Case 15 Discussion Part 2: Treatment of C. difficile infection in IBD

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Learning Objectives:

  1. Identify Clostridioides difficile infection in a patient with IBD
  2. Discuss appropriate management of difficile infection in patients with IBD
  3. Discuss the current data on the safety of fecal microbiota transplant (FMT) in IBD
  4. Discuss potential for microbial manipulation therapy in patients with IBD

IBD EPAs Addressed:

  1. EPA 3: Prescribe and Manage Evidenced-based Inflammatory Bowel Disease Therapies Utilizing Clinical Pharmacologic Principles in Clinical Practice
  2. EPA 4: Manage Adverse Events and Complications of Inflammatory Bowel Disease and Inflammatory Bowel Disease Therapies

 

According to the most recent Infectious Diseases Society of America (IDSA) guidelines, vancomycin and fidoxamicin are preferred treatments for initial episodes of CDI; metronidazole is only acceptable if neither of these agents are available. Due to the cost of fidoxamicin, vancomycin is often the preferred initial agent. For first occurrence of CDI (non-fulminant disease), 125mg 4x daily is the recommended dose for vancomycin. Vancomycin 500 mg is only recommended for fulminant disease (hypotension, sepsis, ileus, toxic megacolon). While most studies of CDI treatments have excluded persons with IBD, vancomycin has been associated with decreased colectomy rate, shorter length of hospital stay, and decreased re-admissions when compared to metronidazole in persons with IBD (Horton et al., Antimicrob Agents Chemother 2014). Data for use of fidaxomicin in IBD is limited but a small study showed this agent to be efficacious (Spiceland et al., JClin Gastro 2018). As such, vancomycin or fidaxomicin are the preferred agents for treatment of first or second episodes of CDI in persons with IBD. A vancomycin pulse and taper regimen is an option for recurrent CDI but is not recommended for initial treatment. A typical pulse/taper is as follows:

  • 125 mg orally 4 times daily for 10 to 14 days, then
  • 125 mg orally 2 times daily for 7 days, then
  • 125 mg orally once daily for 7 days, then
  • 125 mg orally every 2 to 3 days for 2 to 8 weeks

 

Bezlotoxumab is a fully human monoclonal antibody that binds to toxin B produced by Clostridioides difficile. This has been shown to lower the rate of recurrent infection in CDI but is given along with standard of care antibiotics (Wilcox et al., NEJM 2017). Post-hoc analysis of the MODIFY trial demonstrated reduction of recurrent CDI in the IBD patients enrolled in this study. However, sample size was small and larger studies are needed to better understand the position of this therapy in patients with IBD.

FMT is the transfer of stool from a healthy individual to a diseased individual. In 2013, Van Nood et al. published a landmark paper showing the superiority of this therapy for recurrent CDI compared to vancomycin. Multiple subsequent randomized controlled trials also demonstrated excellent efficacy, although IBD patients were largely excluded from these trials. Current IDSA guidelines on the management of CDI recommend FMT for patients after their second recurrence (3rd total episode). Notably, this therapy is considered investigational by the FDA and is currently under enforcement discretion, although currently no investigational new drug application[[ is required to administer this therapy for CDI. Several safety reports regarding transmission of pathogens have been reported but these have been few, and recent data from the AGA indicate overall acceptable safety with this treatment (DeFilipp et al., NEJM 2019).

Early studies demonstrated some concern regarding FMT in immunocompromised persons and in persons with IBD due to concerns with transferring harmful bacteria and that altering the microbiome could precipitate IBD flare. A retrospective multicenter study indicated immunocompromised patients (including IBD patients) had good effect at eradicating C. difficile after FMT (Kelly et al., Am J Gastroenterol 2014). However, this and other early retrospective studies suggested that persons with IBD were at risk of flare after FMT, in up to 25% of cases (Khoruts et al., Clin Gastroenterol Hepatol 2016). More recently, a prospective open-label trial of persons with IBD and recurrent CDI demonstrated success of FMT with respect to eradication of CDI (8% failure rate), and no serious adverse events were reported. Only 1 of 49 patients had an IBD flare and this was felt to be unrelated to FMT (Allegretti et al., Gastroenterology 2020). Therefore, current data suggests that FMT is an effective and safe option for patients with IBD who have experienced at least two recurrences of CDI.

