Clinical Review & Education
JAMA Clinical Evidence Synopsis
Probiotics and the Prevention of Antibiotic-Associated
Diarrhea in Infants and Children
Bradley C. Johnston, PhD; Joshua Z. Goldenberg, ND; Patricia C. Parkin, MD
CLINICAL QUESTION In children prescribed an antibiotic, is the co-administration of a probiotic
associated with lower rates of antibiotic-associated diarrhea without an increase in clinically
important adverse events?
BOTTOM LINE Moderate-quality evidence suggests that probiotics are associated with lower
rates of antibiotic-associated diarrhea in children (aged 1 month to 18 years) without an
increase in adverse events.
Introduction
Antibiotics are the most widely prescribed drug for children.1,2 An-
tibiotics may result in a range of adverse events, including antibiotic-
associated diarrhea. The estimated incidence of antibiotic-
associated diarrhea among children is 11%3 among outpatients and
21% among inpatients.4 Probiotics are nonpathogenic microbial
preparations that may prevent antibiotic-associated diarrhea via nor-
malization of disrupted microbiota and competitive inhibition of
pathogens as a result of antibiotic use. This JAMA Clinical Evidence
synopsis summarizes a recent Cochrane review4 of randomized trials
evaluating probiotics for preventing antibiotic-associated diarrhea
in children, which was an update of a previous Cochrane review.5
Evidence Profile
No. of randomized clinical trials: 23
Study years: Conducted, 1989-2012; published, 1990-2015
Last search date: November 2, 2015
No. of patients: 3938
Boys: 53% Girls: 47%
Race/ethnicity: Not reported
Age, mean (range): 5.6 years (1 month to 18 years)
Clinical settings: Inpatient, outpatient, and mixed (inpatient
and outpatient)
Countries: Australia, Brazil, Bulgaria, China, Czech Republic,
England, Finland, France, Iran, Italy, Philippines, Poland, Thailand,
Turkey, United States
Comparison: Children receiving antibiotics were randomized
to single-strain or multistrain probiotics (typically for a
predefined period [eg, 5-12 days]) vs control (placebo,
no treatment, active treatment) and followed up for 1 to 12
weeks. Probiotic genus administered included Bacillus,
Bifidobacterium, Clostridium, Lactobacilli, Lactococcus,
Leuconostoc, Saccharomyces, Streptococcus.
Primary outcome measures: Incidence of diarrhea and number
and type of adverse events.
Secondary outcome measures: Mean duration of diarrhea
and mean stool frequency.
1484 JAMA October 11, 2016 Volume 316, Number 14 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
Summary of Findings
Probiotics were associated with lower rates of antibiotic-associated
diarrhea (163/1992 [8%]) compared with control (364/1906 [19%])
(risk ratio, 0.46 [95% CI, 0.35-0.61], P < .001; moderate quality evi-
dence using Grading of Recommendations Assessment, Develop-
ment and Evaluation). Similarly, probiotics were associated with lower
rates of antibiotic-associated diarrhea (174/773 [9%]) compared with
placebo (201/802 [20%]) (risk ratio, 0.42 [95% CI, 0.29-0.61],
P < .001; Figure). The number needed to treat (NNT) associated with
1 fewer case of diarrhea was 10 (NNT, 9 [95% CI, 7-12]).
Subgroup results were consistent across trials that adminis-
tered different probiotic species including single vs multistrain pro-
biotic, different probiotic doses, children with different diagnoses (up-
per respiratory, Helicobacter pylori, or studies with mixed infections),
studies at higher vs lower risk of bias, trials enrolling inpatients vs out-
patients, and trials with and without industry sponsorship. Among 5
trials (n = 897), probiotics were associated with a lower mean dura-
tion of diarrhea (3.5 days) compared with the control group (4.1 days)
(absolute difference, 0.6 days fewer [95% CI, 1.18-0.02 days fewer];
P = .04). Among 4 trials (n = 425), probiotics were not associated with
a difference in mean stool frequency (2.1 vs 2.4 stools per day; P = .05).
Sixteen of 23 trials (n = 2455) reported on adverse events. Adverse
event rates were 3.1% (39/1241) in the intervention group and 3.5%
(42/1214) in the control group (P = .84).
Discussion
Among 23 studies comparing probiotics with control for the pre-
vention of antibiotic-associated diarrhea, probiotics were associ-
ated with lower rates of diarrhea and were not associated with higher
rates of adverse events. No trials reported serious adverse events
attributable to probiotics.
Limitations
The trials were small to moderate in size. In addition, most of the stud-
ies assessed the probiotics Lactobacillus rhamnosus (4 trials, n = 711)
and Saccharomyces boulardii (4 trials, n = 1611). It is unknown whether
the results from these probiotic species are generalizable to other pro-
biotics. The findings are based on an aggregate data meta-analysis;
therefore, it was impossible to explore patient- and intervention-
level variables that may be associated with antibiotic-associated
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 JAMA Clinical Evidence Synopsis Clinical Review & Education

