ℹ️ Skipped - page is already crawled
| Filter | Status | Condition | Details |
|---|---|---|---|
| HTTP status | PASS | download_http_code = 200 | HTTP 200 |
| Age cutoff | PASS | download_stamp > now() - 6 MONTH | 1.6 months ago |
| History drop | PASS | isNull(history_drop_reason) | No drop reason |
| Spam/ban | PASS | fh_dont_index != 1 AND ml_spam_score = 0 | ml_spam_score=0 |
| Canonical | PASS | meta_canonical IS NULL OR = '' OR = src_unparsed | Not set |
| Property | Value |
|---|---|
| URL | https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/ |
| Last Crawled | 2026-02-20 14:16:14 (1 month ago) |
| First Indexed | not set |
| HTTP Status Code | 200 |
| Meta Title | Probiotics for antibiotic-associated diarrhea in children - PMC |
| Meta Description | Question I recently had a parent ask me if their child should be taking probiotics to reduce the impending diarrhea while using antibiotic treatment for an ear infection. Are probiotics effective and safe in preventing antibiotic-associated ... |
| Meta Canonical | null |
| Boilerpipe Text | . 2020 Jan;66(1):37–39.
Abstract
Question
I recently had a parent ask me if their child should be taking probiotics to reduce the impending diarrhea while using antibiotic treatment for an ear infection. Are probiotics effective and safe in preventing antibiotic-associated diarrhea, and, if so, what strain and dose are recommended?
Answer
The 2 types of probiotics recommended to prevent pediatric antibiotic-associated diarrhea are
Lactobacillus rhamnosus
GG and
Saccharomyces boulardii
. Although an optimal dose has yet to be established, higher doses in the range of 5 to 40 billion colony-forming units per day were reported to be the most efficacious in trials. The safety profile of probiotics is excellent in healthy children; however, rare serious adverse events have been documented in severely debilitated or immunocompromised children.
Antibiotics account for a quarter of all prescriptions for children and are a common source of adverse events including antibiotic-associated diarrhea (AAD).
1
Antibiotic-associated diarrhea
is defined as 3 or more loose stools within a 24-hour period after antibiotic administration, which might occur within hours or up to 8 weeks following commencement of antibiotic use.
2
Elements associated with AAD include the age of the child and the antibiotic agent used, among other factors, with an estimated incidence of 5% to 30% in children according to a review of 10 studies with 1438 children from 6 different countries.
3
Cephalosporins, clindamycin, and broad-spectrum penicillins have been associated with a higher risk of AAD.
4
Current standard of care treatment for AAD includes discontinuing or changing the inciting antibiotic,
3
providing rehydration,
5
or administering oral metronidazole or vancomycin if
Clostridium difficile
is the suspected culprit.
6
Probiotics for prevention of AAD
Probiotics
are defined by the World Health Organization as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”
7
The mechanisms of action of different probiotics include providing a physical barrier from pathogens, promoting goblet cell mucus secretion, maintaining the integrity of intestinal epithelial tight junctions, producing antimicrobial factors, and stimulating the immune system.
8
A study from almost 30 years ago involving 60 children between the ages of 5 months and 6 years was the first to investigate the relationship between probiotics and AAD in this population.
9
Children requiring treatment with amoxicillin were randomized to receive either 500 million colony-forming units (CFUs) of Lactinex (a combination of
Lactobacillus acidophilus
and
Lactobacillus bulgaricus
) or placebo (lactose) 4 times daily for 10 days, with similar rates of children still experiencing diarrhea (≥ 1 loose stools per day; 66% vs 69.5%, respectively;
P
= .563).
9
Sixteen years later, a meta-analysis (N = 766) examined the use of probiotics in reducing the incidence of pediatric AAD across 6 randomized controlled trials (RCTs), reporting a lower risk for those receiving probiotics (12% and 29% in probiotics and placebo groups, respectively, relative risk [RR] of 0.44, 95% CI 0.25 to 0.77).
10
Particularly,
Lactobacillus rhamnosus
GG (RR = 0.3, 95% CI 0.15 to 0.6; n = 307),
Saccharomyces boulardii
(RR = 0.2, 95% CI 0.07 to 0.6; n = 246) and a combination of
Bifidobacterium lactis
and
Streptococcus thermophilus
(RR = 0.5, 95% CI 0.3 to 0.95; n = 157) were reported to be efficacious in preventing pediatric AAD.
10
However, it is difficult to generalize these conclusions owing to the small sample size in each of the trials.
A recent Cochrane review analyzed 33 studies with 6352 children up to 18 years of age who received antibiotic therapy for 3 to 30 days.
11
The probiotics were coadministered with the antibiotic regimen for infections such as in the respiratory tract, impetigo, and
Helicobacter pylori
.
11
The reported incidence of AAD after follow-up (5 days to 12 weeks) was 8% in those receiving probiotics compared with 19% among those receiving placebo (RR = 0.45, 95% CI 0.36 to 0.56; number needed to benefit of 9, 95% CI 7 to 13), suggesting an important role of probiotics in preventing AAD in children.
11
Choosing probiotics
While the number of probiotic options can be daunting, 2 probiotics in particular have emerged at the forefront for preventing pediatric AAD.
12
,
13
In a 2015 meta-analysis of 5 RCTs with 445 children,
L rhamnosus
GG was associated with an AAD incidence of 9.6% in the probiotic group and 23% in the placebo group (RR = 0.48, 95% CI 0.26 to 0.89).
12
Another meta-analysis from the same group reported that with the use of the yeast
S boulardii
, AAD incidence was 8.8% and 20.9% (probiotic and placebo groups, respectively) among 1653 children across 6 RCTs (RR = 0.43, 95% CI 0.3 to 0.6).
13
Other probiotics including
Lactobacillus reuteri, L rhamnosus
(strains E/N, Oxy, and Pen), combination
Clostridium butyricum
and
Bifidobacterium
, combination
B lactis
and
S thermophilus
, and yogurt (containing active cultures of
S thermophilus
and
Lactobacillus delbrueckii
) have demonstrated efficacy in reducing pediatric AAD incidence in some trials; however, these therapeutic options need further study.
14
Of note, neither
Lactobacillus plantarum
(AAD in 2.8% of probiotic group compared with 4.1% in placebo group [N = 438],
P
= .4)
15
nor kefir beverage (containing lactic acid bacteria such as
Lactobacillus kefiri, Lactobacillus kefiranofaciens, L acidophilus
, and
L plantarum
, as well as yeasts such as
Kluyveromyces marxianus, Saccharomyces unisporus, Saccharomyces cerevisiae,
and
Saccharomyces exiguus
) (RR = 0.82, 95% CI 0.54 to 1.43)
16
were efficacious in their respective studies.
Upon reviewing 21 RCTs involving 3255 children, the Working Group on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) published its 2016 guidelines recommending
L rhamnosus
GG and
S boulardii
as the 2 probiotics with sufficient evidence for AAD prevention.
17
However,
S boulardii
is recommended over
L rhamnosus
GG when
C difficile
–associated diarrhea is isolated.
17
These recommendations were made only if 2 or more RCTs were available for the specific strain of probiotic.
17
Optimal dose
The optimal dose of probiotics remains largely unknown, as evidenced by the range of doses used in pediatric clinical trials from 100 million to 1.8 trillion CFUs per day.
18
Lactobacillus rhamnosus
GG has greater evidence for a dose-dependent response in children.
12
,
13
In a meta-analysis including 445 children up to age 17 from 3 countries (Poland, Finland, and the United States) who received coadministration of
L rhamnosus
GG with antibiotics, the highest dose of
L rhamnosus
GG (10 to 20 billion CFUs per day) achieved a 71% reduction in AAD incidence compared with a dose of 3 billion CFUs per day, which only achieved a 34% reduction in incidence.
12
In contrast, a meta-analysis with 1653 children reported that among 6 trials with a daily dose of
S boulardii
ranging from 50 mg to 1000 mg (1 billion to 20 billion CFUs per day), efficacy in preventing AAD did not demonstrate a clear dose-dependent relationship.
13
The most recent 2016 ESPGHAN guidelines do not affirm specific recommendations for doses of
L rhamnosus
GG and
S boulardii
.
17
The ESPGHAN guidelines suggest that 10 to 20 billion CFUs per day of
L rhamnosus
GG or 250 to 500 mg (5 to 10 billion CFUs per day) of
S boulardii
can be used to match the doses used in some RCTs.
17
This general range of doses was supported by a 2019 Cochrane review that noted that in the 33 included trials, high-dose probiotics (5 to 40 billion CFUs per day) were more effective than low-dose probiotics (RR = 0.37, 95% CI 0.30 to 0.46,
P
= .06; number needed to benefit of 6, 95% CI 5 to 9).
11
Safety
Among 24 studies, rates of mild to moderate adverse events (eg, rash, nausea, gas, flatulence, abdominal bloating, constipation) were low, with an incidence of 4% (86 of 2229) in the probiotic groups compared with 6% (121 of 2186) in the control groups.
