C. Difficile: Are We Making Progress?

Clostridioides difficile is an anaerobic, spore-forming, toxin-producing gram-positive rod that has been identified as a cause of antibiotic-associated colitis. Over the last decade, the frequency and severity of C. difficile infection (CDI) has been increasing worldwide, and it is now one of the most common hospital-acquired infections. We have more reliable surveillance CDI data from the Centers for Disease Control and Prevention (CDC) in part because C. difficile became a reportable infection for all healthcare facilities participating in Medicare and Medicaid since 2013.

In 2017, there were an estimated 223,900 hospitalized cases in the United Sates and 12,800 deaths from C. difficile.¹ The national incidence of community-associated C. difficile infection saw no change, while healthcare-associated C. difficile infection has decreased by 36% from 2011 to 2017.² This decline in healthcare-associated infections can be attributed to antibiotic stewardship programs, reduced use of fluoroquinolones, and testing protocols that limit false-positive results. With an aging population and increased numbers of persons with underlying comorbidities, C. difficile remains a major concern for the US healthcare system.

Most recently, the COVID-19 pandemic has led to an extensive use of broad-spectrum antibiotics for concern of secondary bacterial infections, and one study showed 91% of COVID-19 patients received antibacterial therapy.³ A retrospective study in Italy during the pandemic found a significant decrease in the incidence of healthcare-associated CDI (HA-CDI) in 2020 when compared to the three prior years, possibly related to enhanced pandemic precautions. It is interesting to note that COVID-19 wards actually had a higher incidence of HA-CDI when compared to the non-COVID-19 wards, but this difference was not statistically significant.⁴ One case series of nine patients coinfected with both SARS-CoV-2 and C. difficile reports that all nine patients received antibiotics during their hospitalization.⁵ These reports highlight the importance of focusing efforts on infection control and antibiotic stewardship to prevent further emergence of C. difficile infections.

The North American pulsed-field gel electrophoresis type 1 (NAP1) strain of C. difficile, also known as ribotype 027, is one of several described hypervirulent strains. The NAP1 strain has been implicated in outbreaks for almost 20 years.⁶ Most pathogenic strains of C. difficile produce two toxins, an enterotoxin tcdA and a cytotoxin tcdB. The NAP1 strain has a deletion of the tcdC inhibitory gene which results in higher toxin A and B production. Risk factors for the NAP1 strain include advanced age, fluoroquinolone use, and admission from long-term care facilities.⁷ The CDC's emerging infections program reported a significant decline in healthcare-associated isolates of the NAP1 strain from 21% in 2012 to 15% in 2017, but it remained the most prevalent.⁸ This decrease in the proportion of infections caused by the NAP1 strain has been shown to be associated with decreased fluroquinolone use likely due to awareness and antimicrobial stewardship.⁹

The most recent treatment guidelines by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) were updated in 2017. These guidelines recommend that the initial treatment of non-severe disease is 10 days of either oral fidaxomicin (200 mg 2 times daily) or oral vancomycin (125 mg 4 times daily).¹⁰ Both options are equally effective, but recurrence rates are lower with fidaxomicin than vancomycin (15% vs 25%).¹¹ Metronidazole is no longer recommended unless vancomycin or fidaxomicin is unavailable—a situation that is unlikely in the United States. Metronidazole also has a role in the initial treatment for fulminant disease where vancomycin 500 mg orally four times daily along with metronidazole 500 mg intravenously every eight hours is recommended. Fidaxomicin was included in this updated guideline for the first time, as it was approved by the FDA in 2011. It is important to note there have been no new antibiotics approved since the approval of fidaxomicin almost a decade ago.

Relapse is a major concern for CDI, as up to 25% of patients experience recurrence, usually within 30 days of stopping treatment.¹² The IDSA/SHEA guidelines recommend the first recurrence be treated with 10 days of oral fidaxomicin or with a prolonged tapering course of oral vancomycin for 6 to 12 weeks. Bezlotoxumab is a monoclonal antibody directed against the toxin B produced by C. difficile and was approved in 2016 by the FDA for patients at high risk for recurrence. In a randomized controlled trial, patients given one dose of bezlotoxumab had a lower risk of disease relapse within 12 weeks (16%) than patients given placebo (26%).¹³ Relapse rates were particularly lower among the elderly and cancer patients who were treated with bezlotoxumab.¹³ The addition of bezlotoxumab to antibiotic treatment should be considered in patients at high risk for C. difficile recurrence, including the elderly, those with a recent history of C. difficile, and those with kidney dysfunction.

