Probiotics for the Prevention of Nosocomial Diarrhea in Children

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Probiotics for the Prevention of Nosocomial

Diarrhea in Children

Iva Hojsak,

y

Hania Szajewska,

z§

Roberto B. Canani,

z

Alfredo Guarino,

jj

Flavia Indrio,

y

Sanja Kolacek,

ô

Rok Orel,

#

Raanan Shamir,

Yvan Vandenplas,

yy

Johannes B. van Goudoever,

and

zz

Zvi Weizman, on behalf of the ESPGHAN Working Group for Probiotics/Prebiotics

ABSTRACT

This document provides recommendations developed by the ESPGHAN Working Group on Probiotics and Prebiotics on the role of probiotics in the prevention of nosocomial diarrhea in children based on a systematic review of previously completed systematic reviews and of subsequently published randomized controlled trials. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation guidelines. Recommendations were given only if at least 2 randomized controlled trials examined the same probiotic strain. Based on currently available evidence the Working Group recommends using Lactobacillus rhamnosusGG if the use of probiotics for preventing nosocomial diarrhea in children is considered.

Key Words: guideline, healthcare-associated, hospital-acquired, microbiota, randomized controlled trial, systematic review

(JPGN 2018;66: 3–9)

What Is Known

Nosocomial infections have several negative impacts on patients and on the healthcare system.

_{The incidence of nosocomial diarrhea in children in}

developed countries is still high, regardless of preventive measures.

What Is New

Overall 8 randomized controlled trials investigated the role of probiotics in the prevention of nosocomial diarrhea.

Currently available evidence showed that adminis-tration of Lactobacillus rhamnosus GG reduces the risk of nosocomial diarrhea.

Received January 25, 2017; accepted April 30, 2017.

From theDepartment of Paediatrics, Children’s Hospital Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia, the yDepartment of Paediatrics, The Medical University of Warsaw, Warsaw, Poland, the zDepartment of Translational Medical Science, University of Naples ‘Federico II’, Naples, Italy, the §European Laboratory for the Investi-gation of Food Induced Diseases and CEINGE Advanced Biotechnolo-gies, University of Naples ’Federico II’, Napoli, the jjDepartment of Pediatrics, University Hospital Policlinico, University of Bari, Bari, Italy, the ôDepartment of Gastroenterology, Hepatology and Nutrition, Chil-dren’s Hospital, University Medical Centre, Ljubljana, Slovenia, the #Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Sackler Faculty of Medicine, Tel-Aviv University, Tel Tel-Aviv-Yafo, Israel, theDepartment of Pediatrics, UZ Brussel, Vrije Universiteit Brussel, Brussel, Belgium, the yyDepartment of Pediatrics, Emma Children’s Hospital-AMC, VU Uni-versity Medical Center, Amsterdam, The Netherlands, and the zzFaculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel. Address correspondence and reprint requests to Hania Szajewska, MD,

Department of Paediatrics, The Medical University of Warsaw, 02-091 Warsaw, Zwirkii Wigury 63A, Poland (e-mail: [email protected]). Supplemental digital content is available for this article. Direct URL

citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.jpgn.org).

Drs Hojsak and Szajewska contributed equally to the article.

H.S. has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Arla, Biogaia, Biocodex, Danone, Dicofarm, Hipp, Nestle, Nestle Nutrition Institute, Nutricia, Mead Johnson, Merck, and Sequoia. I.H. has participated as a clinical investigator for Biogaia and Chr Hansen and speaker for Biogaia and

