Comparison of 2021 IDSA and ACG Recommendations for the Treatment of C. difficile Infection

BY MARK H. WILCOX, MD

Clostridioides difficile infection (CDI) remains a considerable challenge to diagnose accurately, prevent, and treat, especially with respect to minimizing the risk for recurrent infection. In 2021, the Infectious Diseases Society of America (IDSA) and the American College of Gastroenterology (ACG) each updated its own CDI management guideline,1,2 from previous versions published in 2018 (but confusingly noted as a “2017 update”) and 2013, respectively.3,4 Both guidelines used the GRADE criteria to determine the strength of evidence underpinning the recommendations. While the ACG 2021 update is a full series of recommendations covering prevention, diagnosis, treatment, prevention of recurrence, and special populations, the IDSA 2021 update is more focused, given the shorter gap since its previous guidelines. Hence, the IDSA 2021 guideline addresses 3 specific questions (Table 1).1 This review compares and contrasts how the ACG and IDSA cover these 3 key practice points for the treatment of CDI.

The IDSA 2021 guideline recommends fidaxomicin (Dificid, Merck) (200 mg orally given twice daily for 10 days) instead of vancomycin (125 mg orally given 4 times daily for 10 days) to treat an initial episode of CDI (conditional recommendation, moderate certainty of evidence), which is a shift from its previous position.1,3 Furthermore, it is noted this recommendation “places a high value in the beneficial effects and safety of fidaxomicin, but its implementation depends upon available resources. Vancomycin remains an acceptable alternative.”1 Continuing its stance from 2018,3 the IDSA guideline prefers both fidaxomicin and vancomycin to metronidazole, commenting that metronidazole (500 mg orally 3 times daily for 10-14 days) is an alternative for nonsevere CDI, if the former agents are unavailable.1

The IDSA recommendation in favor of fidaxomicin was based on a pooled analysis of 4 studies,5-8 including 2 trials7,8 that were not considered in the 2018 version.3 The Guery

et al clinical trial is considered below in more detail.7 The 2021 IDSA guideline panel acknowledged the relatively high acquisition cost of fidaxomicin, but noted that cost-effectiveness analyses probably support its use due to superior sustained clinical response rates compared with vancomycin at 4 weeks after end of therapy (risk ratio, 1.16; 95% CI, 1.09-1.24).1 However, the panel noted that uncertainty remains regarding costeffectiveness estimates. Given the assumptions made, the conclusions are based data inputted into the models, and risk for publication bias, including secondary to commercial sponsorship. Also, the IDSA guideline notes there is a chance that implementing this recommendation “probably reduces equity due to variation in medical insurance coverage.”1

The 2021 ACG guideline is more circumspect in its recommendations for the treatment of primary CDI, with no stated preference for vancomycin or fidaxomicin, and even stating that metronidazole remains a reasonable choice, which is somewhat strange given it reviewed the same evidence demonstrating inferiority of the latter option.2 Instead, this guideline only recommends avoiding metronidazole in severe CDI.2 The key randomized controlled trials (RCTs) that compared the efficacy of vancomycin and metronidazole found that the latter was inferior regardless of CDI severity.9 The ACG guideline is similarly cautious regarding the comparative cost-effectiveness of vancomycin and fidaxomicin: “Although vancomycin is less expensive, lower recurrence rates of fidaxomicin imply overall similar cost-effectiveness for both agents.”2

Therefore, regarding question 1 (and 2) in Table 1, the IDSA and ACG 2021 guidelines agree and disagree, which appears to reflect a different interpretation of the available evidence. On this point, there is a puzzling anomaly; the IDSA 2021 guideline1 does not consider a notable, high-impact 2018 network metaanalysis of studies examining the treatment of nonrecurrent CDI.10 The ACG 2021 guideline discusses this meta-analysis, but states: “In a network meta-analysis comparing 13 agents across 24 trials comprising 5,361 patients, vancomycin was rated the best option for achieving primary cure of severe infection, although fidaxomicin had higher sustained cure (ie, fewer recurrences).”2 Actually, the stated conclusion of this meta-analysis was that “among the treatments for non-multiply recurrent infections by C. difficile, the highest quality evidence indicates that fidaxomicin provides a sustained symptomatic cure most frequently. Fidaxomicin is a better treatment option than vancomycin for all patients except those with severe infections with C. difficile and could be considered as a first-line therapy. Metronidazole should not be recommended for treatment of C. difficile.”10

The higher sustained cure associated with fidaxomicin may be especially beneficial in patients at greater risk for recurrence of CDI,11,12 including those with a history of prior CDI; who are at least 65 years of age; with prior hospitalization, severe CDI, concurrent antibiotics and hypervirulent ribotype (027/078/244) infections.13,14 Given that the high acquisition cost of fidaxomicin remains a potential barrier to its widespread use, further cost-effectiveness analyses are needed that measure the total (patient and insurance) cost savings from reduced CDI recurrences to determine how much the greater initial drug price is offset. Of note, the nonfinancial benefits of reducing CDI recurrences need to be quantified, noting the considerable impacts on patients’ quality of life and families.15-17