Systemic antibiotics are well-known to alter the microbiome of patients leading to a decrease in bacterial diversity.¹⁴ These effects after 1 course of antibiotics have been shown to last for months,¹⁵ and even up to four years.¹⁶ This has formed much interest in biome-based solutions to treatment, such as fecal microbiota transplantation and microbiome-based treatment. Fecal microbiota transplantation (FMT) refers to giving fecal bacteria from a healthy donor or a pool of healthy donors (stool bank) to the patient with recurrent infection via freeze-dried stool capsules, nasoenteric tube, or colonoscope. Randomized studies have shown higher resolution of C. difficile diarrhea with FMT (94%) than vancomycin (31%)¹⁷ and with FMT (92%) versus fidaxomicin (42%) or vancomycin (19%).¹⁸ In 2019, 2 cases of immunocompromised patients infected with extended-spectrum beta-lactamase-producing Escherichia coli after FMT were reported; 1 of the 2 patients died.¹⁹ In 2020, there were also reports of 2 patients developing enteropathogenic E. coli after FMT and 4 patients were infected with shiga toxin-producing E. coli.²⁰ There is concern that safety issues with FMT are underreported, but a prospective cohort study using propensity-score matching showed that patients with recurrent CDI who were treated with FMT had a 23 percentage point lower risk to develop primary blood stream infections than those treated with antibiotics.²¹ Oral partial microbiome fractions are currently being investigated. One gut microbiota capsule SER-109 recently met its primary end point in a phase three trial in recurrent CDI and showed a lower proportion of recurrent CDI within 8 weeks with SER-109 (11.1%) compared to placebo (41.3%).²² Another microbiota-based therapy, RBX2660, is currently under study in a phase three clinical trial for the prevention of recurrent C. difficile infection; it showed 87.1% efficacy, defined as absence of diarrhea through 8 weeks, in its phase 2 trial data.²³

Newer developments related to treatment of C. difficile that are being investigated include new antibiotics and vaccine efforts. A newer antibiotic ridinilazole has limited systemic absorption and has been shown to preserve the gut microbiome diversity when compared to fidaxomicin.²⁴ Early data for ridinilazole suggest it could become a new treatment against CDI, but phase 3 trials are still in process. Another antibiotic, MGB-BP-3, was announced to have met its safety and efficacy endpoints earlier this year in a phase 2 clinical study. Immunization against the toxins produced during infection is another area of interest. One vaccine, PF-06425090, entered phase three testing in 2017 after a phase 2 trial showed it was safe and well-tolerated with a robust immune response.²⁵ Another toxin vaccine, VLA84, has successfully completed a phase 2 study.²⁶ Antibodies directed against toxins are not likely to prevent colonization or prevent transmission. There are early studies looking at vaccines directed against surface-antigens of C. difficile which would reduce colonization and thus help with transmission.

Although its incidence has decreased over the past 10 years, C. difficile remains prevalent in healthcare institutions and the community. The two major challenges are the treatment of severe and fulminant C. difficile and the prevention of infection and relapse. Expansion and improvement of infection control and antibiotic stewardship programs have been successful in reducing C. difficile disease burden, but additional measures are required. The development of an effective vaccine is an important next step in disease prevention. There is ongoing development of additional narrow-spectrum antibiotics to treat C. difficile. Furthermore, the recommendation of fidaxomicin in guidelines, as well as the option of bezlotoxumab, should substantially decrease relapse rates and prevent relapse-related secondary cases. Microbiota-based and metabolomic-based therapies will help restore gut hostility toward C. difficile in a safe way and are expected to prevent disease and relapse. Several ongoing programs show promise. Additional efforts to develop testing that is more specific, while retaining high sensitivity, is required to better identify persons at higher risk of C. difficile infection and relapse.

Charles R. Bornmann, MD, is a clinical fellow in infectious diseases at Tufts Medical Center in Boston.

Yoav Golan, MD, MS, FIDSA, is an attending physician and associate professor of Medicine at Tufts University School of Medicine, in Boston, Massachusetts, with a research interest in hospital-acquired infections and a focus on patient risk stratification, particularly C difficile infections.

