Proton pump inhibitors and risk of Clostridium difficile infection: association or causation?

The rising burden of Clostridium difficile infection (CDI) requires urgent identification of preventable risk factors. Observational studies suggest an association between proton-pump inhibitor (PPI) use and CDI risk.

Key historical literature on PPI and CDI associations is reviewed as a prelude to evaluating the plausibility of a causative association. Impactful literature from the past 18 months is examined in detail and critically appraised through the lens of the Bradford Hill Criteria for determination of causality. The PPI and CDI association has been studied extensively and is valid. Nonetheless, causality is not proven due to extensive and difficult to control confounding in observational studies of CDI patient populations with complex comorbidities.

In the authors' opinion, systematic discontinuation of PPIs in patients at risk for CDI is not warranted based on current evidence. Well controlled prospective human studies are needed. Careful and repeated consideration should be given to all PPI prescriptions to avoid potential adverse effects.