Reducing Recurrence in C Difficile Infection

Clostridioides difficile is a gram-positive, spore-forming, anaerobic bacterium that causes C difficile infection (CDI), defined as 3 or more watery stools within 24 hours in the presence of a positive stool test for C difficile toxin.^1,2 Recurrent CDI (rCDI) is the return of symptoms within 8 weeks following treatment of a previous CDI episode.² Approximately 25% of patients experience a first CDI recurrence; of those, the risk of subsequent recurrences increases substantially, affecting 25% to 65%.³ Several factors increase the risk of recurrence, including antibiotic exposure, advanced age, duration of hospitalization, and proton pump inhibitor use.² 

The burden associated with rCDI is substantial, as the risk of mortality following rCDI is nearly 10-fold higher: 25.4% vs 2.7% after an initial CDI episode. Additionally, rCDI drives higher hospitalization rates, longer lengths of stay, and higher overall health care costs.⁴

Fidaxomicin

Fidaxomicin (Dificid; Merck) has emerged as a preferred option for CDI treatment. The 2021 Infectious Diseases Society of America and Society for Healthcare Epidemiology of America focused guideline update recommends fidaxomicin as the preferred agent over oral vancomycin for both initial and rCDI when available.¹ Fidaxomicin is a narrow-spectrum antibiotic that selectively inhibits C difficile RNA polymerase and demonstrates minimal activity against the normal gastrointestinal microbiota, likely contributing to its lower recurrence rate compared with other therapies.⁵ The standard FDA-approved dosing regimen is fidaxomicin 200 mg by mouth twice daily for 10 days.^6,7 An alternative dosing regimen evaluated in the 2018 EXTEND trial (NCT02254967) consists of fidaxomicin 200 mg by mouth twice daily for 5 days, then 200 mg by mouth every other day for 20 days.⁸ 

Although this regimen involves 25 days of total treatment, it still allows a standard-count bottle to be dispensed and is thought to facilitate recovery of the normal gastrointestinal microbiota. Studies have shown that these regimens are superior to a standard regimen of vancomycin (125 mg by mouth 4 times daily for 10 days) in reducing recurrence and maintaining sustained clinical response in both first and subsequent CDI episodes.^7-9 

Despite these advantages over a standard vancomycin regimen, it remains unclear whether vancomycin taper regimens achieve outcomes comparable to those of fidaxomicin in patients with rCDI. Data are extremely limited, although a recent small randomized trial demonstrated that a tapered regimen of vancomycin (125 mg 4 times daily for 10 days, followed by once daily, every other day, and every third day, each for 7 days) was superior to a standard course of vancomycin for sustained resolution of diarrhea and CDI at day 59 in patients with rCDI. These findings suggest that tapered vancomycin regimens may improve sustained response compared with standard vancomycin therapy; however, direct comparisons with fidaxomicin are limited.¹⁰  

Fecal Microbiota Transplantation: Rebyota and Vowst

Over the past decade, the focus has been on identifying methods to reduce rCDI. Conventional fecal microbiota transplantation (FMT) has historically demonstrated high success rates in patients with rCDI.¹¹ However, the procurement of donor fecal microbiota for FMT has become more difficult in recent years for some institutions due to changes in FDA regulations.¹² Innovation in this area began in 2016 with the approval of bezlotoxumab (Zinplava; Merck), a humanized monoclonal antibody that binds C difficile B toxin approved for prevention of rCDI in high-risk adults; however, in January 2025, it was removed from the market by its manufacturer for unknown reasons.¹³ 

Fortunately, this therapeutic gap has been filled by the approval of 2 new live fecal microbiota–based agents: Rebyota (fecal microbiota, live-jslm; Ferring Pharmaceuticals) in 2022 and Vowst (fecal microbiota spores, live-brpk; Seres Therapeutics) in 2023. 