Table 1. Three Specific Questions Addressed In the 2021 IDSA CDI Guideline

1. In patients with an initial CDI episode, should fidaxomicin be used rather than vancomycin? 2. In patients with recurrent CDI episode(s), should fidaxomicin be used rather than vancomycin? 3. In patients with a CDI episode, should bezlotoxumab be used as a cointervention along with standard-of-care antibiotics rather than standard-of-care antibiotics alone?

CDI, Clostridioides difficile infection; IDSA, Infectious Diseases Society of America.

The ACG 2021 guideline states: “We suggest tapering/pulsed-dose vancomycin for patients experiencing a first recurrence after an initial course of fidaxomicin, vancomycin, or metronidazole (strong recommendation, very low quality of evidence).” In addition, “we recommend fidaxomicin for patients experiencing a first recurrence after an initial course of vancomycin or metronidazole (conditional recommendation, moderate quality of evidence).”2 The recommendation in favor of tapering/pulsed-dose vancomycin, which comes before the one recommending fidaxomicin, is puzzling given the very modest evidence base, including no RCTs, and noting the relatively high cost of a 4- to 6-week course of oral vancomycin. Conversely, the IDSA 2021 guideline states: “The panel suggests the use of fidaxomicin as the preferred therapy for patients with recurrent CDI episode(s) to improve sustained response after therapy. More well-designed RCTs for patients with recurrent CDI, particularly multiply recurrent CDIs, are needed to improve the strength of recommendations. In particular, studies with more appropriate controls for extended-pulsed fidaxomicin should help clarify the role of this dosing strategy for patients with recurrent CDI both in terms of efficacy and quality of life.”1

The latter point follows on from a phase 3b clinical trial in adults older than 60 years of age, 80% of

whom had primary CDI, that compared vancomycin with an extended-dosing fidaxomicin regimen.7 The extended-pulsed regimen comprised the same total dosage as in a standard fidaxomicin course of 200 mg twice daily for 10 days, but instead was 200 mg of fidaxomicin twice daily for 5 days followed by 200 mg once daily on alternate days until day 25. This longer period of fidaxomicin dosing had been shown in a clinically reflective gut model to be associated with less risk for CDI recurrence, likely due to the extended period during which C. difficile inhibitory levels of antibiotic are present in the large intestine.18 The clinical trial found a very low and significantly reduced rate of CDI recurrence in patients receiving the extendedpulsed regimen (4% vs 17% at day 30 after the end of treatment; P<0.001).7 However, the open study design and absence of comparator groups (extended-pulsed vancomycin and standard-dosage fidaxomicin) limit the full interpretation of the study results. Nevertheless, this is further evidence of the reduced risk of CDI recurrence (increased chance of sustained cure) in fidaxomicin versus vancomycin recipients.

Bezlotoxumab (Zinplava, Merck) is a monoclonal antibody against C. difficile toxin B given as an IV infusion at any point during the first 10 days of standard-ofcare (SOC) antibiotic therapy for CDI.19 Bezlotoxumab was the first agent to be licensed for the prevention of CDI recurrence. The ACG 2021 guideline states: “We suggest bezlotoxumab be considered for prevention of CDI recurrence in patients who are at high risk of recurrence (conditional recommendation, moderate quality of evidence).”2 The IDSA 2021 guideline is similar: “For patients with a recurrent CDI episode within the last 6 months, we suggest using bezlotoxumab as a cointervention along with SOC antibiotics rather than SOC antibiotics alone (conditional recommendation, very low certainty of evidence).”1

More than three-fourths of patients recruited to the 2 MODIFY phase 3 trials of bezlotoxumab had 1 or more risk factors for poor CDI outcome, including recurrent infection (Table 2).19-21 Analysis of the treatment outcomes for those with risk factors showed that the benefits of bezlotoxumab were greatest for patients 65 years of age or older, for those experiencing a recurrent episode of CDI, in immunocompromised patients, and in severe CDI.20 More than 30% of patients with any 1 of the risk factors who received placebo (plus SOC antibiotics) had recurrent CDI, compared with about 21% of those without a risk factor. Also, the risk for recurrent CDI was higher for those with more risk factors. Those with 1 risk factor had an increased risk for recurrent CDI of 31.3%, while those with 3 or more risk factors had an increased risk of 46.1%. Conversely, recurrent CDI was not reduced significantly in bezlotoxumab recipients who had none of these predefined risk factors for recurrence. Of note, recurrent CDI, use of fecal microbiota transplants (FMTs), and CDI-associated 30-day readmissions were all reduced in bezlotoxumab recipients who had risk factors for recurrence.20