11
No serious adverse events were reported in either group.
11
However, serious adverse events were reported in a large systematic review of 20 case reports and 52 randomized and non-randomized trials involving 4131 patients (children and adults) who received probiotics through enteral or parenteral nutrition.
19
In the case reports, some of which reported on more than 1 patient, 32 cases of serious adverse events (ie, fungemia, bacteremia) were documented.
19
Eleven of these cases were either preterm neonates, severely debilitated children, or immunocompromised children, and involved risk factors such as central venous catheters and disorders associated with increased bacterial translocation.
19
All 11 recovered from the infection after discontinuing the probiotic, removing the central venous catheter, or administrating an antibiotic or antifungal.
19
While probiotics appear to be safe in healthy children, use in severely debilitated or immunocompromised children requires caution owing to the potential for reversible but serious adverse events as documented in several case reports.
Conclusion
Lactobacillus rhamnosus
GG and
S boulardii
are 2 probiotics that are effective in preventing pediatric AAD when coadministered with antibiotics. While an optimal dose remains unknown, a range of 5 to 40 billion CFUs per day appears to be the most efficacious. There is insufficient evidence to recommend other strains of probiotics at this time. Probiotics appear to be safe in children, with minimal side effects; however, serious adverse events have been documented in case reports of severely debilitated or immunocompromised children.
Child Health Update
is produced by the Pediatric Research in Emergency Therapeutics (PRETx) program (
www.pretx.org
) at the BC Children’s Hospital in Vancouver, BC.
Mr Yan
is a member and
Dr Goldman
is Director of the PRETx program. The mission of the PRETx program is to promote child health through evidence-based research in therapeutics in pediatric emergency medicine.
Do you have questions about the effects of drugs, chemicals, radiation, or infections in children? We invite you to submit them to the PRETx program by fax at 604 875-2414; they will be addressed in future
Child Health Updates
. Published
Child Health Updates
are available on the
Canadian Family Physician
website (
www.cfp.ca
).
Footnotes
Competing interests
None declared
This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to
www.cfp.ca
and click on the Mainpro+ link.
La traduction en français de cet article se trouve Ă
www.cfp.ca
dans la table des matières du numéro
de janvier 2020
Ă la
page e9
.
References
1.
Chai G, Governale L, McMahon AW, Trinidad JP, Staffa J, Murphy D. Trends of outpatient prescription drug utilization in US children, 2002–2010. Pediatrics. 2012;130(1):23–31. doi: 10.1542/peds.2011-2879. Epub 2012 Jun 18.
[
DOI
] [
PubMed
] [
Google Scholar
]
2.
Mcfarland LV. Epidemiology, risk factors and treatments for antibiotic associated diarrhea. Dig Dis. 1998;16(5):292–307. doi: 10.1159/000016879.
[
DOI
] [
PubMed
] [
Google Scholar
]
3.
Alam S, Mushtaq M. Antibiotic associated diarrhea in children. Indian Pediatr. 2009;46(6):491–6.
[
PubMed
] [
Google Scholar
]
4.
Wiström J, Norrby SR, Myhre EB, Eriksson S, Granström G, Lagergren L, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother. 2001;47(1):43–50. doi: 10.1093/jac/47.1.43.
[
DOI
] [
PubMed
] [
Google Scholar
]
5.
Barbut F, Meynard JL. Managing antibiotic associated diarrhoea. Probiotics may help in prevention. BMJ. 2002;324(7350):1345–6. doi: 10.1136/bmj.324.7350.1345.
[
DOI
] [
PMC free article
] [
PubMed
] [
Google Scholar
]
6.
D’Ostroph AR, So TY. Treatment of pediatric Clostridium difficile infection: a review on treatment efficacy and economic value. Infect Drug Resist. 2017;10:365–75. doi: 10.2147/IDR.S119571.
[
DOI
] [
PMC free article
] [
PubMed
] [
Google Scholar
]
7.
Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506–14. doi: 10.1038/nrgastro.2014.66. Epub 2014 Jun 10.
[
DOI
] [
PubMed
] [
Google Scholar
]
8.
Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol. 2010;7(9):503–14. doi: 10.1038/nrgastro.2010.117. Epub 2010 Jul 27.
[
DOI
] [
PMC free article
] [
PubMed
] [
Google Scholar
]
9.
Tankanow RM, Ross MB, Ertel I, Dickinson DG, McCormick LS, Garfinkel JF. A double-blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillin-induced diarrhea. DICP. 1990;24(4):382–4. doi: 10.1177/106002809002400408.
[
DOI
] [
PubMed
] [
Google Scholar
]
10.
Szajewska H, Ruszczyński M, Radzikowski A. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials. J Pediatr. 2006;149(3):367–72. doi: 10.1016/j.jpeds.2006.04.053.
[
DOI
] [
PubMed
] [
Google Scholar
]
11.
Guo Q, Goldenberg JZ, Humphrey C, El Dib R, Johnston B. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2019;(4):CD004827. doi: 10.1002/14651858.CD004827.pub5.
[
DOI
] [
PMC free article
] [
PubMed
] [
Google Scholar
]
12.
Szajewska H, Kołodziej M. Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. Aliment Pharmacol Ther. 2015;42(10):1149–57. doi: 10.1111/apt.13404. Epub 2015 Sep 13.
[
DOI
] [
PubMed
] [
Google Scholar
]
13.
Szajewska H, Kołodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015;42(7):793–801. doi: 10.1111/apt.13344. Epub 2015 Jul 27.
[
DOI
] [
PubMed
] [
Google Scholar
]
14.
Mantegazza C, Molinari P, D’Auria E, Sonnino M, Morelli L, Zuccotti GV. Probiotics and antibiotic-associated diarrhea in children: a review and new evidence on Lactobacillus rhamnosus GG during and after antibiotic treatment. Pharmacol Res. 2018;128:63–72. doi: 10.1016/j.phrs.2017.08.001. Epub 2017 Aug 19.
[
DOI
] [
PubMed
] [
Google Scholar
]
15.
Olek A, Woynarowski M, Ahrén IL, KierkuŚ J, Socha P, Larsson N, et al. Efficacy and safety of Lactobacillus plantarum DSM 9843 (LP299V) in the prevention of antibiotic-associated gastrointestinal symptoms in children—randomized, double-blind placebo-controlled study. J Pediatr. 2017;186:82–86. doi: 10.1016/j.jpeds.2017.03.047. Epub 2017 Apr 21.
[
DOI
] [
PubMed
] [
Google Scholar
]
16.
Merenstein DJ, Foster J, D’Amico F. A randomized clinical trial measuring the Influence of kefir on antibiotic-associated diarrhea: the Measuring the Influence of Kefir (MILK) study. Arch Pediatr Adolesc Med. 2009;163(8):750–4. doi: 10.1001/archpediatrics.2009.119.
[
DOI
] [
PubMed
] [
Google Scholar
]
17.
Szajewska H, Canani RB, Guarino A, Hojsak I, Indrio F, Kolacek S, et al. Probiotics for the prevention of antibiotic-associated diarrhea in children. J Pediatr Gastroenterol Nutr. 2016;62(3):495–506. doi: 10.1097/MPG.0000000000001081.
[
DOI
] [
PubMed
] [
Google Scholar
]
18.
Kligler B, Cohrssen A. Probiotics. Am Fam Physician. 2008;78(9):1073–8.
[
PubMed
] [
Google Scholar
]
19.
Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr. 2010;91(3):687–703. doi: 10.3945/ajcn.2009.28759. Epub 2010 Jan 20.
[
DOI
] [
PubMed
] [
Google Scholar
] |
| Markdown | [Skip to main content](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#main-content)
An official website of the United States government
Here's how you know
Here's how you know
**Official websites use .gov**
A **.gov** website belongs to an official government organization in the United States.
**Secure .gov websites use HTTPS**
A **lock** ( Locked padlock icon) or **https://** means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.
[](https://www.ncbi.nlm.nih.gov/)
 Search
 Log in  
- [Dashboard](https://www.ncbi.nlm.nih.gov/myncbi/)
- [Publications](https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/)
- [Account settings](https://www.ncbi.nlm.nih.gov/account/settings/)
- Log out
Primary site navigation
Logged in as:
- [Dashboard](https://www.ncbi.nlm.nih.gov/myncbi/)
- [Publications](https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/)
- [Account settings](https://www.ncbi.nlm.nih.gov/account/settings/)
Log in
 
- [Journal List](https://pmc.ncbi.nlm.nih.gov/journals/)
- [User Guide](https://pmc.ncbi.nlm.nih.gov/about/userguide/)
- 
- [](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/pdf/0660037.pdf "Download PDF")
-  
- 
- 
## PERMALINK
 Copy
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more: [PMC Disclaimer](https://pmc.ncbi.nlm.nih.gov/about/disclaimer/) \| [PMC Copyright Notice](https://pmc.ncbi.nlm.nih.gov/about/copyright/)
Can Fam Physician
. 2020 Jan;66(1):37–39.
