Breaking the cycle: New treatments for recurrent C diff offer an alternative to repeated antibiotics

Since antibiotics are the primary treatment for CDI, that cycle can repeat itself, leading to recurrence—and even more antibiotics.

McCollister said the rate of recurrence never came up during her treatment.

"I was never informed that I could actually get this again," she said. "It took me and my husband researching for ourselves to figure out that if you get this once, your likelihood of getting it again just drastically increases."

One non-antibiotic option McCollister had was fecal microbiota transplantation (FMT), a procedure in which stool from a healthy donor is transplanted into a patient after antibiotic treatment to help restore the normal gut flora. While several studies have found FMT to be effective in reducing CDI recurrence, it didn't work for McCollister. She felt great for a few days, then took a turn for the worse and ended up back in the hospital and on antibiotics again.

What ultimately cured McCollister, she said, after 18 months of dealing with rCDI, was an infusion of Zinplava (Bezlotoxumab), a human monoclonal antibody that's designed to neutralize one of the C difficile toxins that attack the lining of the colon and is given in combination with antibiotics. Approved by the Food and Drug Administration (FDA) in October 2016 for prevention of rCDI, Zinplava was the first non-antibiotic drug approved for CDI.

"I thank my lucky stars that it was available and cured me," she said.

Over the past year, two more treatments for rCDI that could help break the antibiotic/recurrence cycle have come on the market. In November 2022, the FDA approved Rebyota, a fecal microbiota-based product that is prepared from stool donated by qualified individuals and delivered via enema. It was the first FDA-approved live biotherapeutic.

"We believe this is a major breakthrough in harnessing the power of the human microbiome to address significant unmet medical needs," Ferring Pharmaceuticals President Per Falk said in a company press release.

Then, in April of this year, the FDA approved Vowst, an oral drug developed by Seres Therapeutics that contains live bacteria from human fecal matter.

The randomized controlled trials that led to the approval of the two microbiota-based drugs—which are technically considered preventives—showed that both significantly cut CDI recurrence compared with the standard-of-care antibiotic treatments or placebo and were well-tolerated.

Christian Lillis, executive director of the C diff advocacy group the Peggy Lillis Foundation, says these new non-antibiotic therapies provide "an entirely new world" of treatment options for rCDI and could end a lot of suffering, and peripheral damage, that patients like Pam McCollister have experienced if they're widely adopted.

"If we could get to the point where we have a standard-of-care that doesn't allow people to go 6 months or more of just being bounced from one antibiotic to the other…that would be ideal," Lillis said. "I think you would interrupt that cycle."

"We're hearing from both patients and physicians that they're very happy that this day has finally arrived," said Lisa von Moltke, MD, chief medical officer of Seres Therapeutics, developer of Vowst.

Finding hope in the microbiome

Both Rebyota and Vowst are based on the principle established by FMT, which aims not to treat rCDI but to restore the health of the patient's microbiome following antibiotic therapy in order to prevent more recurrences. Both medicines are given after a patient has completed a course of antibiotics for rCDI.

Vowst, formerly known as SER-109, is composed of purified Firmicutes bacterial spores derived from human fecal samples. Firmicutes is one of the two dominant phyla of bacteria in the gut and includes more than 200 bacterial species, many of them believed to be beneficial.

"Vowst is a targeted approach to microbiome replacement, going after specific kinds of bacteria that are known to be important to creating the right conditions in the intestine that would be hostile to C diff," von Moltke explained. "As soon as the C diff infection is gone and the toxin is gone, we're able to then come in and restore the microbiome and establish conditions so that C diff can't come back again."

Rebyota comprises a consortium of spore-forming and non-spore-forming bacteria, including Firmicutes and Bacteriodetes, the other dominant bacterial phyla in the gut. As with Vowst, Rebyota is screened for any enteric pathogens that could present a threat to patient safety.

Vaccines could be another option for reducing reliance on antibiotics for CDI. Scientists from Pfizer recently reported that the immune response to an investigational vaccine candidate based on modified C difficile toxins remained above baseline levels up to 48 months after the third dose in 300 recipients. And French biotech Valneva has completed phase 2 development of a C difficile vaccine candidate (VLA84) based on a similar concept, although the program is stalled at the moment.

Reducing antibiotics for C diff

Ultimately, while the new wave of microbiome-restoring preventives could help break the antibiotic/recurrence cycle and reduce the use of antibiotics for rCDI, Silber and von Moltke said antibiotics are likely always going to be needed to "knock out" the C difficile bacteria before practitioners can introduce beneficial microbes to colonize the gut and restore the proper balance.

"We need the prior antibiotic to establish the maximal colonization [for VE303]," Silber said. "You need to create a niche where these strains can come in."

"Once that [C difficile] toxin generation starts, that's enough for some people to get ill very quickly…and they can get ill so quickly that the antibiotics at that point are necessary so that you don't end up with toxic megacolon," von Moltke said.

But both companies are looking into the potential for their products to be used in initial CDI episodes. And while Vowst is approved for rCDI only, von Moltke said she can imagine a day where patients who need to be treated with broad-spectrum antibiotics for a life-threatening infection may take it to prophylactically restore the microbiome and prevent CDI from occurring in the first place—an outcome that would also reduce antibiotic use.

"That would be a great goal," she said.

McCollister, who's not had another recurrence since she received Zinplava, said she's just happy that people dealing with rCDI now have more options than she did.

"I haven't taken an antibiotic since the ones I took to get rid of C diff," she said. "And I don't know that I will ever take another one."