Patient Dies After Receiving FMT Capsules Contaminated With ESBL E Coli

Fecal microbiota transplantation (FMT) has become an emerging therapy for Clostridioides difficile infection and is under evaluation for use in other conditions.

FMT has been previously studied for C diff treatment in randomized, controlled trials which have supported its safety and efficacy. The results of a clinical trial, however, highlight an important caveat: rigorous screening for Extended-Spectrum Beta-Lactamase (ESBL) Escherichia coli in donors is vital to preventing infections among patients.

The report in New England Journal of Medicine concerns cases of bacteremia developing in 2 patients who received FMT capsules containing drug resistant ESBL E coli. Both cases were linked to the same donor and of the 2 patients, 1 patient died.

In January 2019, clinicians at Massachusetts General Hospital expanded screening of donor-stool to include ESBL-producing organisms, in response to a regulatory review by the US Food and Drug Administration of a different trial. Regulators did not, however, direct clinicians to test stored materials. The FMT capsules containing drug-resistant ESBL E coli were manufactured in November 2019 and were not revisited for further screening.

Patient 1 was a 69-year old man with cirrhosis of the liver associated with hepatitis C. The patient was enrolled in an open label trial of FMT capsules to treat refractory hepatic encephalopathy. In March and April 2019, the patient received 15 capsules total, 5 times per week. The patient was also receiving rifaximin prophylaxis before, during, and following 3 weeks of FMT.

Patient 1 reported no adverse events until 17 days after the final FMT dose, when the patient developed a fever of 102.02°F. Several treatments were tried without clinical improvement, until ESBL E coli was identified in a blood culture. The patient’s antibiotic therapy was changed to a carbapenem, and the patient completed a 14-day course of meropenem inpatient therapy followed by ertapenem outpatient therapy. The patient recovered following antimicrobial therapy.

Patient 2 was a 73-year old man with myelodysplastic syndrome enrolled in a phase 2 trial to preemptively administer FMT oral capsules before and after allogeneic hematopoietic-cell transplantation. The patient received 15 FMT capsules on days 3 and 4 before hematopoietic-cell transplantation. The patient was allergic to fluroquinolones, so cefpodoxime prophylaxis was initiated before transplantation to minimize the risk of gram-negative bacteremia.

Patient 2 developed adverse symptoms 8 days after the last FMT dose, on day 5 after stem-cell infusion. The patient had a 103.46 °F fever, chills, and altered mental status. The patient was administered cefepime therapy for febrile neutropenia. The condition worsened as the patient developed hypoxia and labored breathing, and the patient was transferred to the intensive care unit for intubation and mechanical ventilation. The patient’s antibiotic regimen was also expanded to include meropenem. Despite maximum efforts, the patient died from severe sepsis 2 days later. Final results of blood cultures showed ESBL-producing E coli.

The similar resistance patterns of the 2 bacteremia prompted testing of reserve FMT capsules from the lot administered to both patients, which were maintained for possible future analysis. All 3 lots of FMT capsules from that donor were found to posses ESBL-producing E coli. Whole-genome sequencing and single-nucleotide polymorphism based analysis was used to establish genomic relatedness between samples.

The FMT capsules containing ESBL E coli were used in more than 20 recipients, all of whom were contacted and offered screening. These cases of severe illness are thus not indicative of all transmission that took place but instead indicate heightened risks for those with immunocompromised states or prior antibiotic treatments active against gut liminal bacteria.

The adverse events were reported to the FDA and to institutional review boards, the trials were halted, and the FDA subsequently mandated additional screening for those conducting FMT research under FDA supervision.

Study authors wrote that “despite the infectious complications reported here, the benefits of FMT should be balanced with the associated risks when considering treatment options…assessment of the risks and benefits of FMT research is needed, as are continuing efforts to improve donor screening to limit transmission of microorganisms that could lead to adverse infectious events.”