Fecal Transplants for C. Difficile Diarrhea Gain Wider Use

Health Letter, August 2016

By Sammy Almashat, M.D., M.P.H.

A new intervention known as fecal microbiota transplantation has the potential to revolutionize treatment of an often persistent and disabling condition known as C. difficile diarrhea. The procedure involves transplanting feces from healthy donors to patients with C. difficile infection; while it does not evoke the most pleasant imagery, it may be effective for patients with recurrent bouts of diarrhea who fail traditional antibiotic treatment.

About C. difficile diarrhea

Numerous bacteria residing in the large intestine, or colon, are necessary for proper digestion and colon health. C. difficile is a type of bacteria that can infect the colon, especially when the colon’s native bacteria are depleted following antibiotic treatment. It then proceeds to secrete a toxin that causes often severe diarrhea or abdominal pain.

C. difficile infection is estimated to cause almost half a million infections, and kill nearly 30,000 patients, every year in the U.S.[1] Patients on antibiotics, older adults and hospitalized patients are at risk for getting the infection.[2]

Certain antibiotics have long been the mainstay of C. difficile treatment. A 2011 systematic review of all randomized trials of antibiotics in the treatment of C. difficile found that different antibiotics available in the U.S. were largely equally effective in treating the infection.[3] The study found that these antibiotics relieved symptoms in about 40 percent of patients and reduced the C. difficile bacteria in 25 to 71 percent of patients.

Even those successfully treated with antibiotics can experience a recurrence of infection, with anywhere from 8 to 50 percent of patients experiencing at least one more bout of the disease.[4] And 40 to 65 percent of patients with one recurrence suffer further infections.[5]

Recognizing the limited effectiveness of repeat rounds of antibiotics in such cases, the American College of Gastroenterology currently recommends considering fecal microbiota transplantation (FMT) as a treatment option for patients with three or more recurrences of C. difficile infection.[6]

Emergence and types of FMT

The transplantation procedure involves diluting and processing the stool of a donor and implanting it into the colon of a C. difficile patient, either through the rectum (enema or colonoscopy) or through a tube inserted via the nose into the stomach.[7]

Usually, stool is transferred from a donor to a recipient on the same day, a procedure known as fresh FMT.[8] Obviously, such a procedure has drawbacks, including inconvenience and sanitary concerns. An alternative method, known as frozen FMT, involves freezing and storing fecal matter until transplantation. Frozen FMT has the advantage of increased flexibility in the timing of transplant as well as ready availability to facilities that do not have the means to perform fresh FMT.[9]

For early FMT procedures, patients had to find stool donors on their own or with the help of their health care practitioners.[10] Eventually, the practice became widespread enough to prompt the formation of stool banks, which collect stool from donors, store it and distribute specimens to hospitals and health care practitioners for use in FMT.[11]

Studies

FMT has been used sporadically for decades, with cases of FMT for an intestinal disorder published as early as 1958.[12] A 2011 review of evidence from case reports found that 92 percent of patients treated with FMT experienced resolution of their disease.[13]

The first randomized trial of FMT (using the traditional fresh FMT procedure) in C. difficile patients was published in 2013 in The New England Journal of Medicine.[14] The trial, which involved patients with recurrent infections, was stopped early because it found that FMT is far superior to standard antibiotic treatment: 94 percent of the subjects receiving FMT were cured without relapse, compared with just 23-30 percent of subjects receiving antibiotics.

The most recent randomized trial of FMT in C. difficile infections, published in January 2016 in the Journal of the American Medical Association (JAMA), compared frozen and fresh FMT in 219 adults with recurrent or treatment-resistant C. difficile infection.[15] The two methods resulted in similar rates of remission: 70 percent of patients receiving fresh FMT were cured, compared with 75 percent of those receiving frozen FMT.

Two recent studies that followed patients with severe C. difficile infection reported cure rates of 66 to 91 percent after a single FMT treatment.[16],[17] In one of the two studies, patients with recurrent infections had a cure rate of 82 percent.[18]

Although FMT seems to be an effective and promising treatment for patients with recurrent C. difficile infection, its safety is as yet largely unknown. A 2016 review of the published literature on FMT found that, while side effects were uncommon and largely restricted to mild gastrointestinal disturbances, there had been reports of severe complications, including bacterial blood infections, perforations of the intestine and even death.[19]

In 2013, given data suggesting the effectiveness of FMT, the FDA released a set of guidelines clarifying that it would allow “the use of FMT to treat C. difficile infection not responding to standard therapies” without its prior authorization, despite its lack of formal approval by the agency.[20] However, noting the lack of rigorous clinical trials testing the treatment,[21] the FDA required that physicians obtain informed consent from every patient prior to treatment and disclose to them the experimental nature and potential risks of the treatment.

In March 2014, the agency reaffirmed this position in an updated set of guidelines that included two new conditions to minimize the risk of spreading infections.[22] The FDA required that the donor stool be obtained from a person known to either the patient or the health care practitioner, and that the stool donor and the stool itself undergo screening and testing (presumably for infectious agents). A third guidance, released in March 2016, explicitly prohibited the use of a stool bank to obtain donor feces without FDA approval of the stool bank’s testing and safety procedures.[23]

Current use and emerging trends

Since the FDA’s 2013 guidance permitting FMT under limited circumstances, more than 7,000 FMT procedures have been performed.[24] A major stool bank, OpenBiome, has reportedly offered potential stool donors who pass an extensive medical screening up to $13,000 per year for regular stool donations.[25]

FMT is still in its infancy, there are very few doctors who perform the procedure, and it is often not covered by health insurance.[26] Consequently, many people are taking matters into their own hands and are performing stool transplantation in their own homes. Brokers are now offering, for a fee, to connect patients with donors.[27] While such practices are understandable given the debilitating nature of C. difficile diarrhea, the lack of oversight by a health care provider raises concerns about the safety and effectiveness of the treatments.

