No Clinical Benefit of Empirical Antimicrobial Therapy for Pediatric Diarrhea in a High-Usage, High-Resistance Setting
No Clinical Benefit of Empirical Antimicrobial Therapy for Pediatric Diarrhea in a High-Usage, High-Resistance Setting
Vu Thuy Duong 1 2
Ha Thanh Tuyen 2
Pham Van Minh 2
James I. Campbell 2
Hoang Le Phuc 1
Tran Do Hoang Nhu 2
Le Thi Phuong Tu 0 2
Tran Thi Hong Chau 2
Le Thi Quynh Nhi 2 6
Nguyen Thanh Hung 1
Nguyen Minh Ngoc 5
Nguyen Thi Thanh Huong 5
Lu Lan Vi 4
Corinne N. Thompson 3
Guy E. Thwaites 2 3
Ruklanthi de Alwis 2 3
Stephen Baker 2 3 7
0 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus , Hinxton, Cambridge , United Kingdom
1 Children's Hospital 1 , Ho Chi Minh City , Vietnam
2 The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit
3 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University
4 The Hospital for Tropical Diseases , Ho Chi Minh City , Vietnam
5 Children's Hospital 2
6 University of Medicine and Pharmacy at Ho Chi Minh City
7 The Department of Medicine, University of Cambridge , United Kingdom
(See the Editorial Commentary by Jones et al on pages 512-3.) Background. Pediatric diarrheal disease presents a major public health burden in low- to middle-income countries. The clinical benefits of empirical antimicrobial treatment for diarrhea are unclear in settings that lack reliable diagnostics and have high antimicrobial resistance (AMR). Methods. We conducted a prospective multicenter cross-sectional study of pediatric patients hospitalized with diarrhea containing blood and/or mucus in Ho Chi Minh City, Vietnam. Clinical parameters, including disease outcome and treatment, were measured. Shigella, nontyphoidal Salmonella (NTS), and Campylobacter were isolated from fecal samples, and their antimicrobial susceptibility profiles were determined. Statistical analyses, comprising log-rank tests and accelerated failure time models, were performed to assess the effect of antimicrobials on disease outcome. Results. Among 3166 recruited participants (median age 10 months; interquartile range, 6.5-16.7 months), one-third (1096 of 3166) had bloody diarrhea, and 25% (793 of 3166) were culture positive for Shigella, NTS, or Campylobacter. More than 85% of patients (2697 of 3166) were treated with antimicrobials; fluoroquinolones were the most commonly administered antimicrobials. AMR was highly prevalent among the isolated bacteria, including resistance against fluoroquinolones and third-generation cephalosporins. Antimicrobial treatment and multidrug resistance status of the infecting pathogens were found to have no significant effect on outcome. Antimicrobial treatment was significantly associated with an increase in the duration of hospitalization with particular groups of diarrheal diseases. Conclusions. In a setting with high antimicrobial usage and high AMR, our results imply a lack of clinical benefit for treating diarrhea with antimicrobials; adequately powered randomized controlled trials are required to assess the role of antimicrobials for diarrhea.
Diarrhea remains the second most significant cause of morbidity
and mortality in children aged <5 years worldwide [
]. In 2010,
the global burden of diarrhea was estimated to be 1.73 billion
episodes, of which 36 million were characterized as moderate or
severe; 26% (9.3 million) of the severe episodes were estimated to
arise in Southeast Asia [
]. Among the bacterial pathogens causing
diarrhea in children Campylobacter spp., nontyphoidal Salmonella
(NTS), Shigella spp., Escherichia coli, and Yersinia enterocolitica are
the most commonly identified [
]. Campylobacter, NTS, and
Shigella are major contributors to the global morbidity of diarrhea
and account for an estimated 7.5, 7.1, and 4.8 million
disability-adjusted life years, respectively; the majority of these occur in
low- to middle-income countries (LMICs) .
