By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: Fidaxomicin is preferred over vancomycin for both initial and recurrent cases. Bezlotoxumab is recommended in many cases of recurrent infection and initial infection in patients at high risk of recurrence.

SOURCE: Johnson S, Lavergne V, Skinner AM, 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. Clin Infect Dis 2021;Jun 24:ciab549. doi: 10.1093/cid/ciab549. [Online ahead of print].

Johnson and colleagues have provided a focused update of the 2017 Infectious Diseases Society of America — Society for Healthcare Epidemiology of America clinical practice guidelines for Clostridioides difficile infection (CDI). The update is limited to three new recommendations — one each dealing with the treatment of initial and recurrent infection, and one dealing with prevention of further recurrences. The following is a brief version of the changed recommendations. All are considered conditional; the first two are based on low certainty evidence and the third is based on very low certainty evidence.

  • For initial episodes of CDI, fidaxomicin therapy is recommended, rather than a standard course of vancomycin.
  • For recurrent episodes of CDI, fidaxomicin therapy is recommended, rather than a standard course of vancomycin.
  • For patients with a recurrence in the previous six months, bezlotoxumab administration is recommended together with standard of care therapy.


The optimal management of CDI is an ever-evolving process. Among the knottier issues is that of diagnosis of the disease in the absence of a gold standard — and this is not addressed by the update. Nonetheless, this document provides useful guidance regarding the relative benefit of fidaxomicin over vancomycin therapy in initial and recurrent episodes of infection, as well as the use of bezlotoxumab in recurrent disease.

No change in the previous recommendation for fecal microbiota transplantation (FMT) has been made, and the “opinion of the panel” is that patients who have had a third recurrence despite appropriate therapy may be offered FMT. However, the panel points out that since 2017 there have been two Food and Drug Administration (FDA) alerts about the treatment modality: two related to transmission of antibiotic-resistant Escherichia coli and one raising issues regarding COVID-19.

The recommendation regarding the preference of fidaxomicin over vancomycin likely could have been made at the time of the 2017 guideline, but the major impediment undoubtedly was the remarkable cost differential between the two therapies. The very high cost of fidaxomicin persists and is addressed in the current document. For this reason, the current recommendation acknowledges the implementation of the fidaxomicin recommendation “depends upon available resources” and includes a statement that vancomycin remains an acceptable alternative. High-dose enteral vancomycin continues to be recommended for cases of fulminant CDI.

The panel noted that for those patients with a first recurrence of CDI, a tapered regimen and a pulsed regimen of vancomycin are acceptable alternatives to fidaxomicin. For patients with multiple recurrences, acceptable options for fidaxomicin are tapered and pulsed vancomycin followed by rifaximin or FMT.

In addition to the use of bezlotoxumab in those with recurrent CDI as indicated earlier, its use may be considered during initial episodes in individuals with risks for recurrence, such as severe CDI on presentation, age > 65 years, or the presence of immunocompromise. It should be noted that the monoclonal should be administered during receipt of standard of care. However, the benefit of both fidaxomicin and bezlotoxumab relates to their ability to prevent recurrent CDI and the evidence is next to nonexistent that the combination is superior in this regard to the use of either agent alone — an important consideration given the potential financial toxicity of each. 


  1. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis 2018;66:e1-e48.