The science of FMT is steadily advancing, with new, potentially more convenient methods on the horizon.[28] Scientists also are considering using the method to treat other diseases.[29],[30] Yet no company has received FDA approval for a standardized FMT procedure.[31] This, coupled with the lack of large randomized, controlled trials assessing the long- term effectiveness and safety of the procedure, makes it difficult to weigh the true benefits and risks of FMT. In the meantime, FMT may be a reasonable last resort for patients with recurrent C. difficile infections not responding to antibiotics, but it is crucial that FMT be performed under the supervision of a health care professional with adequately tested stool.


References

[1] Centers for Disease Control and Prevention. Clostridium difficile infection. https://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html. Accessed June 21, 2016

[2] Ibid.

[3] Nelson RL, Kelsey P, Leeman H, et al. Antibiotic treatment for Clostridium difficile- associated diarrhea in adults. Cochrane Database Syst Rev. 2011;(9):CD004610.

[4] Aslam S, Hamill RJ, Musher DM. Treatment of Clostridium difficile-associated disease: Old therapies and new strategies. Lancet Infect Dis. 2005;5(9):549-557.

[5] Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478-498; quiz 499. http://gi.org/wp-content/uploads/2013/04/ACG_Guideline_Cdifficile_April_2013.pdf. Accessed June 27, 2016.

[6] Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478-498; quiz 499. http://gi.org/wp-content/uploads/2013/04/ACG_Guideline_Cdifficile_April_2013.pdf. Accessed June 27, 2016.

[7] Aroniadis OC, Brandt LJ. Fecal microbiota transplantation: Past, present and future. Curr Opin Gastroenterol. 2013;29(1):79-84.

[8] Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in atients with recurrent clostridium difficile infection: A randomized clinical trial. JAMA. 2016;315(2):142-149.

[9] Ibid.

[10] Smith PA. Fecal transplants made (somewhat) more palatable. New York Times. November 9, 2015. http://www.nytimes.com/2015/11/10/health/fecal-transplants-made-somewhat-more-palatable.html. Accessed July 5, 2016.

[11] Food and Drug Administration. Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. March 2016. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance s/Vaccines/UCM488223.pdf. Accessed June 22, 2016.

[12] Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44:854-859.

[13] Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. 2011;53(10):994-1002.

[14] 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):407-415.

[15] Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: A randomized clinical trial. JAMA. 2016;315(2):142-149.

[16] Aroniadis OC, Brandt LJ, Greenberg A, et al. Long-term follow-up study of fecal microbiota transplantation for severe and/or complicated Clostridium difficile infection: A multicenter experience. J Clin Gastroenterol. 2016;50(5):398-402.

[17] Agrawal M, Aroniadis OC, Brandt LJ, et al. The long-term efficacy and safety of fecal microbiota transplant for recurrent, severe, and complicated Clostridium difficile infection in 146 elderly individuals. J Clin Gastroenterol. 2016;50(5):403-407.

[18] Ibid.

[19] Baxter M, Colville A. Adverse events in faecal microbiota transplant: A review of the literature. J Hosp Infect. 2016;92(2):117-127.

[20] Food and Drug Administration. Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. July 2013. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines /ucm361379.htm. Accessed June 22, 2016.

[21] Ibid.

[22] Food and Drug Administration. Draft Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. March 2014. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance s/Vaccines/UCM387255.pdf. Accessed June 27, 2016.

[23] Food and Drug Administration. Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. March 2016. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance s/Vaccines/UCM488223.pdf. Accessed June 22, 2016.

[24] Perry P. Fecal transplantation: The grossest way to get you well again. Big Think. May 8, 2016. http://bigthink.com/philip-perry/fecal-transplantation-the-grossest-way-to-get-you-well-again. Accessed June 27, 2016.

[25] Maynard J. Your poop could get you $13,000 as fecal transplant for C. difficile patients. Tech Times. January 30, 2015. http://www.techtimes.com/articles/29923/20150130/your-poop-could-get-you-13000-as-fecal-transplant- for-c-difficile-patients.htm. Accessed June 27, 2016.

[26] Perry P. Fecal transplantation: The grossest way to get you well again. Big Think. May 8, 2016. http://bigthink.com/philip-perry/fecal-transplantation-the-grossest-way-to-get-you-well-again. Accessed July 13, 2016.

[27] Perry P. Fecal transplantation: The grossest way to get you well again. Big Think. May 8, 2016. http://bigthink.com/philip-perry/fecal-transplantation-the-grossest-way-to-get-you-well-again. Accessed June 27, 2016.

[28] Lee CH, Steiner T, Petrof EO, et al. Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2016;315(2):142-9.

[29] Moayyedi 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.e6.

[30] Rossen NG, MacDonald JK, de Vries EM, et al. Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review. World J Gastroenterol. 2015;21(17):5359-5371.

[31] Food and Drug Administration. Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. March 2016. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidance s/Vaccines/UCM488223.pdf. Accessed June 22, 2016.