- [Search in PMC](https://pmc.ncbi.nlm.nih.gov/search/?term="Can%20Fam%20Physician"[jour])
- [Search in PubMed](https://pubmed.ncbi.nlm.nih.gov/?term="Can%20Fam%20Physician"[jour])
- [View in NLM Catalog](https://www.ncbi.nlm.nih.gov/nlmcatalog?term="Can%20Fam%20Physician"[Title%20Abbreviation])
- [Add to search](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/?term="Can%20Fam%20Physician"[jour])
# Probiotics for antibiotic-associated diarrhea in children
[Tyler Yan](https://pubmed.ncbi.nlm.nih.gov/?term="Yan%20T"[Author])
### Tyler Yan
Find articles by [Tyler Yan](https://pubmed.ncbi.nlm.nih.gov/?term="Yan%20T"[Author])
, [Ran D Goldman](https://pubmed.ncbi.nlm.nih.gov/?term="Goldman%20RD"[Author])
### Ran D Goldman, MD FRCPC
Find articles by [Ran D Goldman](https://pubmed.ncbi.nlm.nih.gov/?term="Goldman%20RD"[Author])
✉
- Author information
- Copyright and License information
✉
Correspondence: **Dr Ran D. Goldman**; e-mail rgoldman@cw.bc.ca
Copyright© the College of Family Physicians of Canada
[PMC Copyright notice](https://pmc.ncbi.nlm.nih.gov/about/copyright/)
PMCID: PMC7012114
This article is also available in French. See "[Les probiotiques pour la diarrhée liée aux antibiotiques chez l’enfant](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012121/)".
## Abstract
**Question** I recently had a parent ask me if their child should be taking probiotics to reduce the impending diarrhea while using antibiotic treatment for an ear infection. Are probiotics effective and safe in preventing antibiotic-associated diarrhea, and, if so, what strain and dose are recommended?
**Answer** The 2 types of probiotics recommended to prevent pediatric antibiotic-associated diarrhea are *Lactobacillus rhamnosus* GG and *Saccharomyces boulardii*. Although an optimal dose has yet to be established, higher doses in the range of 5 to 40 billion colony-forming units per day were reported to be the most efficacious in trials. The safety profile of probiotics is excellent in healthy children; however, rare serious adverse events have been documented in severely debilitated or immunocompromised children.
***
Antibiotics account for a quarter of all prescriptions for children and are a common source of adverse events including antibiotic-associated diarrhea (AAD).[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b1-0660037) *Antibiotic-associated diarrhea* is defined as 3 or more loose stools within a 24-hour period after antibiotic administration, which might occur within hours or up to 8 weeks following commencement of antibiotic use.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b2-0660037)
Elements associated with AAD include the age of the child and the antibiotic agent used, among other factors, with an estimated incidence of 5% to 30% in children according to a review of 10 studies with 1438 children from 6 different countries.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b3-0660037) Cephalosporins, clindamycin, and broad-spectrum penicillins have been associated with a higher risk of AAD.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b4-0660037)
Current standard of care treatment for AAD includes discontinuing or changing the inciting antibiotic,[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b3-0660037) providing rehydration,[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b5-0660037) or administering oral metronidazole or vancomycin if *Clostridium difficile* is the suspected culprit.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b6-0660037)
## Probiotics for prevention of AAD
*Probiotics* are defined by the World Health Organization as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b7-0660037) The mechanisms of action of different probiotics include providing a physical barrier from pathogens, promoting goblet cell mucus secretion, maintaining the integrity of intestinal epithelial tight junctions, producing antimicrobial factors, and stimulating the immune system.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b8-0660037)
A study from almost 30 years ago involving 60 children between the ages of 5 months and 6 years was the first to investigate the relationship between probiotics and AAD in this population.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b9-0660037) Children requiring treatment with amoxicillin were randomized to receive either 500 million colony-forming units (CFUs) of Lactinex (a combination of *Lactobacillus acidophilus* and *Lactobacillus bulgaricus*) or placebo (lactose) 4 times daily for 10 days, with similar rates of children still experiencing diarrhea (≥ 1 loose stools per day; 66% vs 69.5%, respectively; *P* = .563).[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b9-0660037)
Sixteen years later, a meta-analysis (N = 766) examined the use of probiotics in reducing the incidence of pediatric AAD across 6 randomized controlled trials (RCTs), reporting a lower risk for those receiving probiotics (12% and 29% in probiotics and placebo groups, respectively, relative risk \[RR\] of 0.44, 95% CI 0.25 to 0.77).[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b10-0660037) Particularly, *Lactobacillus rhamnosus* GG (RR = 0.3, 95% CI 0.15 to 0.6; n = 307), *Saccharomyces boulardii* (RR = 0.2, 95% CI 0.07 to 0.6; n = 246) and a combination of *Bifidobacterium lactis* and *Streptococcus thermophilus* (RR = 0.5, 95% CI 0.3 to 0.95; n = 157) were reported to be efficacious in preventing pediatric AAD.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b10-0660037) However, it is difficult to generalize these conclusions owing to the small sample size in each of the trials.
A recent Cochrane review analyzed 33 studies with 6352 children up to 18 years of age who received antibiotic therapy for 3 to 30 days.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) The probiotics were coadministered with the antibiotic regimen for infections such as in the respiratory tract, impetigo, and *Helicobacter pylori*.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) The reported incidence of AAD after follow-up (5 days to 12 weeks) was 8% in those receiving probiotics compared with 19% among those receiving placebo (RR = 0.45, 95% CI 0.36 to 0.56; number needed to benefit of 9, 95% CI 7 to 13), suggesting an important role of probiotics in preventing AAD in children.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037)
## Choosing probiotics
While the number of probiotic options can be daunting, 2 probiotics in particular have emerged at the forefront for preventing pediatric AAD.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037),[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037) In a 2015 meta-analysis of 5 RCTs with 445 children, *L rhamnosus* GG was associated with an AAD incidence of 9.6% in the probiotic group and 23% in the placebo group (RR = 0.48, 95% CI 0.26 to 0.89).[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037) Another meta-analysis from the same group reported that with the use of the yeast *S boulardii*, AAD incidence was 8.8% and 20.9% (probiotic and placebo groups, respectively) among 1653 children across 6 RCTs (RR = 0.43, 95% CI 0.3 to 0.6).[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037)
Other probiotics including *Lactobacillus reuteri, L rhamnosus* (strains E/N, Oxy, and Pen), combination *Clostridium butyricum* and *Bifidobacterium*, combination *B lactis* and *S thermophilus*, and yogurt (containing active cultures of *S thermophilus* and *Lactobacillus delbrueckii*) have demonstrated efficacy in reducing pediatric AAD incidence in some trials; however, these therapeutic options need further study.[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b14-0660037) Of note, neither *Lactobacillus plantarum* (AAD in 2.8% of probiotic group compared with 4.1% in placebo group \[N = 438\], *P* = .4)[15](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b15-0660037) nor kefir beverage (containing lactic acid bacteria such as *Lactobacillus kefiri, Lactobacillus kefiranofaciens, L acidophilus*, and *L plantarum*, as well as yeasts such as *Kluyveromyces marxianus, Saccharomyces unisporus, Saccharomyces cerevisiae,* and *Saccharomyces exiguus*) (RR = 0.82, 95% CI 0.54 to 1.43)[16](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b16-0660037) were efficacious in their respective studies.
