December 19, 2023
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Clostridioides difficile infection presents a unique treatment paradox for clinicians: Antibiotics are often both its cause and its cure.
Broad-spectrum antibiotics used to treat infections radically alter the composition of a patient’s microbiota, wiping out a significant portion of the bacterial community and upsetting the natural balance of gut flora. Without competition from healthy bacteria, the uniquely antibiotic-resistant C. difficile is finally able to flourish.
Two new FDA-approved products mean more patients will have access to C. difficile treatments that can restore their microbiome, according to Paul Feuerstadt, MD.
Source: Paul Feuerstadt, MD
Because antibiotics remain the mainstay treatment for C. difficile infection (CDI), clinicians are left with little choice except to prescribe more antibiotics, which leads to more recurrences of CDI, which are then treated with more antibiotics. As many as 35% of patients with CDI who respond to initial antibiotic therapy will experience a recurrence, and up to 60% of patients who experience recurrence will endure a second or third episode.
Antibiotic overuse has fueled the rise of C. difficile and positioned it among the five pathogens considered urgent public health threats by the CDC. It has become one of the most persistent nosocomial infections in the United States, responsible for approximately 500,000 infections each year. Around 9% of patients aged older than 65 years who develop health care-associated CDI die within 1 month.
“It has been a very interesting journey over the years,” Sahil Khanna, MBBS, MS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, Minnesota, told Healio | Infectious Disease News. “We knew that C. difficile infection is caused by an altered gut microbiome because use of antibiotics can lead to infection. However, we were not correcting the underlying dysbiosis but using more antibiotics, hoping they will continue to cure the infection. Over the last 10 to 15 years now, we have been able to correct the underlying dysbiosis.”
Sahil Khanna
Abandoning the competition to develop stronger antibiotics, providers have instead turned to investigational fecal microbiota transplantation (FMT), in which stool is collected from a healthy individual and their fecal bacteria and microbes are transferred into an infected patient to replenish healthy gut microbiota.
A rarity 20 years ago, there is now more widespread access to FMT. Additionally, in a big advancement in the field, the FDA approved two live biotherapeutic products (LBPs) — standardized agents similarly intended to restore an infected patient’s microbiome following antibiotics to break the cycle of recurrence.
“The future is here,” Paul Feuerstadt, MD, assistant clinical professor of medicine at Yale School of Medicine and attending gastroenterologist at PACT Gastroenterology Center in Hamden, Connecticut, said in an interview. “We have been sprinting toward the horizon for the better part of 15 years, initially with a few providers regionally performing FMT, which evolved into stool banks with better access for providers, yet still single providers and individual specialty practices lack the opportunity to perform this procedure easily. Now, there are two FDA-approved products to really grant much better access to this treatment for patients and providers.”
Story of FMT ‘not over yet’
FMT and the LBPs “have challenged established drug development paradigms, including traditional discovery pathways, the regulatory framework and the science required for mechanistic understanding,” Alexander Khoruts, MD, director of the University of Minnesota Microbiota Therapeutics Program, and colleagues wrote in a review in The American Journal of Gastroenterology. “Importantly, LBP must not be viewed in a one-size-fits-all paradigm.”
Alexander Khoruts
Currently, “FMT hovers between an accepted, widely used therapy and an innovative but experimental treatment,” they continued. “Despite robust clinical data supporting its efficacy for recurrent and refractory C. difficile, FMT is still considered investigational in many countries, including the United States.”
As of now, the FDA considers traditional FMT both a drug and a biologic. It has not been granted FDA approval but instead exists under a discretionary enforcement policy with investigational new drug requirements, which allows it to be used in clinical trials for C. difficile and prescribed for patients with C. difficile who fail to respond to standard therapies.
The FDA approvals of two LBPs — Rebyota in 2022 and Vowst in 2023 — appear to be the next step in FMT evolution. Building on the groundwork laid by FMT, these products add a layer of standardization, with consistent screening procedures that have been difficult to apply in current fecal transplant practice.
