By George Ochoa

Fecal transplant proved more effective than vancomycin for the treatment of recurrent Clostridium difficile infection in a randomized controlled trial in the Netherlands. The study was published online on Jan. 16, in The New England Journal of Medicine (368:407-415; doi: 10.1056/NEJMoa1205037).

“This study is critically important,” Lawrence J. Brandt, MD, MACG, AGAF, FASGE, professor of medicine and surgery, Albert Einstein College of Medicine, and emeritus chief, Division of Gastroenterology, Montefiore Medical Center, Bronx, New York City, said in an interview with General Surgery News. Dr. Brandt was not involved with the study.

“I would call it a landmark study—the first randomized controlled trial of fecal transplant in the treatment of recurrent C. difficile infection. Prior to this publication, although the world’s experience with fecal transplant had been outstanding, with an average cure rate of 92% for more than 375 cases, there were still people who needed evidence-based data to support their beliefs. They still wanted ‘proof,’ and this, by all standards, is ‘proof,’” said Dr. Brandt.

The researchers randomly assigned patients with recurrent C. difficile infection to one of three treatment groups. One group received an initial vancomycin regimen (500 mg orally four times per day for four days), followed by bowel lavage and an infusion of a donor feces suspension through a nasoduodenal tube. The second group was treated with a standard vancomycin regimen (500 mg orally four times per day for 14 days). The third group received the standard vancomycin regimen with bowel lavage.

The study was stopped after an interim analysis showed an “overwhelming difference between treatment groups,” according to senior author Josbert J. Keller, MD, PhD, a gastroenterologist at Haga Teaching Hospital, The Hague, Netherlands. Of 16 patients in the fecal transplant group, 13 (81%) had resolution of C. difficile-associated diarrhea after the first infusion of donor feces. The three other patients received a second infusion of feces from a different donor; of these, two were cured, for an overall cure rate of 15 of 16 patients (94%).

In contrast, the group receiving vancomycin alone achieved resolution of C. difficile infection in four of 13 patients (31%), and the group receiving vancomycin with bowel lavage achieved resolution in three of 13 patients (23%) (P<0.001 for both comparisons with the fecal transplant group). Adverse events did not differ significantly among the three groups except for mild diarrhea and abdominal cramping in the infusion group on the day of infusion.

Fecal transplant increased fecal bacterial diversity, making it similar to that of healthy donors. The authors suggested that the mechanism underlying the fecal transplant’s effectiveness is “probably the reestablishment of the normal microbiota as a host defense against C. difficile.”

Although Dr. Keller acknowledged it as a limitation, the small study size was a result of having the study terminated; initially, 120 patients were planned for inclusion. “Fecal transplantation was so effective that the study was prematurely terminated,” said Dr. Brandt. “It would have been ethically improper to continue it. The small size of the study is testimony to the effectiveness of the treatment.”

Dr. Keller cited two reasons for the study’s importance: first, “that it’s the first randomized study of this treatment for patients with C. difficile infection,” and second, “it shows that this treatment strategy of using donor feces infusion [fecal transplant], which is a kind of a super probiotic, to influence the microflora, can cure people.”

Dr. Keller noted the open-label nature of the study as a limitation. Dr. Brandt said, “The study has no major limitations.”

“I’m doing a randomized controlled trial with Colleen Kelly, MD, of the Miriam Hospital in Providence, R.I.,” added Dr. Brandt. “Under a National Institutes of Health grant, we’re studying patients with at least three recurrences of C. difficile infection. The patients get back their own stool or get donor stool in a blinded fashion. We hope our controlled trial will prove that the technique of fecal microbiota transplantation is rapidly effective and safe.”

Asked how his study could change treatment, Dr. Keller said, “The first and second episodes of C. difficile infection would be treated with antibiotics. The third episode, or the second recurrence, could be treated with antibiotics or you could consider donor feces infusion in certain patients. At the fourth episode, or the third recurrence, consider donor feces infusion as a serious possibility.”

“This will definitely help change the treatment of recurrent C. difficile colitis,” said Dr. Brandt. “My opinion is that for a third recurrence, fecal transplant is the treatment of choice. I personally believe that it should be used more frequently and widely than is currently practiced. I would use it as first-line [therapy] in severely ill patients who may not be able to wait for vancomycin to take effect. I would prefer fecal transplant to antibiotics for the first episode of C. difficile because antibiotics perturb the intestinal microbiome and may lead to antibiotic resistance.”

In future studies, Dr. Keller said, “we need to show that enemas are effective, and whether we can use stored feces and frozen feces. We need to determine which bacteria are responsible for the clinical effect and develop a mixture of bacteria to replace donor feces.”

Dr. Brandt reported receiving a grant for research support by Optimer Pharmaceuticals, Inc.. Dr. Keller reported no relevant financial conflicts of interest.