The prevalence of all-cause diarrhea in children aged <5 years
in Vietnam is estimated to be 7%–11% (Multiple Indicator Cluster
Survey in 2000, 2006, and 2011 [
]) and accounts for as much as
12% of all-cause deaths in this age group [
]. A large burden of
diarrheal disease, combined with the lack of financial and
diagnostic resources in Vietnam, means that the causative agents of
most diarrheal episodes are never determined. As a consequence,
antimicrobials are empirically administered to children with
diarrhea based solely on clinical presentation. A previous study
found that antimicrobials were prescribed in 38% of acute watery
diarrhea episodes in Vietnamese children found to be associated
with a viral pathogen and in 60% of cases with unknown etiology
]. The excessive use of antimicrobials in animals and humans
in Southeast Asia has led to the current antimicrobial resistance
(AMR) crisis in the region, with increasing resistance against
many first-line antimicrobials, including fluoroquinolones and
third-generation cephalosporins, in many gram-negative
pathogens across the region [
]. Therefore, a better understanding of
the bacterial agents of diarrhea, their corresponding AMR
profile, the impact of antimicrobial treatment on clinical outcome,
and the effects of empirical antimicrobials is required.
Little has been reported regarding the disease burden and
clinical management of hospitalized pediatric diarrheal diseases in
Vietnam. Although NTS, Campylobacter, and Shigella have been
identified as major bacterial causes of diarrhea in Vietnamese
], the epidemiology, AMR profiles, treatment,
and the associated outcome of these bacteria in pediatric
diarrhea have not been not well described. The Vietnamese
healthcare system currently follows the World Health Organization
(WHO) guidelines for treatment of pediatric diarrhea. These
guidelines recommend the use of low-osmolarity oral
rehydration solution, zinc, and ciprofloxacin or 1 of the 3 alternatives
(pivmecillinam, azithromycin, or ceftriaxone) for all patients
with bloody diarrhea, irrespective of age [
]. However, as
the prevalence of AMR in enteric pathogens increases across
the region, it is uncertain how existing guidelines correspond
to circulating AMR profiles, antimicrobial treatment practices,
and patient outcomes in children hospitalized with diarrhea.
Therefore, we conducted a prospective multicenter
crosssectional study in Ho Chi Minh City to improve the
understanding of bacteria-associated diarrhea in Vietnamese children
and to assess the duration of hospital stay in diarrheal patients
infected with bacterial pathogens and receiving antimicrobials.
MATERIALS AND METHODS
Ethical approval for this study was provided by the ethics
committees of all 3 participating local hospitals and the University
of Oxford Tropical Research Ethics Committee (OxTREC No.
1045-13). Written consent from parents or legal guardians of all
participants was obtained before enrollment.
Study Design and Enrollment
This study was a prospective, observational, multicenter
crosssectional study to evaluate the etiology, epidemiology, and
outcomes in children (aged <16 years) hospitalized for diarrhea.
Study participants were recruited from 3 tertiary hospitals
(Children’s Hospital 1, Children’s Hospital 2, and the Hospital
for Tropical Diseases) in Ho Chi Minh City, Vietnam, from May
2014 to April 2016.
Children hospitalized with diarrhea, defined as ≥3 passages of
loose stools within 24 hours [
] with ≥1 loose stool containing
blood and/or mucus, were recruited into the study. Based on
characteristics of the diarrheal stools and the duration of illness,
participants were classified into 3 groups: acute nonbloody
diarrhea (diarrhea with mucus, <14 days), acute bloody diarrhea
(diarrhea with blood, <14 days), and persistent diarrhea
(diarrhea with mucus and/or blood, ≥14 days). Children were not
eligible if they had suspected or confirmed intussusception at the
time of enrollment. After enrollment, a short questionnaire was
completed, and a fecal sample was collected and processed within
24 hours. All enrolled patients were provided with the routine
standard-of-care practices at each hospital. Treatment and proxy
outcomes, including patient recovery status at 3 days after
enrollment and duration of hospitalization, were recorded by clinical
staff at study sites. Patient status was recorded as “recovered” if
the patient had <3 passages of loose stools in the past 24 hours
or “improved” if the patient had fewer episodes of diarrhea and/
or less mucus and/or blood compared with status at enrollment.
