probiotics for c.difficile infection 773 Subgroup Analyses
We conducted 4 a priori subgroup analyses. First, as an approximation of baseline CDI incidence, we examined studies with low (<5%) control-group event rates versus those with rates ≥5%.16 Second, we compared no probiotics (ie, control group) to single-species probiotics. Third, we com- pared no probiotics to multispecies ormultistrain probiotics.13 Fourth, we looked at probiotic dose, where participants in the control group had zero colony-forming units (CFU) per day (ie, control group), and we examined the effect of increasing the dose by 1 billion CFU per day in the intervention group.27
Sensitivity Analyses
We conducted 4 a priori sensitivity analyses on our primary outcome. First, we compared the unadjusted analysis (18 stu- dies, n=6,645) with the pooled estimate of effect based on aggregate data (18 studies, n=6,447). Second, we compared the adjusted analysis (13 studies; n=5,074) with the pooled estimate of effect based on aggregate data (13 studies; n=5,341). Third, for the adjusted analysis of CDI, we categorized age (infants 0 to <1 year, children 1 to <18 years, adults 18 to <65 years, older adults 65+ years) to determine whether age groups are more predictive of CDI than continuous linear age. We discerned infants from children because before 1 year of age, C. difficile colonization is common and does not reflect CDI.28 Fourth, for the adjusted analysis, we accounted for clustering using generalized estimation equations (GEE) using the SASGENMODprocedure.
Handling Missing Participant Data
Participants with no reported outcome for CDI were con- sidered as having missing outcome data. If participants with missing CDI outcome data had reported no diarrhea, we assumed they did not have CDI. If participants had reported diarrhea but no CDI test result, we considered this missing outcome data. We conducted a sensitivity analysis using the PROCMI procedure in SAS to impute missing data to create 5 imputed data sets. We examined the effect of multiple impu- tation on regression estimates using PROC MIANALYZE.
results Data Selection and Data Obtained
Of 2,021 articles, we obtained IPD from 18 of 32 confirmed eligible trials29–46 with IPD for 6,851 of 8,713 participants (78.6% of all available data). Among our sample of 6,851, participants had 120 CDI events and 613 SAEs (Table 1). There were 11 formulations of probiotics given, with doses ranging from 0.1 to 900 billion CFUs per day. Most studies (88.9%) used placebo as a control and were conducted in adult hospi- talized participants (72.2%) (Table 1). The proportion of par- ticipants on high risk antibiotics at any given time ranged from 0%30,31 to 85.4%44 (Table 2). For the outcome CDI, 2 studies
(11.1%) did not report participant level data on antibiotics taken,38,39 and 3 studies (16.7%) did not report age.36,37,43 Thus, 1,777 of 6,851 participants (26%) were excluded from the adjusted CDI model (n=5,074). The length of hospital stay and CDI history were not available for most datasets and were not included in the model. In terms of missing outcome data for CDI, study results ranged from zero29,32,35,38,40,41,44–46 to 25.8%.33 For our secondary outcome, 14 of 18 studies provided IPD for SAEs.29–33,35–38,40,41,44–46 Our adjusted model was based on 11 of these 14 studies because 3 studies did not report age (16.7%).36,37,43 Thus, 272 of 4,990 participants (5.5%) were excluded from this model (n=4,718).
Risk of Bias Assessment
For the primary outcome CDI, 4 studies were at high risk of bias for incomplete outcome data because >10% of partici- pants either had no data provided or had diarrhea but no CDI test30,31,33,39 (Appendix Figure 1). Another study was at high risk of bias for blinding of participants and personnel along with blinding for outcome assessment.42 For SAEs, 1 study was at high risk of bias for incomplete outcome data because authors reported SAEs but did not provide the data.34 We identified 2 studies that were at high risk of bias for blinding both of participants and personnel and of outcome data.30,42 Overall, for both CDI and SAEs, 2 studies were at high risk for selective reporting30,34 and 5 studies were at high risk of other bias for potential conflict of interest due to industry funding.35–38,45 There was no suspected publication bias for CDI among the included studies, which was similar for all eligible studies and studies with data available (Appendix Figure 2). (Figure 1)
Primary Outcome: Clostridium difficile Infection
Of the 18 studies reporting on CDI outcomes, 38 of 3,384 of cases (1.1%) were in the intervention group, and 82 of 3,262 (2.5%) were in thecontrol group(Table2). Probioticprophylaxis reduced the unadjusted odds of CDI (OR, 0.37; 95% CI, 0.25–0.55; P<.0001; n=6,645; Figure 2), similar to the pooled estimate for the 14 studies for which IPD was not obtained (OR, 0.30;95%CI, 0.19–0.47; P<.0001; n=2,266; Appendix Figure 3). Of the 13 studies included in the adjusted model, probiotics sig- nificantly reduced the CDI (OR, 0.35; 95% CI, 0.23–0.55; P<.0001; n=5,074; Figure 2). The use of 2 or more antibiotics significantly increased the risk of CDI (OR, 2.20; 95% CI, 1.11–4.37; P=.0243), whereas age, sex, hospitalization status, and high-risk antibiotic exposure did not. Multiple imputation sensitivity analysis provided similar regression estimates to the adjusted analysis (OR, 0.37; 95% CI, 0.25–0.56; P<.001).
Subgroup Analyses
A control group event rate of ≥5% was significantly associated with CDI in the adjusted model (OR, 16.33; 95% CI, 7.79– 34.26; P<.0001; n=5074) (Figure 2) and had significant
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