Upon reviewing 21 RCTs involving 3255 children, the Working Group on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) published its 2016 guidelines recommending *L rhamnosus* GG and *S boulardii* as the 2 probiotics with sufficient evidence for AAD prevention.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) However, *S boulardii* is recommended over *L rhamnosus* GG when *C difficile*–associated diarrhea is isolated.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) These recommendations were made only if 2 or more RCTs were available for the specific strain of probiotic.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037)
## Optimal dose
The optimal dose of probiotics remains largely unknown, as evidenced by the range of doses used in pediatric clinical trials from 100 million to 1.8 trillion CFUs per day.[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b18-0660037) *Lactobacillus rhamnosus* GG has greater evidence for a dose-dependent response in children.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037),[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037) In a meta-analysis including 445 children up to age 17 from 3 countries (Poland, Finland, and the United States) who received coadministration of *L rhamnosus* GG with antibiotics, the highest dose of *L rhamnosus* GG (10 to 20 billion CFUs per day) achieved a 71% reduction in AAD incidence compared with a dose of 3 billion CFUs per day, which only achieved a 34% reduction in incidence.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037) In contrast, a meta-analysis with 1653 children reported that among 6 trials with a daily dose of *S boulardii* ranging from 50 mg to 1000 mg (1 billion to 20 billion CFUs per day), efficacy in preventing AAD did not demonstrate a clear dose-dependent relationship.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037) The most recent 2016 ESPGHAN guidelines do not affirm specific recommendations for doses of *L rhamnosus* GG and *S boulardii*.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) The ESPGHAN guidelines suggest that 10 to 20 billion CFUs per day of *L rhamnosus* GG or 250 to 500 mg (5 to 10 billion CFUs per day) of *S boulardii* can be used to match the doses used in some RCTs.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) This general range of doses was supported by a 2019 Cochrane review that noted that in the 33 included trials, high-dose probiotics (5 to 40 billion CFUs per day) were more effective than low-dose probiotics (RR = 0.37, 95% CI 0.30 to 0.46, *P* = .06; number needed to benefit of 6, 95% CI 5 to 9).[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037)
## Safety
Among 24 studies, rates of mild to moderate adverse events (eg, rash, nausea, gas, flatulence, abdominal bloating, constipation) were low, with an incidence of 4% (86 of 2229) in the probiotic groups compared with 6% (121 of 2186) in the control groups.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) No serious adverse events were reported in either group.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) However, serious adverse events were reported in a large systematic review of 20 case reports and 52 randomized and non-randomized trials involving 4131 patients (children and adults) who received probiotics through enteral or parenteral nutrition.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) In the case reports, some of which reported on more than 1 patient, 32 cases of serious adverse events (ie, fungemia, bacteremia) were documented.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) Eleven of these cases were either preterm neonates, severely debilitated children, or immunocompromised children, and involved risk factors such as central venous catheters and disorders associated with increased bacterial translocation.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) All 11 recovered from the infection after discontinuing the probiotic, removing the central venous catheter, or administrating an antibiotic or antifungal.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) While probiotics appear to be safe in healthy children, use in severely debilitated or immunocompromised children requires caution owing to the potential for reversible but serious adverse events as documented in several case reports.
## Conclusion
*Lactobacillus rhamnosus* GG and *S boulardii* are 2 probiotics that are effective in preventing pediatric AAD when coadministered with antibiotics. While an optimal dose remains unknown, a range of 5 to 40 billion CFUs per day appears to be the most efficacious. There is insufficient evidence to recommend other strains of probiotics at this time. Probiotics appear to be safe in children, with minimal side effects; however, serious adverse events have been documented in case reports of severely debilitated or immunocompromised children.
**Child Health Update** is produced by the Pediatric Research in Emergency Therapeutics (PRETx) program (**[www.pretx.org](http://www.pretx.org/)**) at the BC Children’s Hospital in Vancouver, BC. **Mr Yan** is a member and **Dr Goldman** is Director of the PRETx program. The mission of the PRETx program is to promote child health through evidence-based research in therapeutics in pediatric emergency medicine.
Do you have questions about the effects of drugs, chemicals, radiation, or infections in children? We invite you to submit them to the PRETx program by fax at 604 875-2414; they will be addressed in future **Child Health Updates**. Published **Child Health Updates** are available on the *Canadian Family Physician* website (**[www.cfp.ca](http://www.cfp.ca/)**).
## Footnotes
**Competing interests**
None declared
This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to **[www.cfp.ca](http://www.cfp.ca/)** and click on the Mainpro+ link.
La traduction en français de cet article se trouve à **[www.cfp.ca](http://www.cfp.ca/)** dans la table des matières du numéro **de janvier 2020** à la **[page e9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012121/)**.
## References
- 1\.
Chai G, Governale L, McMahon AW, Trinidad JP, Staffa J, Murphy D. Trends of outpatient prescription drug utilization in US children, 2002–2010. Pediatrics. 2012;130(1):23–31. doi: 10.1542/peds.2011-2879. Epub 2012 Jun 18.
\[[DOI](https://doi.org/10.1542/peds.2011-2879)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/22711728/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Pediatrics&title=Trends%20of%20outpatient%20prescription%20drug%20utilization%20in%20US%20children,%202002%E2%80%932010&author=G%20Chai&author=L%20Governale&author=AW%20McMahon&author=JP%20Trinidad&author=J%20Staffa&volume=130&issue=1&publication_year=2012&pages=23-31&pmid=22711728&doi=10.1542/peds.2011-2879&)\]
- 2\.
Mcfarland LV. Epidemiology, risk factors and treatments for antibiotic associated diarrhea. Dig Dis. 1998;16(5):292–307. doi: 10.1159/000016879.
\[[DOI](https://doi.org/10.1159/000016879)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/9892789/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Dig%20Dis&title=Epidemiology,%20risk%20factors%20and%20treatments%20for%20antibiotic%20associated%20diarrhea&author=LV%20Mcfarland&volume=16&issue=5&publication_year=1998&pages=292-307&pmid=9892789&doi=10.1159/000016879&)\]
- 3\.
Alam S, Mushtaq M. Antibiotic associated diarrhea in children. Indian Pediatr. 2009;46(6):491–6.
\[[PubMed](https://pubmed.ncbi.nlm.nih.gov/19556659/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Indian%20Pediatr&title=Antibiotic%20associated%20diarrhea%20in%20children&author=S%20Alam&author=M%20Mushtaq&volume=46&issue=6&publication_year=2009&pages=491-6&pmid=19556659&)\]
- 4\.
Wiström J, Norrby SR, Myhre EB, Eriksson S, Granström G, Lagergren L, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother. 2001;47(1):43–50. doi: 10.1093/jac/47.1.43.
\[[DOI](https://doi.org/10.1093/jac/47.1.43)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/11152430/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Antimicrob%20Chemother&title=Frequency%20of%20antibiotic-associated%20diarrhoea%20in%202462%20antibiotic-treated%20hospitalized%20patients:%20a%20prospective%20study&author=J%20Wistr%C3%B6m&author=SR%20Norrby&author=EB%20Myhre&author=S%20Eriksson&author=G%20Granstr%C3%B6m&volume=47&issue=1&publication_year=2001&pages=43-50&pmid=11152430&doi=10.1093/jac/47.1.43&)\]
- 5\.
Barbut F, Meynard JL. Managing antibiotic associated diarrhoea. Probiotics may help in prevention. BMJ. 2002;324(7350):1345–6. doi: 10.1136/bmj.324.7350.1345.
\[[DOI](https://doi.org/10.1136/bmj.324.7350.1345)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC1123310/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/12052785/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=BMJ&title=Managing%20antibiotic%20associated%20diarrhoea.%20Probiotics%20may%20help%20in%20prevention&author=F%20Barbut&author=JL%20Meynard&volume=324&issue=7350&publication_year=2002&pages=1345-6&pmid=12052785&doi=10.1136/bmj.324.7350.1345&)\]
- 6\.
D’Ostroph AR, So TY. Treatment of pediatric Clostridium difficile infection: a review on treatment efficacy and economic value. Infect Drug Resist. 2017;10:365–75. doi: 10.2147/IDR.S119571.
\[[DOI](https://doi.org/10.2147/IDR.S119571)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC5655036/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/29089778/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Infect%20Drug%20Resist&title=Treatment%20of%20pediatric%20Clostridium%20difficile%20infection:%20a%20review%20on%20treatment%20efficacy%20and%20economic%20value.&author=AR%20D%E2%80%99Ostroph&author=TY%20So&volume=10&publication_year=2017&pages=365-75&pmid=29089778&doi=10.2147/IDR.S119571&)\]
- 7\.
Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506–14. doi: 10.1038/nrgastro.2014.66. Epub 2014 Jun 10.
\[[DOI](https://doi.org/10.1038/nrgastro.2014.66)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/24912386/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Gastroenterol%20Hepatol&title=The%20International%20Scientific%20Association%20for%20Probiotics%20and%20Prebiotics%20consensus%20statement%20on%20the%20scope%20and%20appropriate%20use%20of%20the%20term%20probiotic&author=C%20Hill&author=F%20Guarner&author=G%20Reid&author=GR%20Gibson&author=DJ%20Merenstein&volume=11&issue=8&publication_year=2014&pages=506-14&pmid=24912386&doi=10.1038/nrgastro.2014.66&)\]
- 8\.
Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol. 2010;7(9):503–14. doi: 10.1038/nrgastro.2010.117. Epub 2010 Jul 27.
\[[DOI](https://doi.org/10.1038/nrgastro.2010.117)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC4748966/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/20664519/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Gastroenterol%20Hepatol&title=Probiotics%20and%20the%20gut%20microbiota%20in%20intestinal%20health%20and%20disease&author=MG%20Gareau&author=PM%20Sherman&author=WA%20Walker&volume=7&issue=9&publication_year=2010&pages=503-14&pmid=20664519&doi=10.1038/nrgastro.2010.117&)\]
- 9\.
