Fecal Transfer Proves Potent Clostridium difficile Treatment

Jenni Laidman

January 16, 2013

The first clinical trial of the infusion of donor feces for the treatment of recurrent Clostridium difficile came to an early halt when feces transfer proved 3 times more effective than antibiotics in curing the infection, according to an article published online January 16 in the New England Journal of Medicine.

Els van Nood, MD, from the Department of Internal Medicine, Academic Medical Center, University of Amsterdam, the Netherlands, and colleagues randomly assigned 43 patients with recurrent infections of C difficile to 1 of 3 treatments: standard 14-day therapy of 500 mg vancomycin, 4 times daily; standard vancomycin therapy plus bowel lavage; and 4 days of 500 mg vancomycin therapy, 4 times daily, followed by bowel lavage and infusion of donor feces through a nasoduodenal tube.

"I think that this study will help bring this approach forward into the era of modern medicine, rather than sitting in the outskirts of sort of bizarre treatments, which is where it's been sitting," Ciarán P. Kelly, MD, professor of medicine, Harvard Medical Schools, Cambridge, Massachusetts, told Medscape Medical News. Dr. Kelly, author of an editorial accompanying this article, is a gastroenterologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts. The editorial calls C difficile "the most commonly identified cause of nosocomial infectious diarrhea in the United States."

Although donor fecal transfer has proved roughly 90% effective in several case studies, this is the first controlled trial of the procedure, Dr. Kelly said.

"Their findings are very consistent with other case series and case reports in the literature," Moshe Rubin, MD, director, Division of Gastroenterology, New York Hospital Queens, told Medscape Medical News. "It's likely going to make this therapy more commonplace." Dr. Rubin is an investigator in a phase 3 clinical trial of monoclonal antibodies against toxin A and toxin B, which attack cells in C difficile infections. He was not associated with the fecal infusion study.

The study was designed to include 40 patients in each group, but a data safety and monitoring board halted the trial for ethical reasons at an interim analysis of the first 43 patients as the study's lopsided results became clear. (One of the 43 patients was subsequently dropped from the analysis.) The authors point to the Haybittle-Peto statistical boundary, which says studies should be halted when the probability that the treatment effects are a result of chance is less than 1 in 1000.

Overall, 94% of the 16 patients in the infusion group were free of C difficile without relapse after 10 weeks. Thirteen of the 16 patients (81%) were disease-free after a single infusion, and 2 more were successfully treated with a second infusion from a different donor. This is compared with a 31% success rate for vancomycin alone, in which only 4 of 13 patients were cleared of the infection, and a 23% success rate in the vancomycin-plus-lavage group, in which 3 of 13 patients were recurrence-free after 10 weeks (P < .001 for both comparisons with the infusion group).

Eighteen of the patients who relapsed after antibiotic treatment were subsequently treated with donor feces off protocol, with an 83% success rate, although 4 of those patients required a second infusion.

An adjudication committee blinded to patient treatment decided when a patient was cured. Cure was defined as 3 consecutive negative stool tests and either absence of diarrhea or diarrhea explained by causes other than C difficile.

After fecal infusion, DNA screening revealed an increase in the diversity of fecal microbiota.

As the first controlled randomized trial, albeit "unblinded and imperfect," the Netherlands study addressed 1 of 3 major impediments to fecal transfer treatment, Dr. Kelly notes in his editorial. Remaining barriers are the logistical challenges in terms of recruiting donors, harvesting and processing suitable material, and the "yuck" factor.

"It's not a particularly appealing treatment," he said. "There's a natural revulsion to stool, and it's challenging to obtain a donation and to process it." An "obvious next step is determining which specific components of stool have this beneficial effect...then simply administering those in a capsule," he said. A Canadian team recently published a proof-of-principal study in Microbiome on 2 patients successfully treated with cultured bacteria.

Also to be determined is the best mode of delivery. Although this study used nasoduodenal infusion, Dr. Kelly said case studies show a slightly higher success rate for infusion via enema or colonoscopy.

Fecal transfer holds promise for the treatment of several other conditions, Dr. Kelly added, including inflammatory bowel disease, irritable bowel syndrome, and severe ulcerative colitis. Others speculate that it may prove a treatment for obesity, given the differing populations of intestinal bacteria in the bowels of obese humans and animals compared to the nonobese.

"We're just at the very beginning in understanding the repopulation of the colon," Dr. Rubin said. "How treatment will be administered in the future is still unfolding."

One coauthor has disclosed that his institution received a grant from the Netherlands Organisation for Health Research and Development. Dr. Rubin reports has disclosed that his institution received support from Merck for the C difficile phase 3 research. The other authors and Dr. Kelly have disclosed no relevant financial relationships.

N Engl J Med. Published online January 16, 2013. Article full text, Editorial full text

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....