October 30, 2019
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After death of FMT recipient, a warning about screening

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In June, the FDA issued a safety alert after two patients who had received investigational fecal microbiota transplants in two separate clinical trials developed invasive infections caused by drug-resistant Escherichia coli, and one died.

In a report summarizing the two cases that was published today in The New England Journal of Medicine, researchers said the stool donor for both transplants had no risk factors that would have indicated they carried multidrug-resistant organisms, and they donated stool before the trials required testing for extended-spectrum beta-lactamase (ESBL)-producing organisms.

“This is a cautionary tale that the screening process for FMT is something that is evolving over time. We are learning from this,” Elizabeth L. Hohmann, MD, physician director of the Partners Human Research Committee — the Intuitional Review Board of Partners HealthCare — and staff physician in the infectious diseases division at Massachusetts General Hospital, told Infectious Disease News.

Hohmann and colleagues described FMT as a novel approach to treat recurrent or refractory Clostridioides difficile infection. They said there are over 300 studies listed on ClinicalTrials.gov investigating FMT as a treatment for gastrointestinal, neurologic, behavioral and metabolic conditions. The procedure is associated with “rare inflammatory, infectious, and procedural complications,” but placebo-controlled trials have not included serious adverse events or infection transmission, the researchers said.

Hohmann and colleagues linked the two patients and the stool donor through whole genome sequencing. In a related editorial, Martin J. Blaser, MD, director of the Center for Advanced Biotechnology and Medicine, the Henry Rutgers Chair of the Human Microbiome and professor of medicine and microbiology at the Robert Wood Johnson Medical School, noted that Hohmann and colleagues also detected the same strain of EBSL-producing E. coli from other patients who received FMT capsules from the donor.

“The two reported cases represent the tip the iceberg of that FMT-transmitted infection,” he wrote.

According to the report, the researchers expanded donor screening to include EBSL-producing organisms in January 2019, following an FDA review of a different trial, but FMT capsules developed before this change were not similarly tested.

The first patient was a 69-year-old man with cirrhosis of the liver related to hepatitis C virus infection. The second patient — the one who died — was a 73-year-old man with therapy-related myelodysplastic syndrome. They both received FMT capsules developed in November 2018.

The first patient was enrolled in a trial to treat refractory hepatic encephalopathy and received 15 FMT capsules five times over a 3-week period between March and April 2019. No adverse events were reported until 17 days after he received the final FMT dose, Hohmann and colleagues explained. He received a 14-day course of meropenem, followed by ertapenem. The researchers reported that his condition remained stable, and a follow-up stool sample was negative for ESBL-producing organisms.

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The second patient was enrolled in a trial and received FMT capsules before and after allogenic hematopoietic cell transplantation. On days 3 and 4 before the transplant, he received 15 FMT capsules. On day 5 following transplant surgery, the patient developed a fever, chills and an altered mental state, the researchers reported. He was immediately started on cefepime therapy and was later transferred to the ICU following signs of hypoxia and labored breathing. Meropenem was added to his antibiotic regimen, but his condition worsened and he died 2 days later.

Blaser said the findings will aid clinicians in identifying the risks conferred by FMT.

“New hazards provide an impetus to develop improved approaches as we explore the clinical dimensions of dysbiosis,” he wrote.

Hohmann noted that FMT is an “active area of research.”

“There are many areas where research needs to go, and is going, for FMT,” she said. “We need to think about the risks and benefits of it and how to actively manipulate people’s microbiomes because I think it is an interesting and fascinating target to improve health.” – by Marley Ghizzone

Disclosures: Blaser reports receiving personal fees from Dupont and P&G, and stock options from Elysium Health, ProdermIQ, Pylem and Seed. Hohmann reports receiving grants from Finch Therapeutics, Kaleido and Seres Therapeutics, and personal fees from Artugen Therapeutics outside of the submitted work. Please see the study for all other authors’ relevant financial disclosures.