Probiotics for the Prevention of Antibiotic-Associated ... · Diarrhea in Children Hania ... European Society for Pediatric Gastro-enterology, Hepatology, and Nutrition, for the use

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CLINICAL GUIDELINE

Probiotics for the Prevention of Antibiotic-Associated

Diarrhea in Children�Hania Szajewska, yzRoberto Berni Canani, yAlfredo Guarino, §Iva Hojsak, jjFlavia Indrio,

§Sanja Kolacek, �Rok Orel, #Raanan Shamir, ��Yvan Vandenplas, yyJohannes B. van Goudoever,

pyright 2016 by

and zzZvi W alf of the ESPGHAN Working Group for Probiotics/Prebiotics

available. The quality of e

Recommendations Assess

Received December 7, 20From the �Medical Univ

Laboratory for The I§Department of PaedUniversity Hospital PUniversity Medical CeIsrael, Sackler FacultBrussels, Belgium, thethe zzPediatric Gastro

Address correspondence aWigury 63A, Poland

Supplemental digital conttext of this article on

H.S. has received researchhas participated as aInstitute, Nutricia, Memember for Fundacjainvestigator, and/or spsupported by Biocoderelated to any of the prnot related to the conteclinical investigator, ctopics within the probifee provided to the insrelated clinical studiesAbbott, Danone, NestlMerck/MSD, HospiraBioGaia (ongoing; invAbbvie, and MSD. RInternational, Danoneadvisory board for ASprobiotic related, somNutricia, Mead JohnsoYakult (grants, study,and founder and direclectures by Danone, Nformula. Z.W. has par

Copyright # 2016 byGastroenterology, He

DOI: 10.1097/MPG.0000

JPGN � Volume 62, N

eizman, on Beh

combinations of strains have been tested, but sufficient evidence is still

lacking.

ABSTRACT

This article provides recommendations, developed by the Working

Group (WG) on Probiotics of the European Society for Pediatric Gastro-

enterology, Hepatology, and Nutrition, for the use of probiotics for the

prevention of antibiotic-associated diarrhea (AAD) in children based on a

systematic review of previously completed systematic reviews and of

randomized controlled trials published subsequently to these reviews.

The use of probiotics for the treatment of AAD is not covered.

The recommendations were formulated only if at least 2 randomized

controlled trials that used a given probiotic (with strain specification) were

ESPGHAN and NASPGHAN. Un

vidence (QoE) was assessed using the Grading of

ment, Development, and Evaluation guidelines. If

15; accepted December 10, 2015.ersity of Warsaw, Department of Paediatrics, Warsaw,nvestigation of Food Induced Diseases and CEINGEiatrics, Children’s Hospital Zagreb, University of Zagoliclinico, University of Bari, Bari, Italy, the �Departntre, Ljubljana, Slovenia, the #Institute of Gastroentero

y of Medicine, Tel-Aviv University, Tel-Aviv, Israel,yyDepartment of Pediatrics, Emma Children’s Hospitaenterology and Nutrition Unit, Soroka Medical Centend reprint requests to Hania Szajewska, MD, Departme

(e-mail: [email protected]).ent is available for this article. Direct URL citations appthe journal’s Web site (www.jpgn.org).support (study products only) from Biogaia and Dicofa

speaker on probiotics/microbiota-related subjects for Aad Johnson, Merck, Sequoia, and Yakult; has been a mem

Nutricia (Nutricia Foundation), funding research graeaker for Dicofarm, Heinz, Mead Johnson Nutrition, Mx, Dicofarm, and Mead Johnson Nutrition. Others (sucoducts mentioned in the article and companies using/or snt of the article: Astellas Pharma. I.H. has participated aonsultant, and speaker for Arla Food, Biogaia, Noos, Notic-related fields (never for probiotic product) from Biotitution in the studies related to probiotic product of Dukreceived from Chr. Hansen and Biogaia. Other activitiee, Nutricia and MSD, and nonrestricted educational granand Pharmas. R.O. has participated as a clinical inve

estigator’s initiated study); has participated as a speaker.S. has a clinical investigator, and/or advisory board, Enzymotec, Nestle, Nestle Nutrition Institute, and NuPEN, Ausnutria, Biocodex, Danone Belgium, and Unitetimes not) for Abbott Nutrition, ARLA foods, ASPENn, Merck, Menarini, Orafti, Pfizer, Phacobel, Sari Husa

and advisory fees always paid to the institution). J.B.G.tor of the Dutch Human Milk Bank; his institute receutricia, Nestle Nutrition Institute; he is consultant for Nuticipated as a clinical investigator, speaker, and consuEuropean Society for Pediatric Gastroenterology,patology, and Nutrition000000001081

umber 3, March 2016

the use of probiotics for preventing AAD is considered because of the

existence of risk factors such as class of antibiotic(s), duration of antibiotic

treatment, age, need for hospitalization, comorbidities, or previous episodes

of AAD diarrhea, the WG recommends using Lactobacillus rhamnosus GG

(moderate QoE, strong recommendation) or Saccharomyces boulardii (mod-

erate QoE, strong recommendation). If the use of probiotics for preventing

Clostridium difficile-associated diarrhea is considered, the WG suggests

using S boulardii (low QoE, conditional recommendation). Other strains or

authorized reproduction of this article is prohibited.