Fecal specimens were inoculated onto MacConkey agar (MC agar;
Oxoid) and xylose-lysine-deoxycholate agar (Oxoid) and into
selenite broth (Oxoid) and incubated at 37°C for 18–24 hours.
Salmonella and Shigella were detected based on their
characteristic appearance on xylose-lysine-deoxycholate and MC agar and
confirmed using matrix-assisted laser desorption/ionization
timeof-flight mass spectrometry (Bruker) and API20E (bioMerieux),
following the manufacturer’s guidelines. Campylobacter was
identified using Campylobacter selective agar (Oxoid) under
microaerophilic conditions, followed by Gram staining and microscopy.
Antimicrobial susceptibility testing was performed using
the Kirby-Bauer disc diffusion method on Mueller-Hinton agar
(Oxoid) for Salmonella and Shigella, and on blood agar
containing 5% sheep blood for Campylobacter and interpreted using
Clinical and Laboratory Standards Institute guidelines [
(Supplementary Table S1). Multidrug resistance (MDR) was
defined as nonsusceptibility to ≥1 agent in ≥3 antimicrobial
categories listed in Supplementary Table S1. Microbiology results were
reported to the collaborating hospitals within 3 days of sampling.
Data were analyzed using Stata (version 11; StataCorp) and R
(versions 3.2.2; R Foundation for Statistical Computing)
software. Figures were constructed with R software, using the
] and prodlim packages. Descriptive comparisons
between groups were conducted using nonparametric tests,
including the Fisher exact test for categorical variables and the
Mann-Whitney U test for continuous data. Statistical
comparisons between >2 groups were conducted using the χ2 test and
the Kruskal-Wallis test for categorical and continuous variables,
respectively. Kaplan-Meier curves for length of hospital stay were
compared between groups, using log-rank tests. The growth
status of participating patients was assessed using the WHO global
Antimicrobial Treatment in Diarrhea • CID 2018:66 (15 February) • 505
database on growth and nutrition [
], the Institute for Clinical
Systems Improvement’s guidelines on preventing and managing
obesity in children and adolescents [
], and the macro package
for Stata software (version 11) developed by WHO.
An accelerated failure time (AFT) regression model
(incorporating all study patients hospitalized for ≥1 day) was constructed
in 3 steps. First, the best AFT distribution fit was identified for
the dependent variable, that is, length of hospital stay. Second, 11
demographic variables (eg, sex and age), clinical symptoms of
disease severity, treatment types, and MDR were tested by means of
univariate analysis, using a log-normal distribution. The 11
variables were chosen because of their potential to affect duration of
hospital stay. Third, a multivariate log-normal model was
constructed using a stepwise backward elimination method, where
variables were removed based on the likelihood ratio test (P < .05).
General Characteristics of Patients Hospitalized With Diarrhea
Between May 2014 and April 2016, a total of 3166 hospitalized
children meeting the study criteria were recruited at the 3 study
hospitals. The majority of patients were male (1945 of 3166;
61.4%), with ages ranging from 1 month to 15 years (median
age, 10 months; interquartile range [IQR], 6.5–16.7 months).
Patients were hospitalized for a median of 5 days (IQR, 3–7 days)
with 88.7% (2808 of 3166) of patients showing improvement or
resolving symptoms within 3 days of enrollment.
Patients were segregated into 3 diarrheal types: acute
nonbloody (1775 of 3166; 56.1%), acute bloody (1096 of 3166;
34.6%), or persistent (295 of 3166; 9.3%) (Table 1). Owing to
the clinical complexity of persistent diarrhea, statistical
comparisons were conducted between the 2 acute diarrhea groups
only. Patients with nonbloody diarrhea were more likely to
experience vomiting than those with bloody diarrhea (66.8%
vs 38.7%; P = .001) and dehydration (15.0% vs 2.6%,
respectively; P = .001). A significantly greater proportion of patients
with bloody diarrhea experienced abdominal pain (26.4% vs
19.3% of those with nonbloody diarrhea; P = .001). Systemic
C-reactive protein (CRP) concentrations were significantly
higher in patients with bloody than in those with nonbloody
diarrhea (21.0 [IQR, 6.7–40.2] vs 7.0 [4.0–24.0] mg/L; P < .001).
