High rates of multidrug resistance among uropathogenic Escherichia coli in children and analyses of ESBL producers from Nepal
Parajuli et al. Antimicrobial Resistance and Infection Control
High rates of multidrug resistance among uropathogenic Escherichia coli in children and analyses of ESBL producers from Nepal
Narayan Prasad Parajuli 0 1
Pooja Maharjan 1
Hridaya Parajuli 1
Govardhan Joshi 1
Deliya Paudel 1
Sujan Sayami 2
Puspa Raj Khanal 0
0 Department of Laboratory Medicine, Manmohan Memorial Institute of Health Sciences , Kathmandu , Nepal
1 Department of Clinical Laboratory Services, Manmohan Memorial Medical College and Teaching Hospital , P.O.B.: 15201Swayambhu, Kathmandu , Nepal
2 Department of Pediatrics, Manmohan Memorial Medical College and Teaching Hospital , Kathmandu , Nepal
Background: Emergence of Extended-spectrum beta-lactamase producing Escherichia coli causing urinary tract infections (UTI) among pediatric patients is an increasing problem worldwide. However, very little is known about pediatric urinary tract infections and antimicrobial resistance trend from Nepal. This study was conducted to assess the current antibiotic resistance rate and ESBL production among uropathogenic Escherichia coli in pediatric patients of a tertiary care teaching hospital of Nepal. Methods: A total of 5,484 urinary tract specimens from children suspected with UTI attending a teaching hospital of Nepal over a period of one year were processed for the isolation of bacterial pathogens and their antimicrobial susceptibility testing. Escherichia coli (n = 739), the predominant isolate in pediatric UTI, was further selected for the detection of ESBL-production by phenotypic combination disk diffusion test. Results: Incidence of urinary tract infection among pediatric patients was found to be 19.68% and E coli (68.4%) was leading pathogen involved. Out of 739 E coli isolates, 64.9% were multidrug resistant (MDR) and 5% were extensively drug resistant (XDR). Extended spectrum beta lactamase (ESBL) was detected in 288 (38.9%) of the E coli isolates. Conclusion: Alarming rate of drug resistance among pediatric uropathogens and high rate of ESBL-producing E. coli was observed. It is extremely necessary to routinely investigate the drug resistance among all isolates and formulate strict antibiotics prescription policy in our country.
Urinary tract infection; Children; E coli; ESBL; Nepal
Urinary tract infection (UTI) is among the most common
causes of febrile illness in children requiring antimicrobial
treatment . Worldwide, an estimated 8% of girls and 2%
of boys experience at least one episode of UTI by the age
of seven years and recurrence occurs in 12-30% of them
within a year . Pediatric UTI in many instances, remain
under-diagnosed because of the absence of specific
symptoms and signs, particularly in infants and young children
[2, 3]. Therefore, accurate diagnosis and appropriate use
of antimicrobials for treatment and prevention of urinary
tract infections (UTIs) is vital to reduce the burden and
also to prevent the possible long-term consequences .
Escherichia coli have been recognised as the most
common pathogen accounting for majority of urinary tract
infections in children . Antimicrobial therapy, usually of
traditional antibiotics, is commonly prescribed to treat
urinary tract infections in pediatric patients. However,
increased rates acquired resistance in E. coli has made usual
antibiotics less acceptable choice for empirical therapy in
recent years . The most common mechanism
associated with acquired resistance in E. coli and other
Enterobacteriaceae is the production of hydrolytic
enzymes called β-lactamases [6, 7]. Extended-spectrum
β-lactamase (ESBL), a major beta lactamase enzyme,
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has the ability to hydrolyze oxyimino-cephalosporins,
and monobactams but not cephamycins or carbapenems
and inhibited in-vitro by inhibitors such as clavulanic acid,
sulbactam and tazobactam . Since their evolution in
1983, more than 300 types of ESBLs have been identified in
various members of the family Enterobacteriaceae and
other non-enteric organisms [3, 6]. The infections
associated with these ESBL producing isolates are difficult to treat
because of their resistance towards beta lactam agents and
also due to the emergence of co-existing resistance
determinants such as aminoglycosides and fluoroquinolones .
