Fecal microbiota transplantation appears effective in C. diff

Last Updated: 2015-05-04

By Will Boggs MD

NEW YORK (Reuters Health) - Fecal microbiota transplantation (FMT) appears to be safe and effective for resolving symptoms of recurrent Clostridium difficile infection (CDI), according to a systematic review.

But the conclusion is based on limited data, one of the authors told Reuters Health by email.

"Although the effect of FMT for the prevention of subsequent CDI episodes is large, the lack of a control group in all but one study should give us pause," said Dr. Dimitri Drekonja, from the Minnesota Veterans Affairs Health Care System and University of Minnesota School of Medicine, Minneapolis.

"Extrapolating the results of this one controlled study of about 40 subjects to the huge numbers of cases of recurrent CDI occurring in the U.S. annually seems premature to me."

Despite the increasing use of FMT for recurrent CDI, guidelines differ in the specifics and strengths of their recommendations. A European guideline strongly recommends FMT after a second recurrence of CDI, for example, the American College of Gastroenterology offers a conditional recommendation, based on moderate-quality evidence, to consider FMT after a third recurrence of CDI after a pulsed vancomycin regimen.

Dr. Drekonja's team undertook a systematic review of the effectiveness of FMT for recurrent, refractory, and initial CDI and assessed the harms and acceptability of the procedure.

They identified 35 studies, only two of which were randomized controlled trials. The rest were case series (n=28) and case reports (n=5). Only one of the randomized controlled trials compared FMT with standard antimicrobial therapy.

In the randomized controlled trials, 27 of 36 patients (75%) with recurrent CDI experienced resolution of symptoms without recurrence after FMT. In the case series, 85% of recurrent CDI episodes treated with FMT resolved without recurrence.

Evidence was far from conclusive regarding the effectiveness of FMT for refractory CDI or initial episodes of CDI, the authors reported online May 4 in Annals of Internal Medicine.

While the case series reported few harms, the randomized controlled trials attributed mild adverse events to FMT, including diarrhea, cramping, belching, nausea, abdominal pain, bloating, transient fever, and dizziness.

Four of the case series reported that patients expressed no concern with any aspect of FMT, and 97% of patients surveyed in one study would be willing to receive FMT in the future. One randomized controlled trial, however, blamed low enrollment of patients on their reluctance to receive FMT at an early stage of recurrence.

"Evidence is insufficient about whether treatment effects vary by FMT donor, preparation, or delivery method," the researchers noted.

"I have referred patients for FMT (the VA does not currently offer it), and as part of that I've had many conversations with patients explaining that while the results seem very promising, we really don't have the level of evidence that we would require of a new drug before licensing it," Dr. Drekonja said.

"Recurrent CDI is sometimes difficult to differentiate from diarrhea due to other causes - especially because the organism, its toxins, or the genetic elements encoding the toxins (all of which are part of CDI testing) can be detected for months post-infection, even in asymptomatic patients," he cautioned. "If one of these carriers develops diarrhea for any cause, clinicians are now very aware of the risk of recurrence. Thus, they test, and the test is often positive, but in many cases the positive test may be completely unrelated to the episode of diarrhea. But in the setting of diarrhea, prior CDI, and a positive test, few clinicians would not treat."

Dr. Christina Surawicz from the University of Washington School of Medicine, Seattle, wrote an editorial related to this report. She told Reuters Health by email, "For recurrent CDI patients who have had multiple recurrences, three or more, there is nothing as effective as FMT. It should be done by a practitioner experienced in the proper indications and patient evaluation, donor selection and screening, administration, risks, benefits, and follow-up at a minimum."

"The role for refractory CDI is less clear," Dr. Surawicz said. "It can be considered on a case-by-case basis, but risks must be balanced overall."

"There is much we don't know about changing the microbiota long term, so the use of FMT for other indications should only be done in a research setting in my opinion," Dr. Surawicz concluded.

Dr. Bruce E. Hirsch, an infectious disease specialist at North Shore-LIJ Health System, Manhasset, New York, told Reuters Health by email, "After multiple relapses, the efficacy of standard treatments with antibiotics . . . is very low. Treatment (with FMT) is efficacious and well tolerated. I have treated approximately 50 cases of CDI utilizing capsules. The procedure is easy on patients."

"Novel therapies, by definition, will have less clinical evidence," Dr. Hirsch said. "The expense of definitive large double blind randomized clinical trials complicates the ability to study treatments not developed by pharmaceutical companies. Few therapeutic decisions in medicine have the luxury of perfect clinical evidence. Our task is to critically evaluate available evidence."

"Our duty is to provide the best treatment for our patients," Dr. Hirsch concluded. "While a blinded design is preferable, the high frequency of clinical success with various FMT modalities will make patients and their physicians wary of enrolling in such studies. In the absence of harm directly related to FMT, the authors do not address the ethics of withholding FMT or justify the use of blinded trials."

Dr. Colleen Kraft, from Emory University Hospital's division of infectious diseases, Atlanta, Georgia, told Reuters Health by email, "Dr. Tanvi Dhere (in the division of digestive diseases at Emory) and I have performed almost 150 FMT for individuals with medically refractory C. difficile and we have seen a very high percentage (approaching 95%) of individuals who have not had recurrences of C. difficile diarrhea after FMT. This is not in the setting of a clinical trial, and the information is collected observationally. We believe that this is a reasonable way to treat C. difficile because it has the added benefit of restoring the disrupted microbiome in these patients."

"By all available data, FMT has substantial benefit, and I would warrant that it has that benefit despite the inconsistencies of donor, preparation, and route of administration," Dr. Kraft said.

She added, "Continued research and long-term follow-up are necessary to determine if this treatment should be moved up as an earlier treatment for C. difficile, rather than after three-plus episodes. There are also different groups of individuals and companies working to find the 'holy grail' of the keystone microbial species that would restore the microbiota ecology without it being delivered in feces."

The Veterans Health Administration funded this research.

SOURCE: http://bit.ly/1EM3ABW

Ann Intern Med 2015.