https://immattersacp.org/archives/2014/11/c-diff.htm

Fecal transplant pills, other innovations in C. difficile treatment

Speakers at IDWeek 2014 discussed the latest developments in treating Clostridium difficile, including more patient-friendly forms of fecal transplantation.


The latest treatment for recurrent Clostridium difficile infection is not really new at all, Ilan Youngster, MD, told attendees during one of many sessions on the topic during IDWeek 2014, held in Philadelphia in October.

“As early as 1,600 years ago, [Chinese author and alchemist] Ge Hong wrote in his book about Chinese medicine that if you take a human fecal suspension and have patients with severe food poisoning and diarrhea drink it, they will get better,” he said.

This petri dish culture plate inoculated with less-thanigreater-thanClostridium difficileless-thanslashigreater-than has been illuminated using long-wave UV irradiation causing the bacterial colonies to emit a fluorescent glow Photo by CDCslash
This petri dish culture plate inoculated with Clostridium difficile has been illuminated using long-wave UV irradiation, causing the bacterial colonies to emit a fluorescent glow. Photo by CDC/Melissa Dankel

That treatment had gone out of style for quite a while, but researchers have begun to bring it back, most recently with a successful pilot trial of frozen fecal capsules led by Dr. Youngster. He and his colleagues at Massachusetts General Hospital in Boston published results of their first 20 treated patients in the Journal of the American Medical Association on Oct. 11.

The researchers had wanted to start a fecal transplant program for recurrent C. difficile patients but concluded it would be “a logistical nightmare,” Dr. Youngster said. “You have to get the donor in, have him do his thing, screen him if he hasn't been screened before, process the stool, and administer it to the patient, all within the span of 4 to 6 hours.”

Instead, the group tried freezing stool and administering it via a nasogastric tube or a colonoscopy. They found that the methods worked equally well in results reported at last year's IDWeek. “The next question was, ‘Why don't we try to get rid of any invasive procedure and just let the patient eat the pill that contains the same mixture?’” said Dr. Youngster.

They found some capsules that would mask the taste of the contents (“which could be important in our case,” Dr. Youngster said to laughter from the audience) and collected stool from young, healthy, carefully screened donors. The stool was blended with saline, particulate was removed, glycerol was added, and the mixture was put into translucent capsules and frozen.

The patients, who had already had at least 2 recurrences of an initial C. difficile infection or 2 severe infections and had been off antibiotics for at least 48 hours, took 15 of the capsules on 2 consecutive days. “We have yet to find one patient who has had any problems with swallowing these capsules. A, They're so sick, they really want to do anything to get rid of the disease, and B, [the pills are] frozen, so they slide down,” said Dr. Youngster.

If the treatment hadn't eliminated their diarrhea in 3 or 4 days, the patients were offered re-treatment. “After 1 dose of [the treatment], 14 patients were cured. Of the 6 [who weren't], we re-treated them all and 4 of them responded to treatment. Our overall cure rate is 90%,” said Dr. Youngster, noting that 1 of the 2 remaining patients has been symptom-free for 7 months after a third treatment, although the study protocol didn't allow him to be counted in the cured group.

The results need confirmation, but they raise some hope that fecal transplant could be provided orally, he concluded. “I think it's safer and it is a step in making this treatment more available to patients, which I think is important, because when patients can't get this treatment from doctors, they go home and Google it, and that's when we hear these horror stories of patients doing fecal transplants at home, unsupervised and without screening,” said Dr. Youngster.

Researchers from the University of North Dakota offered another alternative to the traditional fecal transplant at IDWeek. Paul Mariani, MD, reported on a phase II trial of what he called “a next-generation fecal transplant,” a microbiota suspension derived from donor stool and delivered as a 150-cc enema.

Of the 31 recurrent C. difficile patients treated, 16 had their diarrhea resolve after the first enema, a success rate of 52%, and the rest were re-treated in a couple of weeks. “[Success] was actually higher in those that received the second enema—around 76%,” said Dr. Mariani. “The overall efficacy is around 87%, which is similar to what has been described previously in the literature [with fecal transplant].”

Based on this success, the researchers will be moving on to a double-blind, controlled, randomized trial of the treatment, he reported.

More controlled evidence is needed for most of the promising cutting-edge treatments for recurrent C. difficile, according to Dale Gerding, MD, MACP, who gave an overview of the topic during IDWeek.

Biotherapeutic approaches, like the pills and the enema, hold the most promise for truly eliminating C. difficile in recurrent patients, he added. “It's the only way to stop the recurrences and stop the colonization,” said Dr. Gerding, who is a professor of medicine at Loyola University Chicago Stritch School of Medicine in Maywood, Ill.

Other approaches currently being investigated by researchers include binders like tolevamer, antibodies derived from bovine milk, vaccines, and monoclonal antibodies. “These are antibodies directed just against toxins,” he said, which in early studies look “very effective at reducing recurrence.”

Finally, there's work on new antibiotics. “There's cadazolid, surotomycin, and SMT19969, all of which are currently under development,” Dr. Gerding said. The drugs are in phase II or phase III studies and have shown evidence of reducing recurrence. “I don't know that any of them are going to be better than fidaxomicin, but at least we will have some additional agents available,” Dr. Gerding said.

Fidaxomicin seems to be the most effective currently available antibiotic, he noted. “Uptake of its use clinically has been slow. Possibly the reluctance to use it has been based largely on cost, but it looks like it is clearly the best drug,” Dr. Gerding said.

C. difficile experts are also experimenting with how best to use the antibiotics they have, whether to taper them off, end with pulses of antibiotic therapy, or chase the first antibiotic with another drug, usually rifaximin or fidaxomicin. “Pulse and taper regimens are showing promise. We need more data about the tapering regimens. Chasers are looking interesting and promising, but they need much better validation and randomization,” said Dr. Gerding.

One thing that the data have clearly shown is that metronidazole is not as effective as vancomycin for treating C. difficile, which gives Dr. Gerding pause about the current guideline recommendation to use metronidazole for mild to moderate cases and treat a first recurrence with the same drug that was tried the first time. “That would mean if you treat it with metronidazole, re-treat with metronidazole,” he said. “I don't think that's a good idea any longer.”

The next round of C. difficile guidelines should offer less support for metronidazole as the drug of choice, as well as incorporate treatments developed since the last revision, he concluded.