Perspective

FDA issues safety alert on fecal transplants after patient dies

Two adults with weakened immune systems who received investigational fecal microbiota transplantations developed invasive infections caused by extended-spectrum beta-lactamase-producing Escherichia coli, according to an FDA press release.

One of those individuals subsequently died.

As a result, the FDA issued a safety alert on Thursday to inform health care providers and patients of the possible risks for contracting serious infections when using FMT.

The FMT conducted in the two patients was prepared from stool obtained from the same donor, according to the release. However, according to the release, the donor stool was not tested for extended-spectrum beta-lactamase (ESBL) -producing gram-negative organisms prior to transplant.

Following transplant and the occurrence of the severe adverse events, the donor stool was tested and found to be positive for ESBL-producing E. coli identical to the organisms isolated from the two patients.

Although FMT has been shown to be safe in individuals who are obese, as well as safe and effective in children and adults with Clostridioides difficile infection, it is not an FDA-approved treatment.

Because of these two infections and subsequent death, the FDA has issued added safety requirements for any investigational use of FMT.

Donor stool must be screened for colonization with multi-drug resistant organisms (MDROs) and individuals at higher risk for colonization with MRDOs should be excluded from any FMT use.

If a donor stool tests positive for an MDRO it should be removed from future use, according to the release.

Rebiotix, a clinical-stage microbiome company that develops microbiota restoration therapies for the treatment of gastrointestinal diseases, said in a statement sent to Healio Gastroenterology and Liver Disease that the company supports stringent screening of donor stool for FMT use.

“We have always been a strong proponent of having appropriately screened donor derived microbiota products to avoid a public health problem as described in the FDA safety alert,” the statement said. “We were the first company to engage the FDA in defining a regulatory pathway for microbiota-based therapies and remain committed to working closely with the agency to continue to conduct high-quality clinical trials and stringent donor screening programs.” – by Ryan McDonald

Two adults with weakened immune systems who received investigational fecal microbiota transplantations developed invasive infections caused by extended-spectrum beta-lactamase-producing Escherichia coli, according to an FDA press release.

One of those individuals subsequently died.

As a result, the FDA issued a safety alert on Thursday to inform health care providers and patients of the possible risks for contracting serious infections when using FMT.

The FMT conducted in the two patients was prepared from stool obtained from the same donor, according to the release. However, according to the release, the donor stool was not tested for extended-spectrum beta-lactamase (ESBL) -producing gram-negative organisms prior to transplant.

Following transplant and the occurrence of the severe adverse events, the donor stool was tested and found to be positive for ESBL-producing E. coli identical to the organisms isolated from the two patients.

Although FMT has been shown to be safe in individuals who are obese, as well as safe and effective in children and adults with Clostridioides difficile infection, it is not an FDA-approved treatment.

Because of these two infections and subsequent death, the FDA has issued added safety requirements for any investigational use of FMT.

Donor stool must be screened for colonization with multi-drug resistant organisms (MDROs) and individuals at higher risk for colonization with MRDOs should be excluded from any FMT use.

If a donor stool tests positive for an MDRO it should be removed from future use, according to the release.

Rebiotix, a clinical-stage microbiome company that develops microbiota restoration therapies for the treatment of gastrointestinal diseases, said in a statement sent to Healio Gastroenterology and Liver Disease that the company supports stringent screening of donor stool for FMT use.

“We have always been a strong proponent of having appropriately screened donor derived microbiota products to avoid a public health problem as described in the FDA safety alert,” the statement said. “We were the first company to engage the FDA in defining a regulatory pathway for microbiota-based therapies and remain committed to working closely with the agency to continue to conduct high-quality clinical trials and stringent donor screening programs.” – by Ryan McDonald

    Perspective
    Jasmohan S. Bajaj

    Jasmohan S. Bajaj

    Fecal microbiota transplant is an important tool in our armamentarium, demonstrating clear clinical benefit in diseases such as Clostridioides difficile. It is also gaining importance in diseases where the standard of care is not able to improve outcomes, such as hepatic encephalopathy, on an investigational basis till now.

    The safety alert from the FDA highlights a critical piece of this procedure, which is donor selection. Prior studies have shown that a very miniscule proportion of potential donors are ultimately approved for donation due to multiple testing and interviewing strategies employed by stool banks and investigators. In fact, in multiple studies, FMT from donors that are free of MDROs actually have been shown to reduce the load of the MDROs in the recipients. However, in order to ensure this, potential donors must be extensively tested, including tests for the presence of MDROs, which did not appear to be the case for the patients that resulted in this safety alert.

    Fortunately, most providers of stool under FDA investigational new drug already test for these MDROs and will continue to do so. Specifically, the providers for our prior and upcoming FMT studies for hepatic encephalopathy check for all MDROs through stringent procedures routinely. Therefore, FMT remains a very robust means for potentially improving outcomes in selected patients and only relying on providers that extensively check for MDROs in their donors is important to make sure we “do no harm.”

    References:

    • Kazerouni A, et al. Microbiome. 2015;doi:10.1186/s40168-015-0140-3.
    • Millan B, et al. Curr Infect Dis Rep. 2017;doi:10.1007/s11908-017-0586-5.
    • Saha S, et al. Clin Microbiol Infect. 2019;doi:10.1016/j.cmi.2019.04.006.
    • Jasmohan S. Bajaj, MD
    • Division of Gastroenterology, Hepatology and Nutrition
      Virginia Commonwealth University
      McGuire VA Medical Center

    Disclosures: Bajaj reports no relevant financial disclosures.

    Perspective
    Monika Fischer

    Monika Fischer

    We do not know the details beyond what has been shared publicly, that one patient died of complications of multi-drug resistant E. coli. We also do not know what center this occurred at. However, we do know the center that had the incident screens their own donors. 

    I was quite shocked by that news.

    Indiana University Health uses biobank stool preparations from OpenBiome when we perform fecal microbiota transplantations. In fact, my team stopped performing our own donor screenings back in 2014. Every patient who receives FMT at our center is then entered into the FMT database and we regularly follow-up on those patients.

    I advise against a hospital screening its own donors. The FDA most recently suggested in a guidance that the doctor who administers the FMT should be responsible for the donor selection and screening process. They suggested the doctor should know the donor personally. This guidance, however, was never enacted because there was a large public push-back. We know that most hospitals do not have the funding or the infrastructure to run a donor program and a stool biobank safely.

    Let’s keep in mind that less than 3% of donor applicants at OpenBiome become actual stool donors. Hospitals and academic centers would not have the bandwidth to perform this level of rigorous screening.

    I will still continue to use FMT to treat patients experiencing multiply recurrent or severe C. difficile infection, but after this FDA alert, I would no longer feel comfortable screening our own donors. 

    This alert reassured me that we made the right choice to not screen stool donors and prepare the stool on-site anymore. This process needs to be done in a place where many donors are screened on a regular basis following a rigorous protocol, the stool is quarantined for at least 8 weeks and the donor rescreened before the material is released for treatment. A large biobank not only can assure safety but also is able to achieve economies of scale making FMT more cost-effective. This isn’t possible in most hospitals.

    This incident and subsequent safety alert proved that it’s not just theoretically possible to transplant a deadly infection through FMT. It can happen. It did happen. We can all learn from this.

    • Monika Fischer, MD, MS, FACG, AGAF
    • Gastroenterologist,
      Indiana University Health
      Associate professor of medicine,
      Indiana University School of Medicine

    Disclosures: Fischer reports an unpaid advisory role with OpenBiome.

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