REVIEW

CURRENT
OPINION Bacterial diarrhoea
Karen L. Kotloff

Purpose of review
This review describes recent findings about the burden of bacterial diarrhoea and its potential
complications, newer diagnostics, the emerging threat of multidrug resistance, and the promise of vaccines
in development.
Recent findings
Introduction of rotavirus vaccines in over 110 countries has changed the landscape of diarrheal pathogens.
In upper middle and high-income countries, the incidence of rotavirus-specific and all-cause gastroenteritis
has declined substantially, and norovirus has become the major pathogen in many settings. Bacterial
pathogens cause approximately 10–15% of episodes, most often Shigella, nontyphoidal Salmonella (NTS)
Campylobacter and Shiga toxin-producing Escherichia coli (STEC). In lower income countries, bacterial
pathogens remain a major cause of medically attended diarrhoea with Shigella, Campylobacter and
enterotoxigenic Escherichia coli (ETEC) predominating. Multidrug-resistant strains of Shigella, NTS and,
Campylobacter have emerged globally requiring judicious use of antibiotics according to current guidance.
Summary
Management of bacterial diarrhoea includes standard fluid and electrolyte therapy, vigilance for potential
complications, and use of antibiotics for children who have moderate-severe illness due to pathogens for
which efficacy has been demonstrated, or for those at high risk for severe disease. The threat of multiply
resistant strains provides impetus for preventive strategies such as development of vaccines.
Keywords
acute diarrhoea, bacterial, children, nontyphoidal Salmonella, Shigella

INTRODUCTION medically attended episodes of gastroenteritis in

Substantial reductions in mortality from diarrheal HIC/UMIC are viral in origin, with norovirus now
& &&

diseases among children under 5 years of age during predominating [4 ,5 ], while approximately 10%
&&

the past two decades have been attributed to
improved case management and widespread intro-
duction of rotavirus vaccine for infants. Nonethe-
less, an estimated 15 million cases and 500 000
deaths occur each year globally, with most of the
burden in low-and-lower middle-income countries
(LIC/LMIC). Even in high and upper middle-income
countries (HIC/UMIC), diarrheal diseases remain a
common illness among children [1]. Although
deaths in the U.S are now uncommon, an estimated
are bacterial [6,7 ,8,9]. Because it remains frequent,
it is critical that clinicians worldwide recognize the
epidemiology, clinical presentation and complica-
tions of bacterial enterocolitis so that appropriate
control measures and therapeutic options are
promptly initiated. This article focuses on the five
most common bacterial pathogens observed in HIC/
UMIC [Shigella, nontyphoidal Salmonella (NTS),
Campylobacter and Yersinia] and Shiga-toxin produc-
ing Escherichia coli (STEC), highlighting some perti-
&&

2.1 million outpatient visits, 254 000 emergency
department visits, and 68 600 hospitalizations occur
annually [2 ].
&
Historically, rotavirus has been the most com-
mon cause of viral diarrhoea, but with the dimin-
ishing burden of rotavirus disease globally as a result
of widespread vaccine introduction, re-examination
of the cause of medically attended episodes is essen-
tial to inform treatment and prevention strategies.
In contrast to LIC/LMIC where bacteria tend to be
the predominate cause of diarrhoea [3], most
nent differences seen in LIC/LMIC [7 ].
Division of Infectious Disease and Tropical Pediatrics, Center for Vaccine
Development and Global Health, University of Maryland School of
Medicine, Baltimore, Maryland, USA
Correspondence to Karen L. Kotloff, Division of Infectious Disease and
Tropical Pediatrics, Center for Vaccine Development and Global Health,
University of Maryland School of Medicine, 685 W. Baltimore Street,
HSF 480, Baltimore, MD 21201, USA. Tel: +1 410 706 8765;
e-mail: kkotloff@som.umaryland.edu
Curr Opin Pediatr 2022, 34:147–155
DOI:10.1097/MOP.0000000000001107