Poland, the yDepartment of Translational Medical Science, the zEuropeanAdvanced Biotechnology, University of Naples ‘‘Federico II,’’ Italy, thereb School of Medicine, Zagreb, Croatia, the jjDepartment of Pediatrics,ment of Gastroenterology, Hepatology and Nutrition, Children’s Hospital,logy, Nutrition and Liver Diseases, Schneider Children’s Medical Center ofthe ��Department of Pediatrics, UZ Brussel, Vrije Universiteit Brussel,

l-AMC and VU Universit Medical Center, Amsterdam, The Netherlands, andr. Ben-Gurion University, Beer-Sheva, Israel.nt of Paediatrics, Medical University of Warsaw, 02–091 Warsaw, Zwirki i

ear in the printed text, and links to the digital files are provided in the HTML

rm; has been a clinical investigator for Arla Foods (ongoing), Danone, Nestle;rla, Biogaia, Biocodex, Danone, Dicofarm, Hipp, Nestle, Nestle Nutritionber of Nestle Nutrition Institute faculty; and has served as an advisory board

nts in the field of human nutrition. R.B.C. has participated as a clinicalenarini, Nutricia, and Wyeth (none related to the work submitted). A.G. wash as personal fees for advisory boards, consultancy; personal speakers feeelling them, as well as competitors)—none declared. Other industry relationss a clinical investigator for Biogaia and Chr Hansen. F.I. has participated as aestle, and Nestle Nutrition Institute. S.K. received personal speaker fee for

gaia, Medis, and Arla Foods. Clinical investigator without any personal fee orat. Scientific grants delivered entirely and only to the Institution for probiotic-s nonrelated to probiotics were as follows: personal speaker fee received fromts delivered to the Institution from Nestle, Nutricia, Podravka, AbbVie, Falk,

stigator for United Pharmaceuticals (probiotics were not involved) and forfor Medis, Nutricia, Ewopharma, Biogaia, United Pharmaceuticals, Danone,member, and/or consultant, and/or speaker for Abbott, Danone Institutetricia; none related to the work submitted. Y.V. is consultant or member ofed Pharmaceuticals; has been a clinical investigator and speaker (sometimes, Biogaia, Biocodex, Danone, Dumex, Hero, Hipp, Nestle Nutrition Institute,da, Shire (Movetis), Sucampo, Takeda, United Pharmaceuticals, Wyeth andis member of the Dutch National Health Council, the Breastfeeding Councilived research grants from Danone and MJN; he received compensation fortricia Nederland and holds 3 patents on the amino acid composition of infantltant for Biocodex and Biogaia.Hepatology, and Nutrition and North American Society for Pediatric

495

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http://www.jpgn.org/

http://dx.doi.org/10.1097/MPG.0000000000001081

Co

Key Words: Clostridium difficile, dysbiosis, guideline, infants, microbiota,

probiotics, RCT, systematic review

(JPGN 2016;62: 495–506)

Szajewska et al

A ntibiotic-associated diarrhea (AAD) is a common and chal-lenging complication observed in the ambulatory and hospi-

tal settings alike that occurs in up to a third of all patients treatedwith antibiotics (1). It is defined as diarrhea that occurs in relation toantibiotic treatment with the exclusion of other etiologies. Thisrelation does not necessarily translate into an immediate adversereaction to antibiotics, because AAD may occur after a few weeksand even up to a few months after the administration of theantibiotics (2). Thus, in the latter situation, caution is needed todifferentiate AAD from an episode of infectious gastroenteritis. Therisk of AAD is higher when there is a use of aminopenicillinswithout/with clavulanate, cephalosporins, clindamycin, and, ingeneral, any antibiotic that is active against anaerobes (3). Almostany oral and intravenous antibiotic treatment can, however, causeAAD (3). Clinically, AAD may present as mild diarrhea, but itcan present as well as fulminant pseudomembranous colitis.Usually, no pathogen is identified. In the most severe forms andin an increasing number of patients with chronic conditions such asthose with inflammatory bowel diseases, cystic fibrosis, and cancer,however, the causative agent is often identified as Clostridiumdifficile (4).

