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What are the 2021 guideline updates on the management of Clostridioides difficile infection (CDI) in adults?


Clostridioides difficile infection (CDI) is one of the most common hospital-acquired infections and an increasing cause of morbidity and mortality, especially among older adult hospitalized patients.1-3 Frequently associated with antimicrobial use, the human intestinal tract is colonized by C. difficile after disruption of normal gut flora, a spore-forming, gram-positive bacillus found particularly in hospitals and chronic care facilities.2-4 The C. difficile spores multiply and secrete toxins, causing diarrhea and in severe cases, pseudomembranous colitis. It is estimated that over 450,000 cases of first CDI infections occur annually in the US,1-3 with over 31,000 and 38,000 recurrent cases for community-associated and healthcare-associated cases, respectively, in 2017.1

The Infectious Diseases Society of America (IDSA) provides comprehensive clinical practice guidelines for the management of CDI, with its most recent iteration completed in 2017 and published in 2018.4 A focused guideline update was issued by IDSA in June 2021.1 The American College of Gastroenterology (ACG) last published guidelines on the diagnosis, prevention, and treatment of CDI in 2013.5 They published a new guideline in June 2021.2 This article will review major pharmacotherapy-related recommendations from the 2021 IDSA and ACG guidelines and summarize evidence related to these recommendations (including clinical data that was published after the IDSA guideline’s May 2020 date evidence review cutoff).

Updated Guidelines

The 2021 IDSA guideline update focuses primarily on the use of fidaxomicin over vancomycin for treatment of both initial and recurrent episodes of CDI, and bezlotoxumab as an adjunctive therapy to standard of care antibiotics for the treatment of CDI.1 All 3 recommendations made in their guideline update are conditional recommendations, which are supported by very low to moderate certainty of evidence. Most patients in these clinical situations would benefit from therapy, but healthcare providers should consider other variables, including individualized patient values and preferences, resource availability, and cost of resources, before adopting into regular clinical practice.

The ACG 2021 guideline acts as an update to their previous guidance and complements the recently published IDSA focused guideline update.2 The ACG update focuses on more areas of disease than the IDSA guidelines and focuses on aspects of primary prevention, secondary prevention, diagnosis, classification, and treatment of CDI. The guideline also has a section focusing on the management of CDI in special populations, specifically patients with irritable bowel disease (IBD). Of the 23 total recommendations made by ACG,12 of them are “strong recommendations”, supported by very low to moderate quality of evidence. A recommendation is graded as “strong” when the evidence shows the benefit of the treatment or intervention clearly outweighs any risk. The remaining 11 recommendations are conditional.

Guideline Recommendations

Fidaxomicin versus vancomycin

Fidaxomicin is a macrolide antibiotic approved by the Food & Drug Administration (FDA) for the treatment of C. difficile-associated diarrhea.6 At the time of its approval, it was the first new drug approved for treatment of CDI in 31 years.1 The 2017 IDSA guidelines recommended either oral vancomycin or fidaxomicin for treatment of initial CDI episodes for both nonsevere and severe (but not fulminant) disease, and either was preferred over metronidazole.4 Similarly to vancomycin, fidaxomicin is orally delivered and highly active against C. difficile in vitro.1,6 Resistance to fidaxomicin has rarely been reported in C. difficile.1 However, there are no other treatment indications for fidaxomicin, and it has limited activity against other enteric bacteria. Clinical trial data has demonstrated similar initial clinical response with both vancomycin and fidaxomicin, yet CDI recurrences are fewer following use of fidaxomicin. While more evidence exists to support use of fidaxomicin in initial CDI episodes, recently published studies support its use in recurrent CDI cases as well. The 2021 IDSA update provides a conditional recommendation to consider fidaxomicin 200 mg twice daily for 10 days over a standard course of vancomycin for initial CDI episodes due to lower recurrence rates with fidaxomicin seen in original noninferiority randomized controlled trials (RCTs). The Table summarizes the clinical trials that support recommendations favoring fidaxomicin over vancomycin in treatment of initial and recurrent CDI episodes.

