Antibiotic treatment of_acute_gastroenteritis_in_c

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Antibiotic treatment of acute gastroenteritis in children [version
1; referees: 2 approved]
Eugenia Bruzzese, Antonietta Giannattasio, Alfredo Guarino
Department of Translational Medical Sciences–Section of Pediatrics, University of Naples Federico II, Via S. Pansini 5, Naples, 80131, Italy
Abstract
Antibiotic therapy is not necessary for acute diarrhea in children, as rehydration
is the key treatment and symptoms resolve generally without specific therapy.
Searching for the etiology of gastroenteritis is not usually needed; however, it
may be necessary if antimicrobial treatment is considered. The latter is left to
the physician evaluation in the absence of clear indications. Antimicrobial
treatment should be considered in severely sick children, in those who have
chronic conditions or specific risk factors or in specific settings. Traveler’s
diarrhea, prolonged diarrhea, and antibiotic-associated diarrhea may also
require antibiotic therapy. Depending on the severity of symptoms or based on
risk of spreading, empiric therapy may be started while awaiting the results of
microbiological investigations. The choice of antibiotic depends on suspected
agents, host conditions, and local epidemiology. In most cases, empiric therapy
should be started while awaiting such results. Empiric therapy may be started
with oral co-trimoxazole or metronidazole, but in severe cases parenteral
treatment with ceftriaxone or ciprofloxacin might be considered.
Alfredo Guarino ( )Corresponding author: alfguari@unina.it
: Methodology, Resources, Writing – Original Draft Preparation; : Methodology, Resources, Writing –Author roles: Bruzzese E Giannattasio A
Original Draft Preparation; : Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & EditingGuarino A
No competing interests were disclosed.Competing interests:
Bruzzese E, Giannattasio A and Guarino A. How to cite this article: Antibiotic treatment of acute gastroenteritis in children [version 1;
2018, (F1000 Faculty Rev):193 (doi: )referees: 2 approved] F1000Research 7 10.12688/f1000research.12328.1
© 2018 Bruzzese E . This is an open access article distributed under the terms of the ,Copyright: et al Creative Commons Attribution Licence
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The author(s) declared that no grants were involved in supporting this work.Grant information:
15 Feb 2018, (F1000 Faculty Rev):193 (doi: ) First published: 7 10.12688/f1000research.12328.1
Referee Status:
Invited Referees

version 1
published
15 Feb 2018
1 2
, University of Oxford, UKStephen Baker1
, The Hospital for SickZulfiqar Bhutta
Children, Canada
2
15 Feb 2018, (F1000 Faculty Rev):193 (doi: First published: 7
)10.12688/f1000research.12328.1
15 Feb 2018, (F1000 Faculty Rev):193 (doi: Latest published: 7
)10.12688/f1000research.12328.1
v1
Page 1 of 10
F1000Research 2018, 7(F1000 Faculty Rev):193 Last updated: 15 FEB 2018

Introduction
Acute gastroenteritis (AGE) is one of the most common problems
in infants and young children, especially in poor countries. It is
caused by viral, bacterial, and parasitic agents, with an age-,
host-, and location-based pattern. Etiology usually is not looked
for, and oral rehydration therapy is the universal therapy. Active
treatment with probiotics and antidiarrheal agents is suggested
in adjunct to rehydration, as it reduces the duration and intensity
of symptoms independently from etiology1
. There are no clear
indications for antimicrobial therapy; however, antibiotics are
frequently prescribed. Overuse of antibiotics is associated with
increased rates of antibiotic-resistant bacteria, unnecessary
costs, and significant incidence of adverse events, and current
guidelines are highly restrictive in recommending empiric anti-
microbial therapy for AGE. Bacterial infections may be asso-
ciated with the presence of specific clinical features, notably
fever, abdominal pain, blood in the stool, and fecal leukocytes2
.
