Exploring the Recently Approved and Upcoming Clostridioides difficile Therapeutics

ContagionContagion, October 2023 (Vol. 08, No. 5)
Volume 08
Issue 5

This market has seen a flurry of activity, as shown by a review of the latest agents.

Clostridioides difficile is an obligate, anaerobic, spore-forming, gram-positive bacillus that populates the intestines of approximately 5% to 10% of healthy humans and is acquired in hospitals via the fecal-oral route.1 It is the most common infectious cause of health care–associated diarrhea and is present in the community as well.1 Its spores are ubiquitous in the environment.1 Risk factors for C difficile infection (CDI) include being 65 years or older, use of certain antibiotics (particularly clindamycin, cephalosporins, and fluoroquinolones), and inpatient exposures.2 Cornerstones of CDI management include limiting antibiotic exposure, contact isolation, and treatment with vancomycin or fidaxomicin. Fidaxomicin is now favored as first-line treatment because its observed recurrence rate is approximately 10% lower compared with that of vancomycin, although it is 50 to 70 times more costly per course.3 Unfortunately, recurrence of CDI continues to be a common phenomenon among patients treated with standard-of-care antibiotics, with a 10% to 25% risk of recurrence after treatment for a first episode of CDI and up to 65% risk of recurrence in patients who have already experienced a recurrence.1

This was postulated to be secondary to C difficile’s spore form, which is highly resistant to acid, heat, and antibiotics and can survive almost indefinitely on fomites.1 However, it has recently been shown that collateral intestinal flora deconjugate and dehydroxylate bile acids, which inhibit germination of C difficile spores; the flux of conjugated primary bile acids (some of which promote C difficile spore germination) into the colon plays a role in the loss of host resistance to CDI that occurs with antimicrobial therapy.4 Key to pathogenicity is production of toxin A and toxin B, which are enterotoxic and cytotoxic.1 Prolonged duration of first-line antibiotics such as vancomycin and fidaxomicin is the first line for recurrences.3 However, recurrence rate still tends to be as high as 65% despite these measures. Fecal microbiota transplantation (FMT), an infusion of healthy donor feces for patients with a third or subsequent episode of CDI, was first reported in a clinical trial in 2010 and had high observed rates of success in an initial randomized trial, with 81% (13 of 16) of patients being cured of CDI in the FMT group and 31% (4 of 13) in the vancomycin group.5 However, subsequent trials have reported mixed results, possibly resulting from FMT timing relative to CDI antibiotics, which can interfere with engraftment.6,7

More recently, deaths and illnesses in patients with neutropenia have been attributed to FMT by transmission of pathogenic Escherichia coli and the potential for spread of SARS-CoV-2, which triggered safety alerts by the US Food and Drug Administration (FDA).3 FMT is not currently regulated by the FDA, and because of poorly defined infectious risks, it was only recommended for patients with multiple (≥ 3) recurrent CDI episodes by Infectious Diseases Society of America/Society for Healthcare Epidemiology of America guidelines.3 This review will focus on new therapeutics available for CDI that may replace FMT for recurrent CDI as the first FMT-like products received approval from the FDA.

What You Need to Know

C difficile infection (CDI) is a significant healthcare-associated disease: CDI is the most common infectious cause of healthcare-associated diarrhea and can also be present in the community.

Several new therapeutics have been developed to prevent recurrent CDI.

Cost and logistical considerations may impact access.



Bezlotoxumab is a monoclonal antibody against toxin B of C difficile. From the phase 3 MODIFY I (NCT01241552) and MODIFY II (NCT01513239) trials, it was associated with an absolute risk reduction of 9% compared with placebo in preventing recurrence of CDI.8 It was approved by the FDA in 2016. Bezlotoxumab is recommended to be given as a passive immunization in conjunction with fidaxomicin or vancomycin for a recurrence of CDI within 6 months of the initial episode.3 Bezlotoxumab’s antibodies against toxins A and B (passive immunization) are protective against the toxigenic effect of C difficile in animal models of CDI.8 However, cost may be a logistical barrier, with a base price of $3896 for a single vial of 1000 mg, resulting in hospitals reluctant to position this agent on inpatient formularies.9 Safety considerations must also be given to patients with a history of congestive heart failure.3


In November 2022, the formulation of a live biotherapeutic product, Rebyota, was approved by the FDA for prevention of recurrent CDI after standard-of-care treatment. Findings from the randomized, double-blinded phase 3 trial PUNCH CD3 (NCT03244644) showed a 13.1% increase in treatment success at 8 weeks compared with placebo, with 92.1% of patients remaining free of CDI at 6 months.10 Rebyota is available only for prevention and not for management of CDI. A follow-up study, PUNCH CD3-OLS (NCT03931941), was an open-label study that evaluated safety of Rebyota. Findings from this study showed life-threatening treatment-emergent adverse events (TEAEs) were infrequent at 3%, with none of the TEAEs being attributed to Rebyota.11 There were also no reported infections for which the causative pathogen was determined to be Rebyota. The mechanism of action is postulated to be competitive exclusion of C difficile by donor microbes and reduced toxin production with probable restoration of protective taxa and modulation of the recipient’s microbiome.12 The product is administered as a rectal suspension and shipped frozen to pharmacies in a ready-to-administer enema bag, but receiving pharmacies must have dedicated freezer space for the product because it cannot be stored with non-FMT pharmaceuticals. The product can be shipped on demand and stored in refrigerators not shared with other drugs, but it must be used within 7 days of being thawed.12 Cost may also be a barrier, at $5800 per course, but economic analysis has suggested that it is cost-effective.13 Logistical and cost considerations may limit patient access to Rebyota.