for Dicofarm, Heinz, Mead Johnson Nutrition, Menarini, Nutricia, and Wyeth. A.G. has participated in basic research supported by Biocodex, Mead Johnson and Dicofarm and in clinical trials and/or advisory boards and/or conference grant by Menarini and Biocodex. F.I. has participated as a clinical investigator and/or consultant and/or speaker for Arla Food, Biogaia, Noos, Nestle, and Nestle Nutrition Institute, Wyeth. S.K. has participated as a clinical investigator, and/or speaker for Abbott, Arla, Biogaia, Chr. Hansen, Danone, Dukat, Nestle, Nutricia, and MSD. R.O. has participated as a clinical investigator or speaker for Medis, Nutricia, Ewopharma, Biogaia, United Pharmaceuticals, Danone, Abbvie, and MSD. R.S. has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott, Danone Institute International, Enzymotec, Nestle Nutrition Institute, and Nutri-cia. Y.V. has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott Nutrition, Aspen, Biogaia, Biocodex, Danone, Hero, Kabrita, Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition, Merck, Olygose, Orafti, Phacobel, Rontis, Sari Husada, United Pharmaceuticals, Wyeth, and Yakult. J.B.G. has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Danone, Nestle Nutrition Institute, Nutricia, Mead Johnson Nutrition, United Pharmaceuticals, Wyeth, Nutrinia, and Enzymotec. He serves on the National Institute of Health, Breast Feeding Council and is founder and director of the national donor human milk bank. Z.W. has participated as a clinical investigator, and/or consultant and/or speaker for BioCodex, BioGaia, Hipp, Materna, Mead Johnson, Nestle, and Sensus.

Copyright # _{2017 by European Society for Pediatric Gastroenterology,}

Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

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N

osocomial, hospital-acquired, or healthcare-associated infections, by definition develop during a hospital stay, meaning that they are not present or incubating on hospital admis-sion; usually infections that occur >48 hours after the admission are considered nosocomial (1). Nosocomial infections have several negative impacts on patients and on the healthcare system; they prolong the hospital stay, worsen the treatment outcome, increase resistance of microorganisms to antimicrobials, and therefore, significantly increase the cost of health care (2). The incidence of nosocomial infections in children in developed countries is still high, ranging from 5.1% to 11.6% depending on time of the year and type of a hospital ward (3). In children, gastrointestinal infec-tions account for the majority of hospital-acquired infecinfec-tions (4–6), and rotavirus is still a major pathogen. There are data implying that vaccination against rotavirus decreases the nosocomial diarrhea; however, vaccination is not universally implemented (7). Although standard preventive measures, mainly hand hygiene, isolation of sick children, and reduction in the number of hospitalized patients can decrease infection spreading, they cannot provide total preven-tion (8,9). The administrapreven-tion of probiotics, defined as live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host, on the prevention of nosocomial diarrhea (10) was reported as a measure for the prevention of nosocomial diarrhea (11,12).

The aim of this document by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESP-GHAN) Working Group (WG) on Probiotics and Prebiotics was to perform a systematic review of the literature and, based on relevant evidence, to give recommendations on the use of probio-tics in the prevention of nosocomial diarrhea. Furthermore, this review aims to provide clinically relevant data about specific probiotic strains and doses used in the prevention of nosocomial diarrhea.

METHODS

The same methodology for developing guidelines pre-viously used by the WG (13,14) was applied to the current position paper. The article provides a review of previously completed systematic reviews and of randomized controlled trials (RCTs) published after these reviews. The current meta-analysis includes all published RCTs; this means RCTs included in previous sys-tematic reviews and RCTs published subsequently. For syssys-tematic reviews/meta-analyses, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), and MEDLINE were searched. For subsequently published trials (starting from the date of the most recent search in the included reviews), CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, and EMBASE were searched up to January 2017.

The primary outcome measure was nosocomial diarrhea as defined by the investigators and regardless of the cause. The secondary outcome was nosocomial gastroenteritis caused by rota-virus. Included participants were infants and children up to 18 years of age. Neonates and premature babies were excluded from the analysis. As in previous guidelines, the focus was on 6 taxonomic probiotic groups (Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus).

To assess the methodological quality of the included RCTs, the Cochrane Collaboration’s tool for assessing risk of bias was used. The tool includes the following criteria: adequacy of sequence generation, allocation concealment, and blinding of participants, personnel and outcome assessors; incomplete outcome data; and selective reporting (15).