However, none of these features is reliable to support a bacterial
etiology. In addition, many children with bacterial enteritis have
negative stool cultures and, conversely, it is not uncommon to
detect multiple bacterial and viral pathogens, making it difficult to
give a causative role to a specific microorganism.
The application of a quantitative molecular approach showed
that four agents (rotavirus, Cryptosporidium, enterotoxigenic
Escherichia coli (ETEC) producing heat-stable toxin, and
Shigella) account for the majority of cases of infectious diarrhea
in African and Asian children younger than 5 years old3
. It is a
logical hypothesis that, if bacteria are causing gastroenteritis,
antibiotic therapy could be effective in reducing the intensity
and duration of symptoms and prevent infection spreading.
Furthermore, specific antibiotic treatment may prevent serious
complications such as sepsis and protracted diarrhea in children
with underlying conditions such as immunosuppression or
malnutrition. However, the indications for antibiotic therapy are
not standardized, and randomized controlled trials are not
available in children.
Bacterial etiology of acute gastroenteritis in
developing and developed countries
The etiological pattern of bacteria causing acute diarrhea
depends on geographical area. In developing countries, more
than half a million infants and young children die each year
because of AGE, and Vibrio cholerae still causes epidemics, but
the most common bacterial agent is Shigella4
. In Europe, the most
common bacterial pathogens are Campylobacter, Salmonella
spp., enteropathogenic E. coli (EPEC), and enteroaggregative
E. coli (EAEC)5,6
. Clostridium difficile (Cd) has emerged as a cause
of community-acquired diarrheal illness, but local data report
a relatively low burden7–9
. In Ecuador, sub-Saharan Africa, and
South Asia, Shigella is the main agent3,10
. In a recent study from
central China, pathogens were detected in 20% of 508 fecal
samples from patients with acute diarrhea, under 5 years of age11
.
The most commonly detected pathogens were Salmonella spp.
(8%), diarrheagenic E. coli (5%), Campylobacter jejuni (3%),
and Aeromonas spp. (2%). In the developing region of China,
Shigella was the most common bacterial agent of AGE12
. In India,
E. coli was the most common agent of AGE (31%) followed by
Shigella (24%). Infections with two or more pathogens were
observed in 34% of cases, with a predominant incidence in
children younger than 2 years old13
.
Bacterial pathogens account for 80% of cases of traveler’s
diarrhea14
. ETEC, enteroinvasive E. coli (EIEC), and EAEC
are implicated in the majority of cases, but also Campylobacter,
Salmonella, and Shigella play a substantial role.
Current recommendations for the treatment of acute
gastroenteritis
Evidence-based indications for the management of children
with AGE are that oral rehydration with hypo-osmolar solution is
the key treatment and should be started as soon as possible1
. The
so-called active intervention in adjunct to rehydration includes
specific probiotics such as Lactobacillus rhamnosus strain GG
or Saccharomyces boulardii, or diosmectite or racecadotril.
Active treatment reduces the intensity of symptoms and their
duration independently of etiology15
. However, the concept of
active treatment of gastroenteritis is progressively pursued in
children, and current recommendations for the use of probiotics
and antidiarrheal drugs are available from several regions of the
world, including the Asia-Pacific region15
. According to the
guidelines for the management of AGE, antibiotic therapy should
not be given to the vast majority of children with AGE, unless
specific conditions are present. Even in cases of proven bacterial
gastroenteritis, antibiotic therapy is not routinely needed but
should be considered only for specific pathogens or in defined
clinical settings.
The routine use of antimicrobials for diarrhea in children is
not recommended by the World Health Organization (WHO)
except for clinically recognizable severe cases16
. It is indicated in
the following circumstances: cholera, shigellosis, dysenteric
presentation of campylobacteriosis and non-typhoidal salmo-
nellosis when they cause persistent diarrhea, and when host
immune status is compromised for any reason including severe
malnutrition, chronic disease, or lymphoproliferative disorders.
