Association between Proton Pump Inhibitor and Clostridioides Difficile risk in ICU patients: A Systematic review and meta-analysis of clinical outcomes

Background: Clostridioides difficile infection (CDI) is a leading cause of antibiotic-associated diarrhea in critically ill patients. This meta-analysis evaluated whether proton pump inhibitor-based stress ulcer prophylaxis increases CDI risk and examined associated outcomes, including mortality, gastrointestinal bleeding, and other clinical effects in ICU patients. Methods: The study was prospectively registered on PROSPERO (CRD420251176540). Following PRISMA guidelines, PubMed, Scopus, Cochrane, and Google Scholar were searched (2007-March 2025) for randomized controlled trials (RCTs) and observational studies comparing PPIs with H2 receptor antagonists (H2RAs) or placebo in ICU patients. Data were pooled using a random-effects model, and heterogeneity was assessed using the I2 statistic. Results: Eight studies (~58,000 patients) met inclusion criteria. PPI use did not significantly increase CDI risk (OR 1.12; p = 0.49, I2 = 73%) or mortality (RR 1.01; p = 0.70) but significantly reduced gastrointestinal bleeding risk (RR 0.60; p = 0.02), particularly versus H2RAs (RR 0.72; p = 0.0008). No significant differences were found in ICU or hospital length of stay as well as for mechanical ventilation duration. Conclusion: In ICU patients, PPI prophylaxis was associated with reduced gastrointestinal bleeding but showed no clear benefit for mortality, ICU or hospital length of stay, or duration of mechanical ventilation. The available evidence does not allow firm conclusions regarding CDI risk because of substantial heterogeneity and very low certainty of evidence. Compared with H2RAs, PPIs provide greater bleeding protection, although possible signals of longer ICU stay and slightly higher mortality require further investigation.