For reporting the effect, the results for individual studies and pooled statistics are reported as the risk ratio (RR) between the experimental and control groups with 95% confidence intervals (CIs). All analyses were based on the random effects model.

Each section of the report represents a summary of the evidence followed by the key recommendations. Recommendations are graded by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (16) developed by the Grading of Recommendations Assessment, Development and Evaluations Working Group. In order to follow the suggested presentation of recommendations by GRADE, we used the wording ‘‘the WG recommends’’ for strong recommendations, and ‘‘the WG suggests’’ for conditional (weak) recommendations.

As in our previous documents (13,14), the WG adopted the position of the US Food and Drug Administration Guidance for Industry (17) that at least 2 adequate and well-controlled studies, each convincing on its own, are needed to establish the effectiveness of an intervention. Consequently, the recommendations were for-mulated only if at least 2 RCTs that used a given probiotic were available. If there was only 1 RCT no recommendation was for-mulated. Moreover, if the strain specification was not given and/or the probiotic product was not otherwise identifiable, no recommen-dation was made.

Because of known differences in the effects of different probiotic strains, the WG gave recommendations only for specific probiotic strains or combination of strains. Pooled data of all probiotic trials were presented only for the sake of completeness, but no recommendation on the use of probiotics in general was given.

A draft of the article was sent to the WG members for review and further comments. Comments were discussed by email or in person, and changes were incorporated as necessary. Recommen-dations were formulated and graded and disagreement was resolved by thorough discussion, until full consensus was reached.

RESULTS

Table 1 presents the characteristics of the included RCTs. Majority of RCTs defined nosocomial diarrhea as passage of 3 or more loose or watery stools (2,18–23). Only Saavedra et al (24) defined it as the passage of 5 or more liquid stools a day. Majority of studies did not report on antibiotic treatment during diarrheal episodes (19–23).

For the assessment of methodological quality and potential risk of bias, see Figure 1.

Probiotics Overall

There were 2 systematic reviews and meta-analyses evalu-ating the role of probiotics in the prevention of nosocomial diarrhea (11,12).

A 2011 meta-analysis (search date: June 2011), included only RCTs which investigated the effects of Lactobacillus rhamnosus GG (LGG). Three RCTs involving 1092 children were identified. Over-all, this meta-analysis showed that the administration of LGG for the duration of hospital stay lowered the rate of diarrhea (2 RCTs, RR 0.37, 95% CI 0.23–0.59), and symptomatic rotavirus gastroenteritis (3 RCTs, RR 0.49, 95% CI 0.28–0.86) (11).

A more recent meta-analysis (12) (search date: June 2013) included all probiotic strains. Six RCTs involving 1343 participant met the inclusion criteria. The following strains were evaluated in included trials: LGG (3 RCTs), L reuteri DSM 17,938 (1 RCT), L delbrueckiiH2B20 (1 RCT), and the combination of Bifidobacter-ium bifidumand Streptococcus thermophilus (1 RCT).