We cultured the 3 key bacterial diarrheal pathogens in
Vietnam (ie, NTS, Campylobacter, and Shigella), isolating 816
pathogens from 804 patients (11 coinfections) and stratified
clinical manifestations and treatment data by these organisms.
At least 1 of these bacteria was isolated from the fecal specimens
of 44.3% with bloody diarrhea (485 of 1096) and 17.9% (318 of
1775) with nonbloody diarrhea (P < .001) (Table 1). Overall,
NTS was the most frequently isolated of the 3 bacterial
pathogens from the diarrheal children, accounting for 15.1% (478
of 3166) of all diarrheal cases, followed by Campylobacter and
Shigella. Shigella infections were more common in older
children (median age, 3 years) and were associated with more severe
506 • CID 2018:66 (15 February) • Duong et al
symptoms. However, children with Shigella infections recovered
more rapidly than those infected with NTS or Campylobacter
(Supplementary Table S2).
Antimicrobial Usage for Treatment of Hospitalized Diarrheal Diseases
We also recorded the treatment regimens of the enrolled patients,
which included oral rehydration solution, intravenous
rehydration, zinc, probiotics, and antimicrobials. More than 90% of
patients were administered oral rehydration solution, and >80%
were given zinc supplementation. The use of antimicrobials
within this population was high, with 85.2% of patients (2697 of
3166) receiving empirical antimicrobial treatment after admission
to the hospital and before a bacterial culture result was obtained.
Fluoroquinolones were the most commonly used class of
antimicrobials (1799 of 2697; 66.7%). Differences in standard-of-care
treatment were observed between patients with bloody versus
nonbloody diarrhea (Table 1); antimicrobials were more
regularly administered to patients with bloody diarrhea than to those
with nonbloody diarrhea (P < .001). Antimicrobials, specifically
fluoroquinolones, were commonly (>70%) prescribed before an
etiological diagnosis in those eventually found to be infected with
Campylobacter, Salmonella, or Shigella (Supplementary Table S2).
Campylobacter, Salmonella, and Shigella isolates displayed
a high prevalence of nonsusceptibility against many of the
screened antimicrobials (Figure 1). Notably, a high proportion
of Campylobacter, NTS, and Shigella exhibited nonsusceptibility
against ciprofloxacin: 94.2% (242 of 257), 58.4% (279 of 478),
and 70.4% (57 of 81), respectively. In addition, 56.8% of Shigella
(46 of 81) and 13.8% of NTS (66 of 478) isolated were
nonsusceptible to the third-generation cephalosporins, ceftriaxone
and ceftazidime. A smaller fraction of the Campylobacter, NTS,
and Shigella isolates also exhibited resistance against
azithromycin: 9.7% (25 of 257), 17.4% (83 of 478), and 22.2% (18 of 81),
respectively. The majority of the organisms (65.4%; 531 of 816
isolates) were categorized as MDR. The prevalence of MDR was
highest within the Campylobacter isolates (218 of 257; 84.8%),
with 3 isolates also exhibiting nonsusceptibly to imipenem.
The MDR prevalence in NTS and Shigella was 53.9% (258 of
478) and 67.9% (55 of 81), respectively (Figure 1).
Diarrheal Disease Outcome
We assessed the effect of antimicrobial treatment on 2 proxy
disease outcome measures, clinical outcome (ie, improved/
recovered) at 3 days after enrollment and the duration of
hospital stay. More than 80% of patients showed improvement or had
recovered at 3 days after enrollment, regardless of antimicrobial
treatment (Supplementary Figure S1). However, those given
an antimicrobial, specifically a fluoroquinolone, had a longer
hospital stay than those not receiving an antimicrobial (P < .001
and P = .01, respectively) (Figure 2). Notably, the duration of
hospital stay did not differ significantly between those receiving
Demographic and Clinical Manifestations of Pediatric Patients Admitted With Diarrhea in Ho Chi Minh Citya
Abbreviations: CRP, C-reactive protein; IQR, interquartile range.
