Comparison between days of antibiotic spectrum coverage and days of therapy as risk factors for Clostridioides difficile infection: a multicenter retrospective cohort study

OBJECTIVE: infection (CDI) risk remain unclear. This multicenter study aimed to identify independent risk factors for CDI, differentiate the impact of length of therapy (LOT) from combination therapy intensity (DOT/LOT ratio), and characterize continuous risk profiles to inform actionable antimicrobial stewardship. DESIGN: Retrospective cohort study. SETTING: The study was conducted at two Japanese tertiary hospitals from 2016 to 2024. PATIENTS AND METHODS: Hospitalized patients undergoing CDI testing after receiving systemic antibiotics were classified into CDI and non-CDI groups. Independent risk factors were identified using multivariable logistic regression and restricted cubic spline (RCS) models. Internal validity was evaluated using bootstrap resampling. Propensity score matching (PSM) was performed to achieve balance in baseline CDI risk factors. RESULTS: Among 3,073 patients, 186 developed CDI. Prolonged DOT was independently associated with an increased risk of CDI; RCS analysis demonstrated progressive increase in CDI risk beyond the median DOT of 16 days. Bootstrap validation showed minimal optimism. In the PSM cohort (n = 186 pairs), prolonged DOT remained significantly associated with CDI, and lower DASC emerged as a significant risk factor, reflecting the disproportionate use of specific high-risk, narrow-spectrum antibiotics. Furthermore, supplementary models revealed that both prolonged LOT and higher DOT/LOT ratio were independent risk factors for CDI. CONCLUSIONS: Prolonged DOT was a primary factor associated with CDI. Antimicrobial stewardship interventions could benefit from incorporating duration reduction measures alongside careful evaluation of individual antibiotic CDI risks.