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T ABLE 1. Char acterist ics of the included trial s Refer ence Count ry Participants (ag e) Prob iotic dose, CFU /per day Duration of inte rvention Follo w-up Type of hosp ital Manu fact urer Sponsor Lactob acillu s rhamn osus GG Hojs ak (2010 ) (2) Croat ia Ch ildren > 12 mo to 18 y LGG 10 9 CF U/day Durin g hosp ital stay (medi an 5 days) Yes,7 days afte r dis charge Ac ute an d chronic Dukat (Croat ia), strai n from V alio (Finlan d) – Mast retta (2002 ) (2 3) Italy infant s (1 – 18 mo) LGG 2 10 10 CFU first day and 10 10 CFU/d ay after wards Durin g hosp ital stay (mea n 5.2 days) Yes, 72 h after dis charge Ac ute an d chronic Dicofar m SpA (Rom e, Italy) – Szaj ewska (2001 ) (1 9) Pola nd In fants and children (1– 36 mo) LGG 6 10 9 CFU twic e daily Durin g hosp ital stay (medi an 9 days) Yes, 3 da ys afte r dis charge Ac ute an d chronic Dicofar m SpA (Rom e, Italy) Parti ally by Medic al Unive rsity of Warsaw Lactob acillu s reuteri DSM 17938 Urba nska (2016 ) (2 0) Pola nd In fants and children (1– 48 mo) L reuteri DS M 1793 8 10 9 CFU/d ay Durin g hosp ital stay (mea n 5.6 days) Yes, 3 da ys afte r dis charge Ac ute an d chronic BioGai a A B (Lund , Sweden ) Fully by Medi cal Unive rsity of Warsaw Wanke (2012) (2 1) Pola nd In fants and children (1– 48 mo) L reuteri DS M 1793 8 10 8 CFU/d ay Durin g hosp ital stay (medi an7.5 days) Yes, 3 da ys afte r dis charge Ac ute an d chronic BioGai a A B (Lund , Sweden ) Parti ally by Medic al Unive rsity of Warsaw which received donat ion from BioGai a AB, Sweden Bifidob acteri um animal is subsp lact is (BB -12) Hojs ak (2015 ) (1 8) Croat ia Ch ildren > 12 mo to 18 y B animal is subsp lactis 10 9CFU /day Durin g hosp ital stay (medi an 5 days) Yes,7 days afte r dis charge Ac ute an d chronic Chr Hansen A /S (Ho rsholm , D enmark ) Spo nsored by Chr Hansen A /S (Horshol m, Denm ark) Lactob acillu s delb ruec kii H2B 20 Penn a (2009 ) (2 2) Braz il In fants (1 – 36 mo) L delb ruec kii H2B 20 2.6 10 8CFU/g of supp lement ed powdere d milk Durin g hosp ital stay (mea n 4.5 days) No Ac ute an d chronic Univ ersidad e Feder al de Vi c¸osa, Mi nas G erais N ot men tioned Bifidob acteri um bifidum an d Str ep tococcus therm ophilus Saaved ra (1994 ) (2 4) U SA infant s (5 – 24 mo) B bifidum 1.9 10 8 CFU and S therm ophilu s 0.14 10 8 CFU Durin g hosp ital stay (mea n 81 days) No Long -term care, children wit h chronic illnesse s Carnat ion N utritional Prod ucts (Gle ndale, CA) N ational Institutes of Health and Carnatio n Nutritional Produc ts

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The current review included 8 RCTs (6 RCTs already included in the previous systematic reviews and 2 subsequently published RCTs) involving 2254 children (2,18–24). One RCT published in 2016 (25) was excluded from the analysis because the experimental group received not only a probiotic (LGG) but also vitamins B and C, and zinc; therefore, positive effect of the supplementation cannot be attributed solely to LGG.

Overall, treatment with probiotics (as a group) compared with placebo or no treatment had no effect on the risk of nosocomial diarrhea (2,18–22,24) (7 RCTs, n¼ 2034, RR 0.72, 95% CI 0.40– 1.28, random effect model). Heterogeneity was found (Chi2¼ 19.44, P ¼ 0.003, I2_{¼ 69%; Fig. 2).}

Probiotics reduced the risk of nosocomial rotavirus diarrhea; however, the difference between groups was of a borderline sig-nificance (2,18–21,23,24) (7 RCTs, n¼ 2115, RR 0.65, 95% CI 0.42–1.01). No heterogeneity was found (Chi2¼ 5.89, P ¼ 0.44, I2¼ 0%; Fig. 3).

There was no significant difference in asymptomatic shed-ding of rotavirus (19,23,24) (3 RCTs, n¼ 356, RR 0.87, 95% CI 0.32–2.37). Heterogeneity was found (Chi2_{¼ 5.92, P ¼ 0.05,} I2¼ 66%; Fig. 4).

Probiotic Strains With Recommendation

Lactobacillus rhamnosus

GG

Recommendation: If probiotics for preventing nosocomial diarrhea in children are considered, the WG recommends using L rhamnosus GG (at least 109CFU/day, for the duration of hospital stay).