aData represent No. (%) unless otherwise specified.
bAll children with nonbloody diarrhea had mucus in stools.
cP values represent comparisons between nonbloody and bloody diarrhea using Fisher exact test for categorical data or Mann-Whitney U test for continuous data.
dObese: weight for length z score >3 standard deviations [SDs] in children aged <24 months; body mass index (BMI) for age z score >3 SDs in children aged ≥24 months. Overweight: weight
for length z score >2 SDs in children aged <24 months; BMI for age z score >2 SDs in children aged ≥24 months. Wasted: weight for length z score ≤2 SDs in children aged <24 months;
BMI for age z score ≤2 SDs in children aged ≥24 months. Severely wasted: weight for length z score ≤3 SDs in children aged <24 months; BMI for age z score ≤3 SDs in children aged
≥24 months [
eDehydration classified as described by Basaleem and Amin [
fPercentage of those receiving antimicrobials. Fluoroquinolones included ciprofloxacin and norfloxacin.
gCondition was described as “recovered” if patient had <3 passages of loose stool in the past 24 hours or “improved” if patient had fewer episodes of diarrhea and less mucus and/or blood
than at enrollment.
and those not receiving an antimicrobial among patients with
bloody diarrhea (Figure 2C). However, antimicrobial treatment
in those with nonbloody diarrhea was significantly associated
with a longer hospital stay (median [IQR] hospital stay for
antimicrobial vs no antimicrobial use, 5 [
] vs 4 [
P < .001; (Figure 2C). Similarly, antimicrobial treatment in
patients with low CRP levels (≤5 mg/L) was significantly
associated with an increased hospital stay, compared with patients
with high CRP levels (>5 mg/L) (P < .001; Figure 2D).
We then stratified all patients by antimicrobial treatment,
and within those treated with antimicrobials we compared
disease outcome (ie, duration of hospitalization) between
those infected with MDR or non-MDR organisms and
between those infected with fluoroquinolone-susceptible or
nonsusceptible organisms. In patients empirically treated
with any antimicrobial or a fluoroquinolone, >90% (526 of
564) and 70% (361 of 515) were infected with an MDR or
a fluoroquinolone nonsusceptible organism, respectively.
However, regardless of the MDR status and fluoroquinolone
nonsusceptibility of the infecting organisms, no differences in
the duration of hospitalization were observed among patients
treated with antimicrobials (Figure 3). Comparable findings
were observed for recovery status at 3 days after enrollment
(Supplementary Figure S1).
Antimicrobial Treatment in Diarrhea • CID 2018:66 (15 February) • 507
An AFT multiple regression model was considered to be an
appropriate method for describing how each of the adjusted
variables multiplicatively alters the duration of hospitalization.
Therefore, an AFT was constructed to investigate the effect of
antimicrobials on the duration of hospital stay, adjusting for age,
disease severity, and other prescribed treatments. After
adjustment for age, diarrhea presentation, and dehydration,
antimicrobials were associated with a significant increase in the duration
of hospital stay of diarrheal patients by a time ratio of 1.32 [1.24–
1.41]. Finally, infection with an MDR organism was found to not
significantly prolong hospitalization (P = .55; Table 2).
Moderate-to-severe diarrhea has a significant healthcare burden
in Vietnamese children [
]. Although previous observational
508 • CID 2018:66 (15 February) • Duong et al
studies of diarrhea in Vietnam have described some of the
epidemiological features, the bacterial causes, and their
associated AMR profiles, these studies have focused chiefly on
children with acute watery diarrhea [
]. Little is known about
the epidemiology and clinical management of bloody and/or
mucoid diarrhea in Vietnam. Therefore, we aimed to address
this paucity of data by enrolling >3000 of children
hospitalized with diarrheal. This large sample size not only enabled the
isolation of >800 enteric pathogens, but it also provided data
regarding antimicrobial usage in medical practice and outcome.