Antimicrobial treatment should also be considered for: moder-
ate/severe traveler’s diarrhea or diarrhea accompanied by fever
and/or bloody stools and diarrhea associated with another acute
infection (e.g. pneumonia) requiring specific antimicrobial
therapy. Similar indications are provided at a local level, but
supporting evidence is weak or absent17,18
.
Antimicrobial prescribing patterns for acute
gastroenteritis in developing and developed countries
Antibiotic therapy is sometimes recommended to shorten the
duration and severity of symptoms of AGE as well as to decrease
its transmission19,20
. The emerging challenge of antibiotic resist-
ance complicates treatment for bacterial diarrhea. Antimicrobial
resistance among diarrheal pathogens is high in developing
countries, where the use of antimicrobials is less restricted, and
these rates are on the rise worldwide21,22
.
In developing countries, guidelines for acute diarrhea suggest
that the presence of blood in the stools should always be checked.
Non-bloody diarrhea should be managed with fluids only (unless
co-morbidities are present that may require a different treat-
ment), while dysentery (reported history of blood in the stools
Page 2 of 10

since diarrheal onset) should be managed with antibiotics, as
Shigella infection is suspected23
. This approach is supported by
the evidence that most non-bloody diarrheal episodes in children
under 5 years of age in low-income settings are self-limiting and
are caused by viral pathogens (rotavirus, norovirus, astrovirus,
and enteric adenovirus) or pathogens for which antibiotics are
likely of limited efficacy or even dangerous (e.g. Salmonellae
and Campylobacter)24
. In contrast, a significant proportion of
episodes of bloody diarrhea caused by Shigella is associated
with considerable mortality and should be treated with antibiotic
therapy25
. However, inappropriate antibiotic use remains
common. In a study in 447 Indian children aged between
6 months and 5 years, deviations from WHO protocol for AGE
treatment were found in 78% of cases26,27
. Although in all cases
oral rehydration solution and zinc were prescribed, unneces-
sary antibiotic use was reported in 12% of cases, with cefixime,
ofloxacin, and ceftriaxone being the most frequently prescribed
antibiotics. Hospitalization, longer duration of symptoms prior
to presentation, and fever were associated with prescription of
antibiotics27
. In other studies, the type of physician was related
to antibiotic prescription. Pediatricians working in the govern-
ment sector prescribed antibiotics to only 23% of children, while
private practitioners prescribed antibiotics to 51% of children
with diarrhea28
.
Also, in developed countries, over-prescription of antibiot-
ics for AGE was reported, and physician responses to patients’
treatment expectations was an important cause of inappropriate
antibiotic use29
. However, in as many as 10% of children
admitted to hospital, unnecessary antimicrobial therapy is
prescribed because of a “probable bacterial cause”30
.
Indications for antimicrobial treatment of acute
gastroenteritis
In adults, single cases of acute febrile bloody diarrhea are
more likely to be caused by bacterial pathogens such as
Campylobacter or Shigella species, depending on the epidemio-
logical setting. These patients are likely to benefit from empirical
antimicrobial therapy31
.
In children, there are no clear or validated criteria for antibiotic
therapy. However, the criteria for considering antibiotic treat-
ment include clinical features, host-related and setting-related
conditions, and, of course, etiology.
Because the etiology of diarrhea is not generally looked for, the
decision to treat children with AGE with antibiotics should be
based on the presence of factors that “may require” antibiotic
treatment (see Table 1 and Table 2). Generally, antibiotic choice
should be initially empiric and subsequently tailored on the
results of microbiological investigations. In many conditions,
waiting for microbiological results to confirm the decision to
treat and select the specific drug may be appropriate.
