Proton Pump Inhibitors Associated With Increased Risk of Clostridium difficile–Associated Diarrhea

On February 8, 2012, the FDA issued a safety announcement that individuals taking proton pump inhibitors (PPIs) may be at increased risk of developing Clostridium difficile–associated diarrhea (CDAD). In nursing home residents, C. difficile infection is a leading cause of diarrhea. PPIs, which inhibit gastric acid secretion and are available over-the-counter and by prescription, are a first-line treatment for numerous gastrointestinal ailments, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease, all of which are more commonly encountered in older than in younger adults.

The FDA noted a connection between CDAD incidence and PPI use when reviewing reports from its Adverse Event Reporting System (AERS) and from the medical literature. Many reports in the AERS involved patients who were elderly, had chronic or concomitant underlying medical conditions, or were taking broad-spectrum antibiotics that could have predisposed them to developing CDAD. The FDA’s literature review included 28 observational studies, in which the risk of C. difficile infection, including CDAD, was found to be between 1.4 and 2.75 times higher among patients taking PPIs compared with those not taking PPIs.

Although the FDA review did not produce conclusive evidence linking the risk of C. difficile infection, including CDAD, to PPI dose, duration of PPI use, or use of over-the-counter PPIs in the community setting, it noted in its announcement that “the weight of evidence [nevertheless] suggests a positive association between the use of PPIs and C. difficile infection and disease, including CDAD.” Based on its findings, the FDA advises clinicians to consider a diagnosis of CDAD in patients taking PPIs who develop diarrhea that does not improve. It also notes that patients should receive the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated as a means of reducing the risk of C. difficile infection and CDAD.