“FMT screens the donor and the donor stool for various infections that can be transmitted through the microbiota, but does not necessarily test the groups of microorganisms that are being administered in the treatment,” Feuerstadt said. “LBPs, on the other hand, screen the donors, screen the donor stools and include a standard consortium or group of microorganisms that is their proprietary mix, so there is quality control on the safety and consistency on the treatment.”
However, higher levels of screening for LBPs do not necessarily ensure complete patient safety. The FDA noted in its 2023 approval that Vowst still has the potential to introduce infectious agents or allergens.
“It is great that we finally have FDA-approved options, but the story on traditional FMT is not over yet. It is still a viable therapy that we are continuing to offer for appropriate patients as long as the FDA allows us to,” Jessica R. Allegretti, MD, MPH, medical director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston and associate professor of medicine at Harvard Medical School, told Healio | Infectious Disease News.
Jessica R. Allegretti
“Antibiotics are still the only treatment option we have at our disposal for recurrent C. diff,” she noted. “However, FMT has proven to be a safe and effective preventative strategy.”
Short-term risks
Although the overall safety of FMT is well established infection transmission remains a key concern.
Colleen R. Kelly, MD, a gastroenterologist at Brigham and Women’s Hospital, urged providers to be cautious when using FMT in severely immunocompromised patients, including those with neutropenia or advanced HIV, or patients with cancer receiving active cytotoxic therapy.
Colleen R. Kelly
“Those are the patients you want to be really careful of when thinking about risks vs. benefits, and maybe even hold off on FMT until their immunocompromised situation stabilizes,” she said.
The mode of traditional FMT delivery may also put patients at risk for complications, including procedural risks from sedation or perforation during colonoscopy. She noted there is also a risk for regurgitation of donor stool following an upper GI infusion, which can lead to pneumonia.
“Fecal microbiota transplantation seems to be incredibly safe,” Feuerstadt said. “We have been involved in it for the better part of 15 years, and even with widespread usage, there have only been a couple of concerning safety signals.”
Following a 2019 report of FMT-associated cases of extended-spectrum, beta-lactamase-producing Escherichia coli bacteremia, including one death, the FDA released a safety alert recommending that donor stool be tested for multidrug-resistant organisms. The FDA issued another safety alert in March 2020 after six patients who had received an FMT product later developed enteropathogenic E. coli and Shiga toxin-producing E. coli.
Feuerstadt noted that, as these incidents arose, screening practices for donor stool were quickly modified to enhance the detection of infectious organisms in traditional FMT — practices that have now been applied to FDA-approved LBPs as well.
Long-term, theoretical risks
Despite the success of FMT for the treatment of recurrent C. difficile, the potential long-term consequences of altering a patient’s gut microbiota remain unknown. Given the number of chronic diseases that have been linked to the gut microbiota, Kelly posed the question: “Could [FMT] put patients at higher risk for a disease that they may not have otherwise developed?”
Mounting research has tied microbiota dysbiosis to the development of cardiovascular diseases, cancer, respiratory diseases, diabetes, inflammatory bowel disease, brain disorders, chronic kidney diseases and liver diseases. Although FMT attempts to restore microbiota imbalances caused by antibiotics, the gut remains a fragile ecosystem and largely uncharted territory.
“With respect to FMT in whatever version, we are manipulating a part of the body,” Khoruts told Healio | Infectious Disease News. “There is still potential for transmitting infectious disease or antibiotic-resistant organisms. That is being mitigated with testing; nevertheless, the risk is not eliminated. We should be discussing the potential of transmitting cancer-causing bacteria or [bacteria that can cause] obesity or metabolic syndrome.”
Reports of FMT recipients later developing chronic disorders — such as rheumatoid arthritis, Sjögren’s syndrome, idiopathic thrombocytopenic purpura, peripheral neuropathy and obesity — continue to circulate, but there is currently no evidence to indicate there is a causal relationship between FMT and these types of conditions, according to experts.