Moreover, emergence of ESBL producing bacteria,
particularly E. coli and K. pneumoniae causing pediatric urinary
tract infections is a worldwide concern . Options for the
treatment of such multidrug resistant (MDR) gram negative
bacterial infections are generally limited, and very few
antibiotics are approved for use in children .
In Nepal, pediatric UTIs are usually treated empirically
because of the unavailability of standard therapeutic
guidelines and local susceptibility data [11, 12]. Knowledge of
the etiological agent of UTIs and their antimicrobial
resistance patterns in our setting may help clinicians in choosing
the appropriate antimicrobial treatment. Moreover, most
of the studies on pediatric urinary tract infections caused
by multidrug resistant and ESBL producing bacteria have
been reported from western world [10, 13], but the same
from South Asian region including Nepal are scarce on the
published literature . In this perspective, the present
study was designed to investigate the clinical isolates of
multi-drug resistant and ESBL producing Escherichia coli
causing urinary tract infections in children visiting a
tertiary care teaching hospital in Nepal.
Study design and setup
A cross-sectional study was carried out for 1 year (June
2015 - May 2016) in the department of Microbiology
and Pediatric Medicine, Manmohan Memorial Medical
College and Teaching Hospital (MMCTH), a tertiary
care hospital with 500 patient beds in Kathmandu, the
capital city of Nepal. Study hospital is a referral center
with medical, surgical, gynecological, pediatric, geriatric
and other specialties.
Inclusion and exclusion criteria
During the study period, children up to 14 years of age
presented to the pediatric outpatient department or admitted
to pediatric inpatient ward with a clinical diagnosis of UTI
were included. The clinical diagnosis of UTI was made by
respective unit pediatrician in the presence of fever and/or
any of the symptoms such painful micturition, increased
frequency, burning micturition, or suprapubic pain/flank
pain. Those children who had previous known history of
antimicrobial therapy within 48 h prior to attending the
hospital and samples which grew more than one type of
organism was considered as contaminated and hence,
excluded from the study.
A total of 5,484 non-repetitive urine specimens
(Midstream, Suprapubic, Catheter aspirated and Clean catch)
representing urinary tract infections in pediatric patients
(0-14 years) were processed semi-quantitatively by
inoculating 0.001 ml of the specimen (by using a calibrated wire
loop) onto the cystine lactose electrolyte deficient (CLED)
agar for the isolation and identification of significant
uropathogens . The inoculated plates were incubated
for 24 h at 37 °C in aerobic atmosphere. Growth of a single
organism with a count of ≥105colony-forming units
(CFU)/ml were considered to represent the infection and
were identified using appropriate routine identification
methods including colony morphology, Gram-stain, and
an in-house set of biochemical tests . Escherichia coli,
the predominant uropathogen, was selected for the
determination of antimicrobial susceptibility as well as
identification of the multidrug resistant (MDR), extensively drug
resistant (XDR) and extended spectrum beta lactamase
(ESBL) producing isolates.
Antimicrobial susceptibility testing
The susceptibility of bacterial isolates against different
antibiotics was tested by the disk diffusion method [modified
Kirby-Bauer method] on Mueller Hinton agar (Hi-Media,
India) following standard procedures recommended by
the Clinical and Laboratory Standards Institute (CLSI),
Wayne, USA . Antibiotics that were tested in our
study include Ampicillin (AMP 25 μg), Amoxycillin
clavulanate (AMC20/10 μg), Aztreonam (30 μg) Gentamycin
(GEN10μg), Ciprofloxacin (CIP5μg), Levofloxacin (LEV5μg)
trimethoprim sulfamethoxazole/cotrimoxazole (COT30μg),
Cephalexin (CN30 μg), Cefixime (CFM5μg), Ceftriaxone
(CTR30μg), Ceftazidime (CAZ30μg), Piperacillin
tazobactam (PIT 100/10 μg), Imipenem (IMP 10 μg), Meropenem
(MRP 10 μg) Tigecycline (TGC30μg), and Colistin sulphate
(CT10μg) (HiMedia Laboratories, India). Interpretations of
antibiotic susceptibility results were made according to the
zone size interpretative standards of CLSI . Escherichia
coli ATCC 25922 was used as a control organism for
antibiotic susceptibility testing.