Quality of evidence: Moderate Strength of recommendation: Strong

No new studies were identified after the 2011 systematic review and meta-analysis (11), which included 3 RCTs (2,19,23). The LGG dose used in the included studies varied from 109 CFU/day (2) through 2 1010

CFU/day (23) to 12 109

CFU/day (19).

RCTs varied in the methodological quality; none of the included studies had a low risk of bias. Limitations included unclear random sequence generation, unclear allocation concealment, incomplete outcome data, and selective reporting. Intention-to-treat analysis was performed in 2 trials. Using the GRADE, the overall quality of evidence was rated as moderate (Supplemental Digital Content 1, Table, http://links.lww.com/MPG/B4).

LGG administration reduced the risk of nosocomial diarrhea from 13.9% to 5.2% (2 RCTs, n¼ 823, RR 0.35, 95% CI 0.19–0.65; number needed to treat, number needed to treat (NNT), 12, 95% CI 8–21). No significant heterogeneity was found (Chi2¼ 1.26, P¼ 0.26, I2_{¼ 21%; Fig. 2).}

Three trials (2,19,23) (n¼ 1043) evaluated the effect of LGG on the risk of rotavirus-induced nosocomial diarrhea. Compared with the placebo group, in the LGG group the risk of rotavirus nosocomial diarrhea was reduced; however, the difference between groups was not significant (RR 0.43, 95% CI 0.17–1.13). No significant heterogeneity was found (Chi2¼ 2.56, P ¼ 0.28, I2¼ 22%; Fig. 3).

Two studies evaluated the risk of asymptomatic rotavirus shedding (19,23). There was no difference between groups (RR 1.39, 95% CI 0.74–2.62; Fig. 4).

Lactobacillus reuteri

DSM 17938

Recommendation: Because of the lack of efficacy, L reuteri DSM 17938 should not be considered for the prevention of nosocomial diarrhea in children.

Quality of evidence: High

Strength of recommendation: Strong

The effect of L reuteri DSM 17938 was evaluated in 2 RCTs (n¼ 290) (20,21), which showed no effect toward overall noso-comial diarrhea (RR 1.11, 95% CI 0.68 – 1.81; Fig. 2) and sympto-matic rotavirus infection (RR 1.14, 95% CI 0.52 – 2.52; Fig. 3). Both studies had a low risk of bias. Using the GRADE, the overall quality of evidence was rated as high (Supplemental Digital Content 1, Table, http://links.lww.com/MPG/B4). Studies used different doses of the same probiotic strain (108 CFU/day (21) and 109CFU/day (20)).

Hojsak 2010

Random sequence gener

ation (selection bias)

Allocation concealment (selection bias) Blinding of par

ticipants and personnel (perf

or

mance bias)

Blinding of outcome assessment (detection bias) Incomplete outcome data (attr

ition bias) Selectiv e repor ting (repor ting bias) Other bias + ? + + + + + Hojsak 2015 + + + + + + + Urbanska 2016 + + + + + + + Wanke 2011 + + + + + + + Mastretta 2002 – ? + + – – + Penna 2009 ? ? ? ? + + ? Saavedra 1994 + + + + – + + Szajewska 2001 ? ? + + + + +

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Probiotics With Insufficient Evidence to Make a

Recommendation

Bifidobacterium animalis subsp lactis (BB-12)

One large (n¼ 727) (18), double-blind, placebo-controlled RCT demonstrated that administration of B animalis subsp lactis (BB-12) was not effective in preventing nosocomial diarrhea occurring more than 48 hours after admission in hospitalized children older than 1 year (RR 1.46, 95% CI 0.63 – 3.36; Fig. 2) or rotavirus diarrhea (RR 0.5, 95% CI 0.05 – 5.54; Fig. 3). The incidence of nosocomial gastrointestinal infections was, however, low in both groups that may have negatively influenced the outcome. Because there was only 1 RCT with B animalis subsp lactis (BB-12), the WG cannot make a recommendation for this strain.

