Proton Pump Inhibitor Use for Gastroprotection and Stress Ulcer Prophylaxis Does Not Increase the Risk of Clostridioides difficile Infection or Pneumonia: A Systematic Review and Meta-Analysis of RCTs

Background: Proton pump inhibitors (PPIs) are widely used to prevent acid-related complications, yet concerns persist about infectious harm. Observational studies have linked PPIs to Clostridioides difficile infection (CDI) and pneumonia whereas randomized controlled trials (RCTs) consistently show reductions in upper gastrointestinal bleeding. We therefore conducted a systematic review and meta-analysis restricted to randomized controlled trials to evaluate whether PPIs increase the risk of CDI, and to assess pneumonia and gastrointestinal bleeding to contextualize net clinical benefit. Methods: A comprehensive search of randomized controlled trials (RCTs) was conducted using several databases including PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and SCOPUS until July 2025. All published English-language RCTs that met the inclusion criteria were included. Random-effects models were utilized to calculate pooled odds ratios (ORs) with 95% confidence intervals. The risk of bias was assessed using the Cochrane Risk of Bias 2.0 Tool, and heterogeneity was quantified using I2 statistics. Analysis was performed using STATA version 18 and RevMan 5.3. Results: Across eight RCTs (n = 30,019), PPIs did not increase C. difficile infection versus placebo (OR 1.29, 95% CI 0.82–2.02; p = 0.27; I2 = 16%) with leave-one-out (LOO) analyses showing stable estimates. In six trials reporting pneumonia, there was no significant difference between groups (OR 1.00, 95% CI 0.92–1.09; p = 0.99; I2 = 0%). For clinically important upper GI bleeding (seven trials), PPIs were associated with a statistically significant lower risk when compared to placebo (OR 0.51, 95% CI 0.27–0.94; p = 0.03; I2 = 56%). Conclusions: Across randomized trials with follow-up ranging from 30 days to 3 years, PPI prophylaxis significantly reduced upper gastrointestinal bleeding without increasing the risk of CDI or pneumonia. These findings support the use of PPIs for prophylaxis when clinically indicated, while recognizing that larger trials are needed to better assess rare adverse events.