References

1. ^{CDC. Antibiotic resistance threats in the United States, 2019. Published online November 2019. doi:10.15620/cdc:82532}
2. ^{Guh AY, Mu Y, Winston LG, et al. Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes. New England Journal of Medicine. 2020;382(14):1320-1330. doi:10.1056/nejmoa1910215}
3. ^{Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091. doi:10.1136/bmj.m1091}
4. ^{Bentivegna E, Alessio G, Spuntarelli V, et al. Impact of COVID-19 prevention measures on risk of health care-associated Clostridium difficile infection. American Journal of Infection Control. Published online October 2020. doi:10.1016/j.ajic.2020.09.010}
5. ^{Sandhu A, Tillotson G, Polistico J, et al. Clostridioides difficile in COVID-19 Patients, Detroit, Michigan, USA, March–April 2020. Emerging Infectious Diseases. 2020;26(9):2272-2274. doi:10.3201/eid2609.202126}
6. ^{McDonald LC, Killgore GE, Thompson A, et al. An Epidemic, Toxin Gene–Variant Strain ofClostridium difficile. New England Journal of Medicine. 2005;353(23):2433-2441. doi:10.1056/nejmoa051590}
7. ^{Mani NS, Lynch JB, Fang FC, Chan JD. Risk Factors for BI/NAP1/027 Clostridioides difficile Infections and Clinical Outcomes Compared with Non-NAP1 Strains. Open Forum Infectious Diseases. 2019;6(12). doi:10.1093/ofid/ofz433}
8. ^{Paulick A, Adamczyk M, Korhonen LC, Guh A, Gargis A, Karlsson M. 2404. Molecular Epidemiology of Clostridioides difficile in the United States, 2017. Open Forum Infectious Diseases. 2019;6(Supplement_2):S830-S830. doi:10.1093/ofid/ofz360.2082}
9. ^{Silva SY, Wilson BM, Redmond SN, Donskey CJ. Inpatient fluoroquinolone use in Veterans’ Affairs hospitals is a predictor of Clostridioides difficile infection due to fluoroquinolone-resistant ribotype 027 strains. Infection Control & Hospital Epidemiology. Published online September 23, 2020:1-6. doi:10.1017/ice.2020.383}
10. ^{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). Clinical Infectious Diseases. 2018;66(7):987-994. doi:10.1093/cid/ciy149}
11. ^{Drekonja DM, Butler M, MacDonald R, et al. Comparative Effectiveness of Clostridium difficile Treatments. Annals of Internal Medicine. 2011;155(12):839. doi:10.7326/0003-4819-155-12-201112200-00007}
12. ^{Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clinical Microbiology and Infection. 2012;18:21-27. doi:10.1111/1469-0691.12046}
13. ^{Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence. Clinical Infectious Diseases. 2018;67(5):649-656. doi:10.1093/cid/ciy171}
14. ^{Tosh PK, McDonald LC. Infection Control in the Multidrug-Resistant Era: Tending the Human Microbiome. Clinical Infectious Diseases. 2011;54(5):707-713. doi:10.1093/cid/cir899}
15. ^{Rashid M-U, Zaura E, Buijs MJ, et al. Determining the Long-term Effect of Antibiotic Administration on the Human Normal Intestinal Microbiota Using Culture and Pyrosequencing Methods. Clinical Infectious Diseases. 2015;60(suppl_2):S77-S84. doi:10.1093/cid/civ137}
16. ^{Jakobsson HE, Jernberg C, Andersson AF, Sjölund-Karlsson M, Jansson JK, Engstrand L. Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome. Ratner AJ, ed. PLoS ONE. 2010;5(3):e9836. doi:10.1371/journal.pone.0009836}
17. ^{van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. New England Journal of Medicine. 2013;368(5):407-415. doi:10.1056/NEJMoa1205037}
18. ^{Hvas CL, Dahl Jørgensen SM, Jørgensen SP, et al. Fecal Microbiota Transplantation Is Superior to Fidaxomicin for Treatment of Recurrent Clostridium difficile Infection. Gastroenterology. 2019;156(5):1324-1332.e3. doi:10.1053/j.gastro.2018.12.019}
19. ^{DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. New England Journal of Medicine. Published online October 30, 2019. doi:10.1056/nejmoa1910437}
20. ^{Fecal Microbiota for Transplantation: Safety Alert - Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms. FDA. Published online September 9, 2020. Accessed October 29, 2020. https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission}
21. ^{Ianiro G, Murri R, Sciumè GD, et al. Incidence of Bloodstream Infections, Length of Hospital Stay, and Survival in Patients with Recurrent Clostridioides difficile Infection Treated With Fecal Microbiota Transplantation or Antibiotics. Annals of Internal Medicine. 2019;171(10):695. doi:10.7326/m18-3635}
22. ^{Lashner BA, Korman L, Kraft CS, et al. 8- and 12-week Efficacy and Safety Data from ECOSPOR-III a Phase 3 Double-blind, Placebo-Controlled Randomized Trial of SER-109 an Investigational Microbiome Therapeutic for the Treatment of Patients with Recurrent Clostridioides difficile Infection (rCDI). ACG 2020 Annual Scientific Meeting; 2020.}
23. ^{Orenstein R, Dubberke E, Hardi R, et al. Safety and Durability of RBX2660 (Microbiota Suspension) for Recurrent Clostridium difficile Infection: Results of the PUNCH CD Study. Clinical Infectious Diseases. 2015;62(5):596-602. doi:10.1093/cid/civ938}
24. ^{Mitra S, Chilton C, Freeman J, et al. Preservation of Gut Microbiome Following Ridinilazole vs. Fidaxomicin Treatment of Clostridium difficile Infection. Open Forum Infectious Diseases. 2017;4(suppl_1):S526-S527. doi:10.1093/ofid/ofx163.1372}
25. ^{Kitchin N, Remich SA, Peterson J, et al. A Phase 2 Study Evaluating the Safety, Tolerability, and Immunogenicity of Two 3-Dose Regimens of a Clostridium difficile Vaccine in Healthy US Adults Aged 65 to 85 Years. Clinical Infectious Diseases. Published online May 24, 2019. doi:10.1093/cid/ciz153}
26. ^{Dose Confirmation, Immunogenicity and Safety Study of the Clostridium Difficile Vaccine Candidate VLA84 in Healthy Adults Aged 50 Years and Older. Randomized, Controlled, Observer Blind Phase II Study. clinicaltrials.gov. Published April 25, 2017. Accessed October 29, 2020. https://clinicaltrials.gov/ct2/show/results/NCT02316470}