Abstract
Background/Objectives: Guidelines recommend combination therapy with oral vancomycin and intravenous (IV) metronidazole for fulminant Clostridioides difficile infection (CDI). Although patients with severe CDI are often managed with combination therapy, evidence supporting this practice remains limited. This study was performed to compare the clinical outcomes of vancomycin monotherapy versus combination therapy in patients with severe CDI. Methods: We conducted a multicenter, retrospective, observational cohort study including adult patients with severe CDI who received oral vancomycin between January 2017 and May 2021. Patients were classified as receiving combination therapy if IV metronidazole was administered for at least 72 h within 48 h of initiating oral vancomycin; otherwise, they were classified as receiving vancomycin monotherapy. The primary outcome was a composite of inpatient all-cause death or colectomy within 60 days after CDI diagnosis. The secondary outcomes were the clinical cure rate, CDI recurrence rate, time to discharge after CDI diagnosis, and duration of ICU admission. Results: In total, 215 patients were included, with 100 (46.5%) receiving combination therapy. There were no significant differences in in-hospital mortality or colectomy between the monotherapy and combination therapy groups (25.2% vs. 26.0%, p = 1.00). Recurrence rates (19.1% vs. 16.8%, p = 0.81), total length of stay (31.0 vs. 23.0 days, p = 0.16), and ICU stay duration (35.0 vs. 32.0 days, p = 0.89) were also similar. However, the clinical cure rate was significantly higher in the monotherapy group than in the combination therapy group (79.1% vs. 65.0%, p = 0.03). Conclusions: Combination therapy with oral vancomycin and IV metronidazole was not associated with improved clinical outcomes in patients with severe CDI. Prospective randomized studies are needed to clarify optimal management strategies for severe CDI.