Clinical indications
The guidelines for the treatment of acute diarrhea in children
state that the use of antibiotics is not needed routinely but only
for specific pathogens or in defined clinical settings1
. Clinical
indications for antibiotic therapy include toxic state or signs
of invasive infection (Table 1). These should be considered as
strong indications to parenteral antibiotic treatment. Fever per se
does not require antimicrobial therapy but needs to be considered
in a more global clinical evaluation. It may indicate dehydration
but also spreading of intestinal infection. This could be confirmed
by an increase of inflammatory markers such as C-reactive
protein. Dysentery presentation with abdominal pain and mucoid
or bloody stools (often in multiple outputs of low volume)
has been associated with a bacterial etiology (Campylobacter,
Salmonella, Shigella, Yersinia). In those circumstances, antibiotic
therapy should be provided at least in countries where the mortal-
ity rate is consistent or with limited healthcare facilities, accord-
ing to the WHO. Alternatively, it could be considered but not
necessarily given. Microbiological investigation should always
be obtained in dysenteric diarrhea, but, in severe cases, empiric
therapy should be started while awaiting the results. Finally, a
prolonged course of diarrhea in a child who is losing weight also
requires microbiological investigation and occasionally empirical
antibiotic treatment32
. Prolonged diarrhea may be caused by
a proliferation of intestinal bacteria in the proximal intestine,
Table 1. Clinical conditions and circumstances that may indicate antibiotic therapy.
Condition Putative bacterial agent Suggested antibiotic
Dysenteric diarrhea Shigella, Yersinia, Campylobacter Azithromycin, ciprofloxacin
Fever, increased
inflammation markers
Shigella Azithromycin, ceftriaxone
Prolonged diarrhea Gram-negative enterobacteria,
Clostridium difficile
Metronidazole, co-trimoxazole
SIBO Gram-negative enterobacteria Metronidazole, rifaximin, co-trimoxazole
Antibiotic-associated
diarrhea
Clostridium difficile, others Metronidazole, vancomycin
(only if Clostridium difficile is detected)
Traveler’s diarrhea ETEC, EPEC Azithromycin, ciprofloxacin
Toxic state Gram-negative enterobacteria,
Clostridium difficile
Ceftriaxone
EPEC, enteropathogenic Escherichia coli; ETEC, enterotoxigenic Escherichia coli; SIBO, small intestinal bacterial
overgrowth.
Page 3 of 10

Table 2. Risk factors indicating antibiotic therapy in children with acute
diarrhea.
Risk factors Evidence
Host-related risk factors
Age <3 (or 6) months Poor evidence but strong indication in neonates
Severity of clinical presentation Poor evidence but strong indications
Malnutrition Strong evidence
Chronic underlying disease
Immune deficiency
Strong evidence for children with IBD or HIV
Oncologic patients in immunosuppression
therapy
Setting-related risk factors
Day-care centers, hospitals,
and close institutions
Strong evidence, if spreading of bacterial
infection is an issue
Traveler’s diarrhea Strong evidence in adults, poor evidence in
children
HIV, human immunodeficiency virus; IBD, inflammatory bowel disease.
so-called small intestinal bacterial overgrowth (SIBO). A recent
paper proposes an interesting explanation of the link among
SIBO, infectious irritable bowel syndrome, and tropical sprue,
all conditions that are successfully treated with antibiotics33
.
Microbiological results may support the decision to treat with
antibiotics. Figure 1 shows the criteria for consideration when
deciding on antibiotic treatment for children with infectious
diarrhea.
Antibiotic therapy is always recommended for culture-proven
(or even suspected) Shigella gastroenteritis. Antibiotic therapy of
shigellosis has two purposes: reducing symptoms and steriliz-
ing the source of spreading, since humans are the only host of
Shigella. However, effective treatment of shigellosis is com-
plicated by the emergence of strains resistant to ampicillin,
trimethoprim-sulfamethoxazole, and tetracycline34
. Children with
non-typhoidal Salmonella gastroenteritis should not be treated
Figure 1. Criteria to decide antibiotic treatment in children with infectious diarrhea.
