REVIEW

CURRENT
OPINION Update on nonantibiotic therapies for
acute gastroenteritis
Anna Funk a, David Schnadower b, and Stephen B. Freedman c

Purpose of review
The aim of this review is to provide an update of nonantibiotic therapies for acute gastroenteritis (AGE),
focusing on antiemetics and probiotics.
Recent findings
The mainstay of therapy for nonsevere AGE remains oral rehydration therapy (ORT). Recent randomized
controlled trials and metaanalyses have further strengthened the evidence-base supporting single-dose
ondansetron administration in emergency departments to facilitate ORT based on evidence that it safely
reduces intravenous fluid administration and hospitalization rates. Intravenous ondansetron administration
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and multiple-dose use should be avoided. A bimodal release ondansetron formulation was shown to
improve outcomes in adolescents and adults with AGE in one study, but further evidence is required to
support use. Recent large trials evaluating probiotic administration demonstrated a lack of benefit and
guidelines that recommend their use should reevaluate their positions in light of this evidence. Furthermore,
caution should be exercised when use is considered in high-risk populations and settings.
Summary
The benefits, dosing/route, and target populations most likely to benefit from ondansetron have been
further clarified. Optimization of the real-life effectiveness of this therapy will require implementation
strategies. Recent high-quality evidence showing a lack of efficacy and potential harm associated with
probiotic use suggests that routine use for AGE should be discouraged.
Keywords
acute gastroenteritis, ondansetron, probiotics

INTRODUCTION pathogen panels have become increasingly available

Worldwide, acute gastroenteritis (AGE) is the second
largest contributor to mortality in children aged one
month to five years, accounting for more than
500 000 deaths in this age group in 2015 [1].
In the United States, there are approximately 180
million incidences of AGE each year, resulting in the
hospitalization and death of 600 000 and 5000 per-
sons, respectively [2]. Despite its ubiquitous nature,
quantifying the economic impact is challenging
because of AGE’s syndromic nature. Nonetheless,
the most common cause of medically attended AGE
in children in the United States, norovirus [3],
accounts for over 4 billion USD in direct health
system and 60 billion USD in societal costs annually
[4] with children under five accounting for two-
thirds of these costs [4].
AGE is characterized by vomiting, diarrhea, fever,
and abdominal pain. The relative balance, duration,
and intensity of these symptoms vary according to
host factors and etiologic pathogen. As polymerase
chain reaction-based multiplex gastrointestinal
[5], the ability to rapidly identify pathogens has
increased exponentially. Although these advances
have enabled the identification and study of specific
pathogens [6], the cost of testing is a concern, and
these panels need to be integrated into care wisely [7].
a
Department of Pediatrics, Alberta Children’s Hospital, Alberta Child-
ren’s Hospital Research Institute, Cumming School of Medicine, Univer-
sity of Calgary, Calgary, Alberta, Canada, bDepartment of Pediatrics,
Division of Emergency Medicine Cincinnati Children’s Hospital, Cincin-
nati College of Medicine, Cincinnati, Ohio, USA and cDepartments of
Pediatrics and Emergency Medicine, Sections of Pediatric Emergency
Medicine and Gastroenterology, Alberta Children’s Hospital, Alberta
Children’s Hospital Research Institute, Cumming School of Medicine,
University of Calgary, Calgary, Alberta, Canada
Correspondence to Stephen B. Freedman, MDCM, M.Sc., Alberta
Children’s Hospital Foundation Professor in Child Health and Wellness,
Alberta Children’s Hospital Research Institute, Cumming School of
Medicine, University of Calgary, Calgary, Alberta, Canada.
Tel: +1 403 955 7740; e-mail: Stephen.freedman@ahs.ca
Curr Opin Infect Dis 2020, 33:381–387
DOI:10.1097/QCO.0000000000000670

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Gastrointestinal infections
KEY POINTS
 Randomized controlled trials continue to show benefit
and safety of single-dose oral ondansetron for AGE in
children in emergency departments.
 In retrospective studies, the provision of prescriptions
for home ondansetron use following emergency
department discharge does not appear to
be beneficial.
 Recent large, high-quality randomized trials on
probiotic therapy for AGE have demonstrated no
benefit when compared with placebo.
 Reports of concerning adverse events in high-risk
populations linked to probiotic use indicate the need to
balance the evidence supporting use with the potential
for untoward events.
