ObjectiveAntibiotic utilization stands as the strongest modifiable determinant for Clostridioides difficile infection (CDI). However, previous studies have relied on aggregated antibiotic categories, leaving prescribers without detailed comparative risk information for individual antibiotics. Our objective was to comprehensively estimate CDI risks across specific antibiotics. MethodsWe integrated 2 methodologies to access and rank the CDI risk associated with individual antibiotics or classes. Initially, we conducted a network comparison by analyzing data from randomized controlled trials (RCTs). Subsequently, a real-world disproportionality analysis using the Food and Drug Adverse Event Reporting System (FAERS) database complemented and enriched the findings from RCTs. ResultsThe network comparison, encompassing 61 RCTs with 25,931 patients, revealed that exposure to cefepime (odds ratio [OR] 2.56, 95% confidence interval [CI] 1.20-5.44, P=0.02) and imipenem/cilastatin (OR 3.86, 95%CI 1.61-9.29, P=0.003) exhibited higher frequencies of CDI compared to piperacillin/tazobactam. No statistically significant distinctions emerged among carbapenems, albeit a trend indicating a heightened CDI incidence with imipenem/cilastatin relative to meropenem (OR 3.89, 95%CI 0.94-16.09). In the FAERS disproportionality analysis, nearly all antibiotics displayed associations with CDI, and CDI risk signals often cluster within the majority of antibiotic classes. Among these, lincomycin demonstrated the strongest association (reporting odds ratios 112.17, 95%CI 51.68-243.43). Additionally, oral third-generation cephalosporins tend to exhibit higher CDI risk signals than others. ConclusionsOur findings unveiled substantial diversity in CDI risk, both within and among antibiotic classes, providing valuable guidance for clinicians in antibiotic prescription decisions and for initiatives aimed at antibiotic stewardship.