Page 4 of 10

routinely with antibiotics because treatment is not effective
on symptoms and does not prevent complications; in addition,
the use of antibiotics may be associated with a prolonged fecal
excretion of Salmonella1
. Antibiotic therapy for Campylobacter
gastroenteritis is recommended mainly for the dysenteric form
and to reduce transmission in day-care centers and institutions.
However, antibiotics are effective in reducing symptoms only if
started in the early stage of the disease (within 3 days of onset).
Host-related indications
Host-related indications include age, the finding of specific
pathogens, the presence of chronic underlying diseases, immune
suppression, and malnutrition (see Table 2).
Age. AGE in neonates should be treated with antibiotics.
Also, young infants (under 3 to 6 months of age) are candidates
for antimicrobial therapy according to expert opinion, although
there is no supporting evidence1
. In infants under 3 months of
age, microbiology should always be obtained and antimicrobial
treatment should be considered. If diarrhea is severe or if there
are signs or clinical symptoms of general infection, or also if
symptoms are worsening after 3 or more days from their onset,
antibiotic therapy should be started.
Chronic conditions. International guidelines state that children
with underlying immune deficiency, anatomical or functional
asplenia, corticosteroid or immunosuppressive therapy, cancer,
inflammatory bowel disease (IBD), or achlorhydria should receive
antibiotics when bacterial gastroenteritis is suspected. Although
this approach appears logical, data on efficacy are lacking, the
grade of evidence is weak, and there is no list of specific chronic
conditions that require antibiotic therapy for diarrhea.
Selected agents are associated with immunodeficiency or other
specific diseases, and the major bacterial opportunistic agent is
Cd.
Cd has reached epidemic proportions, particularly in industrial-
ized nations. Cd is a major agent of antibiotic-induced diarrhea
and of severe diarrhea in children with underlying chronic
conditions such as IBDs as well as oncologic diseases. Cd is also
responsible for self-limiting, sporadic cases of AGE in children,
although its pathogenic role is limited or questionable in children
under 36 months of age because of the high frequency of
carriers35
. Cd-induced antibiotic diarrhea often resolves by
discontinuation of the antibiotic. However, hypervirulent strains
may induce severe symptoms and should be treated with oral
metronidazole or vancomycin36
. For moderate or severe disease
particularly in oncologic patients, the first-line treatment is oral
metronidazole (30 mg/kg/day); oral vancomycin is reserved for
resistant strains37,38
. If antibiotic therapy fails, fecal transplantation
remains a feasible and effective option37
.
Patients with IBD are at increased risk of Cd infection.An increased
incidence of Cd infections in this population has been reported
also in pediatric patients37,39
. Nevertheless, there are substantial
problems in defining the role of Cd owing to the frequent
asymptomatic status. IBD patients have a higher asymptomatic
Cd carriage status: as high as 8% compared to a rate of 1% in
healthy subjects40
. Antibiotic exposure seems to be a less impor-
tant factor for clinically significant Cd infections in IBD patients.
The proposed mechanism of Cd infections involves an alteration
of the intestinal flora8
. In addition, clinically, IBD exacerba-
tions and Cd infections are similar in the IBD population, with
bloody diarrhea and systemic symptoms, such as fever, malaise,
anorexia, leukocytosis, hypoalbuminemia, and stool leukocytes
in both conditions. Antibiotics may be useful, although in both
IBD patients and oncologic patients there is a paucity of evidence
to guide antibiotic choice. Metronidazole has been associated
with a high rate of failure, and it may be reasonable to consider
vancomycin as first-line treatment of severe cases41
.
However, all the international guidelines recommend microbio-
logical examination and to start metronidazole or ciprofloxacin
in IBD children with diarrhea recurrence. Again, there are no
controlled studies to support this albeit reasonable strategy. Also,
in children with cancer, intestinal infections are a major threat
and require a comprehensive diagnostic approach38
.
