Mark H. Wilcox, MD, FRCPath, OBE

Introduction

It has proven extremely difficult to improve the therapeutic arsenal for Clostridioides difficile infection (CDI). The development pipeline for novel antibiotics to treat CDI—including cadazolid, LFF571, ramoplanin, ridinilazole, and surotomycin—has been fraught with multiple failures. Of note, “failure” in the context of developing a new antibiotic to treat CDI includes 2 points: noninferiority to the long-standing option of administering oral vancomycin, and difficulty assessing what constitutes cessation of diarrhea.1 Given the very high cost of a clinical development program for a new antibiotic, a novel agent that represents no demonstrable efficacy improvement overall compared with established products for the treatment of CDI is commercially unviable. However, 2 novel antibiotics, ibezapolstat (Acurx Pharmaceuticals) and CRS3123 (Crestone), have completed small phase 2 clinical trials for the treatment of CDI (ClinicalTrials.gov Identifiers: NCT04247542 and NCT04781387, respectively); both are being planned for phase 3 clinical trials.2,3

Nonantibiotic products for the treatment of CDI have also stalled in their development, likely due to lack of funding, which is influenced by risk assessments for likelihood of success and therefore of commercial viability. This includes a nontoxigenic C. difficile strain (M3),4 which completed a successful proof-of-concept phase 2 clinical trial in 2013. NTCD-M3 is a naturally occurring strain that produces C. difficile toxins. When given orally, NTCD-M3 colonizes the human gut without causing any symptoms and provides protection from CDI recurrence during the post–standard-of-care antibiotic treatment period.4

In late 2024, Merck ended the availability of bezlotoxumab (Zinplava), a monoclonal antitoxin B antibody that had obtained FDA approval in 2016. Very little information is available regarding the reasons for the discontinuation. An entry on the FDA Drug Shortages Database was posted on December 23, 2024, regarding bezlotoxumab, simply stating, “To be discontinued on January 31, 2025.”5 No information was provided about the reasons for the discontinuation, but presumably these are dominated by commercial considerations.

image

Given the decision to end the availability of bezlotoxumab, AstraZeneca has announced the development of a novel antitoxin B monoclonal antibody (AZD5148).6 A phase 2 clinical trial is due to commence shortly.7

The antibiotic options in current CDI guidelines have contracted rather than expanded. Metronidazole, once a first-line agent, has been relegated in most guidelines given clear evidence of inferiority to vancomycin (and to fidaxomicin [Dificid, Merck]), poor drug levels at the site of infection in the colon, and increasing reports of resistance. Therefore, despite 2 decades of drug development, the current therapeutic repertoire for CDI has expanded only modestly. Guidelines currently draw from the limited therapies for CDI,8-10 and have been compared/contrasted.11

Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) has been used widely for the prevention of CDI recurrence. However, there are great variances in the reported efficacy of FMT, including a recent randomized controlled trial that recorded no benefit for FMT versus placebo recipients.12-16 Regulators have remained concerned about the variability of donor material used in FMT and related safety issues, including deaths following the inadvertent transmission of pathogens in donor material.12

Prior to the approval of 2 live biotherapeutic products for the prevention of CDI recurrence, the FDA operated an “enforcement discretion” on the use of FMT. An enforcement discretion allows access to a treatment method without the requirement to have obtained the level of evidence, including on safety and effectiveness, of FDA-approved therapies. The FDA has shifted its enforcement discretion position on the use of FMT since it approved fecal microbiota, live-jslm (Rebyota, Ferring) and then fecal microbiota spores, live-brpk (Vowst, Nestlé/Seres).17,18

Instead, an investigational new drug (IND) application is now required to use FMT, which is substantially more difficult to achieve. As such, OpenBiome, which has been the major provider of donor FMT material in the United States, decided in late 2024 to no longer distribute samples of such material. The University of Minnesota has an approved IND for the distribution of FMT samples.19

FMT has been used principally and is recommended in guidelines for the prevention of recurrent CDI (rCDI) in individuals with multiple prior recurrences. FMT is not recommended for the treatment of primary CDI.8-10 A recent open-label but assessor-blinded, multicenter, noninferiority, phase 3 randomized clinical trial compared FMT versus standard-of-care vancomycin therapy (125 mg 4 times daily for 10 days) in adults with primary CDI in hospitals and primary care facilities in Norway.20 CDI was defined as diarrhea (=3 loose stools/day) and a positive stool test result for toxin-producing C. difficile according to local testing, with no diagnosis of CDI in the year before enrollment. Of 104 randomly assigned patients, 100 received FMT or the first dose of vancomycin and were eligible for analysis. The primary end point was clinical cure (firm stools or <3 bowel movements daily) at day 14 and no disease recurrence within 60 days in those who received only the assigned treatment. The trial was terminated early based on a recommendation from the trial data and safety monitoring board as an interim analysis criterion for noninferiority of the primary end point (P=0.001).