Vowst (SER-109)

SER-109 was approved by the FDA in April 2023 to prevent recurrent CDI. SER-109 is an orally administered preparation consisting of undefined population Firmicutes spores, which are processed per an FDA-approved manufacturing process that aims to eliminate the possibility of human viral and bacterial pathogens. As for Rebyota, the mechanism of action is restoration of resistance to C difficile colonization or reinfection by competing metabolically for nutrients and modulating bile acid profiles through repopulation of the colon with normal collateral flora, which inhibit germination of C difficile spores by direct competition, restoration of normal bile acid conjugation, or both.1 Vowst was approved based on phase 3 trial ECOSPOR-IV (NCT03183141) findings, which demonstrated a 28% reduction in recurrence of CDI (12% vs 40%) compared with placebo at 8 weeks.14 This trial was followed up by a safety analysis recently published in the JAMA, which revealed Vowst was well tolerated, with 8 deaths (3%) and 33 patients (12.5%) with serious TEAEs, none of which were considered treatment related by investigators.15 Thus, this serves as a potential oral option for prevention of recurrent CDI. As with Rebyota, Vowst is not approved for the management of CDI and is labeled to be given 2 to 3 days after standard vancomycin or fidaxomicin treatment to prevent recurrence. The dose comprises 4 capsules taken daily for 3 days, and it can be shipped directly to patients or stored with standard pharmaceuticals. However, at a list price of $17,500 per course, cost considerations may be potent initial barriers to access.16 As with Rebyota, engraftment of the product may account for clinical failures if given too soon after completion of antimicrobials for CDI.


Vedanta Biosciences’ VE303 is an agent that recently completed phase 2 trials, in which it reduced the rate of recurrence of CDI compared with placebo.17 High-dose VE303 showed a recurrence rate of 13.8%, whereas low-dose VE303 showed a recurrence rate of 37% compared with 45.5% with placebo at week 8.17 VE303 is a rationally defined consortium of live, nonpathogenic, nontoxigenic, commensal strains of Clostridium instead of highly processed donor feces.17 It will be entering phase 3 trials in 2023.


  1. Czepiel J, Dróżdż M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019;38(7):1211-1221. doi:10.1007/s10096-019-03539-6
  2. Brown E, Talbot GH, Axelrod P, Provencher M, Hoegg C. Risk factors for Clostridium difficile toxin-associated diarrhea. Infect Control Hosp Epidemiol. 1990;11(6):283-290. doi:10.1086/646173
  3. 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. doi:10.1093/cid/ciab549
  4. Reed AD, Theriot CM. Contribution of inhibitory metabolites and competition for nutrients to colonization resistance against Clostridioides difficile by commensal Clostridium. Microorganisms. 2021;9(2):371. doi:10.3390/microorganisms9020371
  5. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415. doi:10.1056/NEJMoa1205037
  6. Hota SS, Sales V, Tomlinson G, et al. Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent Clostridium difficile infection: an open-label, randomized controlled trial. Clin Infect Dis. 2017;64(3):265-271. doi:10.1093/cid/ciw731
  7. Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: a randomized clinical trial. JAMA. 2016;315(2):142-149. doi:10.1001/jama.2015.18098
  8. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317. doi:10.1056/NEJMoa1602615
  9. Chen J, Gong CL, Hitchcock MM, Holubar M, Deresinski S, Hay JW. Cost-effectiveness of bezlotoxumab and fidaxomicin for initial Clostridioides difficile infection. Clin Microbiol Infect. 2021;27(10):1448-1454. doi:10.1016/j.cmi.2021.04.004
  10. Khanna S, Assi M, Lee C, Yoho D, Louie T, Knapple W, Aguilar H, Garcia-Diaz J, Wang GP, Berry SM, Marion J, Su X, Braun T, Bancke L, Feuerstadt P. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection. Drugs. 2022 Oct;82(15):1527-1538. doi: 10.1007/s40265-022-01797-x. Epub 2022 Oct 26. Erratum in: Drugs. 2022 Nov 7;: PMID: 36287379; PMCID: PMC9607700.
  11. Lee C, Louie T, Bancke L, et al. Safety of fecal microbiota, live-jslm (REBYOTA) in individuals with recurrent Clostridioides difficile infection: data from five prospective clinical trials. Therap Adv Gastroenterol. 2023;16:17562848231174277. doi:10.1177/17562848231174277
  12. Walter J, Shanahan F. Fecal microbiota-based treatment for recurrent Clostridioides difficile infection. Cell. 2023;186(6):1087. doi:10.1016/j.cell.2023.02.034
  13. Lodise T, Guo A, Yang M, et al. Cost-effectiveness analysis of REBYOTA (fecal microbiota, live-jslm [FMBL]) versus standard of care for the prevention of recurrent Clostridioides difficile infection in the USA. Adv Ther. 2023;40(6):2784-2800. doi:10.1007/s12325-023-02505-1
  14. Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N Engl J Med. 2022;386(3):220-229. doi:10.1056/NEJMoa2106516
  15. Sims MD, Khanna S, Feuerstadt P, et al; ECOSPOR IV Investigators. Safety and tolerability of SER-109 as an investigational microbiome therapeutic in adults with recurrent Clostridioides difficile infection: a phase 3, open-label, single-arm trial. JAMA Netw Open. 2023;6(2):e2255758. doi:10.1001/jamanetworkopen.2022.55758
  16. Carvalho T. First oral fecal microbiota transplant therapy approved. Nat Med. 2023;29(7):1581-1582. doi:10.1038/d41591-023-00046-2
  17. Louie T, Golan Y, Khanna S, et al. VE303, a defined bacterial consortium, for prevention of recurrent Clostridioides difficile infection: a randomized clinical trial. JAMA. 2023;329(16):1356-1366. doi:10.1001/jama.2023.4314
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