Immunocompromised patients. The major source of informa-
tion on the link between incidence and severity of gastrointestinal
infections and immunodeficiency is derived from children with
AIDS. In 2010, a study from Kenya showed that diarrhea was
more common among human immunodeficiency virus (HIV)-
positive children than among HIV-negative children (321 versus
183 episodes respectively, p<0.01) and that diarrhea was associ-
ated with a 40% fatality rate. In addition, HIV-positive infants were
significantly more likely to experience persistent diarrhea than
HIV-negative infants (p<0.01). Although diarrhea was more
common among HIV-infected children, bacterial pathogens
such as Campylobacter and Shigella were not frequent, suggest-
ing that other pathogens (e.g. viruses, parasites, diarrheagenic
E. coli) or other causes (e.g. malabsorption, metabolic enteritis)
may be important in this population42
. However, Cryptosporidium
parvum is the classical agent of diarrhea in severely immuno-
deficient children, and its detection is considered a hallmark of
severe disease. HIV itself can act as an enteric pathogen through
the production of an enterotoxic effect43
.
Malnutrition. Children with severe acute malnutrition (SAM)
who present with AGE are generally treated with broad-spectrum
antibiotics, even in the absence of overt infection. The ration-
ale is that (a) malnourished children frequently have bacterial
infections (including bacteremia), (b) the diagnosis of infection
in malnourished children is difficult because clinical manifes-
tations (e.g. fever) may not be apparent, and (c) malnourished
children have an increased risk of small intestinal overgrowth.
However, while this approach has a rational basis, there is very
little evidence of its efficacy. A study from Malawi clearly dem-
onstrated the importance of antibiotic administration to children
with SAM even without evident clinical features of infection:
2,767 children with SAM eligible for outpatient care and aged
6–59 months were randomized to 7 days of treatment with oral
amoxicillin, cefdinir, or placebo. The 12-week mortality rates
were 4.8% (amoxicillin), 4.1% (cefdinir), and 7.4% (placebo),
with a relative mortality risk for placebo compared with amoxi-
cillin of 1.55 (95% CI 1.07–2.24) and for placebo compared with
cefdinir of 1.80 (95% CI 1.22–2.64)44
. SAM is associated with
Page 5 of 10

an increased mortality from infectious diseases, suggesting that
children with SAM are severely immunologically impaired.
However, the precise mechanisms underlying this relationship
are unclear. Diarrhea and malnutrition are common in young
children in developing countries, and malnutrition is associated
with increased severity of common infections. Death of severely
malnourished children is often the result of an infection. Children
with AGE were significantly more likely to have malnutrition
(OR=8.57; p<0.001), and malnutrition status was the only inde-
pendent factor associated with infection (OR=8.37; p<0.001)45
.
Environmental enteropathy, recently redefined as environmen-
tal enteric dysfunction, is the combined result of undernutrition,
repeated infections, and environment-related toxic damages occur-
ring in early life, requiring a comprehensive approach with anti-
infective drugs, hygiene measures, and nutritional rehabilitation
to prevent subsequent severe disabilities46
. Therefore, the manage-
ment of infection should be different in malnourished versus well-
nourished children, and a more aggressive antimicrobial strategy is
indicated in the former.
Choice of antimicrobial agent
In the past 10 years, new molecular diagnostic tests with a
multiplex polymerase chain reaction (PCR) panel have been
developed. They are faster than traditional tests, have a higher
sensitivity, and have the possibility to simultaneously test a wide
range of agents47
. Molecular diagnostics would enable the phy-
sician to initiate timely and targeted antibiotic therapy. Early
empiric antibiotic therapy will remain the therapy of choice for
severely affected patients.
The decision to treat a child with AGE and the choice of antimi-
crobial drug is challenging. There is a relatively broad pattern
of pathogens according to age, location, season, vaccine policy
(against rotavirus and others), and symptoms48,49
. Furthermore,
infections with multiple pathogens, which are common among
children with diarrhea, complicate treatment. Antimicrobial
resistance should also be considered in the antibiotic choice.
