Impact of Gastric Acid Suppression on Clostridioides difficile Infection: A Systematic Review

Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated infections, posing significant morbidity, mortality, and financial burden. While antibiotic use remains the primary risk factor, increasing attention has been given to the role of gastric acid suppression-particularly proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H₂RAs)-in facilitating CDI. Gastric acid acts as a natural barrier against ingested pathogens; suppression of this barrier may allow C. difficile spores to survive and colonize the gut. The aim of this article is to systematically review and evaluate existing evidence on the association between gastric acid suppression and the risk of developing CDI, and to explore the potential dose-response relationship and implications for clinical practice. A comprehensive search was conducted using PubMed, Google Scholar, and MEDLINE for studies published between 2007 and 2025. Inclusion criteria focused on human studies evaluating the relationship between acid-suppressive therapy and CDI risk. Studies were appraised using validated tools such as the Critical Appraisal Skills Programme (CASP), A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2), and the Scale for the Assessment of Narrative Review Articles (SANRA). Six studies met the inclusion criteria: two retrospective cohort studies, one meta-analysis, one systematic review, one narrative review, and one case series. Most studies consistently found an association between PPI use and increased CDI risk, including pediatric populations. A dose- and duration-dependent relationship was reported, with longer or higher exposure to PPIs correlating with greater CDI risk. The meta-analysis and systematic review provided the strongest evidence, reinforcing causality and the need for cautious prescribing. Notably, PPIs were often continued even after CDI diagnosis, highlighting gaps in deprescribing practices. There is compelling observational evidence linking PPIs-and, to a lesser extent, H₂RAs-with an elevated risk of CDI. This risk spans age groups and appears to intensify with prolonged use. While randomized controlled trials are needed to confirm causality, current evidence supports more judicious use of acid-suppressive therapy, regular medication reviews, and the incorporation of deprescribing strategies to reduce CDI incidence.