Do Nonantibiotic Medications Increase The Risk for C. difficile Infections? BY DAVID WILD
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wo recent studies have shed light on the impact of nonantibiotic medications on the risk for Clostridioides difficile infection (CDI). In one study, researchers found a twofold increased risk for CDI during proton pump inhibitor (PPI) use, with a lingering risk up to one year after PPI discontinuation, while a separate study found no association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and CDI. “Studies like these are important as we seek to understand environmental influences on gut microbiota which might increase risk for C. difficile infections,” said CDI expert Colleen Kelly, MD, an associate professor of medicine in the Division of Gastroenterology at the Warren Alpert Medical School of Brown University, in Providence, R.I., who was not involved in the research. Malin Inghammar, MD, an associate professor of infection medicine at Lund University, in Sweden, and his co-investigators studied the link between community-acquired CDI and PPIs (Clin Infect Dis 2021;72[12]:e1084-e1089). They noted that prior observational studies have identified a link between PPI use and CDI risk, but that association has remained controversial “due to the absence of data from randomized controlled trials, considerable variability between studies, and insufficient adjustment for confounding in previous studies.” To address these shortcomings, the researchers examined nationwide registry data in Denmark and found 3,583 incident episodes of CDI that occurred between 2010 and 2013 in patients who were not hospitalized within 12 weeks before infection and who did not have a positive C. difficile test in the prior eight weeks. The CDI cases were identified through a positive culture, molecular assay or toxin test, and by definition. Their data set also included C. difficile test results in the Danish Microbiology Database, prescription information and patient characteristics, allowing them to perform analyses
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controlling for the effects of chronic disease, genetics, socioeconomic status, hospital stay, and antibiotic and corticosteroid use. The researchers reported that 964 cases of CDI were diagnosed in patients during PPI treatment; 324 occurred in patients who had discontinued treatment within the previous six months; and 123 occurred six to 12 months after PPI cessation. The remaining patients had not received a PPI during or the year before CDI onset. Dr. Inghammar and his colleagues found the risk for CDI was more than twice as high among current PPI users than for individuals not receiving PPIs (adjusted incidence rate ratio [IRR], 2.03; 95% CI, 1.74-2.36). The PPI-CDI association persisted, with a 54% higher risk for CDI during the six months after PPI cessation (adjusted IRR, 1.54; 95% CI, 1.31-1.80) and a 24% higher risk in the six to 12 months after PPI cessation (adjusted IRR, 1.24; 95% CI, 1-1.53). Sex, age and hospitalization one or more years before CDI did not affect the risk for infection in PPI users, the authors found. “This large study with thorough control for confounding significantly adds to the body of evidence that increased risk of CDI, even in the community setting, should be considered when prescribing PPIs,” the investigators noted. Although Dr. Kelly said these results confirm prior findings, the observational nature of the study is a limitation. She also said the observed increased risks for CDI with PPIs “are extremely small in comparison with known CDI risk factors, and discontinuing antisecretory therapy may leave patients at risk of harm by leaving acid-related conditions, such as peptic ulcer disease and reflux esophagitis, untreated.” Dr. Kelly emphasized that “when used for appropriate indications, the benefits of PPI are clear, and therapy should not be interrupted in patients being treated for CDI or at higher risk of this infection.” In another study, Adam Ressler, MD, from the Department of Internal Medicine, Division of Infectious Disease, at the University of Michigan, in Ann Arbor, and his co-investigators identified 628 CDI cases from a previously published cohort continued on page 33
