the tested antibiotics (OR 1.9, 95% CI 1.3–2.7).

Determinants of resistance in hospitalized patients (group D)

Analysis of determinants for resistance in hospitalized patients

was only performed with resistance to any of the tested anti-

biotics, because single resistance was observed for less than 100

subjects for all tested antibiotics.

The use of any antibiotic (OR 2.5, 95% CI 1.6–3.9),

penicillins (OR 3.2, 95% CI 2.2–4.8), amphenicols (OR 3.9, 95%

CI 1.2–12.8), quinolones (OR 6.8, 95% CI 3.0–15.1) and metro-

nidazole (OR 2.9, 95% CI 1.1–7.6) was associated with carriage

of E. coli with resistance to any of the tested antibiotics.

Logistic regression analysis with only single antibiotic use

changed the ﬁndings signiﬁcantly for carriage of E. coli with

resistance to any of the tested antibiotics: any (single or com-

bined) cephalosporin use was not associated with resistance, but

single cephalosporin use was associated with less carriage of

E. coli with resistance to any of the tested antibiotics (OR 0.2,

95% CI 0.1 –0.5). Single use of other antibiotics was not associ-

ated with carriage of E. coli with resistance to any of the tested

antibiotics (data not shown).

Having no health insurance was associated with less carriage

of E. coli with resistance to any of the tested antibiotics (OR

0.6, 95% CI 0.4 –0.9). Discharge from the hospital in Semarang

was associated with carriage of E. coli with resistance to any of

the tested antibiotics (OR 2.2, 95% CI 1.5–3.3). Discharge from

the Department of Paediatrics (OR 4.3, 95% CI 1.7 –10.7),

rather than from Internal Medicine (reference category) was

associated with carriage of E. coli with resistance to any of the

tested antibiotics. Signiﬁcant differences were observed between

several individual nursing wards, but for most wards the

numbers of patients were too small to draw any conclusions

from these data (data not shown).

Discussion

This study shows that antibiotic use is the most important albeit

not the only determinant of carriage of resistant E. coli. In the

non-hospitalized population, age under 17 and diarrhoea were

independent determinants. Individuals screened upon admission

to hospital carried resistant E. coli more often than patients who

visited a PHC and healthy relatives who accompanied patients at

admission to hospital. In hospitalized patients screened upon dis-

charge, having health insurance was associated with carriage of

resistant E. coli, as were several healthcare-related determinants:

Table 1. Demographic characteristics of community and hospital populations

Community n ¼ 2494 Hospital n ¼ 781 P

Surabaya 1186 (48) 386 (49) NS

Group A (admission) 818 (33) — —

Group B (relatives) 814 (33) — —

Group C (PHC) 862 (35) — —

Group D (discharge) — 781 (100) —

Internal Medicine 197

(24) 192 (25) NS

Surgery 203

(25) 204 (26) NS

Obstetrics and Gynaecology 217

(27) 209 (27) NS

Paediatrics 201

(25) 176 (23) NS

Age above 16 2032 (82) 558 (71) ,0.001

Female sex 1548 (62) 460 (59) NS

Javanese ethnicity 2377 (95) 733 (94) NS

Urban provenance 1615 (65) 497 (64) NS

Health insurance 641 (26) 219 (28) NS

Low income 1084 (57) 360 (46) NS

Primary school completed 1971 (79) 586 (75) NS

Employment 1575 (63) 447 (83) NS

Crowding .8 persons per household 315 (13) 73 (9) NS

Nursing class III 679

(83) 615 (79) NS

Length of stay .8 days — 394 (50) —

Clinical signs of infection 1805 (72) — —

Infection diagnosis in hospital 206

(32) 204 (26) NS

Absolute numbers are shown, with percentages between brackets.

‘NS’ means that no signiﬁcant differences were observed between the populations.

Only calculated for group A; percentages are proportions of patients in group A.

Determinants of resistant E. coli in Indonesia

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hospitalization in Semarang and admission to the Gynaecology

and Obstetrics or Paediatric Departments.

In concordance with our hypothesis, we observed that, for

most antibiotic classes, most resistance was present in the group

most exposed to antibiotics and least resistance in the group

least exposed to antibiotics. In the community, direct associ-

ations were observed between the use of speciﬁc antibiotics

and resistance to those antibiotics, namely between b-lactam

antibiotics and ampicillin resistance and sulphonamide use and

trimethoprim/sulfamethoxazole resistance. Here, the majority of

antibiotic therapy consisted of single therapy.