Identification of Multidrug Resistant (MDR), Extensive
Drug Resistant (XDR) and potential ESBL Escherichia coli
MDR and XDR isolates were identified according to the
combined guidelines of the European Centre for Disease
Prevention and Control (ECDC) and the Centers for
Disease Control and Prevention (CDC) . In this
study, the isolate resistant to at least one antimicrobial
from three different group of first line drugs tested was
regarded as multidrug resistant (MDR). Extensively drug
resistant (XDR) isolates were identified when the isolates
are resistant to at least one agent in all but two or fewer
antimicrobial categories (i.e., bacterial isolates remain
susceptible to only one or two categories).
Isolates of E. coli were examined for their susceptibility
to third generation cephalosporins by using Ceftazidime
(30 μg) and Cefotaxime (30 μg) disks. If the zone of
inhibition (ZOI) was ≤25 mm for Ceftriaxone, ≤22 mm for
Ceftazidime and/or ≤27 mm for Cefotaxime, the isolate was
considered a potential ESBL producer as recommended
by CLSI and further tested by confirmatory methods .
Confirmatory test of ESBL
Isolates considered potential ESBL producers by initial
screening were emulsified with nutrient broth to adjust the
inoculum density equal to that of 0.5 Mac Farland turbidity
standards. Combination Disk test (CDT), as recommended
by the CLSI, was performed in all isolates presumed to be
ESBL producers. In this test, Ceftazidime (30 μg) disks
alone and in combination with clavulanic acid (Ceftazidime
+ clavulanic Acid, 30/10 μg) disks, were applied onto a
plate of Mueller Hinton Agar (MHA) which was inoculated
with the test strain and then incubated in ambient air for
16-18 h of incubation at 35 ± 2 °C. Isolate that showed
increase of ≥ 5 mm in the zone of inhibition of the
combination discs in comparison to that of the Ceftazidime disk
alone was considered an ESBL producer .
The information regarding patient’s profile and the
results were entered into a computer program. Data
analysis was carried out using the Statistical Package for
Social Sciences [SPSSTM] version 20.0 [IBM, Armonk,
NY, USA] and presented in percentage base distribution.
Data with p value of less than 0.05 (CI-95%) was
regarded as significant.
Written approval was taken from Institutional Review
Committee of Manmohan Memorial Institute of Health
Sciences (MMIHS) after submitting and presenting
research proposal. Written informed consent was taken
Cc Contingency coefficient
During the study period, a total of 5,484 representative
specimens of urinary tract from pediatric patients
suspected with urinary tract infections were processed.
Among total clinical specimens, 1079 (19.68%) were found
with growth of at least one significant pathogen confirming
urinary tract infection (UTI). Female (659, 61.0%) were
most affected group of patients in both inpatient and
outpatient department (p < 0.005). Maximum number of cases
was found in the children of age group 1 to 4 years
(Table 1). Escherichia coli (n =739, 68.5%) was the most
common organism isolated from urinary tract infections in
pediatric group in this study.
Antimicrobial resistance pattern of E. coli
High level of drug resistance was noted in E. coli isolates.
Among 739 E. coli isolated, highest resistance (87% each)
were to ampicillin and cephalexin, followed by ciprofloxacin
(78%), cefixime (71%) and levofloxacin (67%) respectively.
