Proton Pump Inhibitor Use Increases the Risk of Recurrent Clostridioides difficile Infection: A Bias-Controlled Nationwide Real-World Data Study.

BACKGROUND/AIMS: The association between proton pump inhibitors (PPIs) and the risk of recurrent Clostridioides difficile infection (CDI) remains unclear. We evaluated whether PPI use after initial CDI treatment increases the risk of recurrence using multicenter electronic health records converted to a Common Data Model (CDM). METHODS: We conducted a retrospective observational cohort study across eight hospitals using the CDM. Patients with newly diagnosed CDI who received adequate initial therapy were included. The target cohort included individuals prescribed a PPI for ≥7 consecutive days within 90 days after CDI diagnosis; the comparator cohort included those with no PPI exposure. Propensity score matching was performed based on age, sex, comorbidities, cardiovascular disease history, and medication use. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CDI recurrence at 1 and 2 years. Study-specific HRs were combined using random-effects meta-analysis. RESULTS: Between 1986 and March 2025, 5,622 PPI users and 6,719 non-users were initially identified. After matching, 1,682 pairs (PPI vs non-PPI) were included in the final analysis. PPI use after CDI treatment was associated with an increased recurrence risk compared with no PPI use during the first year (HR, 1.49; 95% confidence interval [CI], 1.15 to 1.92). The risk of CDI recurrence was even higher in the PPI use group when followed up over 2 years (HR, 1.66; 95% CI, 1.19 to 2.32). CONCLUSIONS: Across eight CDM-based hospital databases, PPI exposure after CDI treatment was significantly associated with an increased recurrence risk, highlighting the need for careful risk-benefit considerations when prescribing PPIs to patients with CDI.