Based in the negative results of this large, high-quality RCT, it is highly unlikely that the same study will be repeated.

Lactobacillus delbrueckii H2B20

One RCT (n¼ 139) (22) investigating L delbrueckii H2B20 found no difference in the risk for nosocomial diarrhea between groups (RR 1.55, 95% CI 0.60–4.03; Fig. 2). The risk for rotavirus infection was not assessed.

Bifidobacterium bifidum and Streptococcus

thermophilus

One RCT (n¼ 55) (24) showed that the combination of B bifidum and Str thermophilus reduced the risk of nosocomial diarrhea (RR 0.22, 95% CI 0.05–0.96; NNT 6, 95% CI 3.0– 248.8; Fig. 2). There was no effect of this combination of probiotics on rotavirus diarrhea (RR 0.36, 95% CI 0.08–1.69; Fig. 3); how-ever, the rotavirus shedding was reduced (RR 0.27, 95% CI 0.08– 0.87; Fig. 4). Study or subgroup 1.1.1 L rhamnosus GG (LGG) Hojsak 2010 19 376 44 366 18.9% 0.42 (0.25, 0.71) Subtotal (95% CI) 421 402 30.4% 0.35 (0.19, 0.65) Szajewska 2001 3 45 12 Total events

Heterogeneity: Tau2_{= 0.06; Chi}2_{= 1.26, df = 1 (P = 0.26); I}2_{= 21%}

Test for overall effect: Z = 3.31 (P = 0.0009)

22 56

36 11.5% 0.20 (0.06, 0.66)

Experimental Control Risk ratio

Events Total Events Total Weight M-H, Random, 95% CI

Risk ratio M-H, Random, 95% CI Risk of bias A B C D E F G + ? + + + + + ? ? + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + – + + ? ? ? ? + + ?

1.1.3 B animalis subsp lactis BB-12

Hojsak 2015 13 362 9 365 15.2% 1.46 (0.63, 3.36)

Subtotal (95% CI) 362 365 15.2% 1.46 (0.63, 3.36)

Total events

Heterogeneity: Not applicable

13 9

1.1.4 B bifidum and S thermophilus

Saavedra 1994 2 29 8 26 9.2% 0.22 (0.05, 0.96)

Subtotal (95% CI) 29 26 9.2% 0.22 (0.05, 0.96)

Total events

2 8

1.1.5 L delbrueckii H2B20

Penna 2009 10 72 6 67 13.8% 1.55 (0.60, 4.03)

Subtotal (95% CI) 72 67 13.8% 1.55 (0.60, 4.03)

Total events

10 6

Total (95% CI)

Risk of bias legend

(A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias)

(C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

1029 1005 100.0% 0.72 (0.40, 1.28)

0.01 0.1 1

Favors experimental Favours control

10 100

Total events

Heterogeneity: Tau2 = 0.39; Chi2 = 19.44, df = 6 (P = 0.003); I2 = 69%

Test for subgroup differences: Chi2 = 15.17, df = 4 (P = 0.004); I2 = 73.6%

72 101 1.1.2 L reuteri DSM 17938 Urbanska 2016 7 91 6 93 12.8% 1.19 (0.42, 3.41) Subtotal (95% CI) 145 145 31.3% 1.11 (0.68, 1.81) Wanke 2011 18 54 16 Total events

25 22

52 18.5% 1.08 (0.62, 1.89)

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Study or subgroup

Risk ratio M-H, Random, 95% CI Risk of bias A B C D E F G + ? + + + + + ? ? + + + + + – ? + + – – + + + + + + + + + + + + + + + + + + + + + + + + + + – + + 1.2.1 L rhamnosus GG (LGG) Hojsak 2010 0 376 2 366 2.0% 0.19 (0.01, 4.04) Subtotal (95% CI) 535 508 58.7% 0.43 (0.17, 1.13) Szajewska 2001 1 45 6 Total events

16 30

36 4.4% 0.13 (0.02, 1.06)