Specifically, the primary end point was achieved in 66.7% of patients treated with FMT versus 61.2% treated with vancomycin (difference, 5.4 percentage points; 95.2% CI, –13.5 to 24.4 percentage points [for noninferiority, P<0.001]). Eleven patients in the FMT group versus 4 in the vancomycin group received additional treatment (predominantly oral vancomycin). Clinical cure by day 14 and no recurrence with or without additional treatment occurred in 40 of 51 patients (78.4%) with FMT versus 30 of 49 (61.2%) vancomycin recipients (difference, 17.2%; 95.2% CI, –0.7% to 35.1%). There were no significant differences in adverse events between the treatment groups, based on short-term follow-up.20 However, the whole system costs of FMT are likely to be considerably greater than those of orally administered vancomycin, and the potential for associated risks do not favor the former being promoted as a primary CDI treatment option.

Live Biotherapeutics for CDI Recurrence

The most striking improvements in therapeutic choices for CDI have been in the field of biotherapeutics. In the United States, there are 2 approved biotherapeutics for CDI, and these represent a triumph for translating the observations around the importance of the microbiome in controlling C. difficile: fecal microbiota, live-jslm and fecal microbiota spores, live-brpk. A recent American College of Gastroenterology Clinical Practice Guideline has provided recommendations on the use of fecal microbiota–based therapies, including live biotherapeutics, in adults with rCDI (Table).9 Of note, cost-effectiveness data are not yet available to help define when and where to best use these agents.

Table. American College of Gastroenterology Clinical Practice Guideline Statements
Fecal microbiota–based therapies include conventional FMT, fecal microbiota, live-jslm, and fecal microbiota spores, live-brpk.
Fecal microbiota–based therapies are effective therapy to prevent recurrent CDI in selected patients.
Prevention with fecal-based therapies can be considered in patients after the second recurrence (third episode) of CDI or in selected patients at high risk for either recurrent CDI or a morbid CDI recurrence. Selected use includes patients who have recovered from severe, fulminant, or particularly treatment-refractory CDI as well as those with significant comorbidities.
There is insufficient evidence to recommend fecal microbiota spores, live-brpk or fecal microbiota, live-jslm in immunocompromised adult patients with recurrent CDI.
Careful consideration before proceeding with fecal microbiota–based therapies is recommended in patients who require frequent antibiotics or long-term antibiotic prophylaxis because ongoing antibiotics may diminish the efficacy of such therapy.
CDI, Clostridioides difficile infection; FMT, fecal microbiota transplant.
Based on reference 9.

Live-jslm (Rebyota)

Fecal microbiota, live-jslm is a fecal microbiota suspension for rectal administration. It is manufactured from human fecal matter sourced from qualified donors and is tested for a panel of transmissible pathogens. Patients should empty their bladder and bowel before administration. A single dose (150 mL) of live-jslm is given 24 to 72 hours after the last dose of antibiotics for CDI.

FDA approval of live-jslm was based on 2 randomized, double-blind clinical studies (Study 1: NCT03244644 and Study 2: NCT02299570) and 3 open-label clinical studies (NCT01925417, NCT02589847, NCT03931941).17 Combined, the researchers enrolled 978 adults 18 years of age and older with a history of 1 or more CDI recurrences, with their symptoms controlled 24 to 72 hours after antibiotic treatment. More than half received 1 (n=595) or more doses of live-jslm. The median age of the participants was 64 years and 67.2% were female in the 5 studies. Studies 1 and 2 excluded individuals with celiac disease, inflammatory bowel disease, irritable bowel syndrome, and chronic diarrhea, but those groups were not excluded in 1 of the open-label studies (NCT03931941). Individuals with food allergies were not excluded in any of the 5 studies.