The use of probiotics, defined as ‘‘live microorganisms that,when administered in adequate amounts, confer a health benefit onthe host,’’ (5) and/or fermented products such as yogurt has beenreported as a measure to prevent the occurrence of AAD. Therationale for the use of these products relies on the hypothesis thatAAD is caused by dysbiosis that is triggered by antibiotic use andthat the probiotic intervention favorably modulates the intestinalmicrobiota (1).

The aim of this position paper by the European Society forPediatric Gastroenterology, Hepatology, and Nutrition (ESP-GHAN) Working Group (WG) on Probiotics and Prebiotics is toprovide recommendations for the use of probiotics for preventingAAD in children.

METHODSThe same methodology that had been used previously by the

WG for developing guidelines on the use of probiotics for themanagement of acute gastroenteritis (6) was applied for developingthe present position paper. In brief, the document provides a reviewof previously completed systematic reviews and of randomizedcontrolled trials (RCTs) published subsequently to these reviews.For systematic reviews/meta-analyses, the Cochrane Database ofSystematic Reviews and the Database of Abstracts of Reviews ofEffects (DARE) were searched. For subsequently published trials(starting from the date of the most recent search in the includedreviews), CENTRAL (Cochrane Central Register of ControlledTrials), MEDLINE, and EMBASE were searched up to July2015 and again in November 2015.

The focus was on 6 taxonomic groups (Lactobacillus,Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus,and/or Bacillus). The list of individual probiotics to be consideredwas established based on the results of the Cochrane reviewevaluating probiotics for preventing AAD in children (7) and thelist of commonly used probiotics developed by the World Gastro-enterology Organization (8).

The WG is aware that taxonomically equivalent probiotic

pyright 2016 by ESPGHAN and NASPGHAN. Un

microorganisms may be supplied by different manufacturers.At least 1 study indicated that the manufacturing process may

496

influence properties of probiotic bacteria (9). At present, whetheror not these manufacturing differences translate into differences invivo, as well as clinical outcomes, however, remains unclear.Consequently, the taxonomically equivalent probiotics are pre-sented jointly, regardless of the manufacturer. The WG alsorealizes that the same brand may have a different compositionin different locations; nevertheless, this position paper deals withstrain(s) rather than brands or commercial names. Finally, depend-ing on the country, the same probiotic microorganism(s) may beavailable as food supplements, available as registered pharmaceu-tical products, and/or incorporated into foods (10). In this docu-ment, the effectiveness of probiotics was analyzed regardless of theregistration status. Health care professionals and consumersshould, however, be aware of possible variations in the manufac-turing and safety profiles of the products, which may be differentwhen the strain is registered as a drug and also with regard to theclaims allowed.

The primary outcome measures were diarrhea/AAD andC difficile-associated diarrhea (all as defined by the investigators).

To assess the methodological quality of the included RCTs(included in the previously published meta-analyses and sub-sequently published RCTs not included in the systematic reviews),the Cochrane Collaboration’s tool for assessing risk of bias wasused. This tool includes the following criteria: adequacy ofsequence generation, allocation concealment, and blinding ofparticipants, personnel and outcome assessors; incomplete outcomedata; and selective reporting (11).

For reporting the effect, the results for individual studiesand pooled statistics are reported as the risk ratio (RR) betweenthe experimental and control groups with 95% confidence intervals(95% CIs). In other circumstances, we report the findings asreported by the authors of the included studies.

When synthesizing the evidence, each section presentsa summary of the evidence followed by the key recommen-dations. The GRADE system, developed by the Grading ofRecommendations Assessment, Development and EvaluationsWorking Group (12), was used to grade the strength of evidenceand grades of recommendations used in these guidelines. In brief,the GRADE system offers 4 categories of the quality of theevidence (ie, high, moderate, low, and very low) and 2 categoriesof the strength of recommendation (ie, strong or conditional[weak]) (Table 1). The GRADE system suggests presentingrecommendations in the active voice (13). Thus, we used thewording ‘‘the WG recommends’’ for strong recommendations,and ‘‘the WG suggests’’ for conditional [weak] recommen-dations.

As in our previous document (6), the WG adopted theposition of the US Food and Drug Administration Guidance forIndustry (14) that at least 2 adequate and well-controlled studies,each convincing on its own, are needed to establish the effec-tiveness of an intervention. Consequently, the recommendationswere formulated only if at least 2 RCTs that used a given probioticwere available. If there was only 1 RCT, regardless of whether ornot it showed a benefit, no recommendation was formulated.Moreover, if the strain specification was not given and/or theprobiotic product was not otherwise identifiable, no recommen-dation was made.

For the sake of completeness, we report the pooled data(meta-analysis) of all probiotic trials. No recommendation onthe use of probiotics in general was, however, made, becausepooling data on different probiotics has been repeatedly ques-tioned (15). Instead, because various probiotic strains differ intheir effects, preference was given to reporting evidence and

JPGN � Volume 62, Number 3, March 2016


recommendations related to a specific probiotic strain or theircombinations separately.