Mastretta 2002 15 114 22 106 52.3% 0.63 (0.35, 1.16)

1.2.3 B animalis subsp lactis BB-12

Hojsak 2015 1 362 2 365 3.3% 0.50 (0.05, 5.54)

Subtotal (95% CI) 362 365 3.3% 0.50 (0.05, 5.54)

Total events

Heterogeneity: Not applicable Test for overall effect: Z = 0.56 (P = 0.58)

1 2

Saavedra 1994 2 29 5 26 7.8% 0.36 (0.08, 1.69)

Subtotal (95% CI) 29 26 7.8% 0.36 (0.08, 1.69)

Total events

2 5

Total (95% CI)

Risk of bias legend

1071 1044 100.0% 0.65 (0.42, 1.01)

Total events

Test for subgroup differences: Chi2_{= 3.22, df = 3 (P = 0.36); I}2_{= 6.9%}

30 46 1.2.2 L reuteri DSM 17938 Urbanska 2016 1 91 0 93 1.9% 3.07 (0.13, 74.28) Subtotal (95% CI) 145 145 30.2% 1.14 (0.52, 2.52) Wanke 2011 10 54 9 Total events

11 9

52 28.3% 1.07 (0.47, 2.42)

0.01 0.1 1

Favors experimental Favors control

10 100

FIGURE 3. Effect of individual probiotic strains and probiotics as a group for preventing nosocomial rotavirus diarrhea.

Study or subgroup

Risk ratio M-H, Random, 95% CI Risk of bias A B C D E F G 1.4.1 LGG Subtotal (95% CI) 159 142 70.1% 1.39 (0.74, 2.62) Szajewska 2001 8 45 4 Total events

22 14

36 31.1% 1.60 (0.52, 4.89)

Mastretta 2002 14 114 10 106 39.0% 1.30 (0.60, 2.80)

Saavedra 1994 3 29 10 26 29.9% 0.27 (0.08, 0.87)

Subtotal (95% CI) 29 26 29.9% 0.27 (0.08, 0.87)

Total events

3 10

Total (95% CI)

Risk of bias legend

188 168 100.0% 0.87 (0.32, 2.37)

Total events

Test for subgroup differences: Chi2_{= 5.81, df = 1 (P = 0.02); I}2_{= 82.8%}

25 24

0.01 0.1 1

Favors experimental Favors control

10 100

– + + + – – + ? ? + + + + +

+ + + + – + +

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Adverse Effects

Altogether, 6 studies (2,18–21,24) mentioned adverse effects. Of these studies, 5 (2,18,19,21,24) found no adverse effects and 1 study (20) reported no significant difference in the incidence of adverse effects (ie, abdominal pain, flatulence) between groups.

SUMMARY

The WG recommends choosing a probiotic, the efficacy of which has been confirmed in well-conducted RCTs, from a man-ufacturer who has a regulated quality control of factors including the composition and content of the probiotic agent. If the use of probiotics for preventing nosocomial diarrhea in children is con-sidered, the WG recommends using L rhamnosus GG.

REFERENCES

1. World Health Organization DOCD, Surveillance and Response. Pre-vention of Hospital-acquired Infections. Geneva, Switzerland: World Health Organization; 2002. Publication WHO/CDS/CSR/EPH/2002.12. 2. Hojsak I, Abdovic S, Szajewska H, et al. Lactobacillus GG in the prevention of nosocomial gastrointestinal and respiratory tract infec-tions. Pediatrics 2010;125:e1171–7.

3. World Health Organisation/Patient Safety. Report on the Burden of Endemic Health Care-associated Infection Worldwide. Geneva, Swit-zerland: World Health Organization; 2011.

4. Muhlemann K, Franzini C, Aebi C, et al. Prevalence of nosocomial infections in Swiss children’s hospitals. Infect Control Hosp Epidemiol 2004;25:765–71.

5. Rutledge-Taylor K, Matlow A, Gravel D, et al. A point prevalence survey of health care-associated infections in Canadian pediatric in-patients. Am J Infect Control 2012;40:491–6.

