Comparative Efficacy of Vancomycin and Fidaxomicin Regimens for the Prevention of Recurrent Clostridioides difficile Infection: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Background The optimal treatment for first episodes and first recurrences of Clostridioides difficile infections (CDI) is unknown and there is emerging evidence for pulse-and-taper (P-T) regimens. Therefore, we sought to estimate the relative efficacy of treatment options. Methods MEDLINE and CENTRAL were searched from database inception to September 11, 2026. Randomized controlled trials (RCTs) on the treatment of first episodes or first recurrences of CDI comparing fixed-dose or P-T regimens of fidaxomicin or vancomycin were included. The primary and secondary outcomes were 40- and 56-day CDI recurrence, respectively. A random-effects network meta-analysis on the risk ratio (RR) scale was conducted using a standard regimen (10-14 days) of vancomycin as the comparator. Treatments were ranked using the surface under the cumulative ranking curve (SUCRA). Results 8 RCTs were included, comprising 2120 patients. For 40-day recurrence, fidaxomicin P-T had the highest probability of ranking best (RR=0.10, 95%Confidence Interval [95%CI]=0.03-0.33, SUCRA=0.99), followed by vancomycin P-T (RR=0.40, 95%CI=0.25-0.63, SUCRA=0.66), fixed-dose fidaxomicin (RR=0.63, 95%CI=0.51-0.78, SUCRA=0.34), and, finally, fixed-dose of vancomycin (SUCRA=0.00). The treatments ranked in the same order for 56-day recurrence, though only 3 RCTs reported on this timepoint and fixed-dose fidaxomicin was no longer significantly better than fixed-dose vancomycin. Conclusion Fidaxomicin P-T and vancomycin P-T were both superior to fixed-dose vancomycin at 40- and 56-days. Head-to-head comparative effectiveness RCTs are needed to quantify their relative effect sizes of and impact on long-term prevention of recurrent CDI.