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of C difficile-associated diarrhea (4 RCTs, n¼ 938, RR 0.34, 95%

QUALITY OF EVIDENCE: Moderate.

TABLE 1. The grades of the quality of evidence and strength of recommendation set by the GRADE Working Group

Quality of evidence High quality We are very confident that the true effect lies close to that of the estimate of the effect.

Moderate quality We are moderately confident in the effect estimate: the true effect is likely to be close to the

estimate of the effect, but there is a possibility that it is substantially different.

Low quality Confidence in the effect estimate is limited: the true effect may be substantially different from

the estimate of the effect.

Very low quality Very little confidence in the effect estimate: the true effect is likely to be substantially different

from the estimate of the effect.

Strength of recommendation Strong When the evidence showed that the benefit of the intervention clearly outweighs the

undesirable effects.

Conditional (weak) When the trade-offs were less certain (either because of the low quality of evidence or because

the evidence suggests that desirable and undesirable effects are closely balanced).

GRADE¼Grading of Recommendations Assessment, Development and Evaluations.

JPGN � Volume 62, Number 3, March 2016 Probiotics for the Prevention of AAD

A draft of the position paper was sent to the WG members forreview and further comments. All of the critical feedback wasdiscussed through e-mail or during personal contacts, and changeswere incorporated as necessary. Recommendations were formulatedand graded. The WG members voted anonymously on each recom-mendation using an online electronic survey tool (SurveyMonkeyInc, Palo Alto, CA, www.surveymonkey.com). Any disagreementfollowing voting was resolved by discussion, and for all recom-mendations, a full consensus was reached. A finalized documentwas submitted to the ESPGHAN Council for final acceptancebefore publication.

The WG recommendations may need to be modified bydifferent countries considering differences in health care systems,local values and preferences, including availability, quality, andcosts of probiotics, and should help local policy makers to decidewhether to use routinely probiotics with documented efficacy forpreventing AAD in children receiving antibiotics based on localcost-effectiveness analysis. This is particularly important in low-and middle-income countries.

Clearly, an individual patient’s risk of developing AAD or Cdifficile-associated diarrhea depends on a number of factors such asclass of antibiotic(s), duration of antibiotic treatment, age, need forhospitalization, comorbidities, and previous episodes of AAD or Cdifficile-associated diarrhea (1–3). These risk factors should beconsidered when making decisions on the use of probiotics inchildren for preventing AAD or C difficile-associated diarrhea.The WG acknowledges that the judicious use of antibiotics remainsthe best method of preventing AAD.

The conclusions of this document may require revision in thefuture as new information becomes available. It is the intention ofthe WG to revise the recommendations not later than 5 years fromnow and produce an updated document.

PROBIOTICS OVERALLA number of systematic reviews and meta-analyses have

shown that probiotics as a group are effective in preventing AAD(7,16,17).

A 2012 meta-analysis by Hempel et al (16) collecteddata from 82 RCTs that evaluated the efficacy of probiotics forpreventing AAD in subjects of all ages. Probiotics, as a group,reduced the risk of AAD (63 RCTs, n¼ 11,811 participants, RR0.58, 95% CI 0.50–0.68). Sixteen RCTs were carried out in infantsand young children and reported a reduced risk of AAD withprobiotic administration (RR 0.55, 95% CI 0.38–0.80). In themajority of trials, Lactobacillus-based interventions, alone or in


combination with other genera, were used. Strains were poorlydocumented. The quality of evidence was low. Of 63 included

www.jpgn.org

trials, 59 lacked adequate information to assess the overall risk ofbias. There was no placebo group in some trials. Included trialsused different definitions of diarrhea/AAD, and in some, nodefinition of these outcomes was provided. Moreover, significantheterogeneity between trials for both primary and secondary out-comes was detected. The authors concluded that the evidence isinsufficient to determine whether this association varies system-atically by population, antibiotic characteristic, or probioticpreparation.

A 2013 systematic review with a meta-analysis assessedthe efficacy and safety of probiotics for preventing C difficile-associated diarrhea or C difficile infection in adults and children(17). A complete case analysis (ie, participants who completedthe study) showed that compared with placebo or no treatment,administration of probiotics reduced the risk of C difficile-associated diarrhea by 64% (23 RCTs, n¼ 4213, RR 0.36, 95%CI 0.26–0.51) in adults and children. In children, probioticadministration reduced the risk of C difficile-associated diarrheafrom 5.9% to 2.3% (3 RCTs, n¼ 605, RR 0.40, 95% CI 0.17–0.96)(17).

