An article appearing in The New England Journal of Medicine (NEJM) on October 30, 2019 reported that “Gram-negative bacteremia has been reported in four patients after they had undergone FMT [fecal microbiota transplantation]. In three of these cases, there was a plausible alternative explanation for the bacteremia, including ventilator-associated pneumonia, toxic megacolon, and Crohn’s disease. The fourth case involved aspiration of feculent material during upper endoscopic FMT delivery, followed by pneumonia, Escherichia coli bacteremia, septic shock, and death.”
The NEJM article states, “Fecal microbiota transplantation (FMT) refers to the administration of intestinal microbes from a healthy donor into a recipient with the intent of modifying the recipient’s intestinal microbiome. FMT is an emerging treatment for recurrent or refractory Clostridioides difficile infection, and randomized, controlled trials and meta-analyses have supported the safety and efficacy of this procedure. FMT is being used experimentally in the treatment of other disease states linked to dysbiosis of the intestinal microbiota. ClinicalTrials.gov currently lists more than 300 studies evaluating FMT for various indications, primarily gastrointestinal, but also for neurologic, behavioral, and metabolic conditions. The investigational use of FMT in oncology, specifically for recipients of an allogeneic hematopoietic-cell transplant, is also of interest to prevent or treat post-transplantation complications such as acute graft-versus-host disease and to enhance the efficacy of newer immunotherapies.”
The NEJM article warns, however, that “FMT is associated with rare inflammatory, infectious, and procedural complications. Placebo-controlled trials have not reported serious adverse events or transmission of infection, and a systematic review of FMT showed similar rates of adverse events in immunocompromised and immunocompetent recipients, including infectious events.” The article discussed “two patients in whom extended-spectrum beta-lactamase (ESBL)–producing E. coli bacteremia occurred after they had undergone FMT in two separate clinical trials; both cases were linked to the same stool donor.”
According to the NEJM article, “[d]uring the donation period, volunteers underwent an interim health query for febrile, systemic, and gastrointestinal symptoms and were deferred for any change in health status. All donations were stored and not used for an additional 4 weeks to allow retesting for certain infections that have a longer incubation period … The frozen FMT capsules were stored for up to 9 months in accordance with approved protocols based on stability test data.”
One patient was a 69-year-old man with cirrhosis of the liver attributed to hepatitis C virus infection. In March and April 2019, the patient received 15 FMT capsules five times over 3 weeks. The man reported no adverse events until 17 days after the final FMT dose (May 2019), when a fever and cough developed. The organism that grew in the blood culture was identified as ESBL-producing E. coli. His condition has remained clinically stable since completing antimicrobial therapy. A follow-up stool sample was screened for ESBL-producing organisms on selective medium and was negative.
The second patient was a 73-year-old man with therapy-related myelodysplastic syndrome who was admitted for allogeneic hematopoietic-cell transplantation after reduced intensity conditioning (melphalan and fludarabine) with the use of a graft from an HLA-mismatched unrelated donor. He was enrolled in a phase 2 trial to preemptively administer FMT oral capsules before and after allogeneic hematopoietic-cell transplantation. He received 15 FMT capsules on day 4 and on day 3 before hematopoietic-cell transplantation. Cefpodoxime prophylaxis was initiated on day 1 before transplantation according to institutional standards to minimize the risk of gram-negative bacteremias, given that the patient was allergic to fluoroquinolones. On day 5 after stem-cell infusion (8 days after the last FMT dose), the patient had development of fever (39.7°C), chills, and altered mental status. Despite maximum supportive measures, the patient’s condition worsened, and he died from severe sepsis 2 days later. The final results of blood cultures showed ESBL-producing E. coli.
A total of 22 patients received FMT capsules generated from a single donor. Of the 12 tested patients who received FMT capsules generated from this donor, 5 had post-FMT samples that grew organisms on an ESBL selective medium. Of the 7 tested recipients who underwent FMT for recurrent or refractory C. difficile infection, 4 had post-FMT samples that showed growth on an ESBL selective medium that was morphologically consistent with E. coli.
The authors of the NEJM article stated, “Although we cannot conclusively attribute positive screening results for ESBL-producing organisms in other asymptomatic recipients to FMT, the rates of positive tests are, in our opinion, unexpectedly high and probably represent transmission through FMT … The stool donor had no risk factors of multidrug-resistant organism carriage and had donated fecal material before we included routine tests for ESBL-producing organisms in our donor-screening protocol. Given that the frozen capsules from all preparations derived from this donor were positive on ESBL screening, it is likely that this donor material would have been disqualified if screened before donation. Subsequent screening for ESBL phenotypes in the other FMT recipients suggests further FMT-related transmission; however, confirmatory identification of ESBL-producing E. coli and an analysis of the relative relatedness of these isolates to one another were not performed. To date, we have not identified related infectious complications involving ESBL-producing organisms in other recipients … Despite the infectious complications reported here, the benefits of FMT should be balanced with the associated risks when considering treatment options for patients with recurrent or refractory C. difficile infection.”
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