6. Kinnula S, Buettcher M, Tapiainen T, et al. Hospital-associated infec-tions in children: a prospective post-discharge follow-up survey in three different paediatric hospitals. J Hosp Infect 2012;80:17–24. 7. Zlamy M, Kofler S, Orth D, et al. The impact of rotavirus mass vaccination

on hospitalization rates, nosocomial rotavirus gastroenteritis and second-ary blood stream infections. BMC Infect Dis 2013;13:112.

8. Posfay-Barbe KM, Zerr DM, Pittet D. Infection control in paediatrics. Lancet Infect Dis 2008;8:19–31.

9. Ejemot-Nwadiaro RI, Ehiri JE, Arikpo D, et al. Hand washing promotion for preventing diarrhoea. Cochrane Database Syst Rev 2015:CD004265. 10. Hill C, Guarner F, Reid G, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics con-sensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506–14.

11. Szajewska H, Wanke M, Patro B. Meta-analysis: the effects of Lacto-bacillus rhamnosus GG supplementation for the prevention of health-care-associated diarrhoea in children. Aliment Pharmacol Ther 2011;34: 1079–87.

12. Wanke M, Szajewska H. Probiotics for preventing healthcare-associated diarrhea in children: a meta-analysis of randomized controlled trials. Pediatria Polska 2014;89:8–16.

13. Szajewska H, Canani RB, Guarino A, et al. Probiotics for the prevention of antibiotic-associated diarrhea in children. J Pediatr Gastroenterol Nutr 2016;62:495–506.

14. Szajewska H, Guarino A, Hojsak I, et al. Use of probiotics for manage-ment of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr 2014;58:531–9.

15. Higgins JPT, Altman DG, Sterne AC. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Sys-tematic Reviews of Interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. www.cochrane-handbook.org. Ac-cessed March 22, 2017.

16. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924–6.

17. Center for Drug Evaluation and Research; Center for Biologics Evalua-tion and Research. Guidance for industry: providing clinical evidence of effectiveness for human drug and biological products. http://www.fda.-gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm078749.pdf. Published May 1998. Accessed July 2015. 18. Hojsak I, Tokic Pivac V, Mocic Pavic A, et al. Bifidobacterium animalis subsp. lactis fails to prevent common infections in hospitalized children: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 2015;101:680–4.

19. Szajewska H, Kotowska M, Mrukowicz JZ, et al. Efficacy of Lactoba-cillus GG in prevention of nosocomial diarrhea in infants. J Pediatr 2001;138:361–5.

20. Urbanska M, Gieruszczak-Bialek D, Szymanski H, et al. Effectiveness of Lactobacillus reuteri DSM 17938 for the prevention of nosocomial diarrhea in children: a randomized, double-blind, placebo-controlled trial. Pediatr Infect Dis J 2016;35:142–5.

21. Wanke M, Szajewska H. Lack of an effect of Lactobacillus reuteri DSM 17938 in preventing nosocomial diarrhea in children: a randomized, double-blind, placebo-controlled trial. J Pediatr 2012;161:40.e1–3.e1. 22. Penna FGC, Loures MD, de Carvalho AB, et al. Lack of effect of Lactobacillus delbrueckii H2B20 in the prevention of diarrhea in children hospitalized for short period. Pediatria (Sao Paulo) 2009;31: 76–80.

23. Mastretta E, Longo P, Laccisaglia A, et al. Effect of Lactobacillus GG and breast-feeding in the prevention of rotavirus nosocomial infection. J Pediatr Gastroenterol Nutr 2002;35:527–31.

24. Saavedra JM, Bauman NA, Oung I, et al. Feeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994;344: 1046–9.

25. Bruzzese E, Fedele MC, Bruzzese D, et al. Randomised clinical trial: a Lactobacillus GG and micronutrient-containing mixture is effective in reducing nosocomial infections in children, vs. placebo. Aliment Phar-macol Ther 2016;44:568–75.