For hospitalized patients, two-thirds of antibiotic treatments

were combined therapies. The use of penicillins, amphenicols,

quinolones and metronidazole was associated with resistance to

any of the tested antibiotics. Epidemiologically one can assume

that it represents a greater exposure to antibiotics, since most

patients took more than one antibiotic. Indeed there was a high

rate of multiple resistances. In the subset of hospitalized patients

treated with a single antibiotic, single use of a cephalosporin

was associated with less resistance to any of the tested anti-

biotics. It is unlikely that cephalosporins actually protect against

resistance. In a hospital population, where 84% of the patients

took antibiotics during admission, single b-lactam use might

reﬂect a relatively healthy population with a relatively low sus-

ceptibility to infections and exposed to relatively low quantities

of antibiotics (e.g. as prophylaxis).

Table 2. Resistance patterns

Number of isolates (%) Ampicillin Chloramphenicol Gentamicin Cefotaxime Ciproﬂoxacin

Trimethoprim/

sulfamethoxazole

1552 (47.4) S S S S S S

361 (11.0) R R S S S R

321 (9.8) R S S S S S

316 (9.6) R S S S S R

185 (5.6) S S S S S R

94 (2.9) R R S S S S

59 (1.8) R R S S R R

41 (1.3) S R S S S S

37 (1.1) R S S S R R

28 (0.9) R R R S R R

22 (0.7) R R R S S R

21 (0.6) R R R R R R

20 (0.6) R R R R S R

19 (0.6) S S S S R S

19 (0.6) S S R S S S

17 (0.5) R S S S R S

17 (0.5) R S R S R R

16 (0.5) S R S S S R

13 (0.4) R S R R R R

11 (0.3) R S S R S R

10 (0.3) R S R S S S

10 (0.3) R S R R S R

9 (0.3) S S S S R R

8 (0.2) R S R R R S

The number of times a given resistance pattern was found is shown in the ﬁrst column, with the prevalence between brackets. Resistance is represented byan

R and susceptibility by an S.

Table 3. Total and single antibiotic use in community and hospital

populations

Community Hospital

Total

use (n)

Single

use (%)

Total

use (n)

Single

use (%)

Tetracycline 37 86 5 20

Penicillins 261 97 440 51

Amphenicols 24 75 52 15

Cephalosporins 0 0 239 30

Carbapenems 0 0 3 0

Sulphonamides 26 88 39 15

Macrolides 10 60 26 15

Aminoglycosides 2 100 92 2

Quinolones 3 100 114 34

Metronidazole 4 100 69 0

Others 0 0 5 0

Total 367 93 1084 33

Total use (n) is the number of antibiotic prescriptions; single use (%) is

single antibiotic use as percentage of total number of prescriptions.

Duerink et al.

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Several other determinants, although independent from anti-

biotic use in the analysis, can still be explained by a relatively

high exposure to antibiotics. Health insurance increased the

probability of carriage of resistant E. coli. This is most likely, at

least partly, due to the different consumption pattern of anti-

biotics. Individuals with health insurance consumed antibiotics

more frequently, took longer antibiotic courses and different

antibiotic classes, namely cephalosporins, macrolides and quino-

lones, than people without health insurance.

In the community, more children than adults carried resistant

E. coli. Several factors may have contributed to carriage of

resistant E. coli in children. Young children generally tend to

receive antibiotics more frequently than adults.

The AMRIN

study conﬁrmed that more children than adults received anti-

biotics. Apart from antibiotic use, children might acquire resist-

ant bacteria more easily than adults, because of their greater

exposure through unhygienic behaviour.

With regard to clinical signs and symptoms, we observed that

individuals who reported diarrhoea had a higher probability of

carriage of resistant E. coli than individuals with other or no

complaints. We must interpret these data carefully, since diar-

rhoea often occurs during antibiotic use and patients may have

incorrectly reported diarrhoea as a symptom instead of an

adverse reaction to an antibiotic.

Our results indicate that the hospital, the department and the

nursing ward to which a patient is admitted are determinants of

carriage of resistant E. coli in hospitalized patients. In hospitals,

transmission of resistant bacteria contributes to the problem of

antibiotic resistance, probably much more so than in the commu-

nity.

31,32

Further investigations are needed to show whether

transmission of resistant strains of E. coli explains the differ-

ences between the two hospitals, the departments and the wards.