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Infectious diseases and immunization
KEY POINTS
 Bacterial diarrhoea continues to produce considerable
morbidity and mortality among infants and young
children globally.
 The inflammatory capability of many bacterial
enteropathogens produces a plethora of acute and
sometimes disabling manifestations (frequent stools,
fever, abdominal cramps and haematochezia), and
intestinal, disseminated and postinfectious
complications that may require hospitalization or repeat
healthcare visits, resulting in increased medical costs.
 Rapid multiplex molecular panels for detection of
gastrointestinal pathogens directly from stool samples
offer the advantage of reduced sample volume
requirements, broad pathogen detection without the
need to select specific tests and rapid turn-around, but
do not provide strain specificity to inform outbreak
evaluation, a positive test does not necessarily indicate
viable organisms, and, most importantly, antimicrobial
susceptibility results are not provided for
treatment decisions.
 Multidrug resistance is increasing among bacterial
enteric pathogens with a high incidence of severe
disease, particularly Shigella, NTS and Campylobacter,
serving is an impetus for developing well tolerated and
effective vaccines.
ETIOLOGIC AGENTS
Shigella, Campylobacter, Yersinia and
Salmonella
These agents all possess an invasive, inflammatory
phenotype and thus can result in blood and mucus
in the diarrhoea. Shigella, a uniquely human path-
ogen, is a major cause of childhood morbidity and
mortality in LIC/LMIC. The epidemiology of Shi-
gella infections varies throughout the world with S.
flexneri being the major cause of shigellosis in LIC/
LMIC, while S. sonnei is the major cause in HIC/
UMIC. S. boydii and S. dysenteriae also are associated
with shigellosis but at much lower frequencies than
the other two species of Shigella. Diarrhoea associ-
ated with Campylobacter, often related to exposure
to infected fowl, is due to two species with C. jejuni
being the major pathogen (causing 90 –95% of
Campylobacter infections) and C. coli associated
with the remaining cases. Yersinia also has two
species (Y. enterocolitica and Y. pseudotuberculosis)
known to cause diarrhoea in humans. In the USA,
diarrheoa caused by Yersinia often is associated
with exposure to pigs and pork products; outbreaks
related to preparation of chitterlings (pig intes-
tines) have been reported. Multiple species of Sal-
monella are associated with diarrheal illnesses. The
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most severe disease is caused by Salmonella enterica
subspecies enterica which is divided into two
groups: the human-restricted typhoidal Salmonella
(S. Typhi and S. Paratyphi A and B, which cause
enteric/typhoid fever), and NTS (most commonly
S. Typhimurium and S. Enteritidis), which com-
prise the majority of other serovars causing human
diarrheal disease globally [10]. Although most NTS
cause diarrheal disease, two strains [S. Typhimu-
rium sequence type (ST)313 and S. Enteritidis ST11]
have emerged in sub-Saharan Africa that are nota-
ble for multidrug resistance and the ability to cause
invasive disease with high mortality but little diar-
&&
rhoea [11 ]. Infants with HIV, malaria and/or mal-
nutrition are at greatest risk for these severe
infections.
Escherichia coli
Five pathotypes of E. coli are associated with diar-
rheal diseases in humans: Shiga toxin–producing E.
coli (STEC), most often due to serotype O157-H7, is a
cause of bloody diarrhoea and haemolytic uremic
syndrome (HUS) predominantly in HIC/UMIC fol-
lowing exposure to cattle or beef products; enter-
oinvasive E. coli (EIEC), a rare cause of foodborne
outbreaks mimicking shigellosis; enteropathogenic
E. coli (EPEC), a cause of watery diarrhoea in infants
in LIC/LMIC; enterotoxigenic E. coli (ETEC), a com-
mon cause of secretory diarrhoea in infants from
LIC/LMIC and travellers to LIC/LMIC; and enter-
oaggregative E. coli (EAEC), associated with acute or
persistent watery diarrhoea in some studies [12].
EPIDEMIOLOGIC FEATURES OF
BACTERIAL DIARRHOEA
Bacterial enteropathogens share many clinical,
epidemiological and pathogenic features, includ-
ing (Table 1) being transmitted by the faecal-oral
route. Shigella, a human-restricted pathogen,
spreads readily from person-to-person directly or
via contaminated fomites, food or water [13]. NTS,
Campylobacter, STEC and Yersinia infect humans
from animal or human reservoirs via contami-
nated food, cross-contaminated of food prepara-
tion areas or foods [14], or contact with infected
animals or their environments [15 – 17]. Most
transmitting animals are asymptomatic, but pup-
pies and kittens with Campylobacter and Yersinia
can have diarrhoea [18,19]. Mass production of
meat and agricultural products enables wide-
spread contamination with the above-mentioned
pathogens, which has resulted in many well docu-
mented food-borne outbreaks [20,21]. The low
infectious dose required by Shigella, STEC and C.
Volume 34  Number 2  April 2022
 Bacterial diarrhoea Kotloff

