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Two immunocompromised trial patients became infected with extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli the day after undergoing fecal microbiota transplant (FMT), researchers said, suggesting a need for stricter stool donor screening and more scrutiny of such transplants' risk-benefit balance.

"Enhanced donor screening to limit the transmission of microorganisms that could lead to adverse infectious events and continued vigilance to define the benefits and risks of FMT across different patient populations are warranted," wrote Zachariah DeFilipp, MD, and colleagues from the Massachusetts General Hospital in Boston, .

After previously receiving reports of the two cases, one of which was fatal, the FDA issued a national alert in June urging more risk awareness of and additional screening for FMT, which has proven effective for treating recurrent and refractory infections, though still considered investigational.

The patients

Enrolled in two separate FMT clinical trials, the patients both received stool from the same donor, who was screened and the stool tested according to national and institutional protocols. However, existing inventory was not retested after a 2019 FDA review prompted expansion of screening to include tests for ESBL-producing organisms.

The first patient, age 69, had liver cirrhosis related to hepatitis C infection. Over 3 weeks in March and April of 2019, he received oral stool capsules in an open-label trial of FMT for refractory hepatic encephalopathy. Adverse effects emerged 17 days after the final dose, at which point he developed a fever and cough. After failing to improve on a pneumonia antibiotic, he tested positive on blood culture for ESBL-producing E. coli and continued to improve on therapy with the beta-lactam carbapenem Merrem, which led to eventual elimination of ESBL-producing organisms from his stool.

The second patient, age 73, had therapy-related myelodysplastic syndrome. He was enrolled in a phase II trial of preemptive oral FMT before and after allogeneic hematopoietic stem-cell transplantation. Eight days after the last FMT dose, and on day 5 after stem-cell infusion, he developed a fever, chills, and altered mental status, followed by hypoxia and labored breathing. Death from severe sepsis occurred 2 days later, with blood cultures showing ESBL-producing E. coli.

All three lots of capsules from the single donor were found to harbor ESBL-producing E. coli with a similar resistance pattern to that in blood isolates from the patients. Pre-FMT stool samples from both recipients were negative for the pathogen. The same strain was also found in post-FMT specimens from several of the more than 20 other recipients of the index donor's stool.

The authors surmised that substantial overlap in bacterial species between donors and recipients may lead to underestimation of FMT-related infection risks. On the other hand, while other cases of have been reported after FMT, the benefits of FMT should be weighed against risks. "The development of defined, cultured, therapeutic microbial mixtures is an obvious and important future goal," they wrote.

According to , recognizing sentinel cases such as these is key to identifying the risks of FMT. "New hazards provide an impetus to develop improved approaches as we explore the dimensions of dysbiosis," wrote Martin J. Blaser, MD, of Rutgers University in New Brunswick, New Jersey, who was not involved in the two trials.

Noting the presence of ostensibly the same strain in other recipients, Blaser said, "The two reported cases represent the tip of the iceberg of that FMT-transmitted infection."

One problem, he pointed out, is that the risks of FMT may be identifiable only after the fact, as the two cases show, and "we often do not recognize new pathogens until after they have been transplanted to new hosts."

As the use of FMT continues to broaden beyond C. difficile treatment and new resistance mechanisms emerge, Blaser added, "the screening of microbiota transplants will need to be reevaluated and updated accordingly."

But a noted that screening FMT donors can be laborious. Zain Kassam, MD, MPH, of Finch Therapeutics in Somerville, Massachusetts, and colleagues pointed out that in evaluating donors for the non-profit stool bank , only 386 out of 15,317 original candidates were deemed suitable.