There are several limitations to the study. Antibiotic use in

the community was self-reported. We may have missed determi-

nants for carriage of resistant E. coli, because, since quantitative

analysis was not feasible with the amount of variables analysed,

we dichotomized the variables for the purpose of analysis. The

design of the study is not useful for making statements about

mechanisms causing resistance, although it is helpful for making

recommendations for further research. Finally, care must be

taken in generalization of our results to the general Javanese

population, as the majority of participants were in contact with

healthcare institutions, in varying levels. The community popu-

lation consisted of several subgroups, with group B being most

representative of the general Javanese population. The hospital

population was approximately representative of urban Javanese

government hospitals, with a tendency towards longer than

average hospital admissions. However, the design proved useful

to show that the more intensively individuals are in contact with

healthcare institutions, the more prone they are to carriage of

resistant E. coli.

In conclusion, antibiotic use was the most important determi-

nant for carriage of resistant E. coli in our study. Most antibiotic

classes were associated with carriage of resistant E. coli.An

aberrant antibiotic consumption pattern of people with health

insurance may explain the role of health insurance. Children,

regardless of more frequent antibiotic use, were at greater risk of

carriage of resistant E. coli than adults, perhaps because of the

greater exposure to (resistant) microorganisms. Differences

between and within hospitals point to transmission of resistant

bacteria within hospitals.

Acknowledgements

We thank the deans of the participating medical faculties and

the directors of participating hospitals, the directors of the parti-

cipating PHC and the heads of the participating departments,

who have facilitated our work in these hospitals. We gratefully

acknowledge the contribution of the data collectors: Diana Huis

in ‘t Veld, Suzanne Werter, Ka-Chun Cheung, Eko Budi

Santoso, Hadi Susatyo, Arwin Achyar, Sony Wibisono,

Bramantono, Vera, Yenni Suryaningtyas, Upik Handayani,

Krisma Irmajanti, Purnomo Hadi, Rianne de Jong and

Rozemarijn van der Meulen, and all those who helped us with

the pilot study and data registration. We also thank Emile

F. Schippers for his very useful comments on the manuscript.

This work was supported by the Royal Netherlands Academy of

Arts and Sciences (KNAW), Science Programme Indonesia, the

Netherlands (project 99-MED-03).

Members of the AMRIN study group:

Dr Soetomo Hospital—School of Medicine Airlangga

University Surabaya, Indonesia: Prof. Widjoseno Gardjito, M.D.;

Erni P. Kolopaking, MPPM; Prof. Karjadi Wirjoatmodjo, M.D.;

Prof. Djoko Roeshadi, M.D., Ph.D.; Prof. Eddy Suwandojo,

M.D.; Hari Parathon, M.D.; Usman Hadi, M.D.; Nun Zairina,

Hosp. Pharm.; Endang Isbandiati, M.D., Ph.D.; Kartuti Deborah,

M.D.; K. Kuntaman, M.D., Ph.D.; Ni Made Mertaniasih, M.D.,

Ph.D; Marijam Poerwanta, M.Sc.

Dr Kariadi Hospital—School of Medicine Diponegoro

University Semarang, Indonesia: Prof. Ariawan Soejoenoes,

M.D.; Budi Riyanto, M.D.; Hendro Wahjono, M.D., Ph.D.;

Musrichan Adhisaputro, M.D.; Bambang Triwara, Pharm.D.;

Johnny Syoeib, M.D.; Endang Sri Lestari, M.D.; Bambang

Wibowo, M.D.; Muchlis AU Sofro, M.D.; H. Farida, M.D.,

M.Sc.; M.M. Hapsari, M.D.; Tri Laksana Nugraha, M.D., M.Sc.

Leiden University Medical Centre, Leiden, The Netherlands:

Prof. P.J. van den Broek, M.D., Ph.D.; D.O. Duerink, M.D., M.A.

Erasmus University Medical Centre, Rotterdam, The

Netherlands: Prof. H.A. Verbrugh, M.D., Ph.D.; I.C. Gyssens,

M.D., Ph.D.

Radboud University Medical Centre, Nijmegen, The

Netherlands: M. Keuter, M.D., Ph.D.

Transparency declarations

None to declare.

Supplementary data

Tables S1, S2 and S3 are available as Supplementary data at

JAC Online (http://jac.oxfordjournals.org/).

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Full-text available

Jan 1999

Antimicrobial-resistant bacteria are known to be prevalent in tertiary-care hospitals in Korea. Twenty hospitals participated to this surveillance to determine the nationwide prevalence of resistance bacteria in 1997. Seven per cent and 26% of Escherichia coli and Klebsiella pneumoniae were resistant to 3rd-generation cephalosporin. Increased resistance rates, 19% of Acinetobacter baumannii to ampicillin/sulbactam, and 17% of Pseudomonas aeruginoa to imipenem, were noted. The resistance rate to fluoroquinolone rose to 24% in E. coli, 56% in A. baumannii and 42% in P. aeruginosa. Mean resistance rates were similar in all hospital groups: about 17% of P. aeruginosa to imipenem, 50% of Haemophilus influenzae to ampicillin, 70% of Staphylococcus aureus to methicillin, and 70% of pneumococci to penicillin. In conclusion, nosocomial pathogens and problem resistant organisms are prevalent in smaller hospitals too, indicating nosocomial spread is a significant cause of the increasing prevalence of resistant bacteria in Korea.

