Fecal Transplant Transmits Fatal Drug-Resistant E coli Infection

Ricki Lewis, PhD

October 31, 2019

Two patients who received fecal microbiota transplant (FMT) in clinical trials contracted extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli bacteremia, and one of them died, according to a report published online October 5 in the New England Journal of Medicine.

FMT introduces stool from a healthy individual to a patient who has a dysbiosis ― a condition that stems from an altered microbiome. More than 10,000 patients receive FMTs in the United States annually to treat Clostridioides difficile infection, and more than 300 clinical trials are pursuing use for other dysbioses.

The first recorded use of FMT was in fourth-century China. The physician Ge Hong used it to treat diarrhea and food poisoning. In diverse times and places, feces have been delivered as "yellow soup" to humans and animals (especially cattle). German soldiers reportedly infused camel feces to treat bacterial diarrhea in soldiers during the First World War.

In 2018, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America updated clinical practice guidelines from 2010 to include FMT to treat new C difficile infections in adults. In 2013, the US Food and Drug Administration (FDA) granted an enforcement discretion ruling that permitted physicians to provide FMT for recurrent or refractory C difficile infection without filing the standard investigational new drug application.

Accounts of do-it-yourself FMT have appeared, often prominently, in the news media.

The clinical trials that led to FDA approval did not report any serious adverse events or the transmission of infection. However, four case reports describe gram-negative bacteremia following FMT. These bacteremia cases occurred in conjunction with ventilator-associated pneumonia, Crohn disease, toxic megacolon, and aspiration pneumonia.

In the new study, Zachariah DeFilipp, MD, of Massachusetts General Hospital, Boston, and colleagues utilized a genomics approach to link two patients with FMT-associated E coli bacteremia to the same stool donor.

The FMT, administered orally in capsules, had been prepared and frozen in November 2018. That was prior to a January 2019 change in regulations to expand donor-stool screening to include tests for ESBL-producing organisms, norovirus, and human T-lymphotropic virus. The FDA did not require retesting of stored materials.

Patient 1 was a 69-year-old man who had liver cirrhosis resulting from hepatitis C infection. The patient had participated in an open-label trial of FMT for refractory hepatic encephalopathy. He developed fever and cough 17 days after taking the last of 15 pills over a 3-week period. Symptoms progressed to pneumonia. Once E coli was identified, the patient's antibiotics were switched to meropenem. The patient recovered, and a follow-up stool sample was negative.

Patient 2 did not fare as well. The 73-year-old man with therapy-related myelodysplastic syndrome received oral FMT before and after a hematopoietic stem cell transplant from an HLA-mismatched donor. The goal was to prevent graft-vs-host disease, for which the patient had also received prophylactic cefpodoxime the day before the transplant.

Symptoms of infection began 5 days post transplant. The man's neutrophil count plunged, and he was treated with cefepime. He required mechanical ventilation and died 2 days later of sepsis.

The two men had received frozen FMT capsules from the same lot and the same donor, whose fecal matter had a similar but not identical roster of bacterial antibiotic resistance genes as that of blood from the patients. Prior to transplant, neither patient's stool harbored ESBL microorganisms.

The researchers sequenced the entire genomes and compared single-nucleotide polymorphism marker patterns in the E coli from the bloodstreams of the two patients and stool from the donor.

Twenty-two patients had received stool from the donor. Of those patients, six had participated in either of the two clinical trials, and 16 had not. The researchers parsed the stool composition in various ways.

  • Pre-FMT stool samples from patients who had been in either of the two clinical trials in which the two case patients had participated showed no growth of ESBL pathogens.

  • Stool samples from 12 patients were tested after FMT. Stool samples from five of those patients grew ESBL microorganisms.

  • Seven patients underwent FMT to treat recurrent or refractory C difficile infection. Stool samples from four of those patients grew ESBL microbes.

The researchers point out that the introduced stool may have lowered the arsenal of antibiotic-resistance genes in the recipients' microbiomes, because healthy individuals tend to have fewer of them, and individuals who harbor C difficile tend to have more.

"When FMT is successful, the recipient's metagenomic burden of antimicrobial resistance genes mimics that of the donor.... [T]he rates of positive tests are, in our opinion, unexpectedly high and probably represent transmission through FMT," they conclude.

Once the adverse events were reported to the FDA, the agency halted the clinical trials, placed an alert on the FDA website, and mandated additional screening of stool that is to be used in clinical trials.

The two patients were at elevated risk for bacteremia because their conditions compromised intestinal permeability, the researchers write. Even a patient's own microbiome can seed bloodstream infections through the intestinal lining.

Another source of vulnerability may have been inadvertent selection of resistant microorganisms through use of antibiotic prophylaxis soon before transplant.

The researchers also suggest that previous studies may have underestimated the infection risk, because the standard methods for comparing antibiotic resistance (antibiogram or pulsed-field gel electrophoresis) might not have been powerful enough to detect exact matches between donor stool and the recipients' bloodstreams, as genome sequencing can.

The researchers conclude that clinicians and patients should carefully consider the risks and benefits of FMT. "Despite its seemingly innocuous, if unpleasant, aspect and possibility to do it oneself at home, FMT carries a risk of infectious hazards that needs to be taken seriously," Martin J. Blaser, MD, of Rutgers University, New Brunswick, New Jersey, writes in an accompanying editorial.

Minimizing the risk for infection from FMT would entail better matching of recipients to donors and better defining of the product, rather than just packaging it in capsules and adopting a "one size fits all" approach. Stool harbors a complex mix of bacteria, protozoa, fungi, viruses, cytokines, and metabolites. "Scientists must determine which of the myriad entities are the salutary agents; the harmful ones will make themselves known," Blaser writes.

In a letter to the editor published in the same issue of the journal, Zain Kassam, MD, PhD, from Finch Therapeutics, and colleagues assess the weeding-out process for donors.

From 2014 through 2018, of 15,317 donor candidates for OpenBiome, only 386 (3%) qualified after undergoing a four-stage weeding out process. OpenBiome is a stool bank in Cambridge, Massachusetts.

Stage 1 of that process was an online prescreening that excluded smokers, those with a body mass index greater than 30, and those who were not able to donate regularly. Stage 2 was a 200-item clinical assessment and in-person interview, conducted to exclude people with microbiome-associated conditions (gastrointestinal, metabolic, autoimmune, atopic, allergic, neurologic, and psychiatric). Stage 3 entailed nasal and stool screening, including asssessment for the presence of key antibiotic-resistant microorganisms, and stage 4 was serology.

Conclude the authors, "This experience highlights the point that healthy, screened donors are not easy to find."

The researchers and commentator have disclosed no relevant financial relationships. Letter authors Kassam and Smith are from Finch Therapeutics; Dubois, Ramakrishna, and Ling are from OpenBiome.

N Engl J Med. Published online October 30, 2019. Abstract, Editorial, Letter

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