Rebyota is a rectal enema administered 24 to 72 hours after the last dose of antibiotic treatment and does not require specific bowel preparation for use.¹⁴ Long-term storage requires an ultracold freezer (–60 °C to –90 °C), and short-term storage can be done in a refrigerator for up to 5 days.¹⁴ Prior to administration, Rebyota must be thawed in a refrigerator for 24 hours.¹⁴ 

Rebyota displayed a treatment success rate of approximately 70.6% at week 8 compared with 58.1% with placebo in patients with 1 or more CDI recurrences in the phase 3 PUNCH CD3-OLS trial (NCT03931941).¹⁵ 

Vowst is an oral, spore-based formulation administered as 4 capsules once daily for 3 days starting 2 to 4 days after completing rCDI treatment.¹⁶ It may be stored in a refrigerator or at room temperature and requires bowel preparation with magnesium citrate on the day before and at least 8 hours prior to initiation to aid live microbiota engraftment.¹⁶ 

Vowst showed a reduction in CDI recurrence at 8 weeks compared with placebo in patients with 3 or more CDI episodes, from 40% in the placebo group to 12% in the Vowst group.¹⁷ Both agents demonstrate similar safety profiles, with gastrointestinal effects being the most common.^14,16 With their relatively recent introduction, there is a lack of data directly comparing the agents with each other or with other established rCDI treatment options. Furthermore, available studies excluded specific populations, such as patients with inflammatory bowel disease, neutropenia, and pediatric patients, necessitating careful consideration for use.^15,17

Oral Vancomycin Prophylaxis

Another challenge that arises is when patients with rCDI require systemic antibiotic therapy for other infections, as this exposure increases their risk of recurrence. Oral vancomycin prophylaxis (OVP) has been proposed as a method to reduce rCDI when systemic antibiotics are needed for patients with rCDI.¹⁸ OVP has been primarily studied in high-risk populations, such as hospitalized older adults, patients with a previous CDI episode requiring systemic antibiotics, and transplant recipients.¹⁹ OVP dosing regimens include 125 mg once or twice daily during systemic antibiotic exposure and for up to 5 days after completion of the systemic antibiotic.¹⁸ 

A meta-analysis demonstrated that overall CDI recurrence was less likely in patients who received OVP compared with controls (OR, 0.245; 95% CI, 0.13-0.48).¹⁹ However, recurrence may occur within 6 to 8 weeks upon discontinuation, suggesting OVP simply suppresses C difficile growth during antibiotic exposure rather than addressing the underlying issue of gastrointestinal microbiome dysbiosis.²⁰ Considering the limited and conflicting data, there is no strong recommendation for OVP, but it could be considered for select patients at high risk of rCDI.¹⁸ 

Alternative prophylaxis methods have been investigated, including fidaxomicin and probiotics, but data are limited. One study showed that fidaxomicin prophylaxis significantly reduced confirmed CDI in patients undergoing hematopoietic stem cell transplantation.²¹ Available data for the use of prophylactic probiotics remain controversial, and guidelines currently do not recommend use.

Conclusion

rCDI remains a significant clinical challenge associated with increased morbidity, mortality, and health care outcomes. Advances in treatment strategies, including fidaxomicin regimens, vancomycin taper approaches, and microbiota-based therapies, have expanded the options to prevent recurrence in patients. Several emerging therapeutic approaches are also under investigation; most notably, a vaccine designed to reduce the severity and recurrence of CDI, as well as an oral β-lactamase intended to degrade excess β-lactam concentrations in the gastrointestinal tract to prevent CDI from occurring. ²²

As strategies to reduce rCDI continue to evolve, future research should focus on identifying optimal strategies to both eradicate infection and restore microbiome resilience.

