These are exciting times in Clostridioides difficile treatment. “The field has really evolved from [where it started], taking poop from anybody and giving it to people,” said Robert Orenstein, DO, an infectious disease specialist, researcher, and professor at Mayo Clinic Arizona in Phoenix.
That practice, known more formally as fecal microbiota transplant (FMT), was an exciting state-of-the-art development for preventing C. diff recurrence a decade ago, noted Paul Feuerstadt, MD, a gastroenterologist, researcher, and assistant professor at Yale University in New Haven, Conn.
“It wasn't widely adopted until the last five to seven years. But the methodologies behind this were very, very variable,” he said. “And the literature around it was very variable.”
Although research had shown that FMT worked better than any other therapy for recurrent C. difficile, it has generally only been available at academic centers, under an FDA “enforcement discretion” policy and accompanied by warnings about potential risks, most recently transmission of monkeypox.
“It has been a very messy process,” said Todd Lee, MD, FACP, a researcher, infectious disease specialist, and associate professor at McGill University in Quebec, Canada. “A lot of places don't even have access. … In Canada, at the beginning, the only way to do a fecal transplant was to do it yourself at home. Unfortunately, in some places it is still like that.”
Physicians, and pharma companies, are hopeful that this is all about to change. In November 2022, the FDA approved a commercial fecal microbiota product, Rebyota, for prevention of C. difficile recurrence for the first time. Another product, currently called SER-109, goes before the agency for review in April.
Experts recently offered their perspectives on how these developments could affect C. difficile care. They also threw in a few top tips for hospitalists.
The new treatment
Dr. Feuerstadt was involved in much of the preapproval research on Rebyota (and he reports payments from manufacturer Ferring Pharmaceuticals). That includes phase 3 trial results, published by Drugs in October 2022, that found a treatment success rate of 70.6% in patients with C. difficile recurrence after standard-of-care antibiotic treatment, compared to 57.5% with placebo.
“This is a really significant step forward. … The microbiota restoration that we did previously, myself included, was very rudimentary,” Dr. Feuerstadt said. “This is a product that goes through cryopreservation. There's a minimum of 15 billion colony-forming units … It's filtered, with much, much wider screening of both the samples but also of the donors.”
The therapy also differs from past options in its administration, which is rectal. “It's basically an enema, but easier to do than an enema. … It takes 15 to 20 minutes,” said Dr. Orenstein, who has also studied the new treatment and serves on the manufacturer's advisory board.
Some experts are doubtful they'll find it so easy. “It kind of gives me the heebie-jeebies to think about setting up [this treatment for] a typical C. diff patient, who is somebody in their 70s, sometimes 80s, who was wheeled into the appointment by their 60-year-old daughter—this is a person who I have a hard time getting on an exam table,” said Elizabeth Hohmann, MD, a researcher, infectious disease specialist, and associate professor at Massachusetts General Hospital in Boston.
It's hard to know how clinicians will adopt this new option, given the novelty of the delivery method, according to Byron Vaughn, MD, a researcher, gastroenterologist, and associate professor at the University of Minnesota in Minneapolis.
“Right now, the vast majority of FMTs being performed in America are either capsules or colonoscopic administration,” he said. “The people that are going to adopt this early on are probably the same centers that have been heavily involved in FMT.”
Dr. Orenstein hopes that use of the new treatment will eventually broaden. “The goal was to take this out of the hands of specialists and allow primary providers to treat their patients,” he said.
The experts all agreed that the biggest determinants of uptake will be cost and coverage. Rebyota has been priced at $9,000 per treatment, and it's yet to be seen how Medicare and other payers will respond. “I worry about Medicare patients that may not be able to get access and are probably the ones who might most need access to it,” said Dr. Orenstein.
“We're not sure right now what the insurance coverage is going to look like,” said Dr. Feuerstadt. “We certainly know that, in the models that consider recurrent C. difficile and hospitalizations associated with it and frequency of sepsis, … if you treated it appropriately upfront you can save a lot of money over the long term.”
Dr. Vaughn has studied the cost-effectiveness of the old treatment methods. “In general, FMT is a cost-effective strategy,” he said, adding that $9,000 sounds “a little expensive, particularly given that we know enema preparations of FMT may be less effective than capsules or colonoscopic administration.”