Bacterial resistance to antimicrobial agents: An overview from Korea

Article

Full-text available

Jan 1999

Antimicrobial resistance of bacteria has become a worldwide problem. Available data suggest that the resistance problem is comparatively more serious in Korea. In large hospitals, the proportion of methicillin-resistant Staphylococcus aureus (MRSA) has been reported at over 70%, and of penicillin-nonsusceptible Streptococcus pneumoniae at around 70%. Infection or colonization of vancomycin-resistant enterococci has started to increase. Extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae has become widespread and even carbapenem-resistant Pseudomonas aeruginosa has been increasing. Community-acquired pathogens such as Salmonella, Shigella and Neisseria gonorrhoeae are often resistant to various antimicrobial agents. The prevalence of resistant bacteria can lead to erroneous empirical selection of either noneffective or expensive drugs, prolonging hospitalization and higher mortality. The emergence and spread of resistant bacteria are unavoidable unless antimicrobial agents are not used at all. The high prevalence of resistant bacteria in Korea seems to be related to antibiotic usage: 1) easy availability without prescription at drug stores, 2) injudicious use in hospitals, and 3) uncontrolled use in agriculture, animal husbandry, and fisheries. Nosocomial infection is an important factor in the spread of resistant bacteria. Antimicrobial resistance problems should be regarded as the major public health concern in Korea. It is urgently required to ban the sale of antibiotics without prescription, to use antibiotics more judiciously in hospitals by intensive teaching of the principles of the use of antibiotics, and to establish better control measures of nosocomial infections. Regulation of antimicrobials for other than human use should also be required. These issues are not easy to address and require the collective action of governments, the pharmaceutical industry, health care providers, and consumers.

In vitro evaluation of cefepime and other broad-spectrum β-lactams against bacteria from Indonesian medical centers

Article

Dec 1999
DIAGN MICR INFEC DIS

The in vitro activity of cefepime and six other broad-spectrum β-lactams (cefpirome, ceftazidime, ceftriaxone, imipenem, piperacillin/tazobactam (4 μg/mL fixed concentration), and oxacillin was evaluated against 191 isolates of clinical bacteria from Indonesia. Susceptibility testing was performed using Etest (AB BIODISK, Solna, Sweden) methodology. Isolates from 10 species groups were selected for analysis: Escherichia coli, Klebsiella spp., Enterobacter spp., indole-positive Proteae, Serratia spp., Acinetobacter spp., Pseudomonas aeruginosa, and oxacillin-susceptible staphylococci. The overall rank order of spectrum of activity was (% resistant): imipenem (2.2%) > cefepime (7.3%) > piperacillin/tazobactam > cefpirome > ceftazidime > ceftriaxone (16.2%). The “fourth-generation” cephalosporins, cefepime and cefpirome, displayed greater activity compared with the “third-generation” cephalosporins, ceftazidime, and ceftriaxone, against the 60 E. coli and Klebsiella spp. (30 each) isolates. Phenotypic extended spectrum β-lactamase occurrence rates among the E. coli and Klebsiella spp. were 23.3 and 33.3%, respectively. Imipenem, cefepime, and cefpirome inhibited 95.7% of the 46 isolates of inducible Amp C cephalosporinase producing Enterobacteriaceae. The majority of the resistance observed to imipenem and cefepime among tested Indoneisian strains was attributable to the nonfermentative Gram-negative bacilli, P. aeruginosa and Acinetobacter spp. These results indicate the presence of β-lactam resistance in Indonesia and the need for continued antimicrobial surveillance in this nation and region of the world, preferably using accurate quantitative methods.

