Carriage of antibiotic-resistant Enterobacteriaceae in hospitalised children in tertiary hospitals in Harare, Zimbabwe
Magwenzi et al. Antimicrobial Resistance and Infection Control
Carriage of antibiotic-resistant Enterobacteriaceae in hospitalised children in tertiary hospitals in Harare, Zimbabwe
Marcelyn T. Magwenzi 0
Muchaneta Gudza-Mugabe 2
Hilda A. Mujuru 1 6
Mutsa Dangarembizi-Bwakura 1 5
Valerie Robertson 0 4
Alexander M. Aiken 3 4
0 College of Health Sciences, Department of Medical Microbiology, University of Zimbabwe , PO Box A178, Harare , Zimbabwe
1 College of Health Sciences, Department of Paediatrics and Child Health, University of Zimbabwe , Harare , Zimbabwe
2 National Microbiology Reference Laboratory, Harare Central Hospital , Harare , Zimbabwe
3 London School of Hygiene and Tropical Medicine , London , UK
4 Biomedical Research and Training Institute , Harare , Zimbabwe
5 Parirenyatwa Group of Hospitals , Harare , Zimbabwe
6 Harare Central Hospital , Harare , Zimbabwe
Background: Extended-spectrum β-lactamase-producing and gentamicin resistant Enterobacteriaceae are increasingly recognised as a major cause of infection in low-income countries. We assessed the prevalence of gastrointestinal carriage of these bacteria in hospitalised children in Harare, Zimbabwe. Methods: We conducted a cohort study in paediatric inpatients at two tertiary-referral hospitals between May and July 2015. Rectal swabs and faecal samples were collected within 24 h of admission and further follow-up samples were collected on alternate days during hospitalization. Disc-based, selective and enrichment methods were used to detect carriage of these two forms of resistance. Standard methods were used to confirm resistance status and determine the susceptibility of resistant isolates to other commonly-used antibiotics. Results: One hundred and sixty four paediatric inpatient admissions (median age = 1.0 year, IQR = 0.2-2.2years) were enrolled, and an average of 1.9 faecal samples per patient were collected. On admission, 68/164 (41%) patients had both ESBL and gentamicin-resistant Enterobacteriaceae detected, 18 (11%) had ESBL only, 17 (10%) had gentamicin resistance only and 61 (37%) had negative screening for both forms of resistance. During hospitalisation, 32/164 (20%) patients were found to have a type of resistant organism which was not present in their admission sample. We found that faecal samples and use of a selective enrichment broth enhanced the detection of resistant organisms. Amongst resistant bacteria isolated, there were high levels of resistance to ciprofloxacin and chloramphenicol, but not ertapenem. Conclusions: More than half of children had enteric carriage of a clinically-relevant form of antibiotic resistance on admission to public-sector hospitals in urban Zimbabwe. Additionally, a fifth of children acquired a further form of resistance during hospitalisation. Urgent action is needed to tackle the spread of antibiotic resistant enteric bacteria in African hospitals.
Enterobacteriaceae; ESBL; Antibiotic resistance; Colonization; Children
Clinically significant levels of resistance to various
antibiotic classes have developed in most Gram-negative
bacteria, though there is marked geographic variation in
the prevalence of resistance . Historically, many forms
of antibiotic resistant organisms emerged in and were
disseminated from healthcare facilities in high-income
settings, but in more recent times, hospitals in low and
middle-income settings appear to have been the origin
and amplifiers of several forms of resistance [2–4]. Weak
antibiotic stewardship and limited infection control
resources promote the spread of antibiotic resistant
organisms in hospitals, especially where there are no
microbiological diagnostic services for the identification
of resistance .
In the family of Enterobacteriaceae, organisms such as
Escherichia coli and Klebsiella pneumoniae can produce
extended-spectrum β-lactamase (ESBL) enzymes, which
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confer resistance to third generation cephalosporins and
most penicillins but are inhibited by agents such as
clavulanate. These types of resistant bacteria are
increasingly implicated as causes of both community- and
hospital-acquired infections [6, 7] and are associated
with higher levels of mortality than non-ESBL producers
. Across sub-Saharan Africa, a limited number of
studies have described high levels of ESBL faecal carriage
in children in association with hospital facilities [9–13].
Gentamicin is an aminoglycoside antibiotic that has been
used for the treatment of Gram-negative infections for
more than 40 years . Its low-cost and broad spectrum
of activity means that it is widely used for treatment of
severe infections in many low-income countries.