Figure. Probiotics for Antibiotic-Associated Diarrhea (AAD) Prevention in 15 Placebo-Controlled Trials

Probiotics Control
No. of AAD No. of No. of AAD No. of Risk Ratio Favors Favors
Study Events Participants Events Participants (95% CI) Treatment Control
Arvola, 1999 3 59 9 60 0.34 (0.10-1.19)
Fox, 2015 1 34 21 36 0.05 (0.01-0.35)
Georgieva (unpublished) 1 49 1 48 0.98 (0.06-15.22)
Jirapinyo, 2002 3 8 8 10 0.47 (0.18-1.21)
Kodadad, 2013 2 33 8 33 0.25 (0.06-1.09)
Kotowska, 2005 4 119 22 127 0.19 (0.07-0.55)
LaRosa, 2003 14 48 31 50 0.47 (0.29-0.77)
Merenstein, 2009 11 57 14 60 0.83 (0.41-1.67)
Ruszczynski, 2008 9 120 20 120 0.45 (0.21-0.95)
Saneeyan, 2011 3 25 13 25 0.23 (0.07-0.71)
Sykora, 2005 3 39 5 47 0.72 (0.18-2.84)
Szajewska, 2009 2 34 6 30 0.29 (0.06-1.35)
Szymanski, 2008 1 40 2 38 0.48 (0.04-5.03)
Tankanow, 1990 10 15 16 23 0.96 (0.61-1.50)
Vanderhoof, 1999 7 93 25 95 0.29 (0.13-0.63)
Total 74 773 201 802 0.42 (0.29-0.61)

0.01 0.1 1.0 10

Risk Ratio (95% CI)

The DerSimonian-Laird random-effects model was used to calculate the risk ratios and 95% CIs.

diarrhea. For example, the largest prospective cohort of children
(n = 650) who were followed up for antibiotic-associated diarrhea risk
suggests that younger children (aged <2 years) and those exposed to
amoxicillin/clavulanate are at the highest risk for antibiotic-
associated diarrhea (18% and 23%, respectively).3 To explore this is-
sue in meta-analysis, individual patient-level data would be required
for all included trials.
Comparison of Findings With Current Practice Guidelines
Our findings are consistent with the European Society for Pediatric
Gastroenterology, Hepatology and Nutrition recommendations, the
only published guideline based on systematic reviews addressing
antibiotic-associated diarrhea, which suggests that L rhamnosus or
S boulardii at 5 to 40 billion colony-forming units/d may be reasonable
to consider among otherwise healthy children receiving antibiotics.6
Areas in Need of Future Study
No trials have focused exclusively on hospitalized children adminis-
tered intravenous antibiotics in North America. Therefore, a large mul-
ticenter, randomized clinical trial addressing the potential benefit of
probiotics in hospitalized children is necessary before probiotics can
be considered for routine clinical use in the hospital setting.

ARTICLE INFORMATION
Author Affiliations: Systematic Overviews through
advancing Research Technology, Child Health
Evaluative Sciences, Hospital for Sick Children
Research Institute, Toronto, Ontario, Canada
(Johnston); Institute of Health Policy, Management
and Evaluation, Dalla Lana School of Public Health,
University of Toronto, Toronto, Ontario, Canada
(Johnston, Goldenberg, Parkin); Prevention Lab,
Child Health Evaluative Sciences, Hospital for Sick
Children, Toronto, Ontario, Canada (Johnston);
Bastyr University Research Institute, Kenmore,
Washington (Goldenberg); Department of
Pediatrics, Child Health Evaluative Sciences,
Hospital for Sick Children Research Institute,
Toronto, Ontario, Canada (Parkin).
Corresponding Author: Bradley C. Johnston, PhD,
SORT Program, Hospital for Sick Children Research
Institute, 686 Bay St, Toronto, ON M5G 0A4,
Canada (bradley.johnston@sickkids.ca).
Section Editor: Mary McGrae McDermott, MD,
Senior Editor.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Drs Johnston and Parkin reported receiving grant
support from BioK+ (a probiotic manufacturer)
to document the incidence of diarrhea among
hospitalized children receiving antibiotics.
No other disclosures were reported.
Submissions: We encourage authors to submit
papers for consideration as a JAMA Clinical
Evidence Synopsis. Please contact Dr McDermott at
mdm608@northwestern.edu.
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