Currently, FMT is not an option for primary therapy for IBD. However, there is great interest in this treatment modality given the intestinal dysbiosis that is present in patients with IBD. To date, four randomized controlled trials have been published investigating the role of FMT for treatment of UC.  One study using FMT via nasoduodenal administration showed no significant response compared to placebo (Rossen et al., Gastroenterology 2015), and a Canadian study using FMT delivered by weekly enema for 6 weeks showed statistically significant response compared to placebo but only in patients who had mild disease and a shorter duration of disease (Moyyaedi et al., Gastroenterology 2015). More recently an Australian group studied multi-donor intense FMT in UC: in this protocol, FMT was administered by enema 5 days per week for 8 weeks. There was a statistically significant increase in steroid free clinical remission and clinical response: 44% vs. 20% (p = 0.02) and 54% vs. 23% (p < 0.01), respectively (Paramsothy et al., Lancet 2017). Another multi-center study with less intense dosing of anaerobically prepared FMT (with goal to optimize the delivery of healthy anaerobes to the colon) demonstrated similar results and raised the question of whether anaerobic preparation could obviate the need for intense dosing of FMT (Costello et al., JAMA 2019). A subsequent meta-analysis also confirmed the potential for FMT to be beneficial in patients with UC (Paramsothy et al., J Crohns Colitis). However, given the heterogeneity of methods and patient population, further investigation is needed to determine the ideal recipient, ideal donor, optimal method of preparation, and intensity of dosing and administration of FMT for treatment of UC. Less robust data exists for the treatment of Crohn’s disease and pouchitis with microbial manipulation: to date, there have been no RCTs of FMT for treatment of Crohn’s disease or pouchitis.

The exact mechanism of how FMT can be beneficial for some patients with UC is unclear, but it has been postulated that an increase in healthy anaerobes produce more anti-inflammatory short chain fatty acids and/or restore a healthy bile acid profile, which may contribute to the improvement of inflammation in IBD. (Paramsothy et al., Gastroenterology 2019). Looking to the future, proprietary combinations of healthy microbes are being developed and tested in patients with UC, representing an exciting potential for microbial manipulation as a treatment modality for persons with UC.

  1. Allegretti JR, Kelly CR, Grinspan A et al. Outcomes of Fecal Microbiota Transplantation in Patients with Inflammatory Bowel Diseases and Recurrent Clostridioides difficile Infection. Gastroenterology 2020;159(5):1982-1984.
  2. Binion DG. Clostridium difficile infection in patients with inflammatory bowel disease. Gastroenterol Hepatol 2012;8:615–617.
  3. Costello SP, Hughes PA, Waters O et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients with Ulcerative Colitis: A Randomized Clinical Trial. JAMA 2019;321(2):156-164.
  4. DeFilipp Z, Bloom PP, Torres Soto M et al. Drug-Resistant E coli Bacteremia Transmitted by Fecal Microbiota Transplant. N Engl J Med. 2019 Nov 21;381(21):2043-2050.
  5. Horton HA, Dezfoli S, Berel D et al. Antibiotics for treatment of Clostridium difficile infection in hospitalized patients with inflammatory bowel disease. Antimicrob Agents Chemother 2014;58:5054-5059
  6. Hourigan SK, Oliva-Hemker M, Hutfless S. The prevalence of Clostridium difficile infection in pediatric and adult patients with inflammatory bowel disease. Dig Dis Sci. 2014;59:2222–2227.
  7. Kelly CR, Ihunnah C, Fischer M et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014;109(7):1065-71.
  8. Kelly CR, Yen EF, Grinspan AM et al. Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results from the FMT National Registry. Gastroenterology 2020.
  9. Khanna S, Shin A, Kelly C. Management of Clostridium difficile Infection in Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates Committee of the AGA Institute. Vol 15, Issue 2, P 166-74.
  10. Khoruts A, Rank KM, Newman KM, et al. Inflammatory bowel disease affects the outcome of fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol 2016;14:1433–1438.
  11. McDonald L, Gerding D, 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):e1-e48.
  12. Moyyaedi P, Surette MG, Kim PT et al. Fecal Microbiota Transplantation Induces Remission in Patients with Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology 2015;149(1):102-109).
  13. Paramsothy S, Kamm MA, Kaakoush NO et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomized placebo-controlled trial. Lancet 2017;389(10075):1218-1228.
  14. Paramsothy S, Nielsen S, Kamm MA et al. Specific Bacteria and Metabolites Associated with Response to Fecal Microbiota Transplantation in Patients with Ulcerative Colitis. Gastroenterology 2019;156(5):1440-1454.
  15. Paramsothy S, Paramsothy R, Rubin DT et al. Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis 2017;11(10):1180-1199.
  16. Rossen NG. Fuentes S, van der Spek MJ et al. Findings from a Randomized Controlled Tiral of Fecal Transplantation for Patients with Ulcerative Colitis. Gastroenterology 2015 Jul;149(1):110-118.e4
  17. Spiceland C, Khanna S, Pardi DS et al. Outcomes of fidaxomicin treatment of Clostridium difficile infection. JClinGastroenterology 2018;Feb;52(2):151-154..
  18. Wilcox, Gerding, Poxton et al. Bezlotoxumab for the Prevention of Recurrent Clostridium Difficile Infection. N Engl J Med 2017; 376:305-317
  19. 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):407-15.

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