“There is still interest in understanding the long-term effects of FMT,” Allegretti said. “Are you potentially putting the recipient at risk for other microbiome-mediated diseases?”
To investigate long-term safety concerns of FMT, including irritable bowel syndrome, obesity, diabetes and Crohn’s disease, the American Gastroenterological Association launched the FMT National Registry in 2016. The registry will assess short-term and long-term risks of FMT among 4,000 patients for 10 years after transplant.
“The purpose of the registry is to look for those long-term things that we might not see coming unless we are looking for them,” said Kelly, who is co-principal investigator of the registry.
Allegretti noted that she maintains her own personal database of FMT patients, which includes approximately 10 years of data, and has not observed any major safety signals related to FMT.
Data derived from CDC.
Patient access, cost concerns
The FDA approvals of Vowst and Rebyota mean they can be included on insurance company formularies and have a wider distribution among patients. For physicians, FDA approval of LBPs is a vote of confidence that patients are receiving a vetted, replicable product of a standardized process — and a more expensive one, as well.
The costs associated with FDA-approved LBPs are unlikely to make them economical options for patients or payers, Khoruts said. The price per course of Vowst therapy is approximately $17,500, while Rebyota is nearly $9,500. FMT, on the other hand, has a sticker price of $1,500, according to the American College of Gastroenterology.
“It is not clear where the [commercial products] are going to fit and how the different payer plans are going to embrace these therapies,” Khoruts said. “They also have failure rates —placebo-controlled trials suggest 20% to 30% of patients are still going to fail these products. What is going to happen to those people?”
In addition to costs, the FDA-approved products may require prior authorizations, depending on insurance coverage, which could further affect patient access, Khanna noted.
“When anything new gets approved, there is an evolving story on how it will be used,” Allegretti said. “What will payer contracts look like and how high will copays be? Will patients be able to afford it and what will the workflows look like? It is important to have [FMT] as a reasonable option for patients right now as we sort out the workflows of the newly approved LBPs. It is nice to have a third option to offer those patients; there should be something for everybody.”
The arrival of FDA-approved LBPs has also sparked widespread concern about whether stool banks like OpenBiome will remain open to provide stool for FMT procedures. As the first nonprofit public stool bank, OpenBiome remains the main source of FMT materials.
“It is critical that a nonprofit option like OpenBiome, which has been a major distributor of FMT products over the past decade, remains viable,” Khoruts said. “Otherwise, we are not going to make a dent in C. diff infection; too many people will be falling through the cracks.”
Compared with the LBPs, OpenBiome’s FMT product costs only $1,695 per unit, according to Justin Chen, PhD, director of external affairs at OpenBiome. To date, the nonprofit has provided nearly 68,000 preparations to more than 1,300 hospitals and clinics, he noted. In the past 12 months alone, nearly 5,000 FMT preparations were provided to 560 health care sites.
“We don’t fully know where OpenBiome, with regards to C. diff infection, is going to rest in the long term because OpenBiome is still an investigational product,” Feuerstadt said. “[Since] they have an investigational new drug (IND) application with the FDA, any patient who receives [their product] would need to sign an informed consent form that they are receiving an investigational product.”
Kelly noted that OpenBiome is set to have a meeting with the FDA, which will determine if it can continue to manufacture and distribute donor stool under a modified IND application, given that there are now FDA-approved therapies for C. difficile prevention.
Possibilities beyond CDI
According to Allegretti, FMT has been “lifesaving,” significantly curbing morbidity and mortality among patients who have been unable to break out of the cycle of recurrent CDI.
“Once a patient has experienced their third episode or second recurrence of C. diff infection, you really should be utilizing FMT or an LBP to prevent subsequent recurrences,” she said.
“It has been very successful,” Khanna added. “There have been some roadblocks or kinks in the way, but we have seen that with FMT, you can reduce the rate of recurrences to 10% or less from 50% to 60% — it has changed people’s lives.”