The gastrointestinal tract is the principal ecological
niche for Enterobacteriaceae. In this environment,
interand intra-species exchange of resistance genes can occur
and under appropriate selective pressure, resistant
species can rapidly emerge and dominate . While faecal
carriage of antibiotic resistant bacteria is not an
immediate threat to a healthy individual, it poses two risks—
firstly, when auto-infection of a sterile body-site
subsequently occurs (for example, hospital-acquired bacteraemia
) treatment is substantially more difficult and secondly,
there may be transmission of the resistant organism to
other individuals .
In order to describe levels of carriage of Gram-negative
antibiotic resistance amongst hospitalised children in
Zimbabwe, we aimed to measure 1) the prevalence of
carriage of ESBL producing and gentamicin-resistant enteric
bacteria in paediatric patients at the time of
admission to hospital and 2) the risk of acquisition for the
same types of bacteria during the corresponding time
of hospitalization. We also sought to evaluate
different methods for screening for the presence of these
This was a prospective observational cohort study
conducted in paediatric wards at two tertiary government
hospitals in Harare, Zimbabwe between May and July
2015. Paediatric patients were recruited within 24 h of
admission to hospital and remained in the study until
discharge from hospital or death. All paediatric patients
were eligible for inclusion in the study regardless of their
presenting illness, provided that they remained in
hospital for at least one night. These hospitals had
paediatric wards divided into cubicles of 6 to 8 beds and limited
isolation rooms. Each cubicle or room had a single
hand-wash basin; alcohol-based hand sanitizers were not
consistently available. There was no established practice
of screening for carriage of resistant organisms in these
wards at the time of this study.
Screening for ESBL and gentamicin resistance
Two rectal swabs and/or a stool sample were collected
within 24 h of admission. Further similar samples were
collected three times per week for all participants. The
swabs and stool samples were directly inoculated onto a
range of screening plates in the Department of Medical
Microbiology laboratory, University of Zimbabwe, as
1) MacConkey agar without salt (Oxoid, UK) plates
with either a Cefpodoxime (10 μg) or a Gentamicin
(10 μg) disc placed on the plate. The plates were
incubated at 37 °C for 24 h. Growth within 5mm of
the margin of the disc was considered potentially
2) Selective ChromID ESBL-agar (Biomerieux, France)
and Gentamicin-MacConkey plates. The latter was
prepared in-house by adding 800 μl Gentamicin
10 mg/ml (Gibco, UK) in 1 L of MacConkey agar
without salt. Any growth on these plates was
considered potentially significant.
3) Samples were selectively enriched overnight in 5 ml
nutrient broth with either a Cefpodoxime (10 μg) or
a Gentamicin (10 μg) disc added to the bijou bottle.
These enriched samples were sub-cultured the
following day and then handled in the same way as
the direct methods above.
Where results were discordant between different
sample types from the same patient using the screening
methods, any detection of a resistant organism was
considered to be the correct identification. A single colony
of each distinguishable type (up to three per sample)
was picked from a resistance screening plate, grown on a
purity plate and subsequently tested as described below.
Identification of isolates
Bacterial isolates expressing either ESBL or Gentamicin
resistance or both were obtained. An oxidase test was
performed (Remel Bactidrop, UK) for all isolates.
Oxidasenegative isolates were identified to the family/genus level
using API10S kits (Biomerieux, France) according to the
manufacturer’s instructions; this system does not
consistently provide identification to the species level. The ESBL
phenotype was confirmed by paired disc tests 
according to the manufacturer’s instructions (Mast Diagnostics,
UK). Where a sample had no isolates confirmed as ESBL
producers by paired disc testing, we considered the
sample to be negative for that type of resistance throughout
Antimicrobial susceptibility testing
Overnight pure cultures confirmed to be ESBL positive
or gentamicin resistant had further susceptibility testing
performed using the standard disc diffusion method
based on Clinical Laboratory Standards Institute (CLSI)
breakpoints for susceptibility testing. The antibiotics
tested were gentamicin (10 μg), chloramphenicol (30 μg),
ciprofloxacin (1 μg), ertapenem (10 μg), cefpodoxime
(10 μg) and ampicillin (10 μg) (Oxoid, England).
Reference strains E. coli ATCC25922 (fully susceptible)
and E. coli NCTC13353 (ESBL CTX-M type and
gentamicin resistant) were used as control organisms. Data were
recorded in a Microsoft Access database and STATA v13
was used to calculate prevalence and acquisition rates of
resistance carriage and perform tests of association.