Knowledge of the local pattern of resistance is crucial to reduce
the number of failures. Antibiotic selection is based on two
major considerations: the chance of obtaining microbiological
results, including resistance pattern, and the severity of clinical
conditions.
The WHO recommends treating all episodes of blood in the
stools with antibiotics and to use ciprofloxacin as the first-line
drug. Alternatives are pivmecillinam, azithromycin, and ceftri-
axone50
. This recommendation has been confirmed, although in
recent years the rates of resistance are increasing25
. Fluo-
roquinolones are often empirically used in adults, and cepha-
losporins are used to treat children with suspected bacterial AGE.
Fluoroquinolones are effective against a wide variety of enteric
infections in adults, including shigellosis, salmonellosis, typhoid
fever, cholera, and Campylobacter infections. Like all quinolo-
nes, ciprofloxacin causes arthropathic effects in immature animals
and their use has been limited in children. However, several
studies have confirmed the safety of ciprofloxacin use in the
pediatric age group. Because of low cost and the availability of
an oral formulation, ciprofloxacin plays an important role in the
treatment of childhood acute invasive diarrhea, especially in poor
countries.
Often, in severe conditions, early empiric therapy is needed while
awaiting the results of investigations. If clinical conditions are
severe, parenteral therapy should be started soon. For parenteral
therapy of diarrhea, ceftriaxone or ciprofloxacin may be con-
sidered, as both are effective against Gram-negative bacteria.
In children with chronic conditions, metronidazole provides
an alternative option, as it is also effective against Cd. Oral
metronidazole can be considered for sequential therapy after
parenteral administration. Oral metronidazole is used for pro-
longed diarrhea, although there is little evidence of efficacy of
antibiotics32
.
SIBO is another indication for antibiotics. It may be difficult to
diagnose, as quantitative cultures of duodenal aspirate as well as
the breath hydrogen test are neither standardized nor reliable51
.
Co-trimoxazole and metronidazole are first-line drugs52
. The
latter is effective for bacterial agents, including Cd, as well as
against Giardia lamblia—all agents implicated in pro-
longed diarrhea. Recently, rifaximin has been used in clinical
(uncontrolled) trials with good results53
.
Co-trimoxazole is still largely used in the antimicrobial
therapy of diarrhea. It has been effective in malnutrition and
HIV-related enteropathy and is a major drug with multiple
indications in developing countries54
.
In high-income countries, untargeted antibiotic therapy should
be avoided. However, azithromycin is the drug of choice for
treating campylobacteriosis and is also appropriate for treating
shigellosis1
. The duration of treatment is 3–5 days.
Non-typhoidal Salmonella infections are common in many
settings and endemic in European children. Usually, they cause
mild, self-limiting gastroenteritis. However, bacteremia may be
a complication—particularly in immunocompromised children,
in those with sickle cell disease, and in young infants—and
in those children antibiotic therapy should be considered55
.
Recommended empiric oral treatment of non-typhoidal salmo-
nellae includes amoxicillin, azithromycin, or co-trimoxazole
and should be considered for at-risk children in relatively good
clinical conditions. Parenteral therapy should be started in chil-
dren with bacteremia or in those with complicated infections
(focal or invasive) and includes cefotaxime or ceftriaxone at high
dose (ceftriaxone 100 mg/kg/day)56
.
In the case of traveler’s diarrhea, antibiotic treatment is effec-
tive in reducing the duration and severity of diarrhea. Because
of the high rates of resistance to ampicillin and trimethoprim-
sulfamethoxazole, currently the drugs recommended include
azithromycin, ciprofloxacin, and rifaximin57
. Rifaximin may be
considered as a first-line treatment option in adults with uncom-
plicated traveler’s diarrhea because of its favorable efficacy,
tolerability, and safety profiles57
.
The choice of antibiotic therapy based on etiology is summarized
in Table 3.