Table 1. Epidemiologic risk factors for bacterial diarrhoea

Exposure Bacterial pathogen

Contact with an ill person Shigella spp., nontyphoidal Salmonella (NTS), Campylobacter spp., Shiga toxin producing E. coli
(STEC)
Travel Shigella spp., NTS, Campylobacter spp.
Foodborne - meat (raw, STEC (hamburger, produce contaminated with feces from ruminant animals), NTS (egg, poultry,
undercooked meat or produce, unpasteurized milk), Campylobacter (poultry, egg, produce, unpasteurized milk), Yersinia
other animal products, enterocolitica (pork, chitterlings, unpasteurized milk), wild game (Y. pseudotuberculosis)
cross-contaminated
foods, surfaces or
equipment)
Surface water Campylobacter spp.
contaminated with
faeces from wild birds
Institutional exposure or Shigella spp., STEC
childcare
Animal-to-human Campylobacter spp. (wild and domestic animals, especially birds; puppies or kittens with diarrhoea);
NTS (domestic animals on farms, asymptomatic pet reptiles, amphibians, birds, puppies, kittens);
STEC (ruminants, petting zoos); Y. enterocolitica (swine, puppies or kittens with diarrhoea); Y.
pseudotuberculosis (ungulates [deer, elk, goats, sheep, cattle], rodents, rabbits, birds)
MSM Shigella spp., NTS
Blood transfusion Yersinia spp.

jejuni facilitate transmission through person-to- CLINICAL FEATURES OF BACTERIAL

person or faecal-oral spread (e.g. particularly in
settings wherein hygiene and sanitation are sub-
optimal, including day care centres and institu-
tional settings). In contrast, NTS and Yersinia have
a higher infectious dose, which usually requires
transmission via a food or water vehicle. The
increased availability of pathogens in the environ-
ment by either prolonged faecal shedding (NTS),
or a large environmental or animal reservoir (e.g.
Campylobacter, NTS, Yersinia, STEC) also increases
opportunities for transmission.
The season of the year and weather may
provide a clue to the cause of the diarrhoea with
NTS, Shigella and Campylobacter peaking in warm
weather, while the cold-tolerance of Yersinia likely
drives the higher prevalence in northern Europe and
Canada and the ability to survive in refrigerated
blood products.
Host factors that increase the risk and severity of
bacterial diarrhoea include age less than 5 years, low
gastric acidity and inflammatory bowel disease. Risk
for invasive disease includes age less than 3 months
and immunodeficiency. NTS risk is associated with
impaired host responses to intracellular organisms
(e.g. HIV, chronic granulomatous disease) and func-
tional asplenia from sickle cell anaemia. Patients
with hemoglobinopathies who are predisposed to
iron overload states and chelation therapy have an
increased risk of sepsis and liver abscesses due to
certain Y. enterocolitica serogroups [22].
DIARRHOEA
Symptoms associated with bacterial diarrhoea are
abrupt onset, frequent stools (more than four per
day), no vomiting at the onset, fever, abdominal
cramps, haematochezia or occult blood
&& &
[7 ,8,23,24,25 ,26]. Children infected with bacte-
rial pathogens generally experience less severe vom-
iting and dehydration than those with viral
diarrhoea but have other indicators of more severe
disease such as increased likelihood of hospitaliza-
tion or a second healthcare visit compared with
those with viruses [27].
The classic bacterial pathogens present with one
of five clinical syndromes. The most common is
simple acute watery diarrhoea, which can be accom-
panied by fever, abdominal cramps and vomiting.
Children under 2 years of age may experience con-
comitant silent bacteraemia, particularly with NTS
[28,29]. Illness is usually self-limited. In a subset of
children, another presentation may occur with
watery diarrhoea progressing (in hours to days) to
frank dysentery with frequent small volume bloody,
mucoid stools often accompanied by tenesmus (rec-
tal straining). A third presentation, often called
enteric fever, is an invasive, blood-borne disease
producing a febrile illness, usually without localized
infection. Children less than 3 months of age and
those with immunodeficiency or haemolytic anae-
mia are at greatest risk [30]. Children less than
3 months old and those with certain comorbidities