Furthermore, this study investigated the clinical role of AMR in
a relevant population empirically prescribed antimicrobials at
presentation to the hospital.
AMR in pathogenic bacteria, including those associated
with diarrhea, is a global public health problem [
Log-rank P < .001
Log-rank P = .01
from Vietnam highlight the increasing trend in diarrheagenic
bacteria of AMR to the current first-line antimicrobials, such
as fluoroquinolones and third-generation cephalosporins.
Moreover, despite recent increases in fluoroquinolone
resistance in Asia and beyond, current guidelines still endorse the
use of this class of antimicrobials to treat bloody diarrhea
]. Many of the organisms isolated during this
investigation were also nonsusceptible to other (nonfluoroquinolone)
antimicrobials, including some “last resort” choices, such as
In comparison to estimates from other industrializing
countries, we observed a similar or elevated prevalence of NTS
exhibiting nonsusceptibility to third-generation
cephalosporins and increased nonsusceptibility to both ciprofloxacin and
]. An extraordinarily high prevalence
(~90%) of fluoroquinolone-resistant Campylobacter has been
recently observed in other industrializing countries [
The situation in Vietnam seems to be exacerbated by the
nonsusceptibility of Campylobacter isolates to macrolides.
The Shigella isolated here also had a high MDR rate;
emerging MDR Shigella isolates with resistance to fluoroquinolones
and extended-spectrum cephalosporins are now commonly
reported across Asia [
10, 30, 31
The treatment of diarrhea with antimicrobials is a
complex issue. Apart from the limited capability of most LMICs
to confirm etiological agents associated with disease and the
current complication of increasing AMR, there are conflicting
data regarding the clinical efficacy of antimicrobials in
reducing symptoms [
]. In line with WHO recommendations, we
observed that >85% of patients hospitalized with diarrhea
containing mucus and/or blood were prescribed an antimicrobial,
most commonly fluoroquinolones (ciprofloxacin/norfloxacin).
Our current analysis found that antimicrobial use during
hospitalized diarrhea did not add benefit to supportive therapy only
(ie, rehydration and zinc supplementation).
The recovery of patients regardless of antimicrobial treatment
or AMR status when treated with a first-line antimicrobial for
bloody diarrhea treatment (eg, ciprofloxacin) may be explained
by either the differing in vivo effects of antimicrobials or the
self-limiting nature of the infections. In addition, in diarrhea
with less pronounced inflammation (indicated by the absence
of blood and/or a low CRP level), the use of antimicrobials was
associated with a prolonged hospital stay. These observations
support previous findings in studies of NTS and Campylobacter,
where antimicrobial treatment did not provide a clinical
advantage and sometimes even caused harm (compared with placebo)
in decreasing the duration of symptoms [
]. The routine
antimicrobial treatment may also affect the transmission of
diarrhea-causing bacteria by increasing fecal carriage and
consequently spreading AMR organisms .
Antimicrobial Treatment in Diarrhea • CID 2018:66 (15 February) • 509
TR (95% CI)b
Log-rank P = .4
Log-rank P = .5
Time in Hospital, d
Time in Hospital, d
The main limitation in the present study is that this investigation
was observational, with patients receiving standard-of-care
treatment, which made it difficult to assess whether our observations
were biased by more severe cases being prescribed
antimicrobials. Furthermore, the duration of hospital stay and recovery of
patients at 3 days after enrollment were proxy measures of clinical
outcome, and we cannot discount that some children may have
been discharged before the cessation of symptoms.
In conclusion, bacteria associated with pediatric diarrhea in
southern Vietnam displayed an extensive AMR profile, thereby
emphasizing the significance of etiological diagnosis of diarrhea
in LMICs. Our key finding was that antimicrobial treatment was
not associated with a reduction in diarrheal symptoms and even
prolonged hospital stay in some groups. Therefore, we urge that
adequately powered randomized controlled trials be conducted
to better assess the potential benefits of antimicrobial therapy
for treatment of diarrhea. These data will become essential for
controlling antimicrobial usage during the present AMR crisis.
