probiotics for c.difficileinfection 779 Our study has several strengths. First, we used a comprehensive
search; we had a high response rate from study authors52;and we were able to obtain 18 of 32 trials, including the 2 of the largest trials to date,41,44 one of which enrolled almost 3,000 participants.41 Our unadjusted effect estimates across primary and secondary outcomes were similar to studies for which we did not have IPD available, making the presence of a selection bias unlikely. Our analyses were robust to sensitivity analyses using different analytic methods, including categorization of age, aggregate-data meta-analyses, GEE analysis, and missing participant outcome data. Several limitations must be emphasized. First, data for adjus-
tedmodelswere not available in~25% of
participants.However, as the estimates were similar for the unadjusted model and adjusted IPDmodel, and the aggregate-datameta-analysis, this is unlikely to have introduced a significant bias. Second, data were too limited to allow an examination of each class of antibiotic separately; thus, we categorized antibiotics as high risk versus not high risk.53 For the same reason, we were unable to follow our a priori protocol to adjust for other potentially important confounding factors such as length of antibiotic exposure and length of hospitalization stay. Third, missing participant outcome data was a common issue across trials. Our multiple imputation analysis, however, suggested that outcomes were similar for participants with and without missing data. The incidence of CDI may be underestimated, given that 71 of 760 participants (9%) with diarrhea were not tested for CDI. This affected participants in the intervention and control groups equally; thus, it is unlikely to have biased the results. Moderate quality (ie, certainty) evidence suggests that pro-
biotic prophylaxis is a useful CDI prevention strategy, parti- cularly among participants taking 2 or more antibiotics and in hospital settings where the risk of CDI is ≥5%. There was no evidence for concern regarding serious adverse events related to the preparations evaluated. Patients may value the absolute risk reduction (1.0%; NNT, 96) we found, specifically among those probiotics with the largest body of evidence for efficacy and safety. The observation that probiotic prophylaxis is of greater benefit in populations with a moderate-to-high base- line risk should inform site selection in future studies, as should the use of probiotics in clinical settings.
acknowledgments
Financial support: No financial support was provided relevant to this article. Potential conflicts of interest: S.J.A. reports other support from Cultech Ltd,
United Kingdom, grants and other from Yakult, United Kingdom, and per- sonal fees from Astellas Pharma, outside the submitted work. H.S. reports grants from Arla and Biogaia, personal fees from Biogaia, Biocodex, Danone/ Nutricia, Hipp, Nestle, Nestle Nutrition Institute, Sequoia, and Yakult, as well as nonfinancial support from Dicofarm and Sequoia, outside the submitted work. M.M. is an employee at BioMerieux. C.P.S. reports unrestricted grants from Ferring Pharmaceuticals during the conduct of the study as well as grants and personal fees from Warner Chilcott, grants and personal fees from Abbvie, personal fees from Dr Falk, Takeda, and M.A.S., outside the submitted work. B.C.J. reports a grant from BioK+ International for work outside the sub- mitted work. All other authors report no conflicts of interest relevant to this article.
Address correspondence to Bradley C. Johnston, PhD, Department of
Community Health and Epidemiology, Faculty of Medicine, Dalhousie University, Centre for Clinical Research, Room 404, 5790 University Avenue, Halifax, Nova Scotia, Canada, B3H 1V7 (
bjohnston@dal.ca).
supplementary material
To view supplementary material for this article, please visit
https://doi.org/10.1017/ice.2018.84.
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