A sepsis death linked to fecal microbiota transplantation

Two cases of bacteremia have been described in two patients who received fecal microbiota transplants from the same donor.

Writing in the New England Journal of Medicine, researchers reported the two case studies of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia, one of which ended in the death of the patient. These cases were previously announced by the Food and Drug Administration in a June 2019 safety alert.

Zachariah DeFilipp, MD, from Massachusetts General Hospital at Harvard Medical School, Boston, and coauthors wrote that fecal microbiota transplantation is rarely associated with complications. Placebo-controlled trials and a systematic review have found similar rates of complications in immunocompromised and immunocompetent recipients. Only four cases of gram-negative bacteremia previously have been reported, and in three of these, there was a plausible alternative explanation for the bacteremia.

In this paper, both patients received fecal microbiota transplantation via frozen oral capsules containing donor stool. These capsules were prepared prior to the implementation of screening for ESBL-producing organisms at the institution, and were not retrospectively tested since this expanded donor screening.

The first patient was a 69-year-old man with liver cirrhosis attributed to hepatitis C infection who was enrolled in a trial of fecal microbiota transplantation via oral capsules to treat hepatic encephalopathy. The first sign of the adverse event was a fever and cough, which developed 17 days after the final dose of 15 capsules. He was treated for pneumonia but failed to improve after 2 days, at which time gram-negative rods were discovered in blood cultures taken at the initial presentation.

After admission and further treatment, blood cultures were found to have ESBL-producing E. coli, and after further treatment, the patient was clinically stable. A stool sample taken after treatment was negative for ESBL-producing E. coli.

The second case study was a 73-year-old man with therapy-related myelodysplastic syndrome who was undergoing allogeneic hematopoietic stem cell transplantation and was receiving fecal microbiota transplantation via oral capsule as part of a phase 2 trial.

Eight days after the last dose of oral capsules, and 5 days after the stem-cell infusion, the man developed a fever, chills, febrile neutropenia and showed altered mental status. He was treated with cefepime but developed hypoxia and labored breathing later that evening, which prompted clinicians to intubate and begin mechanical ventilation.

His blood culture results showed gram-negative rods, and meropenem was added to his antibiotic regimen. However, the patient’s condition worsened, and he died of severe sepsis 2 days later with blood cultures confirmed as positive for ESBL-producing E. coli.

A follow-up investigation revealed that both patients received stool from the same donor. Each lot of three capsules from that donor was found to contain ESBL-producing E. coli with a resistance pattern similar to that seen in the two recipients.

Twenty-two patients had received capsules from this donor. Researchers contacted all the recipients and offered them stool screening for ESBL-producing E. coli. Twelve underwent testing, which found that five had samples that grew on ESBL-producing E. coli–selective medium.

The remaining seven patients who had follow-up testing were receiving treatment for recurrent or refractory Clostridioides difficile infection, and four of these grew samples on the selective medium.

“When FMT is successful, the recipient’s metagenomic burden of antimicrobial resistance genes mimics that of the donor,” the authors wrote. “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 authors said the donor had no risk factors for carriage of multidrug-resistant organism and had previously donated fecal material before the introduction of routine screening for ESBL-producing organisms.

However, they noted that both patients had risk factors for bacteremia, namely advanced cirrhosis and allogeneic hematopoietic stem cell transplantation and they also received oral antibiotics around the time of the fecal microbiota transplantation.

“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,” the authors wrote. “Ongoing assessment of the risks and benefit 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.”

The American Gastroenterological Association FMT National Registry is a critical effort to track short- and long-term patient outcomes and potential risks associated with FMT. The registry's goal is to track 4,000 patients for 10 years. If you perform FMT, please contribute to this important initiative. Learn more at www.gastro.org/FMTRegistry.

The study was supported by a grant from the American College of Gastroenterology. Three authors declared personal fees and grants from the medical sector outside the submitted work, and two were attached to a diagnostics company involved in the study.

SOURCE: DeFilipp Z et al. N Engl J Med. 2019 Oct 30. doi: 10.1056/NEJMoa1910437.