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Infectious diseases and immunization
may present with a clinical picture characterized by
bloodstream invasion followed by systemic spread
that can produce distant infections at any site. NTS
is the most frequent culprit [29] and the major cause
of osteomyelitis in children with sickle cell anaemia.
Toxins associated with Shigella and Campylobacter
may result in seizures and encephalopathy, which
may precede the onset of diarrhoea. The final rec-
ognized syndrome is vertically transmitted perinatal
infection that has a spectrum of illness ranging from
isolated diarrhoea or haematochezia to fulminant
neonatal sepsis. A particularly virulent pathogen is
C. fetus which can cause chorioamnionitis and abor-
tion in pregnant women, as well as neonatal sepsis
and meningitis.
STEC, an organism associated with haemolytic-
uremic syndrome (HUS), presents with crampy
abdominal pain, nonbloody diarrhoea and some-
times vomiting. However, within hours to days, the
abdominal pain worsens and the diarrhoea becomes
bloody, which may last a week or more. A clue to
help differentiate STEC from other causes of bloody
diarrhoea is that the stools associated with STEC
haemorrhagic colitis are large volume and high
fever is uncommon as compared to the small vol-
ume stools and moderate to high fevers associated
with other causes of invasive diarrhoea.
COMPLICATIONS OF BACTERIAL
DIARRHOEA
Bacterial enteropathogens are associated with a pano-
ply of complications which vary by pathogen
(Table 2). Although dehydration and electrolyte
abnormalities are the primary adverse consequences
of diarrhoea regardless of cause, persistent diarrhoea
&
and growth faltering can ensue [3,31 ]. Other less
common but well recognized complications of bacte-
rial diarrhoea include cholecystitis, pancreatitis,
hepatic or splenic abscess, and mesenteric adenitis
mimicking appendicitis. Intestinal injury can lead
to rectal prolapse, toxic megacolon, intestinal obstruc-
tion and perforation, as well as pseudomembranous
colitis and intussusception. Toxins released by Shigella
and Campylobacter can result in end organ damage.
Apart from direct complications of the infec-
tion, bacterial pathogens, particularly Campylobac-
ter, Shigella and NTS, also may induce indirect effects
due to immunological cross-reactivity between bac-
terial antigens and host tissues. One example is
reactive arthritis, seen particularly in persons with
an HLA-B27 haplotype (Table 2) [32]. Campylobacter
infection has been causally linked to Guillain-Barré
syndrome resulting from immunological cross-reac-
tivity between bacterial lipo-oligosaccharides and
peripheral nerve gangliosides and there is some
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evidence suggesting that Campylobacter and NTS
enterocolitis predisposes to inflammatory bowel
disease [33,34].
A dreaded complication of STEC infection is
HUS, the leading cause of acquired renal failure in
children. HUS develops in 5–10% of patients
approximately 2–14 days after diarrhoea begins.
Onset of HUS is unlikely once diarrhoea has resolved
for 2 or 3 days and there is no evidence of haemol-
ysis. Risk factors include age 6 months to 4 years,
bloody diarrhoea, fever, leukocytosis and anti-
motility drugs. Most patients are no longer excreting
STEC when they develop HUS.
PATHOGENESIS
Shigella, NTS, Campylobacter and Yersinia invade the
intestinal epithelium, elicit inflammatory cytokines
with or without toxin production, and subvert the
innate host immune. Intestinal inflammation, epi-
thelial destruction sometimes with ulceration, and
abscess formation may ensue [35]. Shigella and Cam-
pylobacter rarely disseminate beyond the intestine,
while NTS resides within macrophages from which
it can penetrate to the blood stream or reticuloen-
dothelial system. Yersinia notably sequesters in
lymph nodes including Peyer’s patches and mesen-
teric lymph nodes and induces inflammation,
which is why these infections often are misdiag-
nosed as appendicitis. STEC attaches to the colonic
epithelium and elaborates two potent cytokines,
Shiga-like toxins 1 and 2; the latter is more strongly
associated with bloody diarrhoea and HUS.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of acute watery diarrhoea
includes viral gastroenteritis, most commonly due to
norovirus, rotavirus, astrovirus, sapovirus and adeno-
virus serotypes 40 and 41. Clinicians should be cog-
nizant that paediatric SARS-CoV-2 infection and the
associated multisystem inflammatory syndrome in
children (MIS-C) frequently presents with gastroin-
testinal symptoms, sometimes as the sole manifesta-
tion [36]. Intestinal complications of SARS-CoV-2
infection can include bloody diarrhoea, appendicitis,
intussusception, pancreatitis, abdominal fluid collec-
tion and mesenteric adenitis. Bacterial agents seen
mostly in LIC/LMIC, for example ETEC, cholera and
enteropathogenic E. coli as well as protozoal diar-
rhoea should be considered when the clinical and/
or epidemiologic findings are suggestive. Persistent
watery diarrhoea and chronic and relapsing diar-
rhoea suggest noninfectious causes. Noninfectious
causes of bloody diarrhoea include anal fissures, juve-
nile polyps and Meckel’s diverticulum.
Volume 34  Number 2  April 2022
 Bacterial diarrhoea Kotloff