The mainstay of therapy for individuals suffer-
ing from AGE, in the absence of severe dehydration
and intractable vomiting, is oral rehydration (ORT)
&
[8,9 ]. In spite of its effectiveness and relative ease of
administration, this low-cost therapy continues to
be underused [10]. Because of the risk of serious side-
effects and death, antimotility agents continue to be
contraindicated in children [8,11]. Similarly, anti-
biotics are not recommended for use as part of
routine care in high-income countries. Even among
hospitalized patients with presumed sepsis, antibi-
otic use is not associated with improved outcomes
[12]. Moreover, use in Shiga toxin-producing Escher-
ichia coli infection is linked to the development of
hemolytic uremic syndrome [13]. To date, no effec-
tive antiviral therapies have been identified for AGE
[14]. Consequently, the focus of AGE treatment is
the reduction of its most concerning symptoms to
facilitate ORT and limit dehydration. In this review,
we will examine recent developments regarding the
evidence of efficacy and safety of select interven-
tions and discuss areas needing further research.
ANTIEMETICS
Frequent and severe vomiting makes ORT challeng-
ing and increases caregiver and healthcare provider
discomfort, leading to increased use of intravenous
fluids, even in the absence of significant dehydra-
tion. To reduce vomiting and facilitate successful
ORT, antiemetic treatments are commonly provided
to children and adults with AGE. Although several
antiemetics (e.g., domperidone) have been demon-
strated to be ineffective [15], others (e.g., ondanse-
tron) have a strong evidence base of efficacy in select
&
populations [16,17 ]. However, concerns related to
potential side-effects and a lack of clear real-life
382 www.co-infectiousdiseases.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
effectiveness [18,19] have led to variation in guide-
line recommendations. A review of 15 pediatric clin-
ical practice guidelines published between 2005 and
2014 identified conflicting recommendations regard-
ing the use of antiemetics in children with AGE [20].
Although, in 2011, the Canadian Pediatric Society
recommended the use of ondansetron in children
presenting to emergency departments with AGE and
mild–moderate dehydration or oral rehydration
therapy failure [21], in 2009, the United Kingdom’s
National Collaborating Centre for Women’s
and Children’s Health [22] and the 2012 World
Gastroenterology Organisation guidelines [23] do
not recommend use of antiemetics for AGE in
children. More recent recommendations from the
Infectious Disease Society of America contain a weak
recommendation for use of antiemetics in adoles-
cents and children over four years of age to facilitate
oral rehydration [8], whereas the American College
of Gastroenterology guidelines do not mention
&&
antiemetic use at all [24 ].
Children
Of the various antiemetics that are prescribed, ondan-
setron remains the only drug for which there is
convincing and high-quality evidence of efficacy
&
and safety in children [17 ]. In a network metaanaly-
sis published in 2020 that examined the comparative
efficacy and safety of dexamethasone, dimenhydri-
nate, domperidone, granisetron, metoclopramide,
and ondansetron, 24 trials published between 1979
and 2018 were identified. Ondansetron was the only
safe antiemetic associated with the cessation of vom-
iting (odds ratio [OR] ¼ 3.6, 95% confidence interval
[CI]: 2.2–6.3), while decreasing both the likelihood of
hospitalization (OR ¼ 0.3, 95% CI: 0.2–0.6) and intra-
venous rehydration use (OR ¼ 0.3, 95% CI: 0.2–0.5),
&
and also being found to be safe [17 ].
The aforementioned metaanalysis did not
include multiple recent randomized controlled
trials (RCTs) examining the use of single-dose
ondansetron in children with AGE in low-middle
&& &&
income settings [24 ,25 ,26,27]. Two RCTs com-
paring single-dose ondansetron with placebo were
conducted in Karachi, Pakistan, one enrolling dehy-
&&
drated children [24 ], and the other nondehydrated
&&
children [25 ]. Among dehydrated children, ondan-
setron led to a reduction in vomiting (OR ¼ 0.4, 95%
CI: 0.3–0.6) and a decreased in intravenous rehy-
dration administration (OR ¼ 0.7, 95% CI: 0.5–1.0)
&&
[24 ]. However, in nondehydrated children ondan-
setron administration neither reduced vomiting
(OR ¼ 0.8, 95% CI: 0.5–1.1) or intravenous rehydra-
tion fluid administration (OR ¼ 1.0, 95% CI: 0.6–
&&
1.6) [25 ]. In Vietnam, a recent RCT that enrolled
Volume 33  Number 5  October 2020
 Update on nonantibiotic therapies for acute gastroenteritis Funk et al.
children with mild-to-moderate dehydration found
that single-dose ondansetron significantly reduced
vomiting (risk ratio ¼ 0.3, 95% CI: 0.2–0.6) and
intravenous rehydration use (risk ratio ¼ 0.5, 95%
CI: 0.3–0.8) [27].