For this report, 21 RCTs involving 3255 children wereincluded (18–38). Among them, 11 RCTs were included in 2strain-specific systematic reviews initiated as part of the develop-ment of these guidelines (39,40). One unpublished study (29) wasidentified in the systematic review by Johnston et al (7). Forcharacteristics of the included RCTs, see Table 2, and for amethodological quality summary, see Figure 1. The pooled resultsof 21 RCTs showed that compared with placebo or no intervention,probiotics as a class reduced the risk of AAD by 52% (21.2% vs9.1%, respectively; RR 0.48, 95% CI 0.37–0.61) (Fig. 2). Only 2probiotics were evaluated in >1 RCT. These were Lactobacillusrhamnosus GG (LGG) and Saccharomyces boulardii. Comparedwith placebo, the administration of probiotics also reduced the risk

CI 0.15–0.76) (Fig. 3).

PROBIOTICS WITH RECOMMENDATIONS

L rhamnosus GG (LGG)

RECOMMENDATION. If the use of probiotics forpreventing AAD in children is considered, the WGrecommends using L rhamnosus GG.


STRENGTH OF RECOMMENDATION: Strong

497

Copyright 2016 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

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500 www.jpgn.org

Copyright 2016 by ESPGHAN and NASPGHAN. Un

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Kotowska 2005

Merenstein 2009

Ruszczynski 2008

Shan 2013

Szajewska 2009

Szymanski 2008

Tankanow 1990

Vaisanen 1998

Vanderhoof 1999

Zhao 2014

FIGURE 1. Methodological quality summary.


www.jpgn.org

A 2015 systematic review with a meta-analysis (40) ident-ified 5 relevant RCTs (445 participants) (18–22). The methodo-logical quality of the trials varied (Fig. 1). Only 1 trial was at a lowrisk of bias. In the remaining trials, the limitations included unclearrandom sequence generation, unclear or no allocation concealment,


and unclear or no blinding of participants and personnel. Intention-to-treat analysis was performed in only 1 trial. Using the GRADE,

501

Co

1.1.1 S boulardiiKotowska 2005Erdeve 2004Shan 2013Bin 2015Zhao 2014Casem 2013Subtotal (95% CI)Total eventsHeterogeneity Tau2 = 0.07; Chi2 = 8.26, df = 5(P = 0.14); I2 = 39%

Test for overall effect: Z = 4.87 (P < 0.00001)

Vanderhoof 1999Szajewska 2009Arvola 1999King 2010Vaisanen 1998

Total events

1.1.3 B clausiiDestura (unpublished)

Heterogeneity : Not applicable


Total events

Total events

Total events 13

Subtotal (95% CI)

Test for overall effect: Z = 1.25 (P = 0.21)


Heterogeneity : Not applicableTest for overall effect: Z = 0.62 (P = 0.54)

Total eventsHeterogeneity : Not applicableTest for overall effect: Z = 0.19 (P = 0.85)

1.1.4 B lactis & Str themophilus

1.1.6 L acidophilus & bulgaricus

1.1.5 B longum PL03 & L rhamnosus KL53A & L plantrarum PL02

Correa 2005Subtotal (95% CI)

Subtotal (95% CI)Szymanski 2008

Tankanow 1990


Jirapinyo 2002

1.1.7 L acidophilus & B infantis

Total eventsHeterogeneity : Not applicableTest for overall effect Not applicable

Contardi 1991

1.1.8 L acidophilus & B breve

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

4146

122711

72336

21

3

3

1

10

13

1

10

3

3

0

0

13224416710512069

837

9334618

23219

162162

8080

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1515

88

2020

224218264716

74 171

256948

52

7

7

24

24

2

2

16

16

8

8

0

0

137222166100120

71816

9530587

36226

161161

7777

7.4%7.4%

3838

2323

1010

2020

Not estimableNot estimable

4.0%7.6%4.8%7.1%9.7%6.5%

39.7%

0.19 (0.07, 0.53)0.30 (0.17, 0.54)0.33 (0.13, 0.81)0.44 (0.23, 0.82)0.57 (0.39, 0.86)0.71 (0.35, 1.41)0.43 (0.30, 0.60)

5.6%2.2%3.0%3.7%4.7%

19.3%

0.29 (0.13, 0.63)0.29 (0.06, 1.35)0.32 (0.09, 1.11)0.66 (0.22, 1.97)1.17 (0.47, 2.95)0.48 (0.26, 0.89)

2.8%2.8%

0.43 (0.11, 1.62)0.43 (0.11, 1.62)

0.52 (0.29, 0.95)0.52 (0.29, 0.95)

1.0%1.0%

0.47 (0.04, 5.03)0.47 (0.04, 5.03)

9.1%9.1%

0.96 (0.61, 1.50)0.96 (0.61, 1.50)

4.5%4.5%

0.47 (0.18, 1.21)0.47 (0.18, 1.21)

Test for overall effect: Z =2.33(P = 0.02)Heterogeneity Tau2 = 0.07; Chi2 = 8.26, df = 5(P = 0.14); I2 = 40%

Subtotal (95% CI)

1.1.2 Lactobacillus GG

Study or subgroup Events Total EventsProbiotics

Total WeightControl

M-H, Random, 95% CIRisk ratio


A B C D E FRisk of bias

0.01 0.1Favours probiotics Favours control

1 10 100

FIGURE 2. Effect of individual probiotic strains and probiotics as a group for preventing antibiotic-associated diarrhea.

