772 infection control & hospital epidemiology july 2018, vol. 39, no. 7


nistered in adequate amounts, may confer a health benefiton the host, are a potential CDI prevention strategy.11 A 2013 Cochrane meta-analysis of 23 randomized controlled trials (RCTs) demonstrated a 64% decrease (95% confidence interval [CI], 49%–73%) inCDI incidence with probiotic prophylaxis.12 The results of a subsequent large RCT (n=2,941) were indeterminate; however, CDI events were less frequent than anticipated. An updated aggregate data meta-analysis incorporating the study showed that the beneficial effect of the probiotic remained.13 A recent review of clinical practice guidelines on CDI prevention14 found that recommendations mainly revolved around core strategies (eg, education of healthcare staff on CDI, patient isolation, antimicrobial stewardship, and utilization of disinfectants), but none recom- mend probiotics for prophylaxis.15–19 Guidelines cited concerns regarding insufficient evidence,17,20 too much weight given to studies with high baseline CDI risk,16 and safety concerns.16,20 To address some of these concerns and to further investigate


megacolon, and death,2,3 and mortality ranges from 5% to 10%.3 Frequent recurrence, affecting ~20% of treated partici- pants, is particularly challenging for CDI management.4 Most CDI cases occur in higher-income countries,5 but data from middle- and low-income countries are lacking. Surveillance data suggest that the incidence density ranges between 2.45 and 7.5 per 10,000 patient days or between 9 and 80 per 10,000 patient admissions.2,6–8 An individual patient’s risk of devel- oping CDI differs based on numerous host and environmental factors,2,6,9,10 most importantly antibiotic exposure, which is thought to disrupt the intestinal microbiota, allowing C. diffi- cile to proliferate.6 Probiotics, defined as live microorganisms that, when admi-


the effectiveness and safety of probiotics on populations and interventions with varying characteristics, we conducted an individual participant data (IPD) meta-analysis. Our objective was to determine whether adding probiotics to an antibiotic regimen reduces the incidence of CDI among children and adults, when adjusting for age, sex, hospitalization status, the number of antibiotics taken, and the administration of high-risk antibiotics.


methods


We registered the protocol for this IPD meta-analysis in the PROSPERO registry in January 2015.21


Searches We considered all studies deemed eligible in a previous com- prehensive systematic review on probiotics for the prevention of CDI (Appendix Methods 1),12 andwe updated the search on April 11, 2016 (Appendix Tables 1 and 2).


Study Selection


Two reviewers independently screened titles, abstracts, and full-text articles for eligibility and resolved differences through consensus. We included RCTs with children (0 to <18 years)


or adults administered antibiotics (ie, any reason or duration) with concomitant probiotics (ie, any dose, species, strain, or duration), compared to placebo, alternative prophylaxis, or no treatment (standard care), and that reported CDI as an out- come. The latter was our primary outcome, defined as either diarrhea with laboratory confirmation of C. difficile, presence of pseudomembranes on sigmoidoscopy or colonoscopy, histological diagnosis of C. difficile, or diagnosis of toxic megacolon.22 Our secondary outcome was the incidence of serious adverse events (SAEs).


Data Extraction and Quality Assessment


We contacted the authors of all eligible studies and requested ethics-approved, deidentified data including participants’ allocated treatment, age, length of hospital stay, CDI history, antibiotics given, probiotics given, presence of diarrhea, CDI diagnosis, and SAEs. We also requested any information on missing outcome data, such as participants lost to follow up and participants who had diarrhea but no C. difficile test. Reviewer pairs (B.C.J., J.G., L.L.) independently assessed risk


of bias based on the Cochrane Handbook for Systematic Reviews of Interventions.23 For studies fromthe previous review, we used the previous assessment,12 with 6 modifications (Appendix Methods 2). For the overall certainty in estimates for each outcome, we used Grading of Recommendations, Assessment, Development and Evaluation (GRADE), independently and in duplicate.24 Publication bias was evaluated with a funnel plot.25


Data Synthesis and Analysis


We pooled IPD across trials and analyzed it using a generalized linear mixed model using the SAS GLIMMIX procedure using SAS/STAT version 9.4 software (SAS Institute, Cary, NC) and calculated the odds ratio (OR) and 95% CIs. We considered the study level as a random effect and the participant variables as fixed. For our adjusted analysis, based on known CDI risk factors, variables available across datasets, and data provided by authors, we developed a model adjusting for 5 variables: age (years),10 sex, hospitalization status, use of multiple anti- biotics, and exposure to high-risk antibiotics (third- and fourth-generation cephalosporins, lincosamides, and fluor- oquinolones).6 Only hospitalized participants had SAEs; thus, we did not adjust for this variable. Statistical heterogeneity was evaluated using the I2 value,


where an I2 value of 0 to 40%represented lowheterogeneity and an I2 value of 30%–60%represented moderate heterogeneity.26 We used Review Manager version 5.3 software (Copenhagen, Denmark) for aggregate data meta-analyses and funnel plots. Weused SPSS version 20 software (IBMArmonk,NY) and SAS/ STAT version 9.4 software for data cleaning and analysis, respectively. We used Stata version 13 software (StataCorp, College Station, TX) to graph the IPDmeta-analysis forest plots. Given the low event rate for CDI and SAEs (<10%), the OR approximates the relative risk (RR). Thus, we reported relative risk reduction (RRR) for ease of interpretation.


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