Concerns surrounding ondansetron’s potential
side-effects have been a primary reason for the reluc-
&
tance of some guidelines to recommend use [9 ].
Specifically, as with many other widely used drugs
(e.g., macrolides) [28], the serotonin (5-HT3) recep-
tor antagonists are associated with electrocar-
diographic alteration, most notably, prolongation
of the QT interval. An important consideration is
that any QT prolongation is related to mode of
administration. The peak serum level after oral
ondansetron administration is only 3–34% of that
achieved relative to an intravenous dose [29,30].
Given that the goal of ondansetron administration
is to avoid the use of intravenous rehydration, even
though intravenous ondansetron can be beneficial
[31], it should be administered orally, followed by an
ORT period, to hopefully eliminate the need for
intravenous insertion. There has not yet been a
single report describing a ventricular arrhythmia
associated with the administration of a single dose
of oral ondansetron [32]. Moreover, in 2018, two
studies were published regarding the emergency
departments administration of intravenous ondan-
setron to children and both found no differences in
QT prolongation when compared with control
groups [33,34]. In these studies, the mean differ-
ences in the QT interval, adjusted for the heart rate
(i.e. QTc) was 0.4 [33] and 3 ms, respectively.
A separate concern relates to the potential for
increased diarrhea associated with ondansetron use.
However, a network metaanalysis concluded, with
high certainty, that ondansetron was similar to
placebo in terms of overall side-effects and was
possibly similar to placebo, with low certainty, as
&
it related to diarrhea incidence specifically [17 ].
A key unknown element related to ondansetron
remains the efficacy of use following emergency
department discharge. Although no recent clinical
trials have addressed this issue, in a retrospective
comparative cohort study conducted in an urban
pediatric emergency departments, the authors
found that 36% of children with AGE (N ¼ 11 785)
were discharged home with an ondansetron pre-
scription. However, they found no association
between ondansetron prescriptions and emergency
&
departments revisits [35 ]. A similar lack of benefit
was reported from a smaller (N ¼ 996) group of
children with AGE among whom 71% were dis-
&
charged with prescriptions for ondansetron [36 ].
Even though these studies attempted to adjust for
confounding by indication, such approaches are
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
unlikely to capture all relevant factors, thus, a for-
mal clinical trial addressing this topic is needed.
Adults
In adults, there have been few antiemetic trials in
the context of AGE. A recent review identified 6
trials, all focused on nausea as the primary outcome,
and none demonstrated evidence of superiority over
placebo [37]. However, in a recent 21-site RCT which
enrolled adolescents (>12 years old) and adults,
oral bimodal release ondansetron administration,
compared with placebo, significantly improved
the chance of ‘treatment success’ in those with acute
gastroenteritis (risk ratio ¼ 1.3, 95% CI: 1.1–1.5)
&&
[38 ]. The latter was defined as the cessation of
vomiting, and no intravenous fluid or ‘rescue ther-
apies’ over a 24-h period. However, when compared
with placebo, those administered the bimodal
release ondansetron formulation were more likely
&&
to experience constipation and headache [38 ]. The
decision to compare the bimodal release formula-
tion to placebo instead of single-dose ondansetron,
limits the conclusions that can be drawn from this
study. Thus, further research, such as a three-arm
controlled trial comparing bimodal release ondan-
setron, single-dose ondansetron, and placebo, is
required to better understand the potential benefits
associated with this formulation.
An intriguing RCT recently reported that aroma-
therapy using inhaled isopropyl alcohol provided
to emergency departments patients with nausea,
provides greater nausea relief than oral ondansetron
&
[39 ]. Although this approach is inexpensive and low-
cost, the study had limitations that impede our abil-
ity to draw conclusions. Notably, it was an unblinded
trial, the assessment period was timed to correspond
to relief from aromatherapy, but not that of ondan-
setron, and the ondansetron dose employed was
subtherapeutic [40]. It does, however, hold potential
as an approach to rapidly treat nausea in the emer-
gency departments setting allowing for a more rapid
initiation of ORT [40,41].
The remaining issue to be addressed regarding
ondansetron is the translation of clinical trial effi-
cacy into real-world effectiveness. Although RCTs,
especially in children, have demonstrated the effi-
cacy of ondansetron, it is unclear how best to ensure
that usage leads to improved outcomes. Earlier work
showed that when ondansetron usage increases out-
side of a structured quality improvement plan, lim-
ited benefits are seen [19]. However, in the context
of a clinical pathway emphasizing ORT and ondan-
setron therapy, significant and sustained reductions
in intravenous rehydration can be achieved [42].