Table 2. Complications of common bacterial diarrhoea agents

Nontyphoidal Campy Shiga

Salmonella Shigella lobacter Yersinia toxin-producing
Complication (NTS) spp. spp. spp. E. coli (STEC)

Intestinal
Persistent or recurrent diarrhoea
Postinfectious irritable bowel syndrome
Protein-losing-enteropathy
Toxic megacolon
Intestinal perforation
Rectal prolapse
Pseudomembranous colitis
Appendicitis
Intussusception
Chronic carriage
Extra-intestinal complications
Dehydration, metabolic abnormalities,
malnutrition, micronutrient deficiency
Local noninvasive spread
Local invasion
Systemic invasion with bacteraemia and
possible metastatic foci
Seizures, encephalopathy
Leukemoid reaction, bandemia
Exudative pharyngitis, cervical
adenopathy, scarlatiniform rash
Foetal/placental infection
Postinfectious
Reactive arthritis
Guillain-Barré syndrome
Haemolytic uremic syndrome
Myocarditis, pericarditis
Glomerulonephritis
Erythema nodosum
Haemolytic anaemia
x x x X
x x x .
x
x x x x
x x x x x
x x x . x
x x x
x x x
x x x x
x
x x x x
x (vaginitis, urinary x (urinary tract
tract infection) infection)
X (cholecystitis) x (mesenteric x (mesenteric
adenitis, rare) adenitis)
x x x x
x x
x x
x
x X (C. fetus)
x x x x
x
x (S. dysenteriae x
type 1
x x
x x x
x x

EVALUATION factors, such as travel, animal and ill human con-

Clinical assessment
Guidelines for the evaluation and management of
&
infectious diarrhoea are available [37 ]. The initial
approach should focus on the hydration status and
electrolyte balance, evidence of sepsis, invasive bac-
terial infection and known complications of bacte-
rial diarrhoea. Duration of diarrhoea; stool
frequency, amount, presence of blood; vomiting;
solid and liquid oral intake; and presence of comor-
bidities that might increase the risk or severity of
disease should be interrogated. Once the patient is
stabilized, the focus can pivot to detecting risk
tacts, childcare attendance, healthcare exposures,
recent antibiotics, sexual practices and clinical fea-
tures that may suggest specific causes.
Diagnostic testing
Most mild diarrheal illnesses are viral and do not
require diagnostic testing. Stool cultures for bacte-
rial pathogens are expensive so should be restricted
to patients with suspected bacterial infection who
may require antibiotics based on age, underlying
health, immune competence and disease severity. A
suspected outbreak is another indication to search