* This story was updated on Oct. 31, 2019.

Two cases of bacteremia have been described in two patients who received fecal microbiota transplants from the same donor.

Writing in the New England Journal of Medicine, researchers reported the two case studies of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia, one of which ended in the death of the patient. These cases were previously announced by the Food and Drug Administration in a June 2019 safety alert.

Zachariah DeFilipp, MD, from Massachusetts General Hospital at Harvard Medical School, Boston, and coauthors wrote that fecal microbiota transplantation is rarely associated with complications. Placebo-controlled trials and a systematic review have found similar rates of complications in immunocompromised and immunocompetent recipients. Only four cases of gram-negative bacteremia previously have been reported, and in three of these, there was a plausible alternative explanation for the bacteremia.

In this paper, both patients received fecal microbiota transplantation via frozen oral capsules containing donor stool. These capsules were prepared prior to the implementation of screening for ESBL-producing organisms at the institution, and were not retrospectively tested since this expanded donor screening.

The first patient was a 69-year-old man with liver cirrhosis attributed to hepatitis C infection who was enrolled in a trial of fecal microbiota transplantation via oral capsules to treat hepatic encephalopathy. The first sign of the adverse event was a fever and cough, which developed 17 days after the final dose of 15 capsules. He was treated for pneumonia but failed to improve after 2 days, at which time gram-negative rods were discovered in blood cultures taken at the initial presentation.

After admission and further treatment, blood cultures were found to have ESBL-producing E. coli, and after further treatment, the patient was clinically stable. A stool sample taken after treatment was negative for ESBL-producing E. coli.

The second case study was a 73-year-old man with therapy-related myelodysplastic syndrome who was undergoing allogeneic hematopoietic stem cell transplantation and was receiving fecal microbiota transplantation via oral capsule as part of a phase 2 trial.

Eight days after the last dose of oral capsules, and 5 days after the stem-cell infusion, the man developed a fever, chills, febrile neutropenia and showed altered mental status. He was treated with cefepime but developed hypoxia and labored breathing later that evening, which prompted clinicians to intubate and begin mechanical ventilation.

His blood culture results showed gram-negative rods, and meropenem was added to his antibiotic regimen. However, the patient’s condition worsened, and he died of severe sepsis 2 days later with blood cultures confirmed as positive for ESBL-producing E. coli.

A follow-up investigation revealed that both patients received stool from the same donor. Each lot of three capsules from that donor was found to contain ESBL-producing E. coli with a resistance pattern similar to that seen in the two recipients.

Twenty-two patients had received capsules from this donor. Researchers contacted all the recipients and offered them stool screening for ESBL-producing E. coli. Twelve underwent testing, which found that five had samples that grew on ESBL-producing E. coli–selective medium.

The remaining seven patients who had follow-up testing were receiving treatment for recurrent or refractory Clostridioides difficile infection, and four of these grew samples on the selective medium.

“When FMT is successful, the recipient’s metagenomic burden of antimicrobial resistance genes mimics that of the donor,” the authors wrote. “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 authors said the donor had no risk factors for carriage of multidrug-resistant organism and had previously donated fecal material before the introduction of routine screening for ESBL-producing organisms.

However, they noted that both patients had risk factors for bacteremia, namely advanced cirrhosis and allogeneic hematopoietic stem cell transplantation and they also received oral antibiotics around the time of the fecal microbiota transplantation.

“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,” the authors wrote. “Ongoing assessment of the risks and benefit 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.”

The American Gastroenterological Association FMT National Registry is a critical effort to track short- and long-term patient outcomes and potential risks associated with FMT. The registry's goal is to track 4,000 patients for 10 years. If you perform FMT, please contribute to this important initiative. Learn more at www.gastro.org/FMTRegistry.

The study was supported by a grant from the American College of Gastroenterology. Three authors declared personal fees and grants from the medical sector outside the submitted work, and two were attached to a diagnostics company involved in the study.

SOURCE: DeFilipp Z et al. N Engl J Med. 2019 Oct 30. doi: 10.1056/NEJMoa1910437.

* This story was updated on Oct. 31, 2019.

