When Treatment Backfires: Common Drugs and C. difficile
Review by Dr. Edyta Tulewicz-Marti (Poland)
Study Summary
Clostridioides difficile infections (CDIs) are associated with antibiotic use, but links with other drugs remain underexplored and still unknown. This Swedish population-based case–control study, which ran from 2006 to 2019, included 42,921 cases matched to 355,159 population controls by age and sex from multiple linked Swedish registries. The association between antibiotic and non-antibiotic drugs with microbiome-modulating activity and new occurrences of CDI was investigated. Drug exposure within 30 days before the index date was analyzed. Antibiotics with the greatest CDI risk were lincosamides (aOR 31.4, 95% CI 27.9–35.3), combinations of penicillins (aOR 19.8, 95% CI 15.9–24.5), sulfonamides and trimethoprim, and cephalosporins; tetracyclines showed no association. Interestingly, among non-antibiotics, decreased CDI risks were observed for lipid‑modifiers (aOR 0.8, 95% CI 0.8–0.8) and aspirin (aOR 0.8, 95% CI 0.7–0.8), while increased risks were seen for antidiarrheals (aOR 7.3, 95% CI 6.8–7.8), corticosteroids (aOR 2.4, 95% CI 2.3–2.5), proton‑pump inhibitors (aOR 1.8, 95% CI 1.7–1.8), nervous‑system drugs, constipation drugs, H2‑receptor antagonists, antidepressants, and beta blockers. Finally, nonsteroidal anti‑inflammatory drugs showed no significant risk.
Commentary
Oral antibiotics—particularly clindamycin, third‑ and fourth‑generation cephalosporins, fluoroquinolones (e.g., ciprofloxacin, levofloxacin), and broad‑spectrum penicillins—have long been established as the major drivers of Clostridioides difficile infection (CDI), because they directly influence and disrupt gut microbiota.
Acid‑suppressing therapies, notably proton‑pump inhibitors (PPIs) and other potent gastric acid suppressants (oral or IV), have also been repeatedly linked with increased CDI risk. Mechanisms proposed include altered gastric acidity permitting greater survival of ingested spores and downstream changes in gut microbial ecology. Although residual confounding remains a concern in observational studies (sicker patients both receive PPIs and are at higher baseline risk), the repeated associations argue for judicious use of acid suppression—prescribing PPIs only for evidence‑based indications and periodically reassessing ongoing need.
This Swedish population‑based study importantly broadens the pharmacologic landscape implicated in CDI risk beyond antibiotics and PPIs. It corroborates corticosteroids as a risk factor, consistent with immunomodulation and altered host defenses, but also highlights drugs less commonly considered in CDI discussions—most notably antidiarrheals and several classes of nervous‑system agents, including some antidepressants. Antidiarrheals may predispose to symptomatic CDI by slowing intestinal transit and prolonging toxin contact; nervous‑system drugs (e.g., agents with GABAergic activity) could influence gut motility, secretions, or microbial composition through neuroimmune and enteric nervous system interactions. The finding that certain antidepressants associate with increased CDI risk merits further mechanistic and pharmacoepidemiologic study, given their widespread use.
Conversely, the observed modestly reduced CDI risk among users of lipid‑modifying agents—principally statins—adds to a growing, if mixed, literature suggesting potential protective effects. Proposed mechanisms include statins’ anti‑inflammatory and immunomodulatory properties, effects on bile acids that shape the microbiome, or confounding by healthier patient behaviors among statin users. The consistency of this study’s effect estimates with prior meta‑analyses strengthens the signal, but randomized or mechanistic data would be needed to infer causality.
In summary, this study reinforces known antibiotic and PPI risks while expanding attention to additional medication classes that may modulate CDI risk via effects on the microbiome, gut physiology, or host immunity; therefore, we should take these risks into account, especially among those exposed to polypharmacy, such as the elderly, who are already at an increased risk for CDI.
Citation
Boven A, Vranken H, Vlieghe E, et al Commonly prescribed drugs as risk factors for Clostridioides difficile infections: a Swedish population-based case–control study. Gut 2026. [online ahead of print] doi: 10.1136/gutjnl-2025-337629