A total of 164 paediatric inpatients were recruited to the
study out of a total of 1757 paediatric admissions to
these two hospitals in the study period. Most patients
(142/164, 87%) were recruited on the day following their
admission to hospital (hence after spending one night in
hospital), but all within 24 h of their admission. A
summary of these patients is shown in Table 1. The median
age was 1.0 years (IQR 0.2 to 2.2 years). The most
commonly recorded admission diagnoses were “severe
pneumonia”, “sepsis” and “severe malnutrition”. The average
duration of hospitalization was 5.6 days (IQR 2–7.5 days;
Table 1 Summary of study admissions
Number (n =164)
Harare Childrens Hospital, ward B1
Harare Childrens Hospital, ward B2
Parirenyatwa Hospital, admission unit
Parirenyatwa Hospital, ward A4 General
Parirenyatwa Hospital, ward A4 Special
Parirenyatwa Hospital, ward A5
Enteric carriage of resistance on admission
Both ESBL and gentamicin resistance
Gentamicin resistance only
Neither form of resistance
Outcome of admission
range 1–32 days) and the inpatient mortality was 8%
(13 deaths/164 admissions).
Carriage of antibiotic resistance on admission
The prevalence of ESBL carriage was 52% (86/164) and
gentamicin resistance carriage was 52% (85/164), on the
initial sample taken from patients, with 41% of all patients
having both forms of resistance. On admission, ESBL
carriage was higher amongst children in the age groups 29
days-1 year (39/63; 62%) and 1–5 years (37/64; 58%) and
lower in the younger (0–28days (7/19; 37%)) and older
(5+ years (3/18; 18%) age groups; (Fishers exact test
across these categories p = 0.001). We found no difference
in carriage rates by age group for gentamicin resistance on
admission to hospital. Only 37% of children had neither
form of resistance detectable—see Table 1. There was no
association between hospital of admission and prevalence
of carriage of ESBL (χ2-test p = 0.23) or gentamicin
resistance (p = 0.32). Death as an inpatient was associated with
ESBL carriage on admission (Fisher’s exact test p = 0.02)
but not with gentamicin resistance (p = 0.25).
Acquisition of carriage during admission
An average of 1.9 samples were obtained per patient
(range = 1 to 8) with 91 patients having two or more
samples collected. A total of 32 admissions were
detected to have a new form of resistance during their
hospital admission: 17 gained both ESBL and
gentamicinresistance, 12 gained ESBL only and 3 gained gentamicin
resistance only (see Table 2). There was no association
between hospital and acquisition of resistance during
admission for either ESBL (χ2-test p = 0.40) or gentamicin
resistance (χ2-test p = 0.40). The probability of any sample
containing a resistant organism was closely related to the
time since admission to hospital—see Fig. 1. After a
patient had been hospitalised for five or more days, there
was over 90% probability (86/93 samples) that carriage of
both ESBL and gentamicin-resistant organisms would be
detected in a faecal specimen.
Screening methods for detection of resistant organisms
A total of 312 samples were collected, of these 143 were
rectal swabs only, 23 were faecal samples only and 146
had both types of specimen. In the samples with both
rectal swabs and faecal samples, the sensitivity of the
Table 2 Summary of ESBL or Gentamicin resistance acquisition
status during admissions
>1 faecal sample taken during hospital admission
New detection of ESBL during admission
New detection of gentamicin resistance during admission 20/164 (12%)
New detection of either form of resistance
New detection of both forms of resistance
Fig. 1 Probability of detection v time-to-sample
different detection techniques is shown in Table 3.
Broadly speaking, we found that higher sensitivity was
achieved with faecal samples and inclusion of the
enrichment broth step. Use of selective media did not achieve
substantially higher sensitivity, but was noted to be
practically easier to use in the laboratory. Out of the
oxidasenegative Gram-negative isolates detected by the ESBL
screening methods and confirmed as Enterobacteriaceae,
the large majority (190/214; 89%) were confirmed as ESBL
by both disc pairs (cefotaxime/clavulanate pair and
ceftazidime/clavulanate pair) and some were confirmed by only
a single pair of ceftazidime/clavulanate (16/214; 7.5%). A
small number of isolates were not confirmed as
ESBLproducers by either disc pair (8/214; 4%).
Antibiotic resistance profiles
Amongst the isolated Enterobacteriaceae that were
confirmed ESBL (n = 206) or gentamicin resistant (n = 146),
we examined the co-resistance to other commonly used
antibiotics—see Tables 4 and 5. We found high levels of
co-resistance to ampicillin, ciprofloxacin and
chloramphenicol, but virtually no co-resistance to ertapenem.