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Infectious diseases and immunization
for a cause, ideally in coordination with public
health authorities. However, as stool cultures take
several days to yield results, therapeutic decisions
&
may be needed before results are available [37 ].
When a stool specimen cannot be promptly sub-
mitted to the laboratory, a properly collected rectal
swab (discoloured or with visible faecal material) in
transport media is an acceptable alternative. Nosoco-
mial acquisition of bacterial enteric pathogens is rare
so that, with the exception of when Clostrdiodes
difficile is suspected, stool evaluation should not be
performed for patients whose diarrhoea developed
more than 3 days after hospital admission.
Several culture-independent rapid multiplex
molecular panels for detection of viral, bacterial and
protozoal gastrointestinal pathogens directly from
stool samples are FDA-approved. These methods offer
some advantages over conventional diagnostics,
including reduced sample volume requirements,
broad coverage without the need to select specific
tests, enhanced ability to detect coinfections,
increased sensitivity and rapid turn-around. However,
these tests do not provide strain specificity to inform
outbreak evaluation. In addition, a positive test does
not necessarily indicate viable organisms, and antimi-
crobial susceptibility results are not provided for treat-
ment decisions. Therefore, concomitant culture is
advised or required by public health authorities.
A complete blood count and blood culture should
be obtained if the history and physical examination
(such as fever and/or bloody stool, younger than
3 months or immunocompromising conditions) raise
the concern for systemic bacterial infection. Endos-
copy with biopsy may be indicated when diarrhoea
persists with no identifiable cause, the child is immu-
nocompromised or pseudomembranous colitis or
inflammatory bowel disease is suspected.
MANAGEMENT
General principles
The following principles guide the management of
any diarrheal illness in children: rehydration with
an oral rehydration solution (ORS), avoiding fluids
with high glucose (e.g. fruit juices and soda bever-
ages) or high sodium (e.g. chicken broth), which will
exacerbate diarrhoea; continued breastfeeding;
additional ORS for ongoing diarrheal losses; re-feed-
ing with an age-appropriate diet once dehydration is
corrected (complex carbohydrates, fresh fruits, lean
meats, yogurt and vegetables); and no unnecessary
laboratory tests or medications. Indications for hos-
pitalization include severe dehydration or moderate
dehydration with ongoing diarrhoea or vomiting,
suspected or confirmed bacteraemia, metastatic
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bacterial infection, HUS or intra-abdominal compli-
cation.
Antibiotics
Justification for limiting the use of antibiotics for
suspected or proven bacterial diarrhoea in children
include most episodes are viral; most bacterial diar-
rhoea is self-limited among otherwise healthy chil-
dren; antibiotic resistance is increasing; antibiotics
can prolong excretion of NTS without improving
clinical outcome in uncomplicated enterocolitis
[38]; and antibiotic treatment of STEC infection
&&
may increase the risk of HUS [39,40,41 ].
Antibiotic therapy is recommended for children
with pathogens for which efficacy has been demon-
strated (Table 3). The following criteria should
prompt treatment: diarrhoea that is moderate-to-
severe or not improving; age less than 3 months;
suspected sepsis or disseminated infection; and
immune dysfunction or other comorbidity associ-
ated with complications such as haemolytic anae-
&
mia for NTS [42 ] or iron overload syndrome for
Yersinia [43]. Probiotic bacteria for prevention and
therapy of diarrhoea have demonstrated no consis-
tent benefit [44].
High frequencies of resistance to previous first-
line drugs for Shigella, NTS and Campylobacter have
made ciprofloxacin and azithromycin the drugs of
choice for empirical oral therapy, but resistance is
now emerging to these newer drugs. Resistance/non-
susceptibility to ciprofloxacin or azithromycin is
found in 24 and 0.5% of Shigella, 8 and 0.5% of
NTS, and 28 and 4% of Campylobacter, respectively;
3–4% of Shigella and NTS are resistant to ceftriaxone
(https://www.cdc.gov/drugresistance/pdf/threats-
report/2019-ar-threats-report-508.pdf). In parts of
the world, strains have arisen that are resistant to
all first line drugs. Multidrug-resistant strains of
these three pathogens combined are responsible
for more than 730 000 diarrheal episodes and 140
deaths annually in the U.S. Accordingly, the CDC
has declared antibiotic-resistant NTS, Shigella
and Campylobacter serious threats that require
new interventions.
The increasing prevalence of antibiotic resis-
tance among bacterial enteropathogens requires
that susceptibility be tested on all isolates for which
treatment is being considered. Awareness of local
susceptibility patterns is also useful to guide treat-
ment decisions.
The inclusion of fluoroquinolones in the treat-
ment of clinically significant infections that have
developed resistance to previously recommended
regimens is now supported by considerable safety
&&
data in children [45 ].
Volume 34  Number 2  April 2022