(Continued on next page )


the overall quality of evidence was rated as moderate (Table S1,http://links.lww.com/MPG/A587).

Compared with placebo or no treatment, LGG administrationin children reduced the risk of AAD, regardless of the reason forwhich probiotics were used (ie, as part of Helicobacter pylorieradication or for other reasons), from 23% to 9.6% (5 RCTs,n¼ 445, RR 0.48, 95% CI 0.26–0.89; number needed to treat,


NNT, 8, 95% CI 6–40) (Fig. 2). No significant heterogeneity wasfound (x2¼ 6.61, P¼ 0.16, I2¼ 40%). Only 1 trial (19) evaluated the

502

effect of LGG on the risk of C difficile-associated diarrhea in childrenand found no effect (RR 0.95, 95% CI 0.06–14.85) (Fig. 3).

The optimal daily dose of LGG for preventing AAD remainsunclear (40). In children, the best effect (reduction in the risk ofAAD by 71%) was achieved with the highest dose (1–2� 1010

CFU) (18). A similar effect size was, however, not achieved inanother trial using the same dose (19), perhaps because of a lower


baseline risk of AAD. In adults, there was no clear link between theeffect size and the LGG dose.

www.jpgn.org

http://links.lww.com/MPG/A587

Co




1.1.11 L rhamnosus GG & Bb12 & L acidophilus

1.1.9 L acidophilus & L rhamnosus & L bulgaricus & L casei & Str therophilus & B infantis & B breve

Subtotal (95% CI)Khodadad 2013

Total eventsHeterogeneity : Not applicable

Total eventsHeterogeneity : Not applicable


Test for overall effect: Z = 5.80 (P < 000001)

1.1.12 Kefir

Total events

Total events


Heterogeneity Tau2 = 0.13; Chi2 = 34.51, df = 19 (P = 0.02); I2 = 45%

Test for subgroup differences: Chi2 = 16.82, df = 10 (P = 0.08); I2 = 40.6%

1.1.10 L rhamnosus E/N, Oxy, PenRuszczynki 2008

Fox 2015

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)

Merenstein 2009

2

2

9

1

11

148

9

1

11

3333

120120

3434

5757

1625

8

8

20

20

21

21

14

14

343

3333

120120

3636

6060

1620

2.4%2.4%

0.25 (0.06, 1.09)0.25 (0.06, 1.09)

6.0%6.0%

0.45 (0.21, 0.95)0.45 (0.21, 0.95)

1.5%1.5%

0.05 (0.01, 0.35)0.05 (0.01, 0.35)

6.4%6.4%

0.83 (0.41, 1.67)0.83 (0.41, 1.67)

100% 0.48 (0.37, 0.61)

Risk of bias legend

Random sequence generation (selection bias)Allocation concealment (selection bias)Blinding of participants and personnel (performance bias)Blinding of outcome assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reporting bias)

(A)(B)(C)(D)(E)(F)

0.01 0.1Favours probiotics Favours control

1 10 100

FIGURE 2. (Continued )


Saccharomyces boulardii

RECOMMENDATION. If the use of probiotics forpreventing AAD in children is considered, the WG recom-mends using S boulardii for preventing AAD in children.QUALITY OF EVIDENCE: Moderate.STRENGTH OF RECOMMENDATION: Strong.RECOMMENDATION. If the use of probiotics for pre-venting C difficile-associated diarrhea in children isconsidered, the WG suggests using S boulardii.QUALITY OF EVIDENCE: Low.STRENGTH OF RECOMMENDATION: Conditional.

A 2015 systematic review with a meta-analysis (39) ident-ified 6 relevant RCTs (1653 participants) (23–28). The methodo-logical quality of the trials varied. Only 1 trial was at a low risk ofbias. In the remaining trials, the limitations included unclearrandom sequence generation, unclear or no allocation concealment,and unclear or no blinding of participants and personnel. Intention-to-treat analysis was performed in only 2 trials. Using the GRADE,the overall quality of evidence for AAD and C difficile-associateddiarrhea was rated as moderate and low, respectively (Tables S2 andS3, http://links.lww.com/MPG/A587).