Very few isolates (5%) were resistant to imipenem whereas
entire strains revealed high susceptibility (100% each)
towards colistin and tigecycline (Table 2).
Multidrug resistant (MDR) and Extensive drug resistant
Among total 739 E. coli isolates subjected for
antimicrobial susceptibility testing, 480 (64.9%) isolates
were found multidrug resistant (MDR) and 37 (5.0%)
isolates were extensive drug resistant (XDR). MDR
isolates were resistant to ampicillin (100%),
amoxicillin clavulanate (84.7%), cephalexin (81.6%) and
ciprofloxacin (80.6%) respectively. However, MDR isolates
were susceptible towards amikacin (87%), imipenem
(92%) and piperacillin tazobactam (81%). Although
the number of XDR isolates was low, they were
completely resistant to all antibiotics except colistin and
tigecycline (Table 2).
Table 2 Antibiotic susceptibility of MDR, XDR and ESBL E coli isolates
No. of resistant isolates (%)
MDR (n = 480)%
XDR (n = 37)%
ESBL (n = 288)%
ESBL E coli and their susceptibility pattern
Extended spectrum beta lactamase (ESBL) enzyme was
detected in 288(38.9%) E. coli isolates. Penicillins,
cephalosporins and monobactam group of antibiotics were
appeared completely ineffective (100% resistance)
against ESBL producers. However, ESBL producing E
coli strains were susceptible to reserve class of
antibiotics including imipenem (90%), colistin (100%) and
tigecycline (100%) (Table 2).
To the best of our knowledge, this report represents the
first description of ESBL producing uropathogenic E. coli
involved in pediatric cases of urinary tract infections
from our country, Nepal. Urinary tract infections are the
most common infections in children and E. coli being
leading pathogenic agent in these infections; it was our
matter of interest. There was no previous report before
this study to estimate the most common pathogen and
its resistant pattern in pediatrics patients with urinary
tract infection in our hospital.
The incidence of urinary tract infection based on
significant bacterial growth among pediatric patients in this
study was 19.6% and E. coli (68.5%) was the predominant
pathogen. Similar rates have been previously reported
from nearby hospitals [11, 12] and from studies of other
countries [18–22]. Concurrently, significantly more
females (61.0%) were found with UTI corroborating with
other similar studies [12, 19, 20]. In our study, children of
age group 1-4 years were found with highest number of
UTI cases (contingency coefficient 0.104). Similar study
from nearby hospital also reported that children less than
six years of age were found UTI prone . Urinary tract
infection was significantly more prevalent in the female
children of age group 1-4 and 5-9 years and also, more
inpatients were found with UTI (p < 0.05). The higher
rates of UTI in this age group might be due to immune
status, sanitation, and ascending infection with fecal flora.
The high prevalence of ESBL-producing uropathogenic
E. coli (38.9%) among children is reported in this study.
In addition, this study also documents the enhanced
resistance of ESBL producing E. coli to other antimicrobial
groups like aminoglycosides and fluoroquinolones. Indeed,
variations in the prevalence rates of ESBL-producing E.
coli isolates in children around the globe and even among
different hospitals within a country have been reported.
Our prevalence rate of ESBL producing E coli (38.9%) is
close to the findings reported by other studies in different
parts of Asian region including Shettigar et al. (37.7%)
from India , Pourakbari et al. (37%) and Rezai et al.
(30.5%) from Iran [21, 23], Moore et al. (44%) from
Cambodia  and Kizilca et al. (41.4%) from Turkey .