Supplementary materials are available at Clinical Infectious Diseases online.
Consisting of data provided by the authors to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the authors,
so questions or comments should be addressed to the corresponding author.
Acknowledgments. We acknowledge all members of the enteric
infections group at Oxford University Clinical Research Unit (OUCRU) and the
study teams at Hospital for Tropical Diseases (Infectious Pediatric Ward
B), Children’s Hospital 1 (Gastrointestinal Ward), Children’s Hospital 2
(Gastrointestinal Ward), and the Clinical Trial Unit and Data Management
Centre (OUCRU). Importantly, we also thank the enrolled children and
their parents whose consent made this study possible.
Financial support. This work was supported by the Wellcome Trust
and the Royal Society (grant 100087/Z/12/Z). S. B. is a Sir Henry Dale
Fellow, jointly funded by the Wellcome Trust and the Royal Society.
Potential conflicts of interest. All authors: No reported conflicts of
interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
1. Walker CL , Rudan I , Liu L , et al. Global burden of childhood pneumonia and diarrhoea . Lancet 2013 ; 381 : 1405 - 16 .
2. Scallan E , Mahon BE , Hoekstra RM , Griffin PM . Estimates of illnesses, hospitalizations, and deaths caused by major bacterial enteric pathogens in young children in the United States . Pediatr Infect Dis J 2012 ; 32 : 217 - 21 .
3. Fletcher SM , McLaws M-L , Ellis JT . Prevalence of gastrointestinal pathogens in developed and developing countries: systematic review and meta-analysis . J Public Health Res 2013 ; 2 : 9 .
4. Murray CJL , Vos T , Lozano R , et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990 -2010: a systematic analysis for the Global Burden of Disease Study 2010 . Lancet 2012 ; 380 : 2197 - 223 .
5. Lee HY , Van Huy N , Choi S. Determinants of early childhood morbidity and proper treatment responses in Vietnam: results from the Multiple Indicator Cluster Surveys, 2000 - 2011 . Glob Health Action 2016 ; 9 : 1 - 8 .
6. WHO and UN partners . Vietnam: WHO statistical profile , 2015 .
7. Thompson CN , Phan MV , Hoang NV , et al. A prospective multi-center observational study of children hospitalized with diarrhea in Ho Chi Minh City, Vietnam . Am J Trop Med Hyg 2015 ; 92 : 1045 - 52 .
8. World Health Organization. Antimicrobial resistance: global report on surveillance 2014. Bull World Health Organ 2014 ; 61 : 383 - 94 .
9. Thompson CN , Phan VT , Le TP , et al. Epidemiological features and risk factors of Salmonella gastroenteritis in children resident in Ho Chi Minh City, Vietnam . Epidemiol Infect 2013 ; 141 : 1604 - 13 .
10. Vinh H , Nhu NT , Nga TV , et al. A changing picture of shigellosis in southern Vietnam: shifting species dominance, antimicrobial susceptibility and clinical presentation . BMC Infect Dis 2009 ; 9 : 204 .
11. Harrison JW , Dung TT , Siddiqui F , et al. Identification of possible virulence marker from Campylobacter jejuni isolates . Emerg Infect Dis 2014 ; 20 : 1026 - 9 .
12. World Health Organization. The treatment of diarrhoea . 2005 .
13. Legros D. Guidelines for the control of shigellosis, including epidemics due to Shigella dysenteriae type 1 . World Health 2005 ; 1 - 70 .
14. Clinical and Laboratory Standards Institute. M100S performance standards for antimicrobial susceptibility testing . 2016 .
15. Wickham H. Hadley Wickham . Media 2009 ; 35 : 211 . Available at: http://had. co.nz/ggplot2/book.
16. de Onis M , Onyango AW , Borghi E , Garza C , Yang H . Comparison of the World Health Organization (WHO) Child Growth Standards and the National Center for Health Statistics/WHO international growth reference: implications for child health programmes . Public Health Nutr 2007 ; 9 : 942 - 7 .