Our study investigated enteric carriage of
ESBLproducing and gentamicin resistant enteric bacteria in a
sample of 164 hospitalised children drawn from two
tertiary public-sector hospitals in Harare, Zimbabwe
over a 3 month period. The main findings were high
rates of carriage of ESBL and gentamicin resistant
bacteria on admission to hospital and high rates of
acquisition for the same resistance types during the
An initial sample was collected within 24 h of hospital
admission for each patient, so these samples are likely to
represent the carriage status prior to the current hospital
admission. Other studies of ESBL prevalence around the
time of admission to hospital have found carriage rates
of 33% (133/408) in Guinea Bissau , 34% (37/110) in
Gabon  and 22% (54/244) in Madagascar .
Amongst neonates in Tanzania, 25% (32/126) were
found to have ESBL carriage, predominantly Klebsiella
pneumoniae . In a study conducted in a renutrition
centre in Niger , ESBL carriage was 31% (17/55
patients) on admission and by time of discharge a further
15/16 children had acquired carriage. Our study, showed
a higher prevalence of carriage than those previously
described levels, though our methods of screening were
probably more sensitive than the direct plating of rectal
swabs used elsewhere. We are not aware of any previous
African studies specifically investigating carriage of
gentamicin resistance in hospitalised children. Carriage of
resistance amongst hospital admissions is liable to be
higher than carriage in the general community, as sick
individuals probably have exposure to various
healthcarerelated risk factors prior to admission, so we cannot
compare these results to truly community-based studies.
However, the extremely high levels of carriage rates found
suggest that circulation of ESBL and gentamicin resistance
probably occurs in the community in Harare. Although
we found an association between ESBL carriage and
inpatient death, we were not able to assess for the
confounding effects and hence it remains uncertain whether
this is a causal association.
Collection of multiple follow-up samples during the
inpatient period allowed us to observe acquisition of
carriage of resistance over time. An important question is
whether these in-hospital acquisitions are occurring via
endogenous (arising from undetectably low levels already
present in the gastrointestinal tract) or exogenous (arising
THEN plate with disc
THEN selective plate
Table 4 Susceptibility profiles of confirmed ESBL-producing
from cross-infection from an external source) routes. This
distinction has important implications for antibiotic
stewardship and infection control measures. For endogenous
routes of acquisition, antibiotic stewardship activities
focussing on reducing the selective pressure from antibiotic
prescribing are important. For exogenous acquisition,
measures to minimise cross-infection, such as improved
hand hygiene, are priorities. Whilst we cannot be certain,
we feel that both routes are likely to be contributing to the
high levels of nosocomial acquisition seen here. Our
screening methods included an enrichment step so that
we should have been able to detect small quantities of
resistant bacteria, making endogenous acquisition less likely,
though a single faecal specimen is not a representative
sample of the estimated 1014 cells in the intestinal
microbiome. Enrichment broths with supplementary antibiotics
have been used elsewhere to aid detection of resistant
organisms in faecal samples . Our clinical experience in
these hospitals suggests there are substantial challenges
with over-crowding, limited access to hand-hygiene
facilities and high patient:staff ratios. With regard to
handhygiene, at the time the study was conducted, water
supplies in these wards were sporadic and alcohol-based hand
rub (ABHR) was not widely available. Concurrent work
conducted in the same wards as a separate part of this pilot
study showed that hands of adult carers were frequently
contaminated with Gram-negative antibiotic resistant
bacteria . These are all factors that might be expected to
contribute to exogenous routes of transmission.
In line with findings from other studies, we found that
most ESBL-producing bacteria from these children were
also resistant to several other clinically-relevant antibiotic
classes [9–13]. This represents a substantial clinical
challenge for empirical treatment of suspected
hospitalacquired infections—ciprofloxacin (for severe urinary
sepsis) and chloramphenicol (for bacteraemia and
meningitis) represent important and widely used second-line
treatment options in many African hospitals. The level of
carbapenem resistance amongst resistant isolates was very
low, but as these agents are not currently routinely
available through public-sector pharmacies in Zimbabwe,
this information is of limited practical value for local
Due to rapid turnover of patients, we were only able
to collect follow-up samples in a moderate number of
patients; 73 patients had only a single sample collected.
