Management of Clostridioides difficile Infection in Adults: 2021 Clinical Practice Guidelines

Clostridium bacteria
Clostridium bacteria
A multidisciplinary panel comprising members from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America created guidelines for health care professionals caring for patients with C difficile infection.

Treatment options for patients with initial or recurrent Clostridioides difficile infection are highlighted in the 2021 guidelines for the management of adults with C difficile infection, published in Clinical Infectious Diseases.

A multidisciplinary panel from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) created these guidelines to help health care professionals care for patients with initial or recurrent C difficile infection by providing evidence-based recommendations using topic-specific systematic literature reviews and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Recommendations were labeled as either “strong” or “conditional.”

Fidaxomicin vs Vancomycin for Initial C difficile Episode

For patients with an initial C difficile infection, the panel suggested the use of fidaxomicin instead of the standard course of vancomycin (conditional recommendation, moderate certainty of evidence). The investigators also noted that although this recommendation places high value on the benefits and safety of fidaxomicin, vancomycin is still an acceptable alternative, especially when fidaxomicin is not readily available.

Resistance to fidaxomicin has not often been reported in C difficile infection, and clinical studies have showed improved sustained clinical response in patients with these infections. Although the initial clinical responses for vancomycin and fidaxomicin are similar, there are fewer reported cases of recurrent C difficile infection following treatment with fidaxomicin.

“The evidence is more robust for patients with an initial episode of [C difficile infection], but recent additional studies support its use in recurrent [C difficile infection],” the guideline authors noted.

In addition to its superior sustained clinical response, other rationales behind the panel’s decisions favoring fidaxomicin over vancomycin included its significant improvement in desirable outcomes while not increasing undesirable outcomes and its dosing. Vancomycin is administered 4 times a day, but fidaxomicin can be administered 2 times a day.

While cost effectiveness may be more favorable with fidaxomicin compared with vancomycin, the panel noted, “Additional, well-designed, independent, cost-effectiveness studies for patients with [C difficile infection] are needed to improve the strength of this recommendation given that cost is a substantial barrier to fidaxomicin use.” They noted that studies measuring the efficacy of fidaxomicin for fulminant C difficile infection are also warranted.

Fidaxomicin vs Vancomycin for Recurrent C difficile Episode(s)

For patients with recurrent C difficile infections, the panel suggested a standard or an extended-pulsed regimen of fidaxomicin instead of a standard course of vancomycin (conditional recommendation, low certainty evidence).

“Vancomycin in a tapered and pulsed regimen or vancomycin as a standard course are acceptable alternatives for a first [C difficile infection] recurrence,” the panel stated. “For patients with multiple recurrences, vancomycin in a tapered and pulsed regimen, vancomycin followed by rifaximin, and fecal microbiota transplantation are options in addition to fidaxomicin,” they added.

Although the certainty of evidence was low, the overall ratio of benefits to harm was in favor of fidaxomicin. Cost effectiveness, acceptability, and feasibility also supported the panel’s decision for fidaxomicin compared with vancomycin; however, the authors noted that implementation of this recommendation may reduce equity due to variability in health insurance coverage.

To improve the strength of this recommendation, the panel noted the need for additional randomized clinical trials to assess outcomes in patients with recurrent C difficile infection, especially those with multiple recurrent C difficile infections. Studies with more appropriate controls for an extended-pulsed regimen of fidaxomicin are needed to help determine how the role of this dosing strategy may affect long-term efficacy and quality of life in patients with recurrent C difficile infection.

Standard-of-Care Antibiotics With vs Without Bezlotoxumab Cointervention

For patients with recurrent C difficile infection who have had episodes within the past 6 months, the panel suggested the use of bezlotoxumab as a cointervention with standard-of-care antibiotics compared with standard-of-care antibiotics alone (conditional recommendation, very low certainty of evidence).

Although this recommendation puts a high value on the possible clinical benefits, the feasibility of considerations limits its implementation. In a situation where logistics are not an obstacle, the panel noted that patients with a primary C difficile infection episode who have other risk factors contributing to C difficile infection recurrence — such as being aged 65 years and older, having a history of immunosuppressive therapy or being immunocompromised, and having severe C difficile infection on presentation — may benefit from bezlotoxumab.

Data are still limited on the use of bezlotoxumab when fidaxomicin is the standard-of-care antibiotic used, and the US Food and Drug Administration has noted that the use of bezlotoxumab in patients with a history of congestive heart failure should be reserved for when the benefit outweighs the risk.

The panel noted that some challenges with implementation included a target population that is very different from populations used in phase 3 randomized clinical trials and that insurance companies often deny a request for bezlotoxumab even after referral. Despite these obstacles, however, the panel noted that bezlotoxumab is still likely to be acceptable to patients and providers and is feasible to implement.

“Head-to-head trials of differing anti-[C difficile infection] recurrence strategies using narrow-spectrum antibiotics that target C difficile, restoration of the microbiome using biotherapeutics or [fecal microbiota transplantation], or augmentation of the host immune response with agents such as bezlotoxumab given alone or in combination (eg, in combination with fidaxomicin) are needed,” the guideline authors concluded.

Disclosure: Some guideline authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please refer to the original reference for a full list of authors’ disclosures.


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. Published online June 24, 2021. doi:10.1093/cid/ciab549