Tankanow RM, Ross MB, Ertel I, Dickinson DG, McCormick LS, Garfinkel JF. A double-blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillin-induced diarrhea. DICP. 1990;24(4):382–4. doi: 10.1177/106002809002400408.
\[[DOI](https://doi.org/10.1177/106002809002400408)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/2109432/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=DICP&title=A%20double-blind,%20placebo-controlled%20study%20of%20the%20efficacy%20of%20Lactinex%20in%20the%20prophylaxis%20of%20amoxicillin-induced%20diarrhea&author=RM%20Tankanow&author=MB%20Ross&author=I%20Ertel&author=DG%20Dickinson&author=LS%20McCormick&volume=24&issue=4&publication_year=1990&pages=382-4&pmid=2109432&doi=10.1177/106002809002400408&)\]
- 10\.
Szajewska H, Ruszczyński M, Radzikowski A. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials. J Pediatr. 2006;149(3):367–72. doi: 10.1016/j.jpeds.2006.04.053.
\[[DOI](https://doi.org/10.1016/j.jpeds.2006.04.053)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/16939749/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Pediatr&title=Probiotics%20in%20the%20prevention%20of%20antibiotic-associated%20diarrhea%20in%20children:%20a%20meta-analysis%20of%20randomized%20controlled%20trials&author=H%20Szajewska&author=M%20Ruszczy%C5%84ski&author=A%20Radzikowski&volume=149&issue=3&publication_year=2006&pages=367-72&pmid=16939749&doi=10.1016/j.jpeds.2006.04.053&)\]
- 11\.
Guo Q, Goldenberg JZ, Humphrey C, El Dib R, Johnston B. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2019;(4):CD004827. doi: 10.1002/14651858.CD004827.pub5.
\[[DOI](https://doi.org/10.1002/14651858.CD004827.pub5)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC6490796/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/31039287/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Cochrane%20Database%20Syst%20Rev&title=Probiotics%20for%20the%20prevention%20of%20pediatric%20antibiotic-associated%20diarrhea&author=Q%20Guo&author=JZ%20Goldenberg&author=C%20Humphrey&author=R%20El%20Dib&author=B%20Johnston&issue=4&publication_year=2019&pages=CD004827&pmid=31039287&doi=10.1002/14651858.CD004827.pub5&)\]
- 12\.
Szajewska H, Kołodziej M. Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. Aliment Pharmacol Ther. 2015;42(10):1149–57. doi: 10.1111/apt.13404. Epub 2015 Sep 13.
\[[DOI](https://doi.org/10.1111/apt.13404)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/26365389/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Aliment%20Pharmacol%20Ther&title=Systematic%20review%20with%20meta-analysis:%20Lactobacillus%20rhamnosus%20GG%20in%20the%20prevention%20of%20antibiotic-associated%20diarrhoea%20in%20children%20and%20adults&author=H%20Szajewska&author=M%20Ko%C5%82odziej&volume=42&issue=10&publication_year=2015&pages=1149-57&pmid=26365389&doi=10.1111/apt.13404&)\]
- 13\.
Szajewska H, Kołodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015;42(7):793–801. doi: 10.1111/apt.13344. Epub 2015 Jul 27.
\[[DOI](https://doi.org/10.1111/apt.13344)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/26216624/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Aliment%20Pharmacol%20Ther&title=Systematic%20review%20with%20meta-analysis:%20Saccharomyces%20boulardii%20in%20the%20prevention%20of%20antibiotic-associated%20diarrhoea&author=H%20Szajewska&author=M%20Ko%C5%82odziej&volume=42&issue=7&publication_year=2015&pages=793-801&pmid=26216624&doi=10.1111/apt.13344&)\]
- 14\.
Mantegazza C, Molinari P, D’Auria E, Sonnino M, Morelli L, Zuccotti GV. Probiotics and antibiotic-associated diarrhea in children: a review and new evidence on Lactobacillus rhamnosus GG during and after antibiotic treatment. Pharmacol Res. 2018;128:63–72. doi: 10.1016/j.phrs.2017.08.001. Epub 2017 Aug 19.
\[[DOI](https://doi.org/10.1016/j.phrs.2017.08.001)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/28827186/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Pharmacol%20Res&title=Probiotics%20and%20antibiotic-associated%20diarrhea%20in%20children:%20a%20review%20and%20new%20evidence%20on%20Lactobacillus%20rhamnosus%20GG%20during%20and%20after%20antibiotic%20treatment&author=C%20Mantegazza&author=P%20Molinari&author=E%20D%E2%80%99Auria&author=M%20Sonnino&author=L%20Morelli&volume=128&publication_year=2018&pages=63-72&pmid=28827186&doi=10.1016/j.phrs.2017.08.001&)\]
- 15\.
Olek A, Woynarowski M, Ahrén IL, KierkuŚ J, Socha P, Larsson N, et al. Efficacy and safety of Lactobacillus plantarum DSM 9843 (LP299V) in the prevention of antibiotic-associated gastrointestinal symptoms in children—randomized, double-blind placebo-controlled study. J Pediatr. 2017;186:82–86. doi: 10.1016/j.jpeds.2017.03.047. Epub 2017 Apr 21.
\[[DOI](https://doi.org/10.1016/j.jpeds.2017.03.047)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/28438377/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Pediatr&title=Efficacy%20and%20safety%20of%20Lactobacillus%20plantarum%20DSM%209843%20\(LP299V\)%20in%20the%20prevention%20of%20antibiotic-associated%20gastrointestinal%20symptoms%20in%20children%E2%80%94randomized,%20double-blind%20placebo-controlled%20study&author=A%20Olek&author=M%20Woynarowski&author=IL%20Ahr%C3%A9n&author=J%20Kierku%C5%9A&author=P%20Socha&volume=186&publication_year=2017&pages=82-86&pmid=28438377&doi=10.1016/j.jpeds.2017.03.047&)\]
- 16\.
Merenstein DJ, Foster J, D’Amico F. A randomized clinical trial measuring the Influence of kefir on antibiotic-associated diarrhea: the Measuring the Influence of Kefir (MILK) study. Arch Pediatr Adolesc Med. 2009;163(8):750–4. doi: 10.1001/archpediatrics.2009.119.
\[[DOI](https://doi.org/10.1001/archpediatrics.2009.119)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/19652108/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Arch%20Pediatr%20Adolesc%20Med&title=A%20randomized%20clinical%20trial%20measuring%20the%20Influence%20of%20kefir%20on%20antibiotic-associated%20diarrhea:%20the%20Measuring%20the%20Influence%20of%20Kefir%20\(MILK\)%20study&author=DJ%20Merenstein&author=J%20Foster&author=F%20D%E2%80%99Amico&volume=163&issue=8&publication_year=2009&pages=750-4&pmid=19652108&doi=10.1001/archpediatrics.2009.119&)\]
- 17\.
Szajewska H, Canani RB, Guarino A, Hojsak I, Indrio F, Kolacek S, et al. Probiotics for the prevention of antibiotic-associated diarrhea in children. J Pediatr Gastroenterol Nutr. 2016;62(3):495–506. doi: 10.1097/MPG.0000000000001081.
\[[DOI](https://doi.org/10.1097/MPG.0000000000001081)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/26756877/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Pediatr%20Gastroenterol%20Nutr&title=Probiotics%20for%20the%20prevention%20of%20antibiotic-associated%20diarrhea%20in%20children&author=H%20Szajewska&author=RB%20Canani&author=A%20Guarino&author=I%20Hojsak&author=F%20Indrio&volume=62&issue=3&publication_year=2016&pages=495-506&pmid=26756877&doi=10.1097/MPG.0000000000001081&)\]
- 18\.
Kligler B, Cohrssen A. Probiotics. Am Fam Physician. 2008;78(9):1073–8.
\[[PubMed](https://pubmed.ncbi.nlm.nih.gov/19007054/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20Fam%20Physician&title=Probiotics&author=B%20Kligler&author=A%20Cohrssen&volume=78&issue=9&publication_year=2008&pages=1073-8&pmid=19007054&)\]
- 19\.
Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr. 2010;91(3):687–703. doi: 10.3945/ajcn.2009.28759. Epub 2010 Jan 20.
\[[DOI](https://doi.org/10.3945/ajcn.2009.28759)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/20089732/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Clin%20Nutr&title=Safety%20of%20probiotics%20in%20patients%20receiving%20nutritional%20support:%20a%20systematic%20review%20of%20case%20reports,%20randomized%20controlled%20trials,%20and%20nonrandomized%20trials&author=K%20Whelan&author=CE%20Myers&volume=91&issue=3&publication_year=2010&pages=687-703&pmid=20089732&doi=10.3945/ajcn.2009.28759&)\]
***
Articles from Canadian Family Physician are provided here courtesy of **College of Family Physicians of Canada**
## ACTIONS
- [ PDF (116.6 KB)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/pdf/0660037.pdf)
-  Cite
-   Collections
-  Permalink
## PERMALINK
 Copy
## RESOURCES
### Similar articles
### Cited by other articles
### Links to NCBI Databases
## Cite
-  Copy
- [ Download .nbib .nbib](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/ "Download a file for external citation management software")
- Format:
## Add to Collections
Follow NCBI
[NCBI on X (formerly known as Twitter)](https://twitter.com/ncbi)
[NCBI on Facebook](https://www.facebook.com/ncbi.nlm)
[NCBI on LinkedIn](https://www.linkedin.com/company/ncbinlm)
[NCBI on GitHub](https://github.com/ncbi)
[NCBI RSS feed](https://ncbiinsights.ncbi.nlm.nih.gov/)
Connect with NLM
[NLM on X (formerly known as Twitter)](https://twitter.com/nlm_nih)
[NLM on Facebook](https://www.facebook.com/nationallibraryofmedicine)
[NLM on YouTube](https://www.youtube.com/user/NLMNIH)
[National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894](https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/%4038.9959508,%0A%20%20%20%20%20%20%20%20%20%20%20%20-77.101021,17z/data%3D!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb%3A0x19156f88b27635b8!8m2!3d38.9959508!%0A%20%20%20%20%20%20%20%20%20%20%20%204d-77.0988323)
- [Web Policies](https://www.nlm.nih.gov/web_policies.html)
- [FOIA](https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office)
- [HHS Vulnerability Disclosure](https://www.hhs.gov/vulnerability-disclosure-policy/index.html)
- [Help](https://support.nlm.nih.gov/)
- [Accessibility](https://www.nlm.nih.gov/accessibility.html)
- [Careers](https://www.nlm.nih.gov/careers/careers.html)
- [NLM](https://www.nlm.nih.gov/)
- [NIH](https://www.nih.gov/)
- [HHS](https://www.hhs.gov/)
- [USA.gov](https://www.usa.gov/)
Back to Top
 |
| Readable Markdown | . 2020 Jan;66(1):37–39.
## Abstract
**Question** I recently had a parent ask me if their child should be taking probiotics to reduce the impending diarrhea while using antibiotic treatment for an ear infection. Are probiotics effective and safe in preventing antibiotic-associated diarrhea, and, if so, what strain and dose are recommended?
**Answer** The 2 types of probiotics recommended to prevent pediatric antibiotic-associated diarrhea are *Lactobacillus rhamnosus* GG and *Saccharomyces boulardii*. Although an optimal dose has yet to be established, higher doses in the range of 5 to 40 billion colony-forming units per day were reported to be the most efficacious in trials. The safety profile of probiotics is excellent in healthy children; however, rare serious adverse events have been documented in severely debilitated or immunocompromised children.
***
Antibiotics account for a quarter of all prescriptions for children and are a common source of adverse events including antibiotic-associated diarrhea (AAD).[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b1-0660037) *Antibiotic-associated diarrhea* is defined as 3 or more loose stools within a 24-hour period after antibiotic administration, which might occur within hours or up to 8 weeks following commencement of antibiotic use.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b2-0660037)
Elements associated with AAD include the age of the child and the antibiotic agent used, among other factors, with an estimated incidence of 5% to 30% in children according to a review of 10 studies with 1438 children from 6 different countries.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b3-0660037) Cephalosporins, clindamycin, and broad-spectrum penicillins have been associated with a higher risk of AAD.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b4-0660037)
Current standard of care treatment for AAD includes discontinuing or changing the inciting antibiotic,[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b3-0660037) providing rehydration,[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b5-0660037) or administering oral metronidazole or vancomycin if *Clostridium difficile* is the suspected culprit.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b6-0660037)
## Probiotics for prevention of AAD
*Probiotics* are defined by the World Health Organization as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b7-0660037) The mechanisms of action of different probiotics include providing a physical barrier from pathogens, promoting goblet cell mucus secretion, maintaining the integrity of intestinal epithelial tight junctions, producing antimicrobial factors, and stimulating the immune system.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b8-0660037)
A study from almost 30 years ago involving 60 children between the ages of 5 months and 6 years was the first to investigate the relationship between probiotics and AAD in this population.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b9-0660037) Children requiring treatment with amoxicillin were randomized to receive either 500 million colony-forming units (CFUs) of Lactinex (a combination of *Lactobacillus acidophilus* and *Lactobacillus bulgaricus*) or placebo (lactose) 4 times daily for 10 days, with similar rates of children still experiencing diarrhea (≥ 1 loose stools per day; 66% vs 69.5%, respectively; *P* = .563).[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b9-0660037)
Sixteen years later, a meta-analysis (N = 766) examined the use of probiotics in reducing the incidence of pediatric AAD across 6 randomized controlled trials (RCTs), reporting a lower risk for those receiving probiotics (12% and 29% in probiotics and placebo groups, respectively, relative risk \[RR\] of 0.44, 95% CI 0.25 to 0.77).[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b10-0660037) Particularly, *Lactobacillus rhamnosus* GG (RR = 0.3, 95% CI 0.15 to 0.6; n = 307), *Saccharomyces boulardii* (RR = 0.2, 95% CI 0.07 to 0.6; n = 246) and a combination of *Bifidobacterium lactis* and *Streptococcus thermophilus* (RR = 0.5, 95% CI 0.3 to 0.95; n = 157) were reported to be efficacious in preventing pediatric AAD.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b10-0660037) However, it is difficult to generalize these conclusions owing to the small sample size in each of the trials.
A recent Cochrane review analyzed 33 studies with 6352 children up to 18 years of age who received antibiotic therapy for 3 to 30 days.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) The probiotics were coadministered with the antibiotic regimen for infections such as in the respiratory tract, impetigo, and *Helicobacter pylori*.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) The reported incidence of AAD after follow-up (5 days to 12 weeks) was 8% in those receiving probiotics compared with 19% among those receiving placebo (RR = 0.45, 95% CI 0.36 to 0.56; number needed to benefit of 9, 95% CI 7 to 13), suggesting an important role of probiotics in preventing AAD in children.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037)
## Choosing probiotics
While the number of probiotic options can be daunting, 2 probiotics in particular have emerged at the forefront for preventing pediatric AAD.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037),[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037) In a 2015 meta-analysis of 5 RCTs with 445 children, *L rhamnosus* GG was associated with an AAD incidence of 9.6% in the probiotic group and 23% in the placebo group (RR = 0.48, 95% CI 0.26 to 0.89).[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037) Another meta-analysis from the same group reported that with the use of the yeast *S boulardii*, AAD incidence was 8.8% and 20.9% (probiotic and placebo groups, respectively) among 1653 children across 6 RCTs (RR = 0.43, 95% CI 0.3 to 0.6).[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037)
Other probiotics including *Lactobacillus reuteri, L rhamnosus* (strains E/N, Oxy, and Pen), combination *Clostridium butyricum* and *Bifidobacterium*, combination *B lactis* and *S thermophilus*, and yogurt (containing active cultures of *S thermophilus* and *Lactobacillus delbrueckii*) have demonstrated efficacy in reducing pediatric AAD incidence in some trials; however, these therapeutic options need further study.[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b14-0660037) Of note, neither *Lactobacillus plantarum* (AAD in 2.8% of probiotic group compared with 4.1% in placebo group \[N = 438\], *P* = .4)[15](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b15-0660037) nor kefir beverage (containing lactic acid bacteria such as *Lactobacillus kefiri, Lactobacillus kefiranofaciens, L acidophilus*, and *L plantarum*, as well as yeasts such as *Kluyveromyces marxianus, Saccharomyces unisporus, Saccharomyces cerevisiae,* and *Saccharomyces exiguus*) (RR = 0.82, 95% CI 0.54 to 1.43)[16](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b16-0660037) were efficacious in their respective studies.
