Updated Guidelines for Managing Clostridioides Difficile Infection in Adults

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A diagnosis of Clostridioides difficile infection does not instantly require treatment, but new guidelines include recommendations for treatment when warranted.

The epidemiology of Clostridioides difficile infections (CDI) has rapidly changed within the past decade, outlined by an increase in incidence and severity, disproportionally higher in our older patient population.1 Commonly recognized as a nosocomial infection secondary to antibiotic exposure, this issue has spread into the community in areas previously considered low risk.

These rising concerns combined with individual risk factors have presented providers with continued challenges in the management of CDI.1 A meta-analysis by Zhang et al projected that the total annual CDI-attributable cost in the United States is estimated at $6.3 billion. This emphasizes the importance for providers and health care professionals to stay up to date on the evidence-based advancements of CDI management.2,3

The updated guidelines on the diagnosis and treatment of CDI by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) have been recently published. Before this update, the most recent revision to the recommendations was placed in 2010 for the diagnosis and treatment of CDI.3

A lot has happened since the last update, including developments in new therapeutic options for treatment and prevention of recurrence, in addition to rising evidence to support fecal microbiota transplantation (FMT) in recurrent and severe infection. Of note, a diagnosis of CDI does not instantly require treatment, these guidelines include recommendations for treatment when warranted.3,4

The new CDI guidelines come with adjusted recommendations pertaining to the agent of choice in initial and recurrent CDI, the use of monoclonal antibodies, and indications for fecal microbiota transplantation. The previous guidelines had an equal preference toward vancomycin and fidaxomicin use in an initial infection.4 However, with the new evidence that came to light after the 2018 guidelines, the IDSA favors using fidaxomicin as the drug of choice.

The EXTEND trial in Europe studied the superiority of extended-pulsed fidaxomicin dosing (200 mg oral tablets, twice daily on days 1–5, then once daily on alternate days on days 7–25) versus vancomycin (125 mg oral capsules, 4 times daily on days 1–10) for hospitalized patients 60 years of age and older with a confirmed CDI diagnosis.4 The findings suggested that extended-pulsed fidaxomicin was superior to standard-dose vancomycin for the sustained cure of CDI 30 days after the end of treatment. There were no differences in adverse effects between both groups.

A non-inferiority trial in Japan studied the efficacy of fidaxomicin (200 mg twice daily, orally for 10 days) versus vancomycin (125 mg 4-times daily, orally for 10 days) for hospitalized patients 20 years of age and older with a confirmed diagnosis of CDI, which had either received no treatment or had failed therapy with metronidazole.4 Though non-inferiority was not demonstrated for fidaxomicin versus vancomycin, the global cure rate was numerically higher and the recurrence rate lower for fidaxomicin than vancomycin.

The second update in guidelines affects the agent of choice for recurrent infections. Again, fidaxomicin (standard or extended-pulsed regimen) seems to gain traction over vancomycin. However, when fidaxomicin cannot be used, various vancomycin doses or fecal microbiota transplantation are options.4

The guidelines assessed the addition of bezlotoxumab, a novel monoclonal antibody that inhibits the binding of C. difficile toxin B to the standard regimen in recurrent CDI. The MODIFY I and II trials brought solidified evidence regarding the efficacy of bezlotoxumab versus placebo.

It provided a substantially lower rate of recurrent infection and had a similar safety profile. Thus, it should come as no surprise that bezlotoxumab (given IV as 10 mg/kg) is suggested to be added as a co-intervention along with standard-of-care (SOC) antibiotics rather than SOC antibiotics alone for patients with recurrent CDI within 6 months.4 

However, the standard of care regimen for first or consequent recurrences of CDI is fidaxomicin and data regarding the combination of bezlotoxumab and fidaxomicin are limited.

What’s more, the guidelines have taken a stance against the use of probiotics to prevent a CDI. When it comes to fecal microbiota transplantation, the evidence supports its use as soon as the second recurrence, as opposed to the third recurrence in the previous guidelines.4,5 The preferred method of delivery is capsules or colonoscopy as opposed to enemas.

Of note, the updated guidelines do focus on isolation measures, CDI management in children, diagnosis, or infection control and prevention, which were absent from the 2010 guidelines. As CDI continues to be a rising concern in the community and hospital, it is imperative that providers are informed of the most recent data and recommendations provided by the IDSA and SHEA.5

About the Authors

Kevin Nguyen, PharmD, is a PGY-1 pharmacy resident at Albert Einstein Medical Center Philadelphia, Pennsylvania.

Elma Telushi, PharmD candidate 2022 at Jefferson University College of Pharmacy.

Katherine Kim, PharmD candidate 2023 at Temple University School of Pharmacy.


  1. Mada PK, Alam MU. Clostridium Difficile. [Updated 2021 Aug 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431054/
  2. Zhang, D., Prabhu, V. S., & Marcella, S. W. (2018). Attributable Healthcare Resource Utilization and Costs for Patients With Primary and Recurrent Clostridium difficile Infection in the United States. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 66(9), 1326–1332. https://doi.org/10.1093/cid/cix1021
  3. Clostridioides difficile infection. CDC. January 4, 2020. Accessed June 21, 2021. https://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html
  4. Stuart Johnson, Valéry Lavergne, Andrew M Skinner, Anne J Gonzales-Luna, Kevin W Garey, Ciaran P Kelly, Mark H Wilcox, 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, Clinical Infectious Diseases, Volume 73, Issue 5, 1 September 2021, Pages e1029–e1044, https://doi.org/10.1093/cid/ciab549
  5. Czepiel, J., Dróżdż, M., Pituch, H., Kuijper, E. J., Perucki, W., Mielimonka, A., Goldman, S., Wultańska, D., Garlicki, A., & Biesiada, G. (2019). Clostridium difficile infection: review. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology, 38(7), 1211–1221. https://doi.org/10.1007/s10096-019-03539-6