Oral Fidaxomicin versus Vancomycin for Clostridioides Difficile Infection

Oral fidaxomicin was associated with greater global cure rate (clinical cure without recurrence during the follow-up period) and lower recurrence rates

Benefits in NNT

1 in 10 were helped (improved global cure rate)
1 in 10 were helped (recurrence prevented)
11% improvement in global cure rate
11% reduction in recurrent infection

Harms in NNT

None were harmed
None were harmed
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Long B, Gottlieb M. Oral fidaxomicin versus vancomycin for Clostridioides difficile infection. Academic Emergency Medicine. Published online October 11, 2022:acem.14600.

Study Population: Six trials of 1390 patients aged ≥16 years with Clostridioides difficile infection

Efficacy Endpoints

Global cure, clinical cure, and recurrent infection

Harm Endpoints

Adverse events


Clostridioides difficile infection (CDI) is a serious gastrointestinal disease commonly caused by antibiotics.1, 2 In 2019, the Centers for Disease Control and Prevention reported CDI as an urgent threat to public health.3 CDI can range from mild diarrhea to severe disease with toxic megacolon.4 Unfortunately, the disease often recurs after therapy at rates between 30 and 65%.5, 6, 7 Vancomycin and metronidazole are common treatments for CDI, but recent Infectious Diseases Society of America (IDSA) guidelines have added oral fidaxomicin, a narrow-spectrum macrocyclic antibiotic, as a first-line option.8 The systematic review summarized here compared the efficacy of oral fidaxomicin and vancomycin for treatment of CDI.9

The review included randomized controlled trials (RCTs) comparing oral fidaxomicin and vancomycin for treatment of CDI.9 Participants were ≥16  years of age. The primary outcome was global cure, defined as clinical cure without recurrence. Secondary outcomes included clinical cure rate, recurrence rate, and adverse events.

The meta-analysis identified six RCTs (n = 1390 patients), three of which were noninferiority studies. Five studies were performed in the United States, Canada, or Europe, and one study was performed in Japan. One study included patients with initial CDI,10 one study included only patients with recurrent CDI,11 and three studies included patients with both initial and recurrent CDI. Roughly one-third of subjects in the three RCTs that reported severity had severe CDI. Follow-up ranged from 38 to 66 days in the included trials.

Oral fidaxomicin was associated with higher global cure rates (relative risk [RR] 1.2, 95% confidence interval [CI] 1.1–1.3, absolute risk difference [ARD] 10.7%, NNT 10) and lower recurrence rates (RR 0.6, 95% CI 0.5–0.8, ARD 10.6%, NNT 10) compared to vancomycin. There was no difference in clinical cure between fidaxomicin and vancomycin. There were no significant differences for adverse events between fidaxomicin and vancomycin.


Treatment of CDI can be challenging due to the risk of recurrence. While this meta-analysis suggests oral fidaxomicin may be more effective than vancomycin for treatment of CDI, there are several limitations. Industry-sponsored studies represent >90% of the data in this review. Industry funding is a key risk factor for both visible and invisible bias favoring the company's product.12 These RCTs were also structured as noninferiority, not superiority, trials. Two trials were open-label, further increasing the risk of bias. The definitions of outcomes in each study were not identical, which introduces clinical heterogeneity. Outcome definitions varied across the trials, making the final measurement less reliable. Studies also differed in follow-up period and time point for evaluation of outcomes. The inclusion of patients with first-time CDI versus recurrence is another limitation, as these may reflect different populations with different potential risk for recurrence. Most of the studies were performed in western countries, and regional differences may affect the results due to diet, antibiotic use, and C. difficile strains.

Current IDSA guidelines recommend fidaxomicin over vancomycin for treatment of an initial or recurrent episode of CDI.8 Both medications are preferred over metronidazole. However, the IDSA guidelines recommend vancomycin administered orally or by nasogastric tube rather than fidaxomicin for patients with fulminant CDI.8

Based on the available evidence, we have assigned a color recommendation of yellow (unclear if benefit) for oral fidaxomicin compared with oral vancomycin for treatment of CDI. The risk of bias and heterogeneity suggest a need for larger, blinded trials that are not industry-supported. Further data are also needed regarding fidaxomicin for different severities and strains of CDI.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.


Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD


August 4, 2022