Extremely higher rates of ESBL E coli have also been
reported, notably by Chinnasami et al. (83%) from India
, Masud et al. (53.8%) from Bangladesh  and Shah
et al. (50.9%) from Pakistan . The increased rate of
ESBL-producing bacteria causing infection in community
as well as hospital settings constitutes an undeniable
trend. Worldwide, pediatric UTIs due to ESBL-producing
bacteria are an important part of this problem because
they limit therapeutic choices and increases morbidity of
infection . However, lower rates of ESBL-producing E.
coli were also reported, particularly from developed
countries including 9.3% from USA , 10.2% from Korea
, 14% from Taiwan , 14.1% from Lebanon  and
20.2% from Turkey . These variations in the rate of
ESBL producing strains of E coli among UTI cases might
be attributable to the geographical difference, local
antibiotic prescribing policy, the extensive use of broad
spectrum antibiotics especially third generation
cephalosporins and endemicity of drug resistance pathogens in
ESBL producing bacteria causing infections in children
may have various complications and adverse outcomes .
ESBL producers are non susceptible to aminopenicillins and
ureidopenicillins as well as extended-spectrum β-lactam
agents like second- and third-generation cephalosporins.
Use of these agents as the first choice for the treatment of
urinary tract infections may lead to the inappropriate
treatment and predispose to long term renal complications .
Therefore, antimicrobial therapy in infections with ESBL
producing organism is really challenging. Published reports
showed that ESBL- producing strains causing UTI in
children associated with prior hospitalization, beta-lactam
therapy, catheterization, underlying co-morbidity and
In this study, multidrug resistant (MDR) and extensively
drug resistant E coli were found 64.9% and 5.0%
respectively. Increasing pattern of resistance of urinary tract
pathogens against common antibiotics in Nepal have also been
reported by other researchers [12, 31] but MDR rates and
drug resistance pattern among pediatric isolates from Nepal
was not available. It is observed that ampicillin, cephalexin,
ciprofloxacin and cefixime were poorly effective against
uropathogenic E coli. Only 13% of the isolates were found
susceptible to all the antibiotics tested. Cephalosporin, the
commonly prescribed antibiotic as empirical therapy in
pediatric and adults, resistance to this group of antibiotics
was found high. Almost 45% of E coli isolates were resistant
to at least one cephalosporin and monobactam. Similar rates
of antimicrobial resistance was documented in the study
from Bangladesh , Iran  and India . However,
compared to previous reports from Nepal, we observed a
considerable increase in resistance against penicillins,
aminoglycosides, quinolones and ceftriaxone [12, 31]. Lower
rates of resistance among the pediatric isolates causing UTI
have been documented in western countries .
Higher resistance to penicillins third generation
cephalosporins in this study has been attributable to ESBL
production among gram negative isolates. In ESBL producing
isolates, augumentins (combined with beta lactamase
inhibitor) such as amoxicillin clavulanate or piperacillin
tazobactam can be used as alternative antimicrobials .
However, in this study, alarming state of resistance was
observed among ESBL producers towards amoxicillin
clavulanate (100%) and piperacillin tazobactam (27%). In
the case when UTI is caused by an ESBL producing
bacteria in children, the broadest-spectrum antibiotic
agents such as carbapenems are recommended  but
they are only useful in hospitalized patients. In this
study, too, carbapenems were found effective to the
ESBL isolates. Nevertheless, for pediatric UTIs in our
setting, cotrimoxazole, amoxicillin clavulanate,
ciprofloxacin and amikacin can still be used as first line
therapy. Furthermore, other non carbapenem groups of
antibiotics in UTIs due to ESBL-producing strains have
also been described [36, 37]. ESBL stable cephamycins,
fosfomycin and nitrofurantoin were shown effective for
UTIs caused by ESBL-producing strains but their
clinical utility as monotherapy is controversial [38–40].
In addition, ESBLs usually confer resistance to other
classes of antibiotics, such as quinolones and
trimethoprim/sulfamethoxazole, therefore susceptibility testing
of these agents is important . In this study, entire
MDR isolates were resistant to ampicillin and 33%
isolates were resistant to cotrimoxazole, 19% to
piperacillin tazobactam and 8% to imipenem whereas no
isolates were found to be resistant to colistin and
tigecycline. Similarly, all XDR isolates were resistant
to most of the antimicrobials tested whereas colistin
and tigecycline were the most effective regimens
against XDR isolates. Similar rate of resistance has
been documented by Ansari et al.  but their study
included E coli isolates from all age groups.