Table. Evidence supporting use of fidaxomicin in treatment of initial and recurrent CDI episodes.7-10
Study design and durationSubjectsInterventionsResultsConclusions
Mikamo 20187 
Noninferiority, MC, DB, RCT
June 2014 through September 2016
Hospitalized adults with symptomatic and stool toxin-positive CDI (N=212)Fidaxomicin 200 mg twice daily orally for 10 days
Vancomycin 125 mg four times daily orally for 10 days
Global cure rate was 67.3% with fidaxomicin and 65.7% with vancomycin (treatment difference, 1.2%; 95% CI, -11.3 to 13.7). Noninferiority was not demonstrated (noninferiority margin of -10%)
Recurrence rate was lower in fidaxomicin than vancomycin patients (19.5% vs 25.3%)
No differences in ADEs between groups
Although noninferiority margins were not met with fidaxomicin, global cure rate was numerically higher and recurrence rates lower with fidaxomicin compared to vancomycin
Guery 20188
Superiority, OL, RCT
November 6, 2014 through May 5, 2016
Hospitalized adults 60 years of age or older with positive CDI stool toxin test (N=364)
Extended-pulsed fidaxomicin (200 mg orally, twice daily on days 1 through 5, then once daily on alternate days on days 7 to 25)
Vancomycin 125 mg four times daily orally for 10 days
Stratified by CDI severity, age (>75 years vs <75 years), and number of previous CDI episodes
More patients in the mITT fidaxomicin group had sustained clinical cure at 30 days after end of treatment than patients in the mITT vancomycin group (70% vs 59%; OR, 1.62; 95% CI, 1.04 to 2.54; p=0.030). Results in PP group were similar (p=0.001)
In mITT analysis, patients with severe CDI at baseline were less likely to achieve sustained clinical cure than patients with nonsevere CDI (OR, 0.57; 95% CI, 0.36 to 0.91; p=0.019)
More patients in fidaxomicin group than in vancomycin achieved the secondary efficacy endpoint of sustained clinical cure at days 40 (75% vs 59%), 55 (70% vs 55%), and 90 (66% vs 51%) in mITT analysis
Time to CDI recurrence was longer after the end of treatment with fidaxomicin compared with vancomycin (p<0.0001)
No differences in ADEs between groups
Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of CDI
Cornely 20129
Noninferiority, MC, DB, RCT
April 19, 2007 through December 11, 2009
Patients 16 years or older with acute symptoms of CDI and positive stool toxin test (N=509)
Fidaxomicin 200 mg twice daily orally for 10 days
Vancomycin 125 mg four times daily orally for 10 days
Fidaxomicin use was noninferior to vancomycin use in achieving clinical cure in PP analysis (91.7% vs 90.6%) and mITT analysis (87.7% vs 86.8%)
More mITT patients treated with vancomycin had recurrence than those treated with fidaxomicin (26.9% vs 12.7%; p=0.0002)
Higher rate of sustained clinical response with fidaxomicin compared to vancomycin in mITT analysis (76.6% vs 63.4%; p=0.001)
No differences in ADEs between groups
Rates of clinical cure with fidaxomicin were noninferior to those with vancomycin
Patients in the mITT population had higher rates of sustained clinical response with fidaxomicin treatment compared to vancomycin
Louie 201110
Noninferiority MC, DB, RCT
May 9, 2006 through August 21, 2008
Adults with acute symptoms of CDI and positive stool toxin test (N=629)
Fidaxomicin 200 mg twice daily orally for 10 days
Vancomycin 125 mg four times daily orally for 10 days
Fidaxomicin use was noninferior to vancomycin use in achieving clinical cure in PP analysis (92.1% vs 89.8%) and mITT analysis (88.2% vs 85.8%)
Fewer patients in the fidaxomicin group had recurrence of infection compared to vancomycin group in mITT analysis (15.4% vs 25.3%; p=0.005) and PP analysis (13.3% vs 24.0%; p=0.004)
Rate of recurrence was lower with fidaxomicin in non- NAP1/B1/027 strains compared to vancomycin (7.8% vs 25.5%; p<0.001)
Median time to resolution of diarrhea was shorter in fidaxomicin than vancomycin group among inpatients and outpatients, although not significant
No differences in ADEs between groups
Rates of clinical cure with fidaxomicin were noninferior to those with vancomycin
Fidaxomicin associated with lower rate of recurrence of CDI associated with non- NAP1/B1/027
Abbreviations: ADE=adverse events; CDI=Clostridioides difficile infection; CI=confidence interval; DB=double-blind; MC=multicenter; mITT=modified intention-to-treat; NAP1/B1/027= North American Pulsed Field type 1 strains; OL=open label; OR=odds ratio; PP=per protocol; RCT=randomized controlled trial.