In the works
Price is a total unknown for the expected competitor for Rebyota, SER-109, which is being developed by Seres Therapeutics.
Data on this potential therapy were published in the New England Journal of Medicine in January 2022. The manufacturer's phase 3 trial, on which Dr. Feuerstadt was the lead author, found C. difficile recurrence rates of 12% in patients randomized to SER-109, compared to 40% on placebo.
Like Rebyota, SER-109 is derived from stool, but it comes as oral capsules, dosed four a day for three days. “It's basically a small cocktail of residual organisms that are left after the stool is incubated with an alcohol product to kill off a lot of entities like viruses and vegetative bacteria,” said Dr. Hohmann, who did early research on the drug and has reported payments from Seres.
Ideally, patients and physicians dealing with recurrent C. difficile will soon be able to choose the treatment method they prefer, but the reality is more likely to be directed by insurance coverage decisions, according to Dr. Feuerstadt.
“The best treatment will be the one that patients can have access to,” he said. “It will be super exciting if we have two microbiota restoration therapies approved within six months. The more options patients have, the more likely they are to gain access to treatment.”
The experts hope that even more options will be forthcoming within the next few years. “The holy grail, of course, is a cultured product that does not come directly from human stool, further decreasing risks to recipients,” noted Dr. Hohmann.
Dr. Orenstein agreed, offering the analogy of digitalis, which was first taken directly from the plant to treat cardiac conditions before scientists figured out how to synthesize it out of chemicals. “The field is just going to keep moving, from whole poop to more refined poop to grown microbes to probably figuring out what it is the microbes make,” he said.
Synthesized versions of microbiota therapy are currently being tested, the experts reported. These would offer the significant advantage of eliminating any concern about infection risks or the ethics of using donor stool. (The manufacturers of the current products pay their donors for stool, which Dr. Vaughn noted is a concept that hasn't been widely considered by medical ethicists.)
Assuming the synthetic versions work out, they will likely replace their precursors, Rebyota and SER-109, speculated Dr. Orenstein. “I don't think these products are going to be around for that long,” he said.
The first-line therapy for C. difficile remains antibiotics (see sidebar), and that's probably the component of care hospitalists are most likely to handle, the experts said. The new therapies come afterward, but it's useful for all clinicians to know when they're appropriate.
“It's important to realize that microbiota restoration therapy such as Rebyota or SER-109, if it gets approved, needs to be given after the antimicrobial treatment is done for C. difficile. If you give it at the same time, the antimicrobials that are used to treat C. difficile will alter the microbiota,” said Dr. Feuerstadt.
Hospitalists play a key role in connecting patients with these treatments for recurrence, according to the experts.
“Getting the right diagnosis is by far the most important part of C. diff management. One of the reasons I've seen FMT trials fail is because we did not distinguish people colonized with C. diff from those truly infected,” said Dr. Vaughn. “We have probably developed an overreliance on PCR testing alone. This really impacts treatment, because if you diagnose C. diff in a patient who has another cause of diarrhea, you're going to go down a path that's going to prolong hospitalization and delay the underlying diagnosis.”
There are many reasons why a hospital patient may have diarrhea, he noted, and colonization with C. difficile is not rare.
Dr. Orenstein agreed. “In high-probability patients, a PCR is an excellent test,” he said. “In the intermediate- to low-probability patients, you need to make sure that they have the appropriate symptoms and you do a toxin-based assay.”
After a definitive diagnosis of C. diff is made, then consider whether patients might be candidates for the new therapies, and if so, refer them for treatment or prevention.
“It's important for [hospitalists] to identify risk factors for recurrence—the demographic risk factors, the medication exposure risk factors, the environmental risk factors—to predict who potentially would be at greatest risk and to predict who would benefit from microbiota supplementation,” Dr. Feuerstadt said.
If all goes according to plan, these efforts should reward hospitalists with fewer C. difficile cases. “My hope is that we have a conversation in five years where we're saying ‘Look at how C. diff recurrence has decreased,’” said Dr. Feuerstadt.