Whilst this does not affect estimates for the time of
admission, it limits the ability of the study to detect new
acquisition of carriage—in reality, probably even more
children became carriers of resistance during admission
than we detected. Ideally, an additional sample on the
day of discharge would have been collected for all
patients. Our simple screening and identification methods
meant that we could not distinguish the simultaneous
carriage of multiple different resistant organisms. Again,
this means that the acquisition risk described here may
underestimate the true in-hospital acquisition risk. We
did not make use of molecular techniques for
identification of resistance mechanisms or for investigating
transmission of resistance. In this preliminary study, we were
not able to evaluate clinical impacts of antibiotic
resistance, either during hospital inpatient stay or after
discharge. Whilst we did find some evidence that carriage
of ESBL resistance was associated with inpatient
mortality, investigating whether carriage of resistance was
followed by clinical infection with the same organisms
was beyond the scope of the study.
Future research is needed to better understand and
tackle these high levels of antibiotic resistance. This will
take many forms. We did not collect information on risk
factors associated with carriage of resistance—this would
be a valuable first step in understanding why this is
occurring. In other settings, prior use of antibiotics and
recent hospital admission have been associated with
carriage of resistance —we do not know if this is the
case in Zimbabwe. More work is needed to identify the
enzyme types and genes responsible for the forms of
resistance that we detected—this will enable us to start to
understand the dynamics of resistance transmission.
Screening for drug-resistance on admission and
cohorting or isolating patients can result in improved patient
outcomes —but no modelling work has ever been
conducted to explore the value of this in the setting of
African hospitals. We do not know how the acquisition
of antibiotic resistance in hospitals relates to resistance
in the community in Zimbabwe , nor do we know
the wider impact of antibiotic resistance in terms of
mortality, morbidity and costs in sub-Saharan African
countries, though we suspect these to be substantial .
Given that many African hospitals have limited access to
carbapenems, infections caused by ESBL-producers might
have a substantially greater impact than has been seen in
high-income settings .
At a more practical level, immediate action can be taken
in a number of areas such as improving infection control
practices, especially hand hygiene, which has been shown
to reduce infections caused by antibiotic-resistant
Gramnegative bacteria in high-income settings . The use of
alcohol-based hand rub as part of the WHO 5 moments
for hand hygiene approach is a low-cost technology that
could be much more widely adopted in African hospitals.
Ideally, a rigorous evaluation of the implementation of
such new practices would contribute to the evidence-base
for these measures in low-income settings, which is
currently extremely limited .
The rising level of antimicrobial resistance is of great
concern worldwide. These high rates of ESBL and gentamicin
resistance carriage found amongst paediatric inpatients in
Zimbabwe are particularly worrisome. These bacteria pose
risks of multi-drug resistant infections and transmission to
other hospital inpatients. The high levels of carriage at the
time of hospital admissions suggest that they are already in
widespread circulation in the general community. Relevant
infection control measures such as access to alcohol-based
hand rub should be urgently scaled up in these hospitals
and beyond, so that children who arrive at hospital without
carriage of antibiotic resistant bacteria can remain free of
these for the duration of their admissions.
ABHR: Alcohol-based hand rub; CLSI: Clinical Laboratory Standards Institute;
ESBL: Extended- spectrum β-lactamase; IQR: Inter-quartile range
We are grateful to the study nurses Dorah Kaisi and Phillipa Dingiswayo from
the Department of Paediatrics and Child Health UZ for their diligent work on
recruitment of patients and collection of samples. We would like to thank
patients, parents and staff in the participating wards for their assistance with
this work. We thank staff in the Department of Medical Microbiology,
University of Zimbabwe and the Biomedical Research and Training Institute
for their support.
This work was funded by an Academy of Medical Sciences Starter Grant for
Clinical Lecturers (AA, grant reference AMS-SGCL11-AikenA). This work
formed part of a pilot study ahead of a cluster-randomised trial of a
hand-hygiene intervention in hospitals in sub-Saharan Africa.
Availability of data and materials
The dataset and files showing the calculations in the papers are available
from the following link. https://dl.dropboxusercontent.com/u/69222597/
Conceived and designed the experiments: MM, MGM, HAM, MBD, VR, AA.
Performed the experiments: MM MGM. Analysed the data: MM AA. Contributed
reagents/materials/analysis tools: VR AA. Wrote the manuscript: MM AA.
All authors read and approved the manuscript.
Consent for publication
Not applicable—the manuscript does not include details, images, or videos
relating to individual participants but rather presents analysis of aggregated
data on the study population.
Ethics approval and consent to participate
The Institutional Review Boards of both hospitals, the Medical Research
Council of Zimbabwe and the London School of Hygiene and Tropical
Medicine approved the study. Parents or guardians of all participants gave
written informed consent to participate in the study.
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