S2105 Risk of Clostridioides difficile Infection Following Vonoprazan Versus PPI Use: A Real-World Multicenter Study

Introduction: Proton-pump inhibitors (PPIs) are linked to increased Clostridioides difficile infection (CDI). Vonoprazan, a potassium-competitive acid blocker, provides potent acid suppression, but its CDI risk profile is uncertain. We compared CDI incidence after first exposure to vonoprazan versus PPIs in a large multi-institutional electronic-health-record network. Methods: Using the TriNetX Global Collaborative Network, we identified adults ≥18 years whose first prescription for vonoprazan or any PPI occurred between 1 November 2023 and 22 May 2025. Patients with any exposure to the alternate acid-suppressant class before or after index drug initiation were excluded, yielding mutually exclusive cohorts. Propensity score matching based on age, sex and race yielded 7,245 patients per group. Outcomes were assessed 6 and 12 months after medication initiation. CDI was defined strictly by a positive stool C. difficile toxin assay. Patients with prior history of CDI were excluded. Results: In the matched cohorts, CDI occurred in 10 vonoprazan recipients (0.14%) versus 36 PPI users (0.51%) at 6 months, hazard ratio (HR) 0.17 (95% CI 0.07–0.40; P < 0.001). At 12 months, CDI incidence remained 0.14% in the vonoprazan group but rose to 46 cases (0.65%) among PPI users, HR 0.20 (95% CI 0.10–0.41; P < 0.001). Conclusion: Vonoprazan was associated with a lower risk of CDI compared with PPIs at both 6- and 12-month assessments in real-world practice. These findings support vonoprazan as a potentially safer acid-suppressive alternative for patients vulnerable to CDI and warrant prospective confirmation.