REFERENCES

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. doi:10.1093/cid/ciab549

2. van Prehn J, Kuijper EJ, Dubberke ER. Recurrent Clostridioides difficile infections. JAMA. 2025;334(23):2128-2129. doi:10.1001/jama.2025.18089

3. Stefansson M, Bladh O, Nowak P, Rombo L, Hedenstierna M, Ursing J. Risk factors for further recurrences of Clostridioides difficile infection at the first and second recurrence: a retrospective cohort study. BMC Infect Dis. 2025;25(1):1057. doi:10.1186/s12879-025-11495-0

4. Feuerstadt P, Nelson WW, Drozd EM, et al. Mortality, health care use, and costs of Clostridioides difficile infections in older adults. J Am Med Dir Assoc. 2022;23(10):1721-1728.e19. doi:10.1016/j.jamda.2022.01.075

5. Cao X, Boyaci H, Chen J, Bao Y, Landick R, Campbell EA. Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile. Nature. 2022;604(7906):541-545. doi:10.1038/s41586-022-04545-z

6. Label: Dificid-fidaxomicin tablet, film coated; Dificid-fidaxomicin granule, for suspension. DailyMed. Updated October 16, 2024. Accessed February 27, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dd966338-c820-4270-b704-09ef75fa3ceb

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. doi:10.1016/S1473-3099(17)30751-X

8. 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

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. Johnson S, Gerding DN, Donskey C, et al. A randomized, double-blind, controlled trial of vancomycin taper/pulse and fidaxomicin compared to vancomycin for treatment of a first or second recurrence of Clostridioides difficile infection. Open Forum Infect Dis. 2026;13(suppl 1):ofaf695.021. doi:10.1093/ofid/ofaf695.021

11. 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(7):987-994. doi:10.1093/cid/ciy149

12. Yadegar A, Bar-Yoseph H, Monaghan TM, et al. Fecal microbiota transplantation: current challenges and future landscapes. Clin Microbiol Rev. 2024;37(2):e0006022. doi:10.1128/cmr.00060-22

13. Bezlotoxumab injection. American Society of Health-System Pharmacists. February 5, 2025. Accessed February 27, 2026. https://www.ashp.org/Drug-Shortages/Current-Shortages/Drug-Shortage-Detail.aspx?id=1130

14. Label: Rebyota- donor human stool suspension. DailyMed. Updated December 23, 2024. Accessed February 27, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7af8a7f6-a441-4dc6-a151-138a89166fbb

15. Khanna S, Assi M, Lee C, et al. Efficacy and safety of RBX2660 in PUNCH CD3, a phase III, randomized, double-blind, placebo-controlled trial with a Bayesian primary analysis for prevention of recurrent Clostridioides difficile infection. Drugs. 2022;82(15):1527-1538. doi:10.1007/s40265-022-01797-x

16. Label: Vowst- fecal microbiota spores, live-brpk capsule. DailyMed. Updated April 23, 2026. Accessed February 27, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=99e5a37a-930c-4641-bcdd-7013ec1c15fe

17. 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

18. Kociolek LK, Gerding DN, Carrico R, et al. Strategies to prevent Clostridioides difficile infections in acute-care hospitals: 2022 update. Infect Control Hosp Epidemiol. 2023;44(4):527-549. doi:10.1017/ice.2023.18

19. Babar S, El Kurdi B, El Iskandarani M, et al. Oral vancomycin prophylaxis for the prevention of Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2020;41(11):1302-1309. doi:10.1017/ice.2020.277

20. Zhang K, Beckett P, Abouanaser S, Stankus V, Lee C, Smieja M. Prolonged oral vancomycin for secondary prophylaxis of relapsing Clostridium difficile infection. BMC Infect Dis. 2019;19(1):51. doi:10.1186/s12879-019-3676-1

21. Mullane KM, Winston DJ, Nooka A, et al. A randomized, placebo-controlled trial of fidaxomicin for prophylaxis of Clostridium difficile-associated diarrhea in adults undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2019;68(2):196-203. doi:10.1093/cid/ciy484

22. Dieterle MG, Rao K, Young VB. Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections. Ann N Y Acad Sci. 2019;1435(1):110-138. doi:10.1111/nyas.13958