The Challenges of Emerging Infectious DiseasesDevelopment and Spread of Multiply-Resistant Bacterial Pathogens

Article

Jan 1996

THE LIST of emerging infectious diseases is an intriguing constellation of new entities (a previously unrecognized Hantavirus), recognized pathogens that have caused recent outbreaks of unprecedented size (Cryptosporidium in municipal water supplies), outbreaks that have culminated in a reassessment of the issue of food safety (Escherichia coli O157:H7), and traditional nosocomial and community-acquired infections that, due to their resistance to multiple antimicrobial agents, have suggested the possibility of a postantibiotic era.1,2Enterococcus faecium, Streptococcus pneumoniae, and Mycobacterium tuberculosis are just a few of the organisms that have become considerably more difficult to treat due to increasing drug resistance. Examples of the types of resistant bacteria that have emerged around the world are shown in Figure 1, while specific examples of emerging resistance problems in the United States are shown in Figure 2. Clearly, the emergence of resistant organisms has been a global phenomenon. A recent Institute of Medicine report

Changes in Intestinal Flora of Farm Personnel after Introduction of a Tetracycline-Supplemented Feed on a Farm

Article

Oct 1976

A prospective study was undertaken to determine whether feeding farm animals antibiotics in feed caused changes in the intestinal bacterial flora of farm dwellers and their neighbors. Chickens were fed tetracycline-supplemented feed (tet-feed), and, as expected, within one week their intestinal flora contained almost entirely tetracycline-resistant organisms. Increased numbers of resistant intestinal bacteria also appeared, but more slowly, in farm members, but not their neighbors. Within five and six months, 31.3 per cent of weekly fecal samples from farm dwellers contained greater than 80 per cent tetracycline-resistant bacteria as compared to 6.8 per cent of the samples from the neighbors (P less than 0.001). Seven of the 11 farm members, but only three of the 24 neighbors, had two or more fecal samples containing greater than 80 per cent tetracycline-resistant coliforms (P less than 0.01). These resistant bacteria contained transferable plasmids conferring multiple antibiotic resistances. Selective pressure by tet-feed for antibiotic-resistant bacteria in chickens extends to human beings in contact with chickens and the feed.

Trimethoprim Resistance Arising in Animal Bacteria and Transferring into Human Pathogens

Article

Apr 1993

Reasons for the Emergence of Antibiotic Resistance

Article

Feb 1996
AM J MED SCI

The ability of many different species of bacteria, including those that cause diseases in humans, to resist the inhibitory action of antimicrobial agents has become a global problem. Resistance continues to spread not only in nosocomial pathogens but in several key community-acquired organisms as well. Appropriate control measures for such resistant organisms depend in part on the pathways by which resistance has arisen. Unfortunately, these pathways differ greatly from organism to organism and setting to setting. In addition, although the epidemiology of resistant organisms sometimes is similar to that of susceptible organisms of the same kind, in some situations it may be quite different. In this article, the authors highlight some of the pathways leading to the development of resistance in bacteria, the importance of antimicrobial use, and the relevance of these mechanisms to measures for the control of resistant bacteria in hospital and community settings.

In vitro evaluation of cefepime and other broad-spectrum beta-lactams against bacteria from Indonesian medical centers. The Indonesia Antimicrobial Resistance Study Group

Article

Dec 1999
DIAGN MICR INFEC DIS

The in vitro activity of cefepime and six other broad-spectrum beta-lactams (cefpirome, ceftazidime, ceftriaxone, imipenem, piperacillin/tazobactam (4 micrograms/mL fixed concentration), and oxacillin was evaluated against 191 isolates of clinical bacteria from Indonesia. Susceptibility testing was performed using Etest (AB BIODISK, Solna, Sweden) methodology. Isolates from 10 species groups were selected for analysis: Escherichia coli, Klebsiella spp., Enterobacter spp., indole-positive Proteae, Serratia spp., Acinetobacter spp., Pseudomonas aeruginosa, and oxacillin-susceptible staphylococci. The overall rank order of spectrum of activity was (% resistant): imipenem (2.2%) > cefepime (7.3%) > piperacillin/tazobactam > cefpirome > ceftazidime > ceftriaxone (16.2%). The "fourth-generation" cephalosporins, cefepime and cefpirome, displayed greater activity compared with the "third-generation" cephalosporins, ceftazidime, and ceftriaxone, against the 60 E. coli and Klebsiella spp. (30 each) isolates. Phenotypic extended spectrum beta-lactamase occurrence rates among the E. coli and Klebsiella spp. were 23.3 and 33.3%, respectively. Imipenem, cefepime, and cefpirome inhibited 95.7% of the 46 isolates of inducible Amp C cephalosporinase producing Enterobacteriaceae. The majority of the resistance observed to imipenem and cefepime among tested Indoneisian strains was attributable to the nonfermentative Gram-negative bacilli, P. aeruginosa and Acinetobacter spp. These results indicate the presence of beta-lactam resistance in Indonesia and the need for continued antimicrobial surveillance in this nation and region of the world, preferably using accurate quantitative methods.