Upon reviewing 21 RCTs involving 3255 children, the Working Group on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) published its 2016 guidelines recommending *L rhamnosus* GG and *S boulardii* as the 2 probiotics with sufficient evidence for AAD prevention.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) However, *S boulardii* is recommended over *L rhamnosus* GG when *C difficile*–associated diarrhea is isolated.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) These recommendations were made only if 2 or more RCTs were available for the specific strain of probiotic.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037)
## Optimal dose
The optimal dose of probiotics remains largely unknown, as evidenced by the range of doses used in pediatric clinical trials from 100 million to 1.8 trillion CFUs per day.[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b18-0660037) *Lactobacillus rhamnosus* GG has greater evidence for a dose-dependent response in children.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037),[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037) In a meta-analysis including 445 children up to age 17 from 3 countries (Poland, Finland, and the United States) who received coadministration of *L rhamnosus* GG with antibiotics, the highest dose of *L rhamnosus* GG (10 to 20 billion CFUs per day) achieved a 71% reduction in AAD incidence compared with a dose of 3 billion CFUs per day, which only achieved a 34% reduction in incidence.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b12-0660037) In contrast, a meta-analysis with 1653 children reported that among 6 trials with a daily dose of *S boulardii* ranging from 50 mg to 1000 mg (1 billion to 20 billion CFUs per day), efficacy in preventing AAD did not demonstrate a clear dose-dependent relationship.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b13-0660037) The most recent 2016 ESPGHAN guidelines do not affirm specific recommendations for doses of *L rhamnosus* GG and *S boulardii*.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) The ESPGHAN guidelines suggest that 10 to 20 billion CFUs per day of *L rhamnosus* GG or 250 to 500 mg (5 to 10 billion CFUs per day) of *S boulardii* can be used to match the doses used in some RCTs.[17](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b17-0660037) This general range of doses was supported by a 2019 Cochrane review that noted that in the 33 included trials, high-dose probiotics (5 to 40 billion CFUs per day) were more effective than low-dose probiotics (RR = 0.37, 95% CI 0.30 to 0.46, *P* = .06; number needed to benefit of 6, 95% CI 5 to 9).[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037)
## Safety
Among 24 studies, rates of mild to moderate adverse events (eg, rash, nausea, gas, flatulence, abdominal bloating, constipation) were low, with an incidence of 4% (86 of 2229) in the probiotic groups compared with 6% (121 of 2186) in the control groups.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) No serious adverse events were reported in either group.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b11-0660037) However, serious adverse events were reported in a large systematic review of 20 case reports and 52 randomized and non-randomized trials involving 4131 patients (children and adults) who received probiotics through enteral or parenteral nutrition.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) In the case reports, some of which reported on more than 1 patient, 32 cases of serious adverse events (ie, fungemia, bacteremia) were documented.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) Eleven of these cases were either preterm neonates, severely debilitated children, or immunocompromised children, and involved risk factors such as central venous catheters and disorders associated with increased bacterial translocation.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) All 11 recovered from the infection after discontinuing the probiotic, removing the central venous catheter, or administrating an antibiotic or antifungal.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012114/#b19-0660037) While probiotics appear to be safe in healthy children, use in severely debilitated or immunocompromised children requires caution owing to the potential for reversible but serious adverse events as documented in several case reports.
## Conclusion
*Lactobacillus rhamnosus* GG and *S boulardii* are 2 probiotics that are effective in preventing pediatric AAD when coadministered with antibiotics. While an optimal dose remains unknown, a range of 5 to 40 billion CFUs per day appears to be the most efficacious. There is insufficient evidence to recommend other strains of probiotics at this time. Probiotics appear to be safe in children, with minimal side effects; however, serious adverse events have been documented in case reports of severely debilitated or immunocompromised children.
**Child Health Update** is produced by the Pediatric Research in Emergency Therapeutics (PRETx) program (**[www.pretx.org](http://www.pretx.org/)**) at the BC Children’s Hospital in Vancouver, BC. **Mr Yan** is a member and **Dr Goldman** is Director of the PRETx program. The mission of the PRETx program is to promote child health through evidence-based research in therapeutics in pediatric emergency medicine.
Do you have questions about the effects of drugs, chemicals, radiation, or infections in children? We invite you to submit them to the PRETx program by fax at 604 875-2414; they will be addressed in future **Child Health Updates**. Published **Child Health Updates** are available on the *Canadian Family Physician* website (**[www.cfp.ca](http://www.cfp.ca/)**).
## Footnotes
**Competing interests**
None declared
This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to **[www.cfp.ca](http://www.cfp.ca/)** and click on the Mainpro+ link.
La traduction en français de cet article se trouve à **[www.cfp.ca](http://www.cfp.ca/)** dans la table des matières du numéro **de janvier 2020** à la **[page e9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7012121/)**.
## References
- 1\.
Chai G, Governale L, McMahon AW, Trinidad JP, Staffa J, Murphy D. Trends of outpatient prescription drug utilization in US children, 2002–2010. Pediatrics. 2012;130(1):23–31. doi: 10.1542/peds.2011-2879. Epub 2012 Jun 18.
\[[DOI](https://doi.org/10.1542/peds.2011-2879)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/22711728/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Pediatrics&title=Trends%20of%20outpatient%20prescription%20drug%20utilization%20in%20US%20children,%202002%E2%80%932010&author=G%20Chai&author=L%20Governale&author=AW%20McMahon&author=JP%20Trinidad&author=J%20Staffa&volume=130&issue=1&publication_year=2012&pages=23-31&pmid=22711728&doi=10.1542/peds.2011-2879&)\]
- 2\.
Mcfarland LV. Epidemiology, risk factors and treatments for antibiotic associated diarrhea. Dig Dis. 1998;16(5):292–307. doi: 10.1159/000016879.
\[[DOI](https://doi.org/10.1159/000016879)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/9892789/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Dig%20Dis&title=Epidemiology,%20risk%20factors%20and%20treatments%20for%20antibiotic%20associated%20diarrhea&author=LV%20Mcfarland&volume=16&issue=5&publication_year=1998&pages=292-307&pmid=9892789&doi=10.1159/000016879&)\]
- 3\.
Alam S, Mushtaq M. Antibiotic associated diarrhea in children. Indian Pediatr. 2009;46(6):491–6.
\[[PubMed](https://pubmed.ncbi.nlm.nih.gov/19556659/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Indian%20Pediatr&title=Antibiotic%20associated%20diarrhea%20in%20children&author=S%20Alam&author=M%20Mushtaq&volume=46&issue=6&publication_year=2009&pages=491-6&pmid=19556659&)\]
- 4\.
Wiström J, Norrby SR, Myhre EB, Eriksson S, Granström G, Lagergren L, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother. 2001;47(1):43–50. doi: 10.1093/jac/47.1.43.
\[[DOI](https://doi.org/10.1093/jac/47.1.43)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/11152430/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Antimicrob%20Chemother&title=Frequency%20of%20antibiotic-associated%20diarrhoea%20in%202462%20antibiotic-treated%20hospitalized%20patients:%20a%20prospective%20study&author=J%20Wistr%C3%B6m&author=SR%20Norrby&author=EB%20Myhre&author=S%20Eriksson&author=G%20Granstr%C3%B6m&volume=47&issue=1&publication_year=2001&pages=43-50&pmid=11152430&doi=10.1093/jac/47.1.43&)\]
- 5\.
Barbut F, Meynard JL. Managing antibiotic associated diarrhoea. Probiotics may help in prevention. BMJ. 2002;324(7350):1345–6. doi: 10.1136/bmj.324.7350.1345.
\[[DOI](https://doi.org/10.1136/bmj.324.7350.1345)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC1123310/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/12052785/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=BMJ&title=Managing%20antibiotic%20associated%20diarrhoea.%20Probiotics%20may%20help%20in%20prevention&author=F%20Barbut&author=JL%20Meynard&volume=324&issue=7350&publication_year=2002&pages=1345-6&pmid=12052785&doi=10.1136/bmj.324.7350.1345&)\]
- 6\.
D’Ostroph AR, So TY. Treatment of pediatric Clostridium difficile infection: a review on treatment efficacy and economic value. Infect Drug Resist. 2017;10:365–75. doi: 10.2147/IDR.S119571.
\[[DOI](https://doi.org/10.2147/IDR.S119571)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC5655036/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/29089778/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Infect%20Drug%20Resist&title=Treatment%20of%20pediatric%20Clostridium%20difficile%20infection:%20a%20review%20on%20treatment%20efficacy%20and%20economic%20value.&author=AR%20D%E2%80%99Ostroph&author=TY%20So&volume=10&publication_year=2017&pages=365-75&pmid=29089778&doi=10.2147/IDR.S119571&)\]
- 7\.
Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506–14. doi: 10.1038/nrgastro.2014.66. Epub 2014 Jun 10.
\[[DOI](https://doi.org/10.1038/nrgastro.2014.66)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/24912386/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Gastroenterol%20Hepatol&title=The%20International%20Scientific%20Association%20for%20Probiotics%20and%20Prebiotics%20consensus%20statement%20on%20the%20scope%20and%20appropriate%20use%20of%20the%20term%20probiotic&author=C%20Hill&author=F%20Guarner&author=G%20Reid&author=GR%20Gibson&author=DJ%20Merenstein&volume=11&issue=8&publication_year=2014&pages=506-14&pmid=24912386&doi=10.1038/nrgastro.2014.66&)\]
- 8\.
Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol. 2010;7(9):503–14. doi: 10.1038/nrgastro.2010.117. Epub 2010 Jul 27.
\[[DOI](https://doi.org/10.1038/nrgastro.2010.117)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC4748966/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/20664519/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Gastroenterol%20Hepatol&title=Probiotics%20and%20the%20gut%20microbiota%20in%20intestinal%20health%20and%20disease&author=MG%20Gareau&author=PM%20Sherman&author=WA%20Walker&volume=7&issue=9&publication_year=2010&pages=503-14&pmid=20664519&doi=10.1038/nrgastro.2010.117&)\]
- 9\.