The level of drug resistance in uropathogenic E coli
among pediatric patient in this study is a serious issue.
Previous reports have suggested that higher resistance
is likely to be occurring in the communities with higher
proportion of young children and high antibiotic
consumption . In Nepal, higher antimicrobial pressure
for community infections and inappropriate therapeutic
guidelines for pediatric patients might be attributable
to this menacing scenario [12, 31]. Resistance to the
broad spectrum cephalosporins, fluoroquinolones and
aminoglycosides among the ESBL producing E.coli
isolates in this study necessitates the use of carbapenem
as alternative choice for pediatric UTIs. Although we
found carbapenems as the most effective agent against
the ESBL but the high rate of resistance from similar
studies is of special concern . Furthermore, the
genes associated with antibiotic resistance usually
reside in plasmid and may transfer antibiotic resistance
to other wild strains of bacteria . Therefore,
evidence based therapy with broad spectrum antibiotics
for serious or critical cases to prevent bacterial
resistance is extremely needful. Aminoglycosides,
amoxicillin clavulanate and trimethoprim
sulfamethoxazole/cotrimoxazole would be useful alternatives as
empirical antibiotics for children suspected with UTIs
in our scenario.
Limitations of the study
This study has a number of limitations. We could not
evaluate the risk factors and outcome of pediatric UTI
cases in our setting. Further cohort studies with
antimicrobial therapy and outcome would generate more significant
results. Antimicrobial susceptibility testing by dilution
methods and determination of minimum inhibitory
concentration (MIC) of therapeutic antibiotics would be
helpful for treatment and monitoring of the drug resistant
infections. Due to unavailability of resources, we could not
detect the genotype of ESBLs among E coli isolates. Further
investigations with larger patient population and multiple
centers would generate more significant ideas.
We found the menacing state of drug resistance in almost
all of the E coli isolates included in this study. Childhood
UTIs caused by ESBL-producing E. coli has been emerged
as a serious problem in our setting. Aminoglycosides and
carbapenems can be used as alternative regimens for
serious infections caused by MDR E coli. Furthermore, it
is extremely necessary to formulate a strict antibiotics
prescription policy and prudent use antibiotics in our
ASM: American Society for Microbiology; ATCC: American Type Culture
Collection; CDT: Combined Disk Test; CLSI: Clinical and Laboratory Standard
Institute; E coli: Escherichia coli; ESBL: Extended spectrum beta-lactamases;
MDR: Multidrug resistant; MHA: Mueller Hinton Agar; MIC: Minimum
inhibitory concentration; UTI: Urinary tract infection; XDR: Extensive drug
We are deeply thankful to all the patients participating in this study. Our
special thanks go to all the laboratory staffs, management and officials of
Manmohan Memorial Teaching Hospital Kathmandu for providing the
opportunity to carry out this research work.
Availability of data and materials
The primary raw data will be made available to the interested researchers by
the corresponding author of this article if requested.
NPP conceived the design of the study, reviewed the literature and
performed the laboratory investigations. PM, HP and GJ performed the
laboratory tests and helped in manuscript preparation. SS identified the
clinical cases, DP and PRK guided the necessary laboratory tests. NPP
prepared the manuscript with the guidance of PRK. All authors read the
manuscript and approved.
Ethics approval and consent to participate
This research was approved by the Institutional Review Committee of
Manmohan Memorial Institute of Health Sciences (IRC MMIHS), Kathmandu,
Nepal. Letter of approval (Ref No: 005/MMIHS/2071) was obtained after
submitting and presenting the proposal to the committee. Informed consent
was taken from the patients or their parents before participating to the
study. Data regarding personal information and infectious disease were
coded and kept confidential.
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