Further implementation research is needed to focus
www.co-infectiousdiseases.com 383
Gastrointestinal infections
on ensuring optimal use of ondansetron to achieve
maximal benefits.
PROBIOTICS
The role of probiotics, defined as ‘live microorgan-
isms which, when administered in adequate
amounts, confer a health benefit on the host’ [43],
remains a contentious topic. Recommendations
regarding use vary and conflict between leading
organizations [44,45]. Although the 2017 Infectious
Disease Society of America guidelines gives a weak
recommendation for their use in immunocompetent
adults and children with infectious diarrhea [8],
the recently released guidelines from the American
Society of Gastroenterology recommend against
probiotic use in children with AGE [46]. When
endorsed, the strains most often recommended
include Lactobacillus rhamnosus GG, Saccharomyces
boulardii, and L. reuteri DSM 17938.
Recent evidence, however, has shifted the pen-
dulum and suggests that probiotics offer little to no
benefit when routinely administered to children
with AGE [47]. In a six-site trial that enrolled
886 young children with AGE presenting to the
emergency departments and administered either a
combination of L. rhamnosus R0011 and L. helveticus
R0052 or placebo twice daily over a period of five
days, the likelihood of progressing to moderate–
severe gastroenteritis, having further visits to a
healthcare provider, or having any adverse event,
were similar in children receiving the combination
&&
probiotic or placebo [48 ]. The median duration of
diarrhea and vomiting was also similar in the study
groups. Although delayed initiation of administra-
tion of the investigational agents is often cited to
explain these findings, the respective ORs for the
primary outcome (moderate-to-severe disease)
among participants who initiated treatment within
24 and 48 h of symptom onset were 1.05 (95% CI
0.47, 2.33) and 1.20 (95% CI 0.79, 1.83), respectively
&&
[48 ].
A similarly designed 10-site trial evaluated L.
rhamnosus GG compared with placebo, when
administered twice daily over five days to 971 chil-
dren 3–48 months of age with AGE presenting to the
emergency departments. This study also found no
differences in the likelihood of progression to mod-
erate-to-severe gastroenteritis, duration of diarrhea
or vomiting symptoms, day-care absenteeism, or
household transmission, between the probiotic-
&&
treated and control groups [49 ]. Again, when par-
ticipants were stratified according to the duration of
symptoms (<48 h versus 48 h), no significant dif-
&&
ferences were identified [49 ]. Additional analyses
exploring the impact of antibiotic use and etiologic
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
pathogens found these factors had no influence on
&&
the results [49 ].
Another recent RCT enrolled children less than
5 years of age with acute diarrhea. Participants
were randomized to receive L. reuteri DSM 17938 or
placebo for five days. The authors reported no reduc-
tion in diarrhea duration. Although the 6.1-h mean
reduction in duration of hospitalization achieved
statistical significance (P ¼ 0.048; unadjusted for
multiple secondary outcomes), the clinical relevance
of this finding is questionable because of its wide
&
confidence intervals (0.1–17.7 h) [50 ].
Several metaanalyses also warrant consider-
ation. In an updated metaanalysis evaluating the
effect of Saccharomyces boulardii administration to
children with AGE that included 29 studies (4217
participants), use of this probiotic reduced the dura-
&&
tion of diarrhea by 1.1 days [51 ]. The authors
cautiously interpret their findings citing concerns
regarding the small effect size, limited clinical
relevance, and most importantly, methodological
limitations – only one of the included studies was
assessed as being at low risk of bias. The most recent
review of L. rhamnosus GG similarly concluded that
there was a statistically significant but likely clini-
cally insignificant reduction in diarrhea duration
&&
[52 ]. Similar methodological concerns were iden-
tified for this review, because of a high risk of bias in
over 70% of included studies; when the analysis was
repeated including only low risk of bias studies, no
benefit associated with L. rhamnosus GG was
&&
detected [52 ,53]. Lastly, metaanalyses of L. reuteri
have been unable to analyze low risk of bias studies
as only one such study has been published to date
[54]. Concerns regarding the interpretation of these
metaanalyses by guidelines committees as being
supportive of probiotic use have been expressed
[55].