Two cases of bacteremia have been described in two patients who received fecal microbiota transplants from the same donor.

Writing in the New England Journal of Medicine, researchers reported the two case studies of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia, one of which ended in the death of the patient. These cases were previously announced by the Food and Drug Administration in a June 2019 safety alert.

Zachariah DeFilipp, MD, from Massachusetts General Hospital at Harvard Medical School, Boston, and coauthors wrote that fecal microbiota transplantation is rarely associated with complications. Placebo-controlled trials and a systematic review have found similar rates of complications in immunocompromised and immunocompetent recipients. Only four cases of gram-negative bacteremia previously have been reported, and in three of these, there was a plausible alternative explanation for the bacteremia.

In this paper, both patients received fecal microbiota transplantation via frozen oral capsules containing donor stool. These capsules were prepared prior to the implementation of screening for ESBL-producing organisms at the institution, and were not retrospectively tested since this expanded donor screening.

The first patient was a 69-year-old man with liver cirrhosis attributed to hepatitis C infection who was enrolled in a trial of fecal microbiota transplantation via oral capsules to treat hepatic encephalopathy. The first sign of the adverse event was a fever and cough, which developed 17 days after the final dose of 15 capsules. He was treated for pneumonia but failed to improve after 2 days, at which time gram-negative rods were discovered in blood cultures taken at the initial presentation.

After admission and further treatment, blood cultures were found to have ESBL-producing E. coli, and after further treatment, the patient was clinically stable. A stool sample taken after treatment was negative for ESBL-producing E. coli.

The second case study was a 73-year-old man with therapy-related myelodysplastic syndrome who was undergoing allogeneic hematopoietic stem cell transplantation and was receiving fecal microbiota transplantation via oral capsule as part of a phase 2 trial.

Eight days after the last dose of oral capsules, and 5 days after the stem-cell infusion, the man developed a fever, chills, febrile neutropenia and showed altered mental status. He was treated with cefepime but developed hypoxia and labored breathing later that evening, which prompted clinicians to intubate and begin mechanical ventilation.

His blood culture results showed gram-negative rods, and meropenem was added to his antibiotic regimen. However, the patient’s condition worsened, and he died of severe sepsis 2 days later with blood cultures confirmed as positive for ESBL-producing E. coli.

A follow-up investigation revealed that both patients received stool from the same donor. Each lot of three capsules from that donor was found to contain ESBL-producing E. coli with a resistance pattern similar to that seen in the two recipients.

Twenty-two patients had received capsules from this donor. Researchers contacted all the recipients and offered them stool screening for ESBL-producing E. coli. Twelve underwent testing, which found that five had samples that grew on ESBL-producing E. coli–selective medium.

The remaining seven patients who had follow-up testing were receiving treatment for recurrent or refractory Clostridioides difficile infection, and four of these grew samples on the selective medium.

“When FMT is successful, the recipient’s metagenomic burden of antimicrobial resistance genes mimics that of the donor,” the authors wrote. “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 authors said the donor had no risk factors for carriage of multidrug-resistant organism and had previously donated fecal material before the introduction of routine screening for ESBL-producing organisms.

However, they noted that both patients had risk factors for bacteremia, namely advanced cirrhosis and allogeneic hematopoietic stem cell transplantation and they also received oral antibiotics around the time of the fecal microbiota transplantation.

“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,” the authors wrote. “Ongoing assessment of the risks and benefit 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.”

The American Gastroenterological Association FMT National Registry is a critical effort to track short- and long-term patient outcomes and potential risks associated with FMT. The registry's goal is to track 4,000 patients for 10 years. If you perform FMT, please contribute to this important initiative. Learn more at www.gastro.org/FMTRegistry.

The study was supported by a grant from the American College of Gastroenterology. Three authors declared personal fees and grants from the medical sector outside the submitted work, and two were attached to a diagnostics company involved in the study.

SOURCE: DeFilipp Z et al. N Engl J Med. 2019 Oct 30. doi: 10.1056/NEJMoa1910437.

* This story was updated on Oct. 31, 2019.