Antimicrobial Combinations as Novel Indicators for Clostridioides difficile infection development: Population-Based, Nested Case-Controlled Study in Japan-The Shizuoka Kokuho Database Study.

Background: Clostridioides difficile is a major cause of antimicrobial-associated colitis. While antimicrobial stewardship has reduced the incidence of C. difficile infection (CDI), managing CDI is challenging because knowledge about preventing it is limited among healthcare professionals. To address this, we examined associations between antimicrobial use and CDI development.

Methods: This observational, nested case-controlled study was conducted using the Shizuoka Kokuho Database (SKDB). Individuals with no record of CDI or antimicrobial-associated enterocolitis within 1 year after SKDB enrolment, but who subsequently developed CDI, were included as the Case group. The Control group comprised individuals selected via 1:4 matching sampling without replacement for sex, age, and month of CDI onset. Conditional logistic regression analysis was performed to assess associations between antimicrobial use (number and combination) and CDI development, controlling for matched variables, background factors, and underlying conditions.

Results: Of the 2,398,393 individuals, 4917 were assigned to the Case group and 19,668 to the Control group. The adjusted odds ratios (ORs) for CDI were 3.65 for one antimicrobial and 8.58, 17.3, and 38.9 for combinations of two, three, or four or more agents (all p < 0.001). Penicillins, fourth-generation cephems, and carbapenems exhibited high ORs. Similar results were observed in certain demographic and comorbidity-free subgroups. Several combinations (penicillins + carbapenems, penicillins + cephems + carbapenems, cephems + fluoroquinolones, and penicillins + cephems + carbapenems) were notably associated with CDI development.

Conclusion: CDI prevalence increased with the number of antimicrobial classes used in combination. Certain types or combinations of antimicrobials may increase the OR for CDI.