Proton pump inhibitors and the risk of Clostridioides difficile infection: A systematic review and dose-response meta-analysis

Clostridioides difficile is a leading cause of healthcare-associated infections globally with proton pump inhibitor (PPI) use as important modifiable risk factor. This study aimed to systematically synthesise global evidence on the dose-response relationship of PPI usage and the Clostridioides difficile infection (CDI) risk and to identify potential safe thresholds of PPI usage regarding CDI.

PubMed, Embase, Web of Science, and Cochrane Library were searched for longitudinal studies regarding PPIs and CDI. Aggregated data were included in two separate two-stage random-effects dose-response meta-analyses regarding Defined Daily Dose (DDD) and PPI therapy duration. Pooled adjusted relative risks (RRs) with 95% confidence intervals compared to non-users of PPIs were estimated.

Overall, 15 observational cohort and case-control studies were included with 7 studies (n=483,821) in the meta-analysis per DDD and 7 studies (n=516,441) per PPI therapy duration. The risk of bias was modest. Pooled dose-response estimates suggest linear trends with a RR of 1^.05 (95% CI 0^.89,1^.23) per 10 mg DDD and of 1^.02 (95% CI 1^.00,1^.05) per day of PPI therapy. Substantial residual heterogeneity was detected in both analyses (I2=91^.4% per DDD and I2=99^.4% per therapy duration), but inferring potential sources was limited.

Our results indicate a possible increase in the risk of CDI with increasing dose and duration of PPI therapy. Underlying mechanisms and dosage thresholds for a clinically relevant risk increase remain unclear.