Tankanow RM, Ross MB, Ertel I, Dickinson DG, McCormick LS, Garfinkel JF. A double-blind, placebo-controlled study of the efficacy of Lactinex in the prophylaxis of amoxicillin-induced diarrhea. DICP. 1990;24(4):382–4. doi: 10.1177/106002809002400408.
\[[DOI](https://doi.org/10.1177/106002809002400408)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/2109432/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=DICP&title=A%20double-blind,%20placebo-controlled%20study%20of%20the%20efficacy%20of%20Lactinex%20in%20the%20prophylaxis%20of%20amoxicillin-induced%20diarrhea&author=RM%20Tankanow&author=MB%20Ross&author=I%20Ertel&author=DG%20Dickinson&author=LS%20McCormick&volume=24&issue=4&publication_year=1990&pages=382-4&pmid=2109432&doi=10.1177/106002809002400408&)\]
- 10\.
Szajewska H, Ruszczyński M, Radzikowski A. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials. J Pediatr. 2006;149(3):367–72. doi: 10.1016/j.jpeds.2006.04.053.
\[[DOI](https://doi.org/10.1016/j.jpeds.2006.04.053)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/16939749/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Pediatr&title=Probiotics%20in%20the%20prevention%20of%20antibiotic-associated%20diarrhea%20in%20children:%20a%20meta-analysis%20of%20randomized%20controlled%20trials&author=H%20Szajewska&author=M%20Ruszczy%C5%84ski&author=A%20Radzikowski&volume=149&issue=3&publication_year=2006&pages=367-72&pmid=16939749&doi=10.1016/j.jpeds.2006.04.053&)\]
- 11\.
Guo Q, Goldenberg JZ, Humphrey C, El Dib R, Johnston B. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2019;(4):CD004827. doi: 10.1002/14651858.CD004827.pub5.
\[[DOI](https://doi.org/10.1002/14651858.CD004827.pub5)\] \[[PMC free article](https://pmc.ncbi.nlm.nih.gov/articles/PMC6490796/)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/31039287/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Cochrane%20Database%20Syst%20Rev&title=Probiotics%20for%20the%20prevention%20of%20pediatric%20antibiotic-associated%20diarrhea&author=Q%20Guo&author=JZ%20Goldenberg&author=C%20Humphrey&author=R%20El%20Dib&author=B%20Johnston&issue=4&publication_year=2019&pages=CD004827&pmid=31039287&doi=10.1002/14651858.CD004827.pub5&)\]
- 12\.
Szajewska H, Kołodziej M. Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. Aliment Pharmacol Ther. 2015;42(10):1149–57. doi: 10.1111/apt.13404. Epub 2015 Sep 13.
\[[DOI](https://doi.org/10.1111/apt.13404)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/26365389/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Aliment%20Pharmacol%20Ther&title=Systematic%20review%20with%20meta-analysis:%20Lactobacillus%20rhamnosus%20GG%20in%20the%20prevention%20of%20antibiotic-associated%20diarrhoea%20in%20children%20and%20adults&author=H%20Szajewska&author=M%20Ko%C5%82odziej&volume=42&issue=10&publication_year=2015&pages=1149-57&pmid=26365389&doi=10.1111/apt.13404&)\]
- 13\.
Szajewska H, Kołodziej M. Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2015;42(7):793–801. doi: 10.1111/apt.13344. Epub 2015 Jul 27.
\[[DOI](https://doi.org/10.1111/apt.13344)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/26216624/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Aliment%20Pharmacol%20Ther&title=Systematic%20review%20with%20meta-analysis:%20Saccharomyces%20boulardii%20in%20the%20prevention%20of%20antibiotic-associated%20diarrhoea&author=H%20Szajewska&author=M%20Ko%C5%82odziej&volume=42&issue=7&publication_year=2015&pages=793-801&pmid=26216624&doi=10.1111/apt.13344&)\]
- 14\.
Mantegazza C, Molinari P, D’Auria E, Sonnino M, Morelli L, Zuccotti GV. Probiotics and antibiotic-associated diarrhea in children: a review and new evidence on Lactobacillus rhamnosus GG during and after antibiotic treatment. Pharmacol Res. 2018;128:63–72. doi: 10.1016/j.phrs.2017.08.001. Epub 2017 Aug 19.
\[[DOI](https://doi.org/10.1016/j.phrs.2017.08.001)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/28827186/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Pharmacol%20Res&title=Probiotics%20and%20antibiotic-associated%20diarrhea%20in%20children:%20a%20review%20and%20new%20evidence%20on%20Lactobacillus%20rhamnosus%20GG%20during%20and%20after%20antibiotic%20treatment&author=C%20Mantegazza&author=P%20Molinari&author=E%20D%E2%80%99Auria&author=M%20Sonnino&author=L%20Morelli&volume=128&publication_year=2018&pages=63-72&pmid=28827186&doi=10.1016/j.phrs.2017.08.001&)\]
- 15\.
Olek A, Woynarowski M, Ahrén IL, KierkuŚ J, Socha P, Larsson N, et al. Efficacy and safety of Lactobacillus plantarum DSM 9843 (LP299V) in the prevention of antibiotic-associated gastrointestinal symptoms in children—randomized, double-blind placebo-controlled study. J Pediatr. 2017;186:82–86. doi: 10.1016/j.jpeds.2017.03.047. Epub 2017 Apr 21.
\[[DOI](https://doi.org/10.1016/j.jpeds.2017.03.047)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/28438377/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Pediatr&title=Efficacy%20and%20safety%20of%20Lactobacillus%20plantarum%20DSM%209843%20\(LP299V\)%20in%20the%20prevention%20of%20antibiotic-associated%20gastrointestinal%20symptoms%20in%20children%E2%80%94randomized,%20double-blind%20placebo-controlled%20study&author=A%20Olek&author=M%20Woynarowski&author=IL%20Ahr%C3%A9n&author=J%20Kierku%C5%9A&author=P%20Socha&volume=186&publication_year=2017&pages=82-86&pmid=28438377&doi=10.1016/j.jpeds.2017.03.047&)\]
- 16\.
Merenstein DJ, Foster J, D’Amico F. A randomized clinical trial measuring the Influence of kefir on antibiotic-associated diarrhea: the Measuring the Influence of Kefir (MILK) study. Arch Pediatr Adolesc Med. 2009;163(8):750–4. doi: 10.1001/archpediatrics.2009.119.
\[[DOI](https://doi.org/10.1001/archpediatrics.2009.119)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/19652108/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Arch%20Pediatr%20Adolesc%20Med&title=A%20randomized%20clinical%20trial%20measuring%20the%20Influence%20of%20kefir%20on%20antibiotic-associated%20diarrhea:%20the%20Measuring%20the%20Influence%20of%20Kefir%20\(MILK\)%20study&author=DJ%20Merenstein&author=J%20Foster&author=F%20D%E2%80%99Amico&volume=163&issue=8&publication_year=2009&pages=750-4&pmid=19652108&doi=10.1001/archpediatrics.2009.119&)\]
- 17\.
Szajewska H, Canani RB, Guarino A, Hojsak I, Indrio F, Kolacek S, et al. Probiotics for the prevention of antibiotic-associated diarrhea in children. J Pediatr Gastroenterol Nutr. 2016;62(3):495–506. doi: 10.1097/MPG.0000000000001081.
\[[DOI](https://doi.org/10.1097/MPG.0000000000001081)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/26756877/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Pediatr%20Gastroenterol%20Nutr&title=Probiotics%20for%20the%20prevention%20of%20antibiotic-associated%20diarrhea%20in%20children&author=H%20Szajewska&author=RB%20Canani&author=A%20Guarino&author=I%20Hojsak&author=F%20Indrio&volume=62&issue=3&publication_year=2016&pages=495-506&pmid=26756877&doi=10.1097/MPG.0000000000001081&)\]
- 18\.
Kligler B, Cohrssen A. Probiotics. Am Fam Physician. 2008;78(9):1073–8.
\[[PubMed](https://pubmed.ncbi.nlm.nih.gov/19007054/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20Fam%20Physician&title=Probiotics&author=B%20Kligler&author=A%20Cohrssen&volume=78&issue=9&publication_year=2008&pages=1073-8&pmid=19007054&)\]
- 19\.
Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr. 2010;91(3):687–703. doi: 10.3945/ajcn.2009.28759. Epub 2010 Jan 20.
\[[DOI](https://doi.org/10.3945/ajcn.2009.28759)\] \[[PubMed](https://pubmed.ncbi.nlm.nih.gov/20089732/)\] \[[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Clin%20Nutr&title=Safety%20of%20probiotics%20in%20patients%20receiving%20nutritional%20support:%20a%20systematic%20review%20of%20case%20reports,%20randomized%20controlled%20trials,%20and%20nonrandomized%20trials&author=K%20Whelan&author=CE%20Myers&volume=91&issue=3&publication_year=2010&pages=687-703&pmid=20089732&doi=10.3945/ajcn.2009.28759&)\] |
| Shard | 129 (laksa) |
| Root Hash | 7295144728021232729 |
| Unparsed URL | gov,nih!nlm,ncbi,pmc,/articles/PMC7012114/ s443 |