A pooled analysis of the 4 RCTs in the Table demonstrated that fidaxomicin increased sustained clinical response of CDI 4 weeks after the end of therapy compared with standard vancomycin (risk ratio [RR], 1.16; 95% confidence interval [CI], 1.09 to 1.24).1 Its use resulted in comparable CDI initial clinical cure (RR: 1.00; 95% CI, 0.96 to 1.04) and failed to demonstrate a reduction in mortality (RR, 0.90; 95% CI, 0.66 to 1.23). Fidaxomicin did not result in an increase in drug-related adverse events based on this analysis (RR, 1.02; 95% CI, 0.76 to 1.36).

Unlike the IDSA guidelines, the ACG guidelines recommend oral vancomycin, oral fidaxomicin, and oral metronidazole all as potential first-line treatment of initial nonsevere CDI.2 They do produce a caveat with their recommendation of oral metronidazole: that it should only be considered for treatment of an initial nonsevere CDI in low-risk patients, specifically younger outpatients with minimal comorbidities. The primary driver for metronidazole remaining a recommended first-line agent is its low cost compared to both oral vancomycin and oral fidaxomicin. The 2021 IDSA guidelines only recommend metronidazole in initial nonsevere CDI cases when oral vancomycin or oral fidaxomicin are unavailable.1 The ACG guidelines recommend oral vancomycin (strong recommendation) or oral fidaxomicin (conditional recommendation) as initial therapy for severe CDI (but not fulminant).2

The 2021 IDSA guidelines favor fidaxomicin (either standard or extended-pulsed regimen) over a standard course of vancomycin in patients with recurrent CDI episodes, although they state that oral vancomycin (tapered and pulsed regimen or standard course) is an acceptable alternative for a first CDI recurrence.1 In patients with multiple recurrences, fidaxomicin is still preferred, but vancomycin (tapered and pulsed regimen), vancomycin followed by rifaximin, and fecal microbiota transplantation (FMT) are viable additional options. The ACG guidelines suggest either a tapered and pulsed vancomycin regimen (strong recommendation) or fidaxomicin (strong recommendation) for treatment of a first recurrence of CDI after initial course of vancomycin or metronidazole.2

Cost of fidaxomicin remains a substantial barrier to its use and cost-effectiveness studies are needed to improve strength of recommendations.1,2 Of note, the 2017 IDSA guidelines recommend oral vancomycin over fidaxomicin for treatment of fulminant CDI and this recommendation remains unchanged.1,4 There are no available data supporting the use of fidaxomicin for the treatment of fulminant CDI, as clinical trials have excluded patients with fulminant CDI.1


Bezlotoxumab is a monoclonal antibody which targets toxin B produced by C. difficile.11 It is FDA-approved to reduce recurrence of CDI in adult patients receiving antibacterial drugs for treatment of CDI and at high risk of CDI recurrence. Bezlotoxumab is suggested for use in patients with a recurrent CDI episode within the past 6 months as an adjunctive therapy to standard-of-care antibiotics over antibiotics alone by both the IDSA and ACG guidelines.1,2 These recommendations are based on a pooled analysis of 2 double-blind, placebo-controlled, phase 3 trials evaluating the safety and efficacy of bezlotoxumab as an adjunct therapy in adult patients receiving standard-of-care antibiotics for primary or recurrent CDI (N=2655 in modified intention-to-treat analysis). Standard-of-care antibiotics in these trials included vancomycin (48%), metronidazole (47%), and fidaxomicin (4%). At the time of the trials, the IDSA 2010 Clinical Practice Guidelines for CDI recommended metronidazole for mild to moderate CDI and oral vancomycin for more severe CDI, which is likely why most patients received either metronidazole or oral vancomycin.1 In addition to standard-of-care antibiotics, patients received a 60-minute intravenous infusion of bezlotoxumab 10 mg/kg.1,2 The pooled analysis demonstrated that bezlotoxumab given in addition to standard-of-care antibiotics reduced CDI recurrence after initial clinical cure at 12 weeks significantly more compared to placebo (63.5% vs 53.7% sustained cure, respectively; RR, 0.62; 95% CI, 0.51 to 0.75), demonstrating a number needed to treat of 10 patients to prevent 1 episode of recurrent CDI with bezlotoxumab. Additionally, bezlotoxumab reduced CDI-associated hospital readmission at 30-days (RR, 0.46; 95% CI, 0.29 to 0.71), but failed to show a reduction in mortality (RR, 0.94; 95% CI, 0.66 to 1.34).