Study 1 evaluated sustained clinical response, which was defined as treatment success at 8 weeks and no CDI up to 6 months after the last dose during the blinded period. The difference in sustained clinical response rate (9.1%; 95% CI, –3.6% to 21.7%) was not statistically significant between the live-jslm (65.5%) and placebo groups (56.5%). However, the efficacy was evaluated using a Bayesian analysis of data from Study 1 and Study 2. This found that the estimated rate of treatment success was significantly higher in live-jslm (70.6%) versus placebo (57.5%) recipients at 8 weeks after completing blinded treatment (difference, 13.1%; 95% CI, 2.3%-24.0%).17

Live-brpk (Vowst)

Live-brpk comprises capsules (for oral administration) of a spore suspension that is derived from human fecal matter sourced from qualified donors. The donations are tested routinely for a panel of transmissible pathogens. The spore suspension is generated by treating fecal matter with ethanol to kill organisms that are not spores, followed by filtration steps to remove solids and residual ethanol.

Live-brpk is indicated to prevent CDI recurrence in adults following antibacterial treatment for rCDI. Antibiotic treatment for rCDI should be completed 2 to 4 days before initiation of live-brpk. The dosage is 4 capsules taken orally once daily for 3 consecutive days, and a 10-oz (296-mL) drink of magnesium citrate is given 1 day before (=8 hours prior to) the first dose of live-brpk.

The efficacy of live-brpk was evaluated in a randomized, placebo-controlled, multicenter study.18 The primary objective was to demonstrate the reduction of CDI recurrence at 8 weeks (but longer follow-up also took place). In the intent-to-treat population consisting of all 182 randomized participants, 89 received live-brpk. Participants had a mean age of 65.5 years (range, 18-100 years) and 73.1% received vancomycin. After 8 weeks, CDI recurrence in live-brpk-treated participants was lower compared with that in placebo-treated participants (12.4% vs. 39.8%; relative risk, 0.32; 95% CI, 0.18-0.58). After 12 weeks, the respective CDI recurrence rates were 18.0% (16/89) and 46.2% (43/93) with a relative risk of 0.40 (95% CI, 0.24-0.65). After 24 weeks the rates were 21.3% (19/89) and 47.3% (44/93) with a relative risk of 0.46 (95% CI, 0.30-0.73).18

Investigational live biotherapeutic VE303

Vedanta is developing a novel live biotherapeutic, VE303, to prevent CDI recurrence. VE303 is an oral microbiome-directed therapy comprising nonpathogenic, nontoxigenic, commensal clostridial strains. The researchers used a prespecified combined clinical and laboratory definition to quantify rCDI: diarrhea consistent with CDI plus laboratory confirmation or, in the absence of a stool sample, treatment with a CDI antibiotic. The results of a phase 2 clinical trial showed that by 8 weeks after administration, rCDI was 13.8% versus 37.0% for the high- versus low-dose VE303 groups compared with 45.5% for placebo recipients, respectively (high-dose VE303 vs placebo, P=0.006).21 These promising results have led to the initiation of a phase 3, double-blind, placebo-controlled clinical trial, RESTORATiVE303, which will evaluate the safety and efficacy of a 14-day course of VE303 (in addition to standard-of-care treatment) to prevent CDI at week 8.22

Conclusion

Although there remains a limited number of therapy options for CDI with proven efficacy, newer live biotherapeutics have expanded the available treatment options for those with the most difficult-to-treat scenarios (ie, multiple rCDIs). Cost-effectiveness data are needed to better define when these latter therapies are best used.