Both guideline panels reviewed the cost-effectiveness data for the use of bezlotoxumab and broadly agreed that such analyses favor the addition of bezlotoxumab to SOC antibiotics in patients with a high risk for recurrence, particularly those with a recurrent CDI episode within the last 6 months.1,2 The number needed to treat (NNT) with bezlotoxumab to prevent a case of recurrent CDI is low for patients with risk factors for recurrence, especially for those who have had a recurrent CDI in the previous 6 months (NNT=2.5) (Table 2).21 However, it was noted that the high acquisition cost of bezlotoxumab means that “implementing this recommendation also probably reduces equity due to variation in medical insurance coverage.”1

For patients with multiple CDI recurrences, both guidelines consider a role for FMT. While the use of FMT is beyond the scope of this review, safety concerns

Table 2. Effectiveness of Bezlotoxumab With SOC Antibiotics, According to Risk Factors for CDI Recurrence

Patients aged ≥65 y

Patients who are immunocompromised

Patients with severe CDI on presentation

Patients aged ≥65 y and ≥1 previous episode in prior 6 mo

Patients who are immunocompromised and ≥1 previous episode in prior 6 mo

Patients with severe CDI on presentation and ≥1 previous episode in prior 6 mo

CDI, Clostridioides difficile infection; SOC, standard of care.

3.8

4.7

5.1

2.5

3

2.5

remain regarding the potential for inadvertent transmission of pathogens via donor fecal samples.22-24 Such concerns have been extended to SARS-CoV-225 and, most recently, adenoviruses that are associated with severe hepatitis.26 While the newly recognized severe hepatitis cases have occurred primarily in children, the epidemiology and transmission of potential viral cause(s) are poorly characterized. The need for extensive screening/testing of donors/samples adds to the associated costs of FMT. It is probable that the regulatory position on FMT will change as defined microbiome-based products become available.

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):e1029-e1044. 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. Erratum in:

Am J Gastroenterol. 2022;117(2):358. 3. 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. 4. 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. 5. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431. 6. 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, randomized controlled trial. Lancet Infect Dis. 2012;12(4):281-289. 7. 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 randomized, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018;18(3):296-307. 8. 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. 9. Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354. 10. Beinortas T, Burr NE, Wilcox MH, et al. Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis. Lancet Infect Dis. 2018;18(9):1035-1044. 11. Madoff SE, Urquiaga M, Alonso CD, et al. Prevention of recurrent

Clostridioides difficile infection: a systematic review of randomized controlled trials. Anaerobe. 2020;61:102098. 12. Crook DW, Walker AS, Kean Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55(suppl 2):S93-S103. 13. Wilcox MH. Progress with a difficult infection. Lancet Infect Dis. 2012;12(4):256-257. 14. Davies K, Lawrence J, Berry C, et al. Risk factors for primary

Clostridium difficile infection; results from the observational study of risk factors for Clostridium difficle infection in hospitalized patients with infective diarrhea (ORCHID). Front Public

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French hospital setting. Health Qual Life Outcomes. 2019;17(1):6.

18. Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated

Clostridium difficile infection in an in vitro human gut model.

J Antimicrob Chemother. 2015;70(9):2598-2607.

19. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317.

20. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence. Clin Infect Dis. 2018;67(5):649-656.

21. Prabhu VS, Dubberke ER, Dorr MB, et al. Cost-effectiveness of bezlotoxumab compared with placebo for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis. 2018;66(3):355-362.

22. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J

Med. 2019;381:2043-2050.

23. FDA. Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms. 2019. Accessed

May 10, 2022. https://bit.ly/3gKXZEDidse

24. FDA. Update to March 12, 2020 safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse events likely due to transmission of pathogenic organisms. 2020.

Accessed May 10, 2022. https://bit.ly/3yx1REnIDSE

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SARS-CoV-2 and COVID-19. 2020. Accessed May 10, 2022. https://bit.ly/2U0DUAbIDSE

26. European Centers for Disease Control. Increase in severe acute hepatitis cases of unknown aetiology in children. April 28, 2022.

Accessed May 10, 2022. https://bit.ly/3stbOitIDSE

Mark H. Wilcox, MD, is a consultant/ the head of microbiology research & development and the infection lead of the NIHR Leeds Diagnostic Technologies Medical Technology and In Vitro Diagnostics Co-operative, Leeds Teaching Hospitals National Health Service (NHS) Trust; a professor of medical microbiology and the Sir Edward Brotherton Chair of Bacteriology, the University of Leeds, in the United Kingdom; the lead on Clostridioides difficile infection for Public Health England; and the national clinical director, Antimicrobial Resistance & Infection Prevention and Control, for the NHS England.