In post hoc analyses, bezlotoxumab failed to show a benefit in patients without any risk factors for recurrence, including patients younger than 65 years of age, with or without additional risk factors.1,2 Subgroup analyses and 2 real-world studies demonstrated the most benefit in patients 65 years of age or older, those experiencing a recurrent episode of CDI, immunocompromised patients, and those with severe CDI, further supporting the pivotal clinical trial data.1,2

Bezlotoxumab is administered as a single dose of 10 mg/kg via intravenous infusion.11 Due to its administration requirements, feasibility of administration limits its applicability and may particularly benefit patients with a primary CDI episode and risk factors for recurrence, especially patients >65 years of age, immunocompromised patients, and patients with severe CDI.1,2 Bezlotoxumab in combination with fidaxomicin has limited data to support its use. Additionally, the FDA urges caution for use in patients with congestive heart failure (CHF).1,11 A post hoc analysis showed that patients with a history of CHF may be at increased risk of heart failure and mortality in the 12 weeks following infusion (RR, 2.64; 95% CI, 1.00 to 7.03 and 1.56; 95% CI, 0.83 to 2.92, respectively).1

Management of CDI in the setting of IBD

The ACG guideline update provides additional recommendations on the management of CDI specific to patients with concomitant IBD.2 They recommend oral vancomycin 125 mg 4 times daily for a minimum of 14 days in this patient population (strong recommendation). There are no published RCTs comparing treatments for CDI in adults with IBD. A retrospective cohort including 503 patients with IBD showed that 32% of patients with IBD were likely to experience recurrent CDI compared with 24% of the general population without IBD (p<0.01), thus reducing recurrence is of high importance in this patient population. In a retrospective study, longer duration of vancomycin therapy (21 to 42 days) compared to shorter duration (<21 days) reduced the rate of CDI recurrence from 11.7% to 1.8% (odds ratio [OR], 0.13; p=0.043). There is very limited data on use of fidaxomicin in patients with IBD, consisting only of small single-center studies.

The ACG also recommends consideration of FMT for patients with IBD and recurrent CDI (strong recommendation).2 This recommendation is based on data demonstrating benefits of FMT in patients with IBD, with a 79% to 91% success rate in preventing CDI recurrence in numerous single and multi-center retrospective cohorts. One prospective study reported a 91% success rate in eradicating CDI measured by resolution of symptoms and undetectable CDI toxin. Although not specific to patients with IBD, 3 separate safety alerts have been published by the FDA since June 2019 highlighting adverse events or potential adverse events among recipients of FMT.1 Two alerts document transmission of Escherichia coli from donor to recipient, which proved fatal in some cases. The other alert documents the potential for transmission of severe acute respiratory syndrome coronavirus 2. Although it can be a life-changing therapy in some cases, FMT is recommended only for patients with multiple recurrences of CDI who have failed recommended antibiotic therapy and have undergone appropriate screening of donor fecal specimens.1,2


Management of CDI remains a common and challenging clinical problem. The 2021 IDSA and ACG guidelines are evidence-based tools that provide recommendations for treatment of both initial and recurrent CDI episodes.1,2 Implementation of the recommendations from these updates require assessment of resource availability, patient preference, clinical situation, cost, and provider experience. As new evidence emerges, these recommendations may change, and clinicians are encouraged to stay up to date on emerging data to support or refute current treatment recommendations for CDI.


  1. 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;73(5):755-757. doi:10.1093/cid/ciab718
  2. Kelly CR, Fischer M, Allegretti JR, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021;116(6):1124-1147. doi:10.14309/ajg.0000000000001278
  3. Gerding D, Johnson S. Clostridium difficile Infection, Including Pseudomembranous Colitis. In: Jameson J, Fauci A, Kasper D, Hauser S, Longo D, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. McGraw-Hill; 2018. Accessed October 21, 2021.
  4. Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017;65(12):1963-1973. doi:10.1093/cid/cix959
  5. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478-498; quiz 499. doi:10.1038/ajg.2013.4
  6. Dificid. Package insert. Merck Sharp & Dohme Corp. 2021.
  7. Mikamo H, Tateda K, Yanagihara K, et al. Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative Phase III study in Japan. J Infect Chemother. 2018;24(9):744-752. doi:10.1016/j.jiac.2018.05.010
  8. Guery B, Menichetti F, Anttila VJ, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018;18(3):296-307. doi:10.1016/s1473-3099(17)30751-x
  9. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289. doi:10.1016/s1473-3099(11)70374-7
  10. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431. doi:10.1056/NEJMoa0910812
  11. Zinplava. Package insert. Merck Sharp & Dohme Corp. 2016.

Prepared by:
Rachel Brunner, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
November 2021

The information presented is current as of October 12, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.