The issue of probiotic safety also merits consid-
eration in light of recent publications. Although
regulatory authorities have defined safety standards,
and probiotics have a long history of safe use in
foods, the standard for probiotics sold as dietary
supplements in the United States only requires that
they not present ‘a significant or unreasonable risk
of illness or injury under conditions of use recom-
mended or suggested in labeling’ [56]. However,
although generally safe when administered to
healthy individuals, probiotic administration to
neonates, critically ill children, and adults and those
with significant comorbidities (e.g., congenital
heart disease, central venous lines, pancreatitis)
has been associated with bacteremia [57]. A notable
publication recently reported that 1.1% of children
administered L. rhamnosus GG in an intensive care
unit developed L. rhamnosus bacteremia compared
Volume 33  Number 5  October 2020
 Update on nonantibiotic therapies for acute gastroenteritis Funk et al.
with 0.009% of intensive care unit patients who
&&
were not administered the probiotic [58 ]. More-
over, genomic analysis determined that the strains
recovered in the blood cultures were phylogeneti-
cally identical to that found in the administered
probiotic, and some of these strains also contained
de-novo mutations including a nonsynonymous
&&
SNP conferring antibiotic resistance [58 ]. Thus,
given the paucity of evidence supportive of probi-
otic administration to children with AGE, along
with the potential, albeit low, risk for harm, and
the cost of the intervention, in our opinion, routine
probiotic administration is not recommended to
children with AGE.
OTHER
A few final topics deserve mention. Gelatin tannate,
a complex consisting of tannic acid suspended in a
protective gelatin, has recently become increas-
ingly available and marketed in many countries
for the treatment of AGE [59]. Although the precise
mechanism of its action is unknown, the suspen-
sion forms a biofilm, which inhibits the growth of
intestinal bacteria and causes precipitation of
proinflammatory proteins [60]. A recent clinical
trial evaluated the potential benefits of gelatin tan-
nate in children with AGE; however, the duration of
diarrhea did not differ between groups [54]. The
results of this trial are in keeping with the conclu-
sions of a recent metaanalysis which found no
benefit associated with its use when compared with
&
placebo [61 ].
Despite its widespread usage, few robust studies
had previously evaluated rapid intravenous rehydra-
tion for severely dehydrated children. A recent
open-label trial that occurred in Kenya and Uganda
found that slower intravenous rehydration (over
8 h) appears to be as safe and likely to be easier to
implement that than the WHO Plan C (100 ml/kg
over 3 h with additional boluses for children in
shock). There were no differences between study
groups in time to reversal of dehydration, weight
&&
gain, and length of hospital stay [62 ,63 ]. These
&
findings support those of a metaanalysis which
found limited evaluations of rapid rehydration in
both resource-limited and high-income settings
[64]; given the concerns over aggressive fluid expan-
sion [65], its widespread use in children with AGE
should not be encouraged at this time.
Finally, an RCT conducted in Thailand con-
firmed the efficacy of zinc supplementation in
reducing the duration of diarrheal symptoms, in
&
this case by a median of 8 h [66 ], highlighting
the use of this therapy in regions where deficiency
is common [67]. Interestingly, a systematic review
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
focused on high-income countries concluded there
is sufficient evidence to recommend zinc therapy in
such settings; however, no metaanalysis was per-
formed to support this recommendation [68].
CONCLUSION
In summary, ondansetron therapy continues to
evolve, with its role and benefits increasingly clari-
fied, enabling clinicians to optimally administer it
to improve AGE outcomes, particularly in children.
The emphasis should continue to be on use of
single-dose oral administration in emergency
departments to children with evidence of dehydra-
tion. On the other hand, robust research increas-
ingly points toward probiotics being ineffective with
insufficient evidence to recommend their routine
use. Hopefully, future interventions targeting
specific AGE-causing pathogens, or common mech-
anisms of action, will emerge.
Acknowledgements
We thank Dr. Lise Nigrovic MD, MPH, for her review of
the manuscript.
Financial support and sponsorship
A.F. is supported by an Eyes-High Post-Doctoral Fellow-
ship through the University of Calgary. S.B.F. is sup-
ported by the Alberta Children’s Hospital Foundation
Professorship in Child Health and Wellness.
Conflicts of interest
D.S. has received in-kind study drug and placebo from
iHeath Inc. and is supported in part by the Richard and
Barbara Ruddy Endowed Chair in Emergency Medicine
at Cincinnati Children’s Hospital Medical Center. S.B.F.
has received in-kind study drug and placebo from Glax-
oSmithKline and Lallemand Health Solutions Inc. He
serves as a consultant to Eligo Bioscience, Takeda Phar-
maceuticals Company and Redhill Biopharma Ltd.
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One of two RCTs performed in Pakistan (see above). This trial enrolled children
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these children while also being safe. This trial provides a robust piece of
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One of two RCTs performed in the same low-middle income setting, in Pakistan.
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between children provided with a discharge ondansetron prescription compared
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Similar to the study commented on above, this study found that oral ondansetron
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adults within AGE quite quickly (i.e., within 30 min of administration). There are
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