To perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI). METHODS We conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran's Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS).

Fifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002).

This meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.

BACKGROUND Clostridium difficile is the principal infectious cause of antibiotic-associated diarrhea and accounts for 12% of hospital-acquired infections. Recent literature has shown an increased risk of C. difficile infection (CDI) with proton pump inhibitor (PPI) use. OBJECTIVE To conduct a systematic assessment of the risk of hospital-acquired CDI following exposure to PPI. METHODS We searched multiple databases for studies examining the relationship between PPI and hospital-acquired CDI. Pooled odds ratios were generated and assessment for heterogeneity performed. RESULTS We found 23 observational studies involving 186,033 cases that met eligibility criteria. Across studies, 10,307 cases of hospital-acquired CDI were reported. Significant heterogeneity was present; therefore, a random effects model was used. The pooled odds ratio was 1.81 (95% CI, 1.52-2.14), favoring higher risk of CDI with PPI use. Significant heterogeneity was present, likely due to differences in assessment of exposure, study population, and definition of CDI. DISCUSSION This meta-analysis suggests PPIs significantly increase the risk of hospital-acquired CDI. Given the significant health and economic burden of CDI and the risks of PPI, optimization of PPI use should be included in a multifaceted approach to CDI prevention. Infect Control Hosp Epidemiol 2016;1408-1417.