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

C difficile bacteria

CDC / Jennifer Oosthuizen

It's no secret that antibiotics are one of the foundations of modern medicine.

Since penicillin was first introduced in the early 1940s, antibiotics have turned once-deadly infections into easily treatable conditions, made surgery and childbirth safer, enabled cancer patients to withstand immune system–sapping chemotherapy, and rendered organ transplants much less risky.

But antibiotics don't come without their own risks. Just ask Pamela McCollister.

In June 2017, McCollister was given clindamycin for 40 days to prevent a potential infection of a surgical wound that refused to close following back surgery. The wound never became infected, but what resulted was much worse.

In September of that year, McCollister began experiencing pain around the incision, cramping in her lower abdomen, fever, and diarrhea. After a trip to her primary care provider and then to the emergency department, she was diagnosed with what would be the first of five episodes of recurrent Clostridioides difficile infection (rCDI), four of which required hospitalization and more antibiotics. She became septic during each of her hospitalizations.

There were moments when she didn't think she was going to survive.

"I took every antibiotic that there is to combat C diff, and none of them worked," McCollister told CIDRAP News. "And it threw me so low emotionally that I'd given up…I was just ready to be done."

The cycle of antibiotic treatment and recurrence

Pam McCollister
Photo courtesy of Pam McCollister

McCollister is among the tens of thousands of people who suffer from rCDI, a common healthcare-associated infection that causes severe diarrhea and inflammation of the colon. According to the Centers for Disease Control and Prevention, C difficile bacteria are responsible for nearly half a million infections and 29,000 deaths in the United States each year.

While the public has become more aware of CDI in recent years as incidence has increased, what hasn't gained as much attention is the high rate of recurrence. As many as 35% of patients who initially respond to antibiotic therapy (the standard treatment for CDI) experience a recurrence, and the risk of subsequent recurrence goes up with each case. Up to 65% of people who have a recurrence may experience a second or third episode.

A primary risk factor for CDI, and subsequent recurrence, is antibiotics. C difficile bacteria are considered a normal part of the human gut microbiome, but their growth is suppressed by the thousands of other bacterial species in the gut. When a patient takes antibiotics for an infection, particularly broad-spectrum antibiotics, the drugs target not only the infecting bacteria but also the beneficial bacteria in the gut, creating an environment whereby C difficile, now free of competing microbes, can flourish and release toxins in the colon that cause diarrhea.

I took every antibiotic that there is to combat C diff, and none of them worked.

Pam McCollister

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.

Fecal microbiota pill
TopMicrobialStock / iStock

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.

The patient and physician communities have said that prevention of recurrence is the greatest unmet medical need in this area.

Jeffrey Silber, MD, Vedanta Biosciences

Both treatments are essentially a standardized version of FMT, which isn't approved by the FDA but is recommended by several medical societies for treating patients who've had two or more recurrences and failed antibiotic treatment. While it didn't work for Pam McCollister, FMT has been a welcome alternative to antibiotics for many rCDI patients. At least 10,000 FMT procedures for rCDI using screened stool from healthy donors are performed each year.

"The patient and physician communities have said that prevention of recurrence is the greatest unmet medical need in this area," said Jeffrey Silber, MD, chief medical officer of Vedanta Biosciences, which is developing another microbiota-based therapy for rCDI. "I think the spread of fecal transplants, despite not being officially FDA approved, really showed just how much the community wanted and needed an alternative."

Gut microbione
Donny Bliss, NIH / Flickr CC

But FMT has posed regulatory problems for the FDA, which considers human stool more a drug than human tissue and has argued that FMT hasn't been fully evaluated for safety and efficacy in randomized controlled trials.

While the procedure is considered safe, some patients have become infected by pathogens introduced through FMT. In March 2020, the FDA issued a safety alert after six patients were infected with diarrhea-causing Escherichia coli infections following FMT.

Lillis, while noting that he doesn't want FMT to be taken away as an option, said having standardized, approved products is a step forward.

"Having FDA-approved treatments where we know exactly what people are getting and it's replicable, that is obviously ideal," he said.

More non-antibiotic options for recurrent C diff could soon be on the way.

Vedanta's candidate for rCDI, while also based on the proof-of-concept established by FMT, doesn't use any human fecal matter. VE303, as it's currently known, is a defined consortium of eight non-toxigenic, non-pathogenic commensal strains of Clostridia bacteria, grown from clonal cell banks though bacterial fermentation. The strains were selected by mining the databases from FMT research to determine which species were associated with a beneficial effect and then whittling the results down to the essential species, Silber explained.

"They're really more akin to monoclonal antibodies in the way they're developed," he said.

The results of a phase 2 trial, published in April in JAMA, showed that CDI recurrence occurred in only 13.8% of patients who received a high dose of VE303 over 14 days, compared with 45.5% of those who received placebo. Silber noted that all the recurrences occurred by day 11, when the drug was still being administered.

"From day 11 to the 8-week primary time point, we had zero cases in our high-dose group," he said.

The company, which recently received an investment from the AMR Action Fund to support the development of VE303, is now preparing for a phase 3 trial that will further evaluate its safety and efficacy.

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.

Christian Lillis, Peggy Lillis Foundation

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."

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