References

  1. Gonzales-Luna AJ, Skinner AM, Alonso CD, et al. Redefining Clostridioides difficile infection antibiotic response and clinical outcomes. Lancet Infect Dis. 2023;23(7):e259-e265.
  2. Ibezapolstat clinical development program. Acurx Pharmaceuticals. Accessed September 4, 2025. acurxpharma.com/pipeline/ibezapolstat
  3. Crestone announces positive data from phase 2 clinical trial of CRS3123 for C. difficile infections (CDI). New release. Business Wire. September 5, 2024. September 5, 2025. businesswire.com/news/home/20240904819996/en/Crestone-Announces-Positive-Data-From-Phase-2-Clinical-Trial-of-CRS3123-for%C2%A0C.-Difficile%C2%A0Infections-CDI
  4. Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA. 2015;313(17):1719-1727.
  5. FDA drug shortages: current and resolved drug shortages and discontinuations reported to FDA. FDA. December 23, 2024. Accessed September 4, 2025. dps.fda.gov/drugshortages/discontinuations/bezlotoxumab-injection
  6. Tkaczyk C, Dayao D, Girouard D, et al. P-1055. Anti-toxin B neutralizing monoclonal antibody AZD5148 provides protection in a Clostridioides difficile gnotobiotic piglet model. Open Forum Infect Dis. 2025;12(suppl 1):ofae631.1244.
  7. A study to evaluate the safety, tolerability and pharmacokinetics of AZD5148 in healthy adults. AstraZeneca. Accessed September 4, 2025. astrazenecaclinicaltrials.com/study/D8820C00002/
  8. 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.
  9. 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.
  10. Peery AF, Kelly CR, Kao D, et al. AGA clinical practice guideline on fecal microbiota-based therapies for select gastrointestinal diseases. Gastroenterology. 2024;166(3):409-434.
  11. Sehgal K, Feuerstadt P, Wilcox MH. Making sense of differing guidelines for Clostridioides difficile infection. Infect Dis Clin North Am. Published online August 11, 2025. doi:10.1016/j.idc.2025.07.010
  12. Fecal Microbiota for Transplantation: Safety Alert - Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms. FDA. April 7, 2020. Accessed August 30, 2025. fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission
  13. Tariq R, Pardi DS, Bartlett MG, et al. Low cure rates in controlled trials of fecal microbiota transplantation for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Clin Infect Dis. 2019;68(8):1351-1358.
  14. Drekonja DM, Shaukat A, Huang Y, et al. A randomized controlled trial of efficacy and safety of fecal microbiota transplant for preventing recurrent Clostridioides difficile infection. Clin Infect Dis. 2025;80(1):52-60.
  15. Faecal microbiota transplantation EU-IN Horizon Scanning Report. European Medicines Agency. Updated June 6, 2025. Accessed September 4, 2025. ema.europa.eu/en/committees/working-parties-other-groups/eu-innovation-network-eu
  16. Rodriguez J, Cordaillat-Simmons M, Pot B, et al. The regulatory framework for microbiome-based therapies: insights into European regulatory developments. NPJ Biofilms Microbiomes. 2025;11(1):53.
  17. Reyota. Package insert. Ferring Pharmaceuticals; 2025. Accessed September 4, 2025. fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert-REBYOTA.pdf
  18. Vowst. Package insert. Seres Therapeutics; 2025. Accessed September 4, 2025. fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Package-Insert-VOWST.pdf
  19. Investigational FMT for recurrent C. difficile. FMT Life. Accessed September 4, 2025. fmt.life/access-fmt
  20. Dehlholm-Lambertsen E, Hall BK, Jørgensen SMD, et al. Cost savings following faecal microbiota transplantation for recurrent Clostridium difficile infection. Therap Adv Gastroenterol. Published online April 10, 2019. doi:10.1177/1756284819843002
  21. 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.
  22. RESTORATiVE303. Vedanta Biosciences. Accessed September 4, 2025. vedantabio.com/commitment-to-patients/restorative303/

About the authors:

img-button

Mark H. Wilcox, MD, FRCPath, OBE, is a consultant microbiologist and the lead of antimicrobial resistance & infection for the Leeds NIHR Biomedical Research Centre at the Leeds Teaching Hospitals NHS Trust; a professor of medical microbiology at the University of Leeds; the lead expert on CDI at the UK Health Security Agency; and the national clinical director of infection prevention and control and antimicrobial resistance/diagnostics at NHS England, all in the United Kingdom.

Dr. Wilcox reported that he has received consulting fees from AstraZeneca, Ferring, Nestlé, Pfizer, Tillotts, and Vedanta; lecture fees from Seres and Tillotts; and grant support from Seres and Tillotts.

Copyright © 2025 McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

Download to read this article in PDF document:
Changing Paradigms for Treating C. difficile Infection

This article is in PDF format and it requires Abobe Reader. If you do not have Adobe Reader installed on your computer then please download and install from the link below.
Download Adobe Reader