Updated C. Diff Guidelines Recommend Fidaxomicin, Not Vancomycin, in Patients with Initial, Recurrent Infection

Panelists also recommended the use of bezlotoxumab as a co-intervention with standard of care antibiotics in patients with a recurrent C. diff infection within the past 6 months.

New guidelines from the Infectious Diseases Society of America say patients with an initial Clostrioides difficile (C. diff) infection should receive fidaxomicin rather than a standard course of vancomycin, although they note that implementation of this recommendation is dependent on available resources.

Fidaxomicin was approved by the FDA in May 2011 and was the first new drug approved for C. diff infections in 31 years, according to the recommendation. It is an oral medication with minimal systemic absorption and resistance against fidaxomicin has rarely been reported. It also differs from vancomycin because it is only indicated for the treatment of C. diff.

Initial clinical responses are similar for both fidaxomicin and vancomycin, although recurrences of C. diff are fewer following treatment with fidaxomicin. The investigators noted that there is more robust evidence to support its use in patients with an initial infection, but recent studies support its use in patients with recurrent C. diff infections as well.

The best evidence supporting its use in recurrent C. diff episodes comes from 3 separate randomized, controlled clinical trials, according to the guidelines. Researchers conducted a pooled analysis of the 3 subgroups, which included patients with a first C. diff infection and patients with recurrent infections. They found that fidaxomicin increased the sustained response of C. diff infection 30 days after the end of therapy compared with vancomycin, although they did not find a beneficial effect of fidaxomicin on sustained response at 90 days.

Notably, the evidence regarding the reduction in serious adverse events at 90 days was very uncertain, according to the guidelines. The overall certainty of the evidence was rated “low,” because of serious concerns about the small number of events and small sample sizes of the subgroups, as well as the risk of bias because of the unblinded design of one trial.

Achieving both initial and sustained responses are important goals of therapy for C. diff infections, according to the updated guidelines. Quality-of-life evaluations show lower scores among patients with recurrent infections compared to patients with an initial episode of C. diff, and recurrence can also lead to additional diagnostic and treatment costs. Based on these findings with fidaxomicin, the panelists recommended that it be used instead of vancomycin when available, although they noted that vancomycin is an acceptable treatment when necessary.

In addition to the updated guidelines about fidaxomicin, the panelists also recommended the use of bezlotoxumab as a co-intervention along with standard of care antibiotics in patients with a recurrent C. diff infection within the past 6 months. In particular, the guidelines said patients with a primary C. diff episode and other risk factors for recurrence may especially benefit from bezlotoxumab.

A pooled analysis of 2 randomized clinical trials demonstrated that the addition of bezlotoxumab to the standard of care antibiotics reduced C. diff recurrence after initial clinical cure at 12 weeks, as well as hospital readmission rates at 30 days; however, it failed to show a reduction in mortality. The certainty of this evidence was initially rated as moderate due to indirectness of the evidence of fidaxomicin used as the standard of care antibiotic.

All 3 of these updated recommendations are dependent on logistical considerations in some settings, the panelists said. They also noted moderate cost and potential reductions in equity as potential barriers to implementation. However, they emphasized that patients’ values and preferences, cost-effectiveness, and acceptability for providers all support the use of fidaxomicin and bezlotoxumab in patients with both initial and recurrent C. diff infections.


Johnson S, Lavergne V, Skinner A, Gonzales-Luna A, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Oxford Academic. June 24, 2021. Accessed June 24, 2021. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab549/6298219