FMT is currently being investigated in inflammatory bowel disease, with more data currently available for ulcerative colitis, Kelly said. Thus far, randomized controlled trials have shown FMT has some benefit in ulcerative colitis. Additionally, FMT is being investigated in irritable bowel syndrome and liver disorders such as nonalcoholic fatty liver disease, hepatic encephalopathy and graft-versus-host disease.
“It is not just GI conditions,” Khoruts said. “Given the active investigations exploring the role of the gut microbiome in so many diseases, it is almost difficult to think where [FMT] is not being considered.”
He added: “The change in the paradigm in medicine is that we consider the gut microbiome to be integral to human physiology and play a role in many disease processes. It becomes a therapeutic target, whereas in the past it was largely ignored, and physicians prescribed antibiotics with impunity, not really thinking about the potential harm they could be doing to that part of the body.”
FMT is also being explored for non-GI conditions, including bipolar disease, food allergies, cancer, obesity and metabolic disease. Kelly said she is interested in seeing how it is being explored in autism in children.
“There have been a whole host of clinical trials looking at the utility of microbiome therapeutics, and I do not believe that FMT is an end-all be-all cure for everything,” Allegretti said. “It has really allowed us to understand how the microbiome is pathogenic in many of these diseases and allowed for the development of more precision-based therapeutics.”
Feuerstadt said his hope is that “with more widespread access to the sequencing processes that we need to understand the microbiota in other diseases, we can develop products that will supplement or restore those deficiencies and develop live biotherapeutic products for those respective disease states.”
The hope and expectation with the rapid approval of Rebyota and Vowst is there will be a more expedited process for other treatments coming to the market where there are signals of efficacy, Feuerstadt said.
“In the future, LBPs for the treatment of C. diff infection will probably include earlier usage and greater access for patients,” he said. “It should not be something special anymore. It should be something that all patients have access to.”
- References:
- Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridioides difficile infection not responsive to standard therapies. https://www.federalregister.gov/documents/2022/11/29/2022-26000/enforcement-policy-regarding-investigational-new-drug-requirements-for-use-of-fecal-microbiota-for. Published Nov. 29, 2022. Accessed Aug. 28, 2023.
- Fecal microbiota transplantation national registry. https://gastro.org/research-and-awards/registries-and-studies/fecal-microbiota-transplantation-national-registry/. Accessed Aug. 22, 2023.
- Fecal microbiota for transplantation: Safety alert – risk of serious adverse events likely due to transmission of pathogenic organisms. https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission. Published April 7, 2020. Accessed Sept. 17, 2023.
- Feuerstadt P, et al. BMC Infect Dis. 2023;doi:10.1186/s12879-023-08096-0.
- Guh AY, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1910215.
- Gulati AS, et al. Am J Gastroenterol. 2023;doi:10.14309/ajg.0000000000002167.
- Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse. Published June 13, 2019. Accessed Sept. 17, 2023.
- Wang J, et al. J Formos Med Assoc. 2019;doi:10.1016/j.jfma.2018.08.011.
- For more information:
- Jessica R. Allegretti, MD, MPH, can be reached at [email protected].
- Paul Feuerstadt, MD, can be reached at [email protected].
- Colleen R. Kelly, MD, can be reached at [email protected].
- Sahil Khanna, MBBS, MS, can be reached at [email protected].
- Alexander Khoruts, MD, can be reached at [email protected].
Click here to read the Guest Editorial “FMT future ‘still being written,’ ideally with more options for recurrent C. difficile.”
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Sources/Disclosures
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Source:
Healio Interviews
Disclosures:
Allegretti reports consulting for Ferring Pharmaceuticals and Seres Therapeutics. Feuerstadt reports financial relationships with Ferring Pharmaceuticals, Regeneron Pharmaceuticals, Seres Therapeutics and Takeda Pharmaceuticals. Khanna reports receiving research support from Ferring Pharmaceuticals, Finch Therapeutics, Pfizer, Rebiotix (a Ferring Company), Seres Therapeutics and Vedanta Biosciences and consulting for Immuron, Niche, ProbioTech and Takeda. Kelly and Khoruts report no relevant financial disclosures.
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