Common drugs linked to C. diff risk, study

A large Swedish population-based study found that many commonly prescribed drugs beyond antibiotics are associated with an increased risk for Clostridioides difficile infection, with some medications showing several-fold higher odds.

In the case-control analysis of 42,921 patients with Clostridioides difficile infection (CDI) and 355,159 matched controls published in Gut, investigators evaluated prescription drug exposure within 30 days before diagnosis using national registry data.

Although CDI is a leading cause of antibiotic-associated diarrhea, the study broadened the risk profile to include a wide range of nonantibiotic medications. Corresponding author Nele Brusselaers, MD, of the Department of Women’s and Children’s Health at the Karolinska Institutet in Stockholm, and colleagues highlighted the potential contribution of these medications to CDI risk.

Antibiotics carried the highest risks overall. Lincosamides were associated with 31 times the odds of CDI, combinations of penicillins with nearly 20 times the odds, and cephalosporins and trimethoprim-sulfamethoxazole combinations also showed strong associations. Tetracyclines were the only antibiotic class not associated with increased risk after adjustment.

Among nonantibiotic drugs, several commonly used classes were linked to increased CDI risk. Antidiarrheal agents were associated with more than seven times the odds of CDI, corticosteroids with more than two times the odds, and analgesics with nearly three times the odds. Proton pump inhibitors were associated with about 1.8 times the odds, while histamine H2-receptor antagonists showed a smaller increase.

Other drug classes with increased odds included antidepressants, beta blockers, constipation medications, and nervous system drugs such as antiepileptics and psycholeptics. In contrast, lipid-modifying agents and aspirin were associated with reduced odds, each showing about 20% lower risk. Nonsteroidal anti-inflammatory drugs were not significantly associated with CDI after adjustment.

The investigators used conditional logistic regression with multiple modeling approaches, including a lasso penalty to reduce overfitting. Results were consistent across models and sensitivity analyses, including restriction to healthcare-associated infections and varying exposure windows. Most infections (about 92%) were healthcare-associated, and patients with CDI had higher comorbidity burdens than controls.

Effect sizes varied widely. For example, nitroimidazole antibiotics and intestinal anti-infective agents showed extremely high odds ratios, although the authors noted these likely reflect reverse causation because these drugs are often used to treat CDI before diagnosis.

Population attributable fractions showed how much these exposures affect health outcomes. Among nonantibiotics, analgesics accounted for about 14% of CDI cases, proton pump inhibitors for about 9%, and antidiarrheals for about 10%, reflecting both effect size and high prescribing prevalence.

Subgroup analyses showed broadly similar associations across sexes and time periods. Additional analyses that accounted for health care use and removed long-term medication users showed similar results, confirming the findings are robust.

The authors pointed out several limitations of their analysis, including that some findings may be due to patients’ underlying conditions or the reasons certain drugs like corticosteroids and pain relievers were prescribed. The study also lacked data on hospital and over-the-counter medications, infection severity, and may have misclassified when infections occurred. Still, the large sample size and nationwide registry design strengthen the findings.

“Given their high prevalence and strong associations with CDI, our findings underscore the importance of prudent prescribing and regular medication review,” the authors concluded.

The study was supported by the Karolinska Institute and the Swedish Research Council, with additional collaboration funding from Ferring Pharmaceuticals. Authors reported no competing interests.

Expert Analysis

GI & Hepatology News invited corresponding author Nele Brusselaers, MD, of the Department of Women’s and Children’s Health at the Karolinska Institute in Stockholm, to elaborate on the findings.

Why does this study matter?

Dr. Brusselaers: Clostridioides difficile infection (CDI) is a very serious and sometimes life-threatening infection, even among younger and generally healthier people. There seems to be a strong link between disruption of the (intestinal) microbiome and CDI. While many studies have confirmed the strong association between antibiotics and CDI, not many large studies have explored other drug groups that affect the microbiome. Our findings may help clinicians better understand how everyday prescribing decisions, beyond antibiotics alone, can influence CDI risk and support more evidence‑based prescribing practices.

When you had all the data in front of you, was there a finding, or perhaps more than one, that surprised you?

Dr. Brusselaers: Yes, several findings were unexpected. Most notably, we observed a strong association between CDI and prior use of corticosteroids and analgesics, with effect sizes that were even more pronounced than those seen for proton pump inhibitors (PPIs), which are more commonly implicated in CDI risk.
We were also surprised by the association with beta‑blockers, a drug class that has received relatively little attention in CDI research to date. These findings suggest that the relationship between medication use, microbiome disruption, and CDI may be broader and more complex than previously appreciated.

How might the findings influence clinical practice?

Dr. Brusselaers: We hope these results encourage more cautious, evidence‑based prescribing across several drug categories. While antibiotic stewardship remains crucial, our findings suggest that certain widely used antibiotic classes, such as penicillins, may carry a higher CDI risk than is often assumed. Importantly, non‑antibiotic medications including PPIs, analgesics, and corticosteroids are frequently prescribed and may also contribute to CDI risk. Greater awareness of these associations could help clinicians weigh risks and benefits more carefully, especially in patients who are already vulnerable to CDI.

Is there anything else you’d like to say about this work?

Dr. Brusselaers: Although reducing unnecessary antibiotic use remains a cornerstone of CDI prevention, our findings highlight that other medication classes should not be overlooked. Drugs such as gastric acid suppressors, opioids, and corticosteroids may also play an important role in CDI development and deserve greater attention in both research and clinical practice.

Dr. Brusselaers reported having no disclosures.