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2019-12-02| R&D

Combating Clostridium difficile infections using Fecal Microbiota Transplant

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By Atmaja Saxena, Ph.D.

Fecal Microbiota Transplantation has been demonstrated to be over 90% effective for treating Clostridium difficile infections in patients who were unresponsive to previous antibiotic therapies. Here we present a review of some of the recent achievements of this promising investigational treatment.

Clostridium difficile infections (CDI) are the most common cause of healthcare-associated diarrhea occurring in 12 to 64% of patients. As per the 2011 CDC data report, there is a rising incidence of >450,000 cases of CDI and 29,000 CDI-related death rates with annual health care costs up to $5.9 billion a year (1). It has become the most common nosocomial pathogen accounting for 12.1% of all hospital-acquired infections (2).

Active CDI is characterized by typical symptoms including diarrhea (> 3 unformed stools per day) with a positive stool PCR for C. difficile toxin. CDI is usually managed with antibiotics; however, severe disease may be refractory to medication therapy. Fecal Microbiota Transplantation (FMT) is a procedure where a fecal preparation from a carefully screened, healthy stool donor is transplanted into the colon of the patient. There are multiple routes of administration; via colonoscopy: 91% effective (3), naso-duodenal tube: 81% effective (4), rectal enema: 83.5% effective (5), and oral capsules (6), each of which has unique risks and benefits.

 

History of Fecal Matter Usage in Therapy
  • 4th Century: Human fecal suspension was used for food poisoning or severe diarrhea.
  • 16th -17th Century: yellow soup was used to treat diarrheal illnesses.
  • Transfaunation by veterinarians
  • 1958 in Denver: fecal enema for fulminant, life-threatening pseudo-membranous enterocolitis
  • 1983: FMT enema given to a 65-year-old woman with CDI
  • 1991: FMT administered via NG tube
  • 2000’s: Colonoscopy FMT

 

Present Day Evolution of FMT
  • OpenBiome, a non-profit organization established in 2012 in Medford, MA which is currently supported largely by charitable donations, increased the accessibility and ease of FMT.
  • Donors: Young researchers and scientists within the MIT, Harvard, and Tufts communities and young professionals from the Tufts University area were screened and tested every 60 days.
  • Three products at OpenBiome (7):
    • FMP250: 250mL fecal microbiota preparation for lower delivery (colonoscopy, enema)
    • FMP30: 30mL fecal microbiota preparation for upper delivery.
    • FMT Capsule DE: (30 frozen capsules consumed within 90

FMT durably restores the normal fecal microbiota which is important to resolve refractory CDI. FMT appears to be safe and should be considered in patients with 3rd recurrence after a pulsed vancomycin regimen. The risk of transmission of infectious agents may be reduced by obtaining stool samples from healthy donors that have been tested for common viral, bacterial pathogens and parasites.

 

Recommendations from Medical Authorities

Based on the current body of evidence, various medical professional societies have advocated FMT as a standard of care for CDI patients who have been unresponsive to standard therapies. This includes the American College of Gastroenterology, the Infectious Disease Society of America, the Society for Healthcare Epidemiology of America, and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Additionally, the European FMT Working Group, the British Society of Gastroenterology and the Healthcare Infection Society, and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition have rendered their support. Given the lack of viable alternative options, the US Food and Drug Administration (FDA) has allowed clinicians to provide FMT to patients with recurrent CDI outside of clinical trials.

 

Changing Regulatory Landscape

In 2018, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America updated the clinical practice guidelines from 2010 to include FMT to treat new CDIs in adults. In 2013, the FDA granted an enforcement discretion ruling that permitted physicians to provide FMT for recurrent or refractory CDI without filing the standard investigational new drug application (8). This allows physicians to treat patients with FMT that does not have approval yet.

However, the recent turn of events has called for a reconsideration of this policy by the FDA. The placebo-controlled clinical trials have not reported any serious adverse events or transmission of infections (9). However, four case reports described gram-negative bacteremia that occurred in conjunction with ventilator-associated pneumonia, Crohn’s disease, toxic megacolon, and aspiration pneumonia. Two patients contracted extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli bacteremia, and one of them died, according to a report published in the New England Journal of Medicine in October (9). The FMT, administered orally in capsules, had been prepared and frozen in November 2018. That was before a January 2019 change in regulations to expand donor-stool screening to include tests for ESBL-producing organisms, norovirus, and human T-lymphotropic virus. The FDA did not require retesting of stored materials.

 

FDA Public Hearing on the Use of FMT

On November 4th, the FDA held a public hearing in Washington, D.C., to obtain comments from researchers, physicians, industry manufacturers and patients on the agency’s policy towards the use of FMT in patients (10). Although the death of the FMT administered patient was a point of discussion, the American Gastroenterological Association presented evidence assuring that the majority of FMT patients experienced no adverse effects.

Conflicting opinions were expressed at the public hearing. While many companies spoke in favor of stricter policies and rigorous clinical trials, some stool banks and clinicians argued that the current policy of enforcement discretion has helped many patients and must be persisted with. “What if we were wrong about C. difficile? What if the bug-killing thousands every year doesn’t spread in hospitals but develops by what we put in our body?” questioned Progenabiome CEO Dr. Sabine Hazan.

Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health-funded national FMT registry, presented new data showing that 75% (263 respondents) of patients had a “sustained cure” in 3-year multi-center follow-up study and 95% (152 “initially cured” patients) remained cured 6 months post-FMT (11). Experts in the field are anticipated to further discuss these topics in detail at the Malibu Microbiome Meeting on March 28-29, 2020.

Editor: Rajaneesh K. Gopinath, Ph.D.

References
  1. Lessa FC, et al. N Engl J Med. 2015;372:825-834
  2. Magill, et al. N Engl J Med. 2014;370(13):1198-1208
  3. Kelly, C et al. Ann Intern Med. 2016;165(9):609-616
  4. van Nood E et al. N Engl J Med. 2013;368:407-415
  5. Lee, C et al. JAMA. 2016;315(2):142-149
  6. Fischer M et al. Inflammatory bowel diseases. 2016;22(10):2402-2409
  7. http://www.openbiome.org/
  8. https://www.fda.gov/media/86440/download
  9. DeFilipp, Z et al. N Engl J Med. 2019;381(21):2043-2050
  10. Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Public Hearing; Request for Comments. November 4, 2019.
  11. https://www.prnewswire.com/news-releases/doctors-come-together-at-fda-during-cdiff-awareness-month-advocate-for-treatments-300957686.html

 

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