17. Fitch A , Fox C , Bauerly K , et al. Prevention and management of obesity for children and adolescents . Inst Clin Syst Improv 2013 : 10 .
18. de Onis BM , Blössner M. WHO global database on child growth and malnutrition . World Heal Organ 2016 ; 25 : 228 - 34 .
19. Basaleem HO , Amin RM . Integrated management of childhood illness in Lahej, Yemen: a qualitative analysis from the perspective of health providers . East Mediterr Health J 2011 ; 17 : 101 - 8 .
20. Anders KL , Thompson CN , Thuy NT , et al. The epidemiology and aetiology of diarrhoeal disease in infancy in southern Vietnam: a birth cohort study . Int J Infect Dis 2015 ; 35 : 3 - 10 .
21. Collignon PC , Conly JM , Andremont A , McEwen SA , Aidara-Kane A ; members of the World Health Organization Advisory Group B. World Health Organization ranking of antimicrobials according to their importance in human medicine: a critical step for developing risk management strategies to control antimicrobial resistance from food animal production . Clin Infect Dis 2016 ; 63 : 1087 - 93 .
22. Jean SS , Hsueh PR . High burden of antimicrobial resistance in Asia . Int J Antimicrob Agents 2011 ; 37 : 291 - 5 .
23. Meng CY , Smith BL , Bodhidatta L , et al. Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia . Pediatr Infect Dis J 2011 ; 30 : 331 - 5 .
24. Pathania M. Clinical study of acute childhood diarrhoea caused by bacterial enteropathogens . J Clin Diagnostic Res 2014 ; 1 - 5 .
25. Zhang H , Pan F , Zhao X , et al. Distribution and antimicrobial resistance of enteric pathogens in Chinese paediatric diarrhoea: a multicentre retrospective study, 2008 - 2013 . Epidemiol Infect 2015 ; 1 - 8 .
26. Langendorf C , Le Hello S , Moumouni A , et al. Enteric bacterial pathogens in children with diarrhea in Niger: diversity and antimicrobial resistance . PLoS One 2015 ; 10 : e0120275 .
27. Li Y , Xie X , Xu X , et al. Nontyphoidal salmonella infection in children with acute gastroenteritis: prevalence, serotypes, and antimicrobial resistance in Shanghai, China. Foodborne Pathog Dis 2014 ; 11 : 200 - 6 .
28. Ghosh R , Uppal B , Aggarwal P , Chakravarti A , Jha AK . Increasing antimicrobial resistance of Campylobacter jejuni isolated from paediatric diarrhea cases in a tertiary care hospital of New Delhi, India . J Clin Diagn Res 2013 ; 7 : 247 - 9 .
29. Pollett S , Rocha C , Zerpa R , et al. Campylobacter antimicrobial resistance in Peru: a ten-year observational study . BMC Infect Dis 2012 ; 12 : 1 .
30. Von Seidlein L , Deok RK , Ali M , et al. A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology . PLoS Med 2006 ; 3 : 1556 - 69 .
31. The HC , Rabaa MA , Thanh DP , et al. South Asia as a reservoir for the global spread of ciprofloxacin resistant Shigella sonnei . PLoS Med 2015 ; 1 - 12 .
32. Fischer Walker CL , Fontaine O , Young MW , Black RE . Zinc and low osmolarity oral rehydration salts for diarrhoea: a renewed call to action . Bull World Health Organ 2009 ; 87 : 780 - 6 .
33. Traa BS , Fischer Walker CL , Munos M , Black RE . Antibiotics for the treatment of dysentery in children . Int J Epidemiol 2010 ; 39 : 70 - 4 .
34. Onwuezobe IA , Oshun PO , Odigwe CC . Antimicrobials for treating symptomatic non-typhoidal Salmonella infection . Cochrane Libr 2012 ; 11 : 1 - 50 .
35. Ternhag A , Asikainen T , Giesecke J , Ekdahl K. A meta-analysis on the effects of antibiotic treatment on duration of symptoms caused by infection with Campylobacter species . Clin Infect Dis 2007 ; 44 : 696 - 700 .