Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508.
This is a systematic review of fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI). The data examined in this review are from 20 case series and 15 case reports and only 1 randomized controlled trial (RCT). This reflects the landscape of FMT research at the time the publication search was performed in February 2013 when FMT was an essentially unregulated therapy. Now that FMT has been classified as a drug, data from controlled trials will become increasingly available in the coming years.
The included studies had a total of 536 human participants, ages ranging from 6 to 95 years, both male and female. FMT was variously delivered via nasogastric tube, colonoscopic instillation, or retention enema. The majority of participants included were treated for recurrent CDI, with only 4 being treated for a first occurrence.
Primary Outcome Measures
The outcome measures were resolution of diarrhea and negative C difficile toxin test. Most of the cases did not perform posttreatment testing, as it is possible to test positive for the toxin even after diarrhea has resolved. Clinical resolution is generally considered the best indicator of cure.
Fecal microbiota transplant has an average 87% cure rate for recurrent CDI after a single treatment across gender, age, number of recurrences, and method of instillation of the fecal transplant. The efficacy of specific delivery sites was as follows: 94% cure with delivery to cecum/ascending colon, 86% cure via the duodenum/jejunum, 84% cure via the distal colon, and 81% cure with instillation in the stomach.
Fecal microbiota transplantation is an exceptionally promising therapy for the treatment for C difficile–associated diarrhea (CDAD), with an overall cure rate following a single treatment determined in this systematic review to be 87% and comparable efficacy apparent across a variety of delivery methods.
The overarching impression regarding fecal transplants with more than 50 years of case reports is that of a remarkably safe and effective treatment.
While FMT first appears in modern medical literature in 1958, the first findings from a RCT were not published until 2013 when van Nood et al published their findings comparing FMT with vancomycin, a current standard therapy for the treatment of relapsed CDI.1 At the time of the literature search conducted for this review, the aforementioned study was the solitary RCT available for inclusion. While this does limit the conclusions we can draw from this review, the resolution rate reported corresponds with that calculated in other meta-analyses2–4 and anecdotal reports.
In May 2013, the US Food and Drug Administration (FDA) ruled that fecal transplants are a drug and a biologic and that any use of FMT moving forward must be under the auspices of an FDA-approved clinical trial with investigational new drug (IND) status.5 This has restricted the use of FMT in clinical practice, with the notable exception of refractory CDAD that can be treated with FMT without IND status under the current policy of discretionary enforcement as set forth in July 2013.6 This ruling has triggered a flurry of new FDA-approved clinical trials examining the safety and efficacy of FMT for CDAD, as well as other conditions, including inflammatory bowel diseases and metabolic disorders.7 The FDA has updated its stance on FMT for CDI by adding the requirement in March 2014 that any stool donor must be known to either the patient or the physician,8 which has limited the utility of stool-banking services like OpenBiome that have made FMT more accessible for patients and physicians.
The overarching impression regarding fecal transplants with more than 50 years of case reports is that of a remarkably safe and effective treatment. The most significant adverse events reported have been of flares in quiescent ulcerative colitis patients when treated for CDAD,9 and 1 death when a patient aspirated as a result of anesthesia given for colonoscopic delivery.10 The value of FMT in an environment of increasingly antibiotic-resistant and virulent CDIs and the potential fatality of chronic diarrhea is difficult to argue against. That said, RCTs are very much needed to shed light on nearly all of the variables involved. Treatment with as little as 10 g and as much as 300 g has been reported to be curative4 in clinical practice with volumes of diluent ranging from 50 mL to 500 mL. Most FMT is performed with antibiotic pretreatment, but evidence demonstrating the importance of this preconditioning is not clear in the literature. The majority of FMT is preceded by some form of bowel preparation. We need to know what preparatory protocol is best and its utility when using a noncolonoscopic delivery method. Other important questions that are more inherently complex include the importance of donor matching; the literature to date generally seems to demonstrate that nearly any reasonably healthy donor can be used and be curative for CDI, but what long-term side effects might be present, positive or negative? We see early suggestions that metabolic conditions, autoimmune processes, and mood disorders can all be positively impacted by fecal transplants.11 What else might FMT be capable of, good or bad? We do not yet have good information about possible long-term effects of this therapy.
The majority of cases in the literature are patients who were treated with FMT after experiencing multiple recurrences of CDAD. While the FDA discretionary enforcement specifies that FMT may be used for refractory C difficile, it is worth noting that the efficacy of FMT in the treatment of relapsed CDAD in the aforementioned clinical trial was much greater (93.8%) than that of vancomycin (30.8%). Additionally, enrollment in that trial was closed by the data safety monitoring board after only 43 of a planned 120 participants received treatment because nearly all of the controls experienced recurrence.12 The 4 patients included in this review who were experiencing their first bout of CDAD achieved full resolution of symptoms following a single FMT treatment. Patient and physician attitudes are probably a significant barrier beyond current FDA regulations, but 81% of respondents (n=154) elected to have FMT rather than antibiotics when given efficacy information about the 2 treatments. When a pill form was offered, the rate of FMT preference increased to 90%; preference was even higher (94%) if a participant’s physician recommended the treatment, with 77% willing to pay out of pocket for the therapy.13
Treatment with encapsulated FMT is so new that it was not present in the literature at all at the time of this review; however, reports from the pioneer of this delivery method, Thomas Louie, MD, of the University of Calgary, indicate cure rates of 100% (n=27) for recurrent CDI.14 The convenience and relative appeal of the capsule treatment have made for a 6-month or longer wait time to receive capsules from Louie’s facility. Bruce Hirsch, MD, at the North Shore University Hospital, Manhasset, New York, also reports being unable to keep up with demand for FMT pills.15
Although FMT is largely the domain of gastroenterologists and infectious disease specialists with many treatments being delivered via colonoscopy or endoscopy, it appears to have comparable effectiveness when given by retention enema, which can readily be performed in an outpatient clinical setting without anesthesia. This therapy is not FDA-approved, and if a practitioner wishes to provide this service, adequate consent must be obtained to ensure that the patient is made fully aware that this is an unproven, experimental therapy with unknown risks. Health Canada does not exercise discretionary enforcement; therefore, FMT may not be given outside of an approved clinical trial in Canada, even in the case of refractory CDI. Consensus guidance on best practices for stool-donor screening is available from the American Gastroentrology Association.16