Page 6 of 10

Table 3. Antibiotic choice based on etiology.
Organism Preferred therapy Alternative agents Efficacy
Campylobacter jejuni Azithromycin Ciprofloxacin,
vancomycin
Proven if started within 3 days of
symptom onset
Clostridium difficile Metronidazole Vancomycin Proven in severe cases
Non-typhoidal
Salmonella
Amoxicillin or ceftriaxone Trimethoprim-
sulfamethoxazole
Proven in children with toxic status,
in children under 3 months of age,
in at-risk children, and if systemic
or focal infections
Salmonella typhi Third-generation
cephalosporins
Chloramphenicol Proven
Shigella Azithromycin, ceftriaxone Cefixime, ciprofloxacin Proven
Yersinia Trimethoprim-
sulfamethoxazole
Ceftriaxone Proven in severe disease or
bacteremia
Vibrio cholerae Azithromycin Doxycycline
(>8 years), ciprofloxacin
Reduces duration by 50% and
shedding
ETEC Azithromycin (only for
traveler’s diarrhea)
Trimethoprim-
sulfamethoxazole
To be considered in selected cases
ETEC, enterotoxigenic Escherichia coli.
Conclusions
Rehydration is the key treatment for AGE, and active treat-
ment of diarrhea with probiotics or diosmectite should always be
considered, independent of etiology. Antibiotics are gener-
ally not necessary and can even be harmful in children, but they
should be given in selected circumstances. There are three
distinct sets of criteria that should be carefully considered: clini-
cal conditions, host-related factors, and setting. When there is a
potential indication for antibiotics, microbiological investiga-
tions should always be obtained prior to the start of therapy.
Empiric antibiotic therapy should be started soon after specimen
collection in infants and children in severe conditions. Co-
trimoxazole and metronidazole are to be considered for oral
administration. Azithromycin and rifaximin may also be used,
based on local consideration or if signs of colitis are observed.
Ceftriaxone, metronidazole, and ciprofloxacin may be considered
in children with systemic and invasive diseases. Young infants,
children with chronic conditions, and those in a toxic state or
with signs of systemic infection should be considered at risk of
systemic infections, and oral or parenteral antibiotic therapy may
be indicated. If mild symptoms are present and close observation
is feasible, it may be better to wait for microbiological results.
Antibiotic therapy in specific settings is also indicated if spread-
ing is an issue. Traveler’s diarrhea may require antibiotic therapy.
The choice of specific antibiotic should be based on etiology and
local resistance pattern.
In conclusion, while it is important to reduce the use of unnec-
essary antibiotics, there are circumstances in which these drugs
are needed and are potentially life-saving. However, their use is
far from being supported by evidence and requires careful
consideration of clinical and epidemiological issues.
Abbreviations
AGE, acute gastroenteritis; EAEC, enteroaggregative
Escherichia coli; EPEC, enteropathogenic Escherichia coli;
ETEC, enterotoxigenic Esherichia coli; Cd, Clostridium difficile;
HIV, human immunodeficiency virus; IBD, inflammatory bowel
disease; SAM, severe acute malnutrition; SIBO, small intestinal
bacterial overgrowth; WHO, World Health Organization.
Competing interests
The authors declare that they have no competing interests.
Grant information
The author(s) declared that no grants were involved in supporting
this work.
Acknowledgements
AG conceived the study. AGi and EB carried out the system-
atic literature research. AGi and EB prepared the first draft.
AG provided substantial contribution to the preparation of the
manuscript. EB and AGi prepared figures and tables. All authors
were involved in the revision of the draft manuscript and have
agreed to the final content.
Page 7 of 10

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Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON, CanadaZulfiqar Bhutta
No competing interests were disclosed.Competing Interests:
1
Centre for Tropical Medicine, University of Oxford, Oxford, UKStephen Baker
No competing interests were disclosed.Competing Interests:
1
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