Fecal transplant ‘not over yet’ for C. difficile despite boom in live microbiota therapies
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Clostridioides difficile infection presents a unique treatment paradox for clinicians: Antibiotics are often both its cause and its cure.
The broad-spectrum antibiotics doled out to treat infections also radically alter the composition of the 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 in the colon.
Source: Paul Feuerstadt, MD, FACG, AGAF
As antibiotics remain the mainstay treatment for C. diff infection, clinicians are left with little choice except to prescribe more antibiotics, which leads to more recurrences of C. diff infection, which are then treated with more antibiotics. As many as 35% of patients with C. diff who respond to initial antibiotic therapy will experience a recurrence, while up to 60% of patients who experience recurrence will endure a second or third episode.
Antibiotic overuse has fueled the rise of C. diff and positioned it among the five pathogen types considered to pose an “urgent public health threat” by the CDC. In the 45 years since it was identified as the culprit behind pseudomembranous colitis, C. diff has become one of the most persistent nosocomial infections in the United States, responsible for approximately 500,000 infections and as many as 30,000 deaths each year.
“It has been a very interesting journey over the years,” Sahil Khanna, MBBS, MS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, told Healio Gastroenterology. “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 [gut] dysbiosis, but [rather] 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.”
In this escalating antibiotic arms race, the only winning move for clinicians appeared to be not to play. Abandoning the competition to develop stronger antibiotics, providers have instead turned to investigational fecal microbiota transplantation, or stool transplant, 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, most tertiary referral centers today have a provider dedicated to performing FMT, ensuring more widespread access to treatment. However, the status quo of FMT was recently shaken by FDA approvals for 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, FACG, AGAF, assistant clinical professor of medicine at Yale School of Medicine and attending gastroenterologist at PACT Gastroenterology Center, said in an interview. “We have been sprinting towards the horizon for the better part of 15 years, initially with a few simple providers regionally performing FMT, which evolved into stool banks with better access for providers, yet still single providers and individual specialty practices lacking 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.”
Healio Gastroenterology spoke with experts across the field to understand the shift in C. diff treatment, how LBPs in the pipeline might change the paradigm pioneered by FMT and potential risks for these new therapies that have yet to been explored.
Experimental Treatment or Accepted Therapy?
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.”
They added: “In its current form, FMT hovers between an accepted, widely used therapy and an innovative but experimental treatment. 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. diff and prescribed for patients with C. diff who fail to respond to standard therapies.
The recent FDA approvals of two LBPs — the whole-stool enema Rebyota (fecal microbiota, live-jslm, Ferring Pharmaceuticals) in 2022 and Vowst (fecal microbiota spores, live-brpk, Nestlé Health Science/Seres Therapeutics), the 12-capsule Firmicutes spores regimen 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 told Healio Gastroenterology. “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,” Jessica R. Allegretti, MD, MPH, medical director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, told Healio Gastroenterology. “[FMT] is still a viable therapy that we are continuing to offer for appropriate patients as long as the FDA allows us to.
“Antibiotics are still the only treatment option we have at our disposable 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, FACG, 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 infection or cancer patients receiving active cytotoxic therapy.
“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, which involved the death of a patient, the FDA released a safety alert recommending that donor stool be tested for multidrug-resistant organisms. Another FDA safety alert was issued in March 2020, after six patients who had received a stool company’s 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 detection of infectious organisms in traditional FMT — practices that have now been applied to FDA-approved LBPs as well.
Exploring Long-Term, Theoretical Risks
Despite the success of FMT for treatment of recurrent C. diff, 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, it 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 Gastroenterology. “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 causing obesity or metabolic syndrome.”
Reports of FMT recipients later developing chronic disorders, such as rheumatoid arthritis, Sjogren’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.
“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 AGA launched the FMT National Registry in 2016. The registry will assess short-term and long-term risks of FMT in 4,000 patients for 10 years after transplant — thus far, 700 patients have been enrolled.
“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,” Kelly, co-principal investigator of the registry, said. As of this report, no significant safety signals have been observed.
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.
Patient Access, Cost Concerns
The FDA approval of Vowst and Rebyota represents a significant step forward for FMT, but Kelly noted that this approval “may change a lot of things.”
With backing by the FDA, these LBPs can be included on insurance company formularies and have a wider distribution among patients; for physicians, the FDA approval for LBPs is a vote of confidence that their patients are receiving a vetted, replicable product of a standardized process — and a more expensive product as well.
The costs associated with FDA-approved LBPs are unlikely to make them economical options for patients or payers, Khoruts noted. 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 ACG. With a comparable treatment success rate, it may be difficult to justify the expenditure.
“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 there will be 20% to 30% of patients who 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 one of, if not the only, centralized stool banks in the U.S. and is 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, and 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 application with the FDA, any patient that 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 soon, which will determine if the nonprofit can continue to manufacture and distribute donor stool under a modified IND application, given that there are now FDA-approved therapies for C. diff prevention.
Beyond C. difficile Infection
According to Allegretti, FMT has been “lifesaving,” and has significantly curbed morbidity and mortality among patients who have been unable to break out of the cycle of recurrent C. diff infection.
“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 IBD with more data currently available for ulcerative colitis, Kelly said. Thus far, randomized controlled trials have shown FMT has some benefit in UC. Additionally, FMT is being investigated in IBS and liver disorders such as nonalcoholic fatty liver disease, hepatic encephalopathy and graft-vs-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 in non-GI conditions, including bipolar disease, food allergies, cancer, obesity and metabolic disease. Kelly noted she is interested in seeing how it is being explored in autism spectrum disorder 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, director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, can be reached at jallegretti@bwh.harvard.edu.
- Paul Feuerstadt, MD, FACG, AGAF, assistant clinical professor of medicine at Yale School of Medicine and attending gastroenterologist at PACT Gastroenterology Center, can be reached at pfeuerstadt@gastrocenter.org.
- Colleen R. Kelly, MD, FACG, a gastroenterologist at Brigham and Women’s Hospital, can be reached at ckelly42@bwh.harvard.edu.
- Sahil Khanna, MBBS, MS, a gastroenterologist and hepatologist at the Mayo Clinic in Rochester, can be reached at khanna.sahil@mayo.edu.
- Alexander Khoruts, MD, director of the University of Minnesota Microbiota Therapeutics Program, can be reached at khoru001@umn.edu.
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