Compared with placebo or no treatment, S boulardii admin-istration in children reduced the risk of diarrhea, regardless of the


reason for which probiotics were used (ie, as part of H pylorieradication or for other reasons), from 20.9% to 8.8% (6 RCTs,

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n¼ 1653, RR 0.43, 95% CI 0.30–0.60, NNT 9, 95% CI 7–12). Nosignificant heterogeneity was found (x2¼ 8.26, P¼ 0.14, I2¼ 39%)(Fig. 2).

The administration of S boulardii also reduced the risk of Cdifficile-associated diarrhea in children (2 RCTs, n¼ 579, RR 0.25,95% CI 0.08–0.73) (Fig. 3).

The optimal dose of S boulardii has not been established. A2015 meta-analysis showed that various doses of S boulardii wereused with no clear dose-dependent effect (39). Until more data onthe optimal dose of S boulardii become available, a daily dose of not<250 mg but not >500 mg in children and not >1000 mg in adultscould be used to match the doses used in RCTs.

PROBIOTICS WITH INSUFFICIENT EVIDENCETO MAKE A RECOMMENDATION

Single ProbioticsBacillus clausii

A 2011 Cochrane review (7) identified 1 unpublished RCT(29). Compared with no intervention, administration of Bacillusclausii (strain specification not given) had no effect on the risk ofAAD (n¼ 323, RR 0.43, 95% CI 0.11–1.62).

Mixtures of Probiotics

Bacillus lactis/Streptococcus thermophilusOne RCT (n¼ 157) conducted in inpatients who were chil-

dren (aged 6–36 months) showed that compared with the control


formula, the administration of infant formula supplemented with Blactis Bb-12 and Streptococcus thermophilus significantly reduced

503

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Co

Study or subgroup Events TotalTreatment

Events Total WeightControl



A B C D E FRisk of bias

Risk of bias legendRandom sequence generation (selection bias)Allocation concealment (selection bias)Blinding of participants and personnel (performance bias)Blinding of outcome assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reorting bias)

(A)(B)(C)(D)(E)(F)

Kotowska 20051.2.1 S boulardii

1.2.3 L rhamnosus E/N, Oxy, Pen

1.2.2 Lactobacillus GG

Shan 2013Subtotal (95% CI)

119167

108

286

127166293

40.1%15.0%55.1%

0.32 (0.09, 1.14)0.12 (0.02, 0.98)0.25 (0.08, 0.73)

Subtotal (95% CI) 61 58 8.5% 0.95 (0.06, 14.85)Arvola 1999 61 58 8.5% 0.95 (0.06, 14.85)

Subtotal (95% CI) 120 120 36.4% 0.43 (0.11, 1.62)

467 471 100.0% 0.34 (0.15, 0.76)

Ruszczynski 2008 120 120 36.4% 0.43 (0.11, 1.62)

Total eventsHeterogeneity: Tau2 = 0.00; Chi2 = 0.60, df = 1 (P =0.44); I2 = 0%Test for overall effect: Z = 2.54 (P = 0.01)

Total events

Total events

Total (95 % CI)

Heterogeneity: Tau2 = 0.00; Chi2 = 1.61, df = 3 (P = 0.66); I2 = 0%

Heterogeneity: Not applicable



Heterogeneity: Not applicableTest for overall effect: Z = 0.04 (P = 0.97)

Test for subgroup differences: Chi2 = 0.99, df = 2 (P = 0.61), I2 = 0%

3

73

73

Total events 11

11

268

1

4

0.01 0.1Favours treatment Favours control

1 10 100

oup


the risk of AAD (31.2% vs 16.3%, respectively; RR 0.52, 95% CI0.29–0.95, NNT 7, 95% CI 4–62) (30).

L acidophilus/L bulgaricus

One small RCT (n¼ 38) showed that compared with placebo(lactose), administration of L acidophilus/L bulgaricus (strainspecification not given) had no effect on the risk of AAD (RR0.96, 95% CI 0.61–1.5) (31).

L acidophilus/Bifidobacterium infantis

One small RCT (n¼ 18) showed that compared with placebo(sugar), administration of L acidophilus/B infantis (strain specifica-tion not given) had no effect on the risk of AAD (8/10 vs 3/8,respectively; RR 0.47, 95% 0.18–1.21) (32).

L acidophilus/Bifidobacterium breve

One small RCT (n¼ 40) showed no cases of AAD in eitherthe L acidophilus/B infantis (strain specification not given) groupor the placebo (sugar) group (0/20 vs 0/20, respectively). Thus,the efficacy of this probiotic combination could not be evaluated(37).