Table 3. Antibiotic therapy
Enteropathogens Antimicrobials for simple diarrhoea
Campylobacter Moderate-to-severe:
Azithromycin or ciprofloxacin (oral)
Nontyphoidal Salmonella Not indicated
Shigella Moderate to severe:
Ciprofloxacin or azithromycin (oral); For
susceptible strains: ampicillin, trimethoprim/
sulfamethoxazole or cefixime
Yersinia Not recommended (efficacy unproven)
Shiga toxin-producing E. coli (STEC) Not indicated
a
Antibiotics should be considered for children with severe enterocolitis, sepsis, or disseminated disease, or those with increased risk of disseminated disease:
young age (<3 months), immunodeficiency, hemolytic anemia, and asplenia.
VACCINE DEVELOPMENT
There are no licensed vaccines against the bacterial
diarrheal pathogens that are the focus of this review.
Renewed global health interest in vaccine develop-
ment for Shigella and NTS in particular is driven by
increasing recognition of the burden of severe dis-
ease, concerns about the continuing emergence of
multidrug-resistant strains, and by hopes that pre-
vention of illness by vaccination will reduce the
burden of disease for which unnecessary antibiotic
treatment is administered. For Shigella, vaccine
development aims to mimic the serotype-specific
immunity that has been observed in animal models,
field observations and in controlled human chal-
lenge trials. Although several live-attenuated and
conjugate vaccine candidates have shown promis-
ing results in adults and older children, none
appeared efficacious against shigellosis in young
children living in endemic regions who weather
the greatest disease burden. Of the candidates cur-
rently under development [13,46], S. flexneri 2a
bioconjugate (Flexyn2a) developed by Limmatech
(GSK) did not reach its primary endpoint in a Shi-
gella-controlled human infection model (CHIM)
study but protected against moderate to severe shig-
ellosis/dysentery [47]. The quadrivalent vaccine is
being tested in Kenya. Also in the clinical pipeline is
an S. flexneri 2a synthetic O-antigen conjugated to
tetanus toxoid developed by investigators at Institut
Pasteur [48]. The vaccine was highly immunogenic
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Bacterial diarrhoea Kotloff
Antimicrobials for complicated infection (sepsis,
intestinal complications, disseminated foci), or at
a high risk for complicated illnessa
Complicated enterocolitis:
Longer duration of oral therapy or carbapenams if
intravenous route required; add aminoglycosides if
life-threatening.
Complicated enterocolitis:
Ciprofloxacin, third-generation cephalosphorins or
azithromycin. For susceptible strains: ampicillin and
trimethoprim/ sulfamethoxazole Duration of therapy
is guided by the site of infection and sterilization of
blood cultures
Ceftriaxone if intravenously therapy needed;
ampicilllin or trimethoprim/ sulfamethoxazole
intravenously if strain is susceptible
Ceftriaxone intravenously. Add gentamicin if life-
threatening. Ciprofloxacin or trimethoprim-
sulfamethoxazole in lieu of the third-generation
cephalosporin for susceptible strains.
Consult infectious disease specialist
in Israeli adults and will proceed to a CHIM in the
U.S. in parallel with dose-descending Phase 1-2 trials
in Kenya with the goal of conducting a Phase 3
efficacy trial of a multivalent formulation in infants
around 6–9 months of age. Another promising strat-
egy is to confer protection against both Shigella and
ETEC using a live, oral, multivalent vaccine contain-
ing attenuated Shigella strains expressing the immu-
noprotective colonization factor antigens and the
heat label toxin binding domain of ETEC [49]. The
combination vaccine targets two pathogens that are
important causes of disease among infants and
young children in LIC/LMIC as well as travellers.
In a similar vein, a trivalent typhoid as well as
invasive NTS Salmonella glycojugate vaccine are in
clinical development [50] in parallel with a live
attenuated vaccine development programme [51].
CONCLUSION
Bacterial enteropathogens are an important cause of
acute diarrhoea among children worldwide. Knowl-
edge of the epidemiology informs the clinician how
to counsel families about safe food handling and
hygienic practices that can prevent zoonotic trans-
mission (see https://www.cdc.gov/onehealth/basics/
zoonotic-diseases.html). Although most episodes are
self-limited, the clinician must learn to recognize the
episodes that are likely to benefit from antibiotics
while minimizing unnecessary treatment. Multidrug
www.co-pediatrics.com 153
Infectious diseases and immunization
resistance among enteric pathogens with high inci-
dence of severe disease, particularly Shigella and NTS,
is an impetus for developing well tolerated and effec-
&
tive vaccines [52 ].
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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