Proton Pump Inhibitor Use and Risk of Clostridioides difficile Infection: An Umbrella Review of 11 Meta-Analyses

Proton pump inhibitors (PPIs) are widely used for acid-related conditions. However, multiple studies have reported a potential link between PPI use and an increased risk of Clostridioides difficile infection (CDI), raising concerns about overuse. The aim of this umbrella review was to evaluate the overall association between PPI use and CDI risk by synthesizing evidence from published meta-analyses and assessing consistency across key patient subgroups. This review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. A systematic search of PubMed, Cochrane Library, Google Scholar, and ClinicalTrials.gov identified meta-analyses published between 2012 and 2024. Eleven meta-analyses were included. A citation matrix was used to assess primary study overlap. Forest plots were used to summarize pooled odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses were performed for intensive care unit (ICU) patients, individuals with recurrent CDI, and the general population. A funnel plot assessed publication bias, and a sensitivity analysis was performed after excluding a study with an inverse effect and unverifiable overlap. All included meta-analyses reported a significant association between PPI use and increased CDI risk, with pooled ORs ranging from 1.26 to 2.34. The highest risk was observed in the ICU (OR 1.81) and recurrent CDI (OR 1.69) subgroups. Moderate overlap was noted in the citation matrix without critical redundancy. Sensitivity analysis confirmed consistent findings. The updated funnel plot showed mild asymmetry, suggesting possible publication bias favoring positive associations. PPI use is consistently associated with an increased risk of CDI across multiple patient populations. Given the strength of this association, clinicians should re-evaluate the necessity of ongoing PPI therapy, especially in high-risk individuals. Deprescribing should be considered when no clear indication exists.