L rhamnosus GG/Bb-12/L acidophilus La-5

In a multisite, double-blind, placebo-controlled RCT, chil-

FIGURE 3. Effect of individual probiotic strains and probiotics as a gr


dren (n¼ 70), age 1 to 12 years, who were prescribed antibioticswere randomized to receive 200 g/day of either a yogurt containing

504

L rhamnosus GG, Bb-12 and L acidophilus La-5 or a pasteurizedplacebo yogurt (containing Streptococcus thermophilus plus Lbulgaricus) for the same duration as their antibiotic treatment.Compared with the placebo group, children in the probiotic groupexperienced a significant reduction in the risk of diarrhea (RR 0.05,95% CI 0.01–0.35) (33).

B longum PL03/L rhamnosus KL53A/Lplantarum PL02

One RCT (n¼ 78) showed that compared with placebo, theadministration of B longum, L rhamnosus, and L plantarum had noeffect on the risk of AAD (RR 0.47, 95% CI 0.04–5.03) (34).

L rhamnosus E/N, Oxy, Pen

One RCT involving 240 children showed that compared withplacebo, the administration of L rhamnosus (strains E/N, Oxy andPen) reduced the risk of any diarrhea (RR 0.45, 95% CI 0.21–0.95),but it did not have an effect on the risk of C difficile-associateddiarrhea (RR 0.43, 95% CI 0.11–1.62) (35).

L acidophilus/L rhamnosus/L bulgaricus/Lcasei/Str thermophilus/B infantis/B breve

One RCT involving 66 children showed that comparedwith placebo, the administration of L acidophilus/L rhamnosus/Lbulgaricus/L casei/Str thermophilus/B infantis/B breve (strain

for preventing Clostridium difficile-associated diarrhea.


specification not given) reduced the risk of diarrhea (RR 0.25,95% CI 0.06–1.09) (38).

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Kefir

One RCT evaluated the effect of kefir (ie, a fermented milkcontaining Lactococcus lactis, Lactococcus plantarum, Lacto-coccus rhamnosus, Lactococcus casei, Lactococcus lactis sub-species diacetylactis, Leuconostoc cremoris, B longum, B breve,Lactobacillus acidophilus, and 1 yeast, Saccharomyces florentinus)on the risk of AAD. There was no significant difference between thekefir group and the group receiving heat-treated kefir (RR 0.83,95% CI 0.41–1.67) (36).

Yogurt

Yogurt is a form of fermented milk that contains symbioticcultures of Streptococcus thermophilus and L delbrueckii subsp.bulgaricus. A 2015 systematic review with a meta-analysis ident-ified 2 relevant RCTs, both low in methodological quality. Com-pared with no intervention, yogurt consumption had no effect on therisk of AAD (2 RCTs, n¼ 314, RR 0.45; 95% CI 0.11–1.75) (41).

SAFETYThe WG abstained from evaluating the safety of probiotics,

as this was thoroughly reviewed in 2011 by the US Agency forHealthcare Research and Quality (for review, (42)). Althoughprobiotics are safe for use in otherwise healthy populations, cautionshould be taken in specific patient groups. Risk factors for adverseevents include immunosuppression, prematurity, critical illness,presence of structural heart disease, presence of a central venouscatheter, and the potential for translocation of probiotics across thebowel wall. There is a lack of data that specifically address thesafety of probiotics for preventing AAD in these vulnerable popu-lations. The risk of side effects is, however, greater in people whohave severe underlying health conditions.


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SUMMARY

The WG questions pooling different probiotic strains togetherin a meta-analysis. Probiotic effects against AAD are strainspecific; thus, the efficacy and safety of each should be
e stablished and recommendations for using these strainsshould be made accordingly.
� T
he safety and clinical effects of 1 probiotic microorganismshould not be extrapolated to other probiotic microorganisms.A lack of evidence regarding the efficacy of a certain �p robiotic(s) does not mean that future studies will notestablish efficacy in preventing AAD.There is a lack of data that specifically address the safety of �p robiotics for preventing AAD in children who have severeunderlying health conditions.The WG recommends choosing a probiotic, the efficacyof which has been confirmed in well-conducted RCTs,from a manufacturer who has a regulated quality control of f actors including the composition and content of theprobiotic agent.Risk factors for the occurrence of AAD or C difficile-associated diarrhea such as class of antibiotic(s), duration ofantibiotic treatment, age, need for hospitalization, comorbid-ities, and previous episodes of AAD or C difficile-associated d iarrhea should be considered when making decisions on theuse of probiotics in children for preventing AAD.If the use of probiotics for preventing AAD is considered, the
ht 2016 by ESPGHAN and NASPGHAN. Un

WG recommends using L rhamnosus GG or S boulardii(moderate quality of evidence; strong recommendation).

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If the use of probiotics for preventing C difficile-associated

Probiotics for the Prevention of AAD

�diarrhea is considered, the WG suggests using S boulardii(low quality of evidence; conditional recommendation).

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