Clinical trial of fecal transplant gets impressive results; synthetic poop is in the works

Over the past few years, the incidence of Clostridium difficile infections has risen in the US, and 14,000 people have died from the persistent diarrhea this bacteria causes. Some patients who haven’t been cured by antibiotics have turned to “fecal transplants” – the introduction of a healthy person’s feces into a patient’s digestive system – with, according to case reports and news stories, great success. Now, the New England Journal of Medicine has published results of a randomized clinical trial of the treatment. Of 16 C. diff sufferers given fecal transplants, 15 were cured

Most of us carry thousands of strains of bacteria on and in our bodies, and evidence is mounting our collections of microbes (or microbiomes) perform important functions that keep us healthy. Antibiotics can kill off beneficial bacteria as well as pathogenic ones, and many C. diff sufferers develop the infection after a course of antibiotics. In most sufferers, additional antibiotics can cure the infections, but around 20% of patients relapse. The idea behind a fecal transplant is that it can re-populate the gut with good bacteria that keep C. diff in check. (For more on the evolving knowledge of the microbiome, check out Michael Specter’s recent New Yorker story.)

The Clinical Trial
The study by Els van Nood et al and conducted at the Academic Medical Center in Amsterdam involved 43 patients (41 of whom completed the study protocol) who’d had a relapse of C. diff infection after a course of the antibiotics vanomycin or metronidazole. The primary endpoint was cure of C. diff infection, without relapse, within 10 weeks following the start of treatment.

Sixteen patients were assigned to get fecal infusions following a 4- or 5-day course of vanomycin and a bowel lavage (or “intestinal wash,” in the New York Times article about the study). For the control groups, 13 patients got a 14-day course of vanomycin, and another 13 got a 14-day course of vanomycin followed with a bowel lavage on day four or five. “Bowel lavage was incorporated to reduce the pathogenic bowel content, facilitating colonization of healthy donor microbiota” in the fecal infusion treatment group, the researchers explain, and the third treatment group also got it to test the unlikely possibility that the intestinal washing itself can cure C. diff infections.

The fecal infusions consisted of feces from healthy donors diluted with saline, strained, and administered through a tube running through the nose to the small intestine. Researchers used a lengthy process to create a pool of healthy feces donors; it involved repeated health questionnaires, screening of feces for parasites and pathogenic gut bacteria, screening of feces for antibodies to HIV and many other diseases. Feces were collected and transported to the hospital on the day of the infusion. Researchers ended up using feces from 15 donors.

The results were striking: Of the 16 patients who got fecal infusions, 13 were cured after the first infusion and another two were cured after receiving a second infusion from a different donor – adding up to 15 out of 16, or 94% of this group’s members being cured. (To be cured, a patient had to have had three negative stool tests for C. diff toxin, and the cure adjudication committee members were blinded to treatment group assignments.) The cure rates in control groups were much lower: 4 of 13 (31%) for those getting vanomycin only, and 3 of 13 (23%) for those getting vanomycin plus bowel lavage. Most patients in both control groups experienced relapses.

Because so many of the control-group patients had relapses, the study’s data safety and monitoring board advised that the study be ended early. Eighteen of the patients experiencing relapses then received fecal infusions, and 15 of them were cured.

The researchers also studied the microbiota in nine patients prior to their treatment with fecal infusion, and found it to the diversity of microbes to be low. The diversity increased during follow-up, and the researchers report, “In eight patients for whom samples were available, the diversity of fecal microbiota remained undistinguishable from that of the donor during follow-up.” This lends support to the idea that the mechanism by which fecal infusions cure C. diff is re-establishment of a healthy microbiome.

Prospects for future treatment
The Boston Globe’s Carolyn Y. Johnson gives a snapshot of the current spotty use of fecal treatments for persistent C. diff infections:

Since the procedure was described by a Colorado medical team that used the technique in 1958, hundreds of success stories have accumulated in the medical literature and many hospitals have begun trying the procedure in an effort to control the growing public health threat of C. difficile. In New England, a gastroenterologist at the Women’s Medicine Collaborative in Providence has done 90 fecal transplants; at Massachusetts General Hospital, 10 children and a handful of adults have been treated; and at New England Baptist Hospital, 27 patients have received donor feces.

Having a clinical trial published in the NEJM will probably increase doctors’ willingness to consider using fecal infusions, and Johnson reports that more research on the procedure – including its use in patients with Crohn’s disease or inflammatory bowel disease – is underway. But, in Denise Grady’s New York Times article about the Dutch study, a doctor sounds a note of caution about a potential FDA barrier to more widespread adoption:

Dr. Lawrence J. Brandt, a professor at the Albert Einstein College of Medicine in New York, said that the Food and Drug Administration had recently begun to regard stool used for transplant as a drug, and to require doctors administering it to apply for permission, something that he said could hinder treatment.

In her piece, Johnson points out that “a lack of consensus about how to select and screen donors for infectious diseases” has been one obstacle to greater use of fecal infusions. One answer to that comes from doctors in Ontario, Canada, who’ve developed a brilliantly named synthetic stool called RePOOPulate. NPR’s Michaeleen Doucleff explains:

[Infectious disease specialist Elaine] Petrof and her team took a stool sample from a healthy, 40-year-old woman, who hadn't taken antibiotics in 10 years.

Microbiologist Emma Allen-Vercoe, who invented the Robogut [a mechanical device that mimics the conditions in your colon], grew the bacteria from her stool and then sequenced the bugs' DNA to figure which species were present. Using her clinical experience, Petrof selected 33 bacteria that she knew were healthy. The result was an opaque mixture of bacteria, which Allen-Vercoe describes as a "vanilla milkshake." Really.

Petrof then put the bacterial cocktail into the intestines of the two patients during colonoscopies.

The new bacteria slowly grew in the patients' guts and pushed out the toxic C. difficile. Both patients eventually stopped having diarrhea, and the transplanted bacteria were still present six months after the procedure.

Having a uniform, lab-produced bacteria could help researchers study the use of bacterial infusions by different administration routes and for different conditions (e.g., if it turns out that you can swallow a capsule rather than getting a tube down your nose, that would be great). It would probably also be easier for the FDA to approve the use of such a standardized product, rather than requiring any doctor treating C. diff patients to recruit and monitor the health of fecal donors.

Given how quickly bacteria are evolving resistance to the antibiotics we rely on, it's helpful to have a new prospect on the horizon for treating infections.

van Nood, E., Vrieze, A., Nieuwdorp, M., Fuentes, S., Zoetendal, E., de Vos, W., Visser, C., Kuijper, E., Bartelsman, J., Tijssen, J., Speelman, P., Dijkgraaf, M., & Keller, J. (2013). Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. New England Journal of Medicine DOI: 10.1056/NEJMoa1205037