Data show these cases pose some of the most significant threats to patients and health systems.
Clostridioides Difficile (C diff) is an anaerobic, spore-forming, toxin-producing gram-positive bacillus that can colonize the human intestinal tract.1 Colonization may progress to active C diff infection (CDI) that presents as an acute diarrheal illness due to colitis, which often develops upon exposure to antibiotics. CDI is the most common health care–associated infection in the United States and is an urgent threat to public health.2
The Society for Healthcare Epidemiology of America published an updated guideline on CDI in acute-care hospitals in April 2023. This update provides recommendations that support essential practices toward addressing CDI, as well as antimicrobial stewardship and diagnostic stewardship.3
CDI cases can be broken down into 3 epidemiologic categories that define the type of case occuring3: health care facility–onset CDI (HO-CDI); community-onset, health care facility–associated CDI (CO-HCFA-CDI); and community-associated CDI (CA-CDI). HO-CDI is defined as CDI symptom onset at least 4 days after admission to a health care facility, with the day of admission counting as day 1. CO-HCFA-CDI is CDI symptom onset in the community, or less than 4 days from health care facility admission if symptom onset was less than 4 weeks after the last discharge from a health care facility. Lastly, CA-CDI is CDI symptom onset in the community, or less than 4 days from admission if symptom onset was more than 12 weeks after the last health care facility discharge.
However, data show that HO-CDI poses some of the most significant threats to patients and health systems, with more than 225,000 cases of HO-CDI reported each year, resulting in longer hospital stays (an additional 3-5 days). Further, when compared with CA-CDI, HO-CDI poses significantly increased costs to the patient and hospital and can lead to mortality in adult and pediatric patients.3 Although the incidence of HO-CDI in acute-care hospitals has decreased over the past decade, those reductions may be leveling off, which is evidenced by the plateauing of the national standardized infection ratio since 2020.4
Despite being thought of as a hospital problem, HO-CDI is also intimately intertwined within communities. Incidence of HO-CDI is associated with levels of community claims for antimicrobial agents and acid suppressants, often resulting in patients being discharged from the hospital to higher levels of care, such as a transitional care unit.3,5 Overall, the impact of HO-CDI on the entire spectrum of care to the US health care system measures in the billions.1
Prevention of HO-CDI is complex and multifaceted, with pharmacists playing a key role in the implementation of recommendations through both antimicrobial and diagnostic stewardship. Currently, there are also several promising CDI therapeutics in clinical development for prevention and treatment for which pharmacists would play a significant role.
Of the 6 CDI-directed antibiotics with active clinical trials, ridinilazole is the only agent to have progressed to phase 3 clinical trials.6 In the phase 3 trials Ri-CoDIFy 1 (NCT03595553) and Ri-CoDIFy 2 (NCT03595566), ridinilazole resulted in significantly fewer recurrent CDI episodes when compared with vancomycin (8.1% vs 17.3%; P < .01). However, ridinilazole did not meet the primary superiority end point, leading the FDA to likely require an additional clinical trial before approval is considered.7,8
Live biotherapeutic products (LBPs) are novel microbiome products that are given post–CDI treatment to restore dysbiosis and prevent recurrent CDI. LBPs differ from probiotics from a regulatory perspective, as LBPs must abide by FDA manufacturing standards. Two LBPs have recently been approved for prevention of recurrent CDI: RBX2660 (Rebyota; Ferring Pharmaceuticals) in November 2022 and SER-109 (Vowst; Seres Therapeutics, Inc) in April 2023.9,10
RBX2660 is prepared from donor stool and is administered rectally by a health care professional as a single-dose enema, starting 24 to 72 hours after the last dose of CDI antibiotics.9,11 In the phase 3 trials investigating RBX2660, it was found to significantly reduce CDI recurrence through 8 weeks compared with placebo (29.4% vs 42.5%, mean difference = 13.1% [95% credible interval, 2.3-24.0).11
SER-109 is also prepared from donor stool and is administered as 4 oral capsules taken once daily for 3 days, starting 2 to 4 days after the last dose of antibiotics.10,12 In its phase 3 trial, SER-109 significantly reduced CDI recurrence through 8 weeks compared with placebo (12.4% vs 39.8%, relative risk = 0.32 [95% CI, 0.18-0.58]).12
Lastly, although several vaccines have been evaluated in phase 3 trials for CDI, only 1 bivalent toxoid vaccine (PF-06425090) remains in active development.6Although the vaccine did not meet its primary end point of primary CDI prevention in the phase 3 trial (NCT03918629), PF-06425090 significantly shortened time to resolution of CDI in those who received 3 doses and resulted in reduced hospitalization rates.13
HO-CDI places significant burden on the lives of patients and the operations and economics of the entire health care system. Although our understanding of CDI prevention and treatment has improved in recent years, there are still many unanswered questions.
Pharmacists are uniquely positioned to reduce the burden of CDI by adhering to current guidelines, functioning as effective antimicrobial stewards (regardless of their practice setting), educating other clinicians and patients on the importance of antimicrobial stewardship, and staying current on emerging CDI prevention and treatment options.
1. Gerding DN, Young VB, Donskey CJ. Clostridioides difficile (formerly Clostridium difficile) infection. In: Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Ninth edition. Elsevier; 2020:243.
2. Antibiotic resistance threats in the United States: 2019. CDC. Updated December 2019. Accessed April 21, 2023. https://ndc.services.cdc.gov/wp-content/uploads/Antibiotic-Resistance-Threats-in-the-United-States-2019.pdf
3. 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
4. Current HAI progress report. CDC. Updated November 4, 2022. Accessed April 21, 2023. https://www.cdc.gov/hai/data/portal/progress-report.html
5. Zacharioudakis IM, Zervou FN, Shehadeh F, Mylona EK, Mylonakis E. Association of community factors with hospital-onset Clostridioides (Clostridium) difficile infection: a population based U.S.-wide study. EClinicalMedicine. 2019;8:12-19. doi:10.1016/j.eclinm.2019.02.001
6. Gonzales-Luna AJ, Carlson TJ, Garey KW. Emerging options for the prevention and management of Clostridioides difficile infection. Drugs. 2023;83(2):105-116. doi:10.1007/s40265-022-01832-x
7. Bassères E, Endres BT, Khaleduzzaman M, et al. Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficileinfection. J Antimicrob Chemother. 2016;71(5):1245-1251. doi:10.1093/jac/dkv498
8. Summit Therapeutics provides update on ridinilazole. Summit Therapeutics Inc. July 14, 2022. Accessed April 20, 2023. https://www.smmttx.com/app/uploads/2022/07/2022_PR_0714_Ridinilazole-Update-_-FINAL-1.pdf
9. FDA approves first fecal microbiota product. FDA. Updated November 30, 2022. Accessed May 4, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product
10. FDA approves first orally administered fecal microbiota product for the prevention of recurrence of Clostridioides difficile infection. FDA. Updated April 26, 2023. Accessed May 4, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides
11. Rebyota. Prescribing information. Ferring Pharmaceuticals Inc; 2022. Accessed May 4, 2023. https://www.fda.gov/media/163587/download
12. Vowst. Prescribing information. Seres Therapeutics Inc; 2023. Accessed May 4, 2023. https://www.fda.gov/media/167579/download
13. Clostridium difficile vaccine efficacy trial (Clover). ClinicalTrials.gov. Updated February 13, 2023. Accessed April 21, 2023. https://clinicaltrials.gov/ct2/show/NCT03090191