FDA Alert: Fatal Infection Following Fecal Transplant
C. diff patient dies of E. coli infection
Multidrug-resistant organisms (MDROs) are infecting new patients via transplantation, putting recipients at risk of infections and threatening to spur larger hospital outbreaks. Two recently reported incidents underscore the threat, with one described in an alert by the FDA about fecal microbiota transplantation (FMT) to treat Clostridioides difficile infections.
“Two immunocompromised adults who received investigational FMT developed invasive infections caused by extended-spectrum beta-lactamase [EBSL]-producing Escherichia coli. One of the individuals died,” according to the FDA alert.1
C. diff kills some 15,000 patients annually, often emerging after antibiotics used for other infections disrupts the commensal bacteria in the gut. FMT is an option for patients with recurring C. diff infections.
In the case reported by the FDA, the fecal microbiota transplanted to the two patients came from the same donor. The donor stool and resulting FMT used in the patients were not tested for ESBL-producing, gram-negative organisms like E. coli.
“After these adverse events occurred, stored preparations of FMT from this stool donor were tested and found to be positive for ESBL-producing E. coli identical to the organisms isolated from the two patients,” the FDA reported.
In light of the cases, the FDA recommended patients considering FMT for C. diff infections talk to providers and understand the potential risks associated with the procedure.
In addition, the FDA notified those physicians performing FMTs under Investigational New Drug (IND) provisions of new requirements, effective as of July 15, 20191:
1. Donor screening must include questions that specifically address risk factors for colonization with MDROs, and individuals at higher risk of colonization must be excluded from donation. Examples of patients at higher risk include:
- Healthcare workers;
- Those recently hospitalized or discharged from long-term care facilities;
- People who regularly attend outpatient medical or surgical clinics;
- Those who recently participated in medical tourism.
2. FMT donor stool testing must include MDRO testing to exclude use of stool that tests positive for MDRO. The MDRO tests should, at minimum, include ESBL-producing Enterobacteriaceae, vancomycin-resistant enterococci (VRE), carbapenem-resistant Enterobacteriaceae (CRE), and methicillin-resistant Staphylococcus aureus (MRSA). Culture of nasal or peri-rectal swabs is an alternative to stool testing for MRSA only. Bookend testing (no more than 60 days apart) before and after multiple stool donations is acceptable if stool samples are quarantined until the post-donation MDRO tests are confirmed negative.
3. All FMT products currently in storage for which the donor has not undergone screening and stool testing for MDROs as described above must be placed in quarantine until the donor is confirmed to be not at increased risk of MDRO carriage, and the FMT products have been tested and found negative. In the case of FMT products manufactured using pooled donations from a single donor, stored samples of the individual donations prior to pooling must be tested before the FMT products can be administered.
4. The informed consent process for subjects being treated with FMT product under the IND should describe the risks of MDRO transmission and invasive infection, as well as the measures implemented for donor screening and stool testing.
MDRO Via Organ Transplant
Another case was recently reported at the CDC’s annual Epidemic Intelligence Service conference.
The investigation began in August 2018, when the Connecticut Department of Health notified the CDC that a highly drug-resistant strain of Acinetobacter baumannii had been identified in a deceased organ donor.2
The isolate carried the OXA-23 gene, conferring resistance to carbapenems, last-line drugs against MDROs that are virtually untreatable. The donor had been admitted to a hospital with on ongoing outbreak of OXA-23 carbapenem-resistant A. baumannii (CRAB) nine days prior the positive culture.
The lungs, liver, and kidneys from the donor were transplanted into four patients in three transplant facilities in Connecticut and Massachusetts. The facilities were not notified of the donor’s MDRO status until 53 days after the transplants, said Ana Bardossy, MD, an EIS officer in the CDC Division of Healthcare Quality Promotion (DHQP).
“CRAB is not currently included in pathogens of special interest that are required to be reported for further investigation to the Organ Procurement and Transplantation Network, but this is now under consideration,” she said.
Notifications of pathogens of special interest must occur within 24 hours. However, post-transplant cultures were obtained from the organ recipients as part of routine follow-up. CRAB was identified in the lung transplant recipient, but did not transmit to the other organ recipients. The lung transplant patient required prolonged antibiotic prophylaxis for CRAB colonization, but did not develop clinical infection.
Two CRAB isolates, one from the donor and one from the recipient, were resistant to 16 antibiotics. However, they remained susceptible to colistin and polymyxin b, she said.
“There was a second isolate from the recipient that was pan-resistant, including resistance to colistin and polymyxin b,” Bardossy said.
The case shows the potential for transplants to spark an MDRO outbreak at an organ recipient facility.
“It important to note that OXA-23 CRAB has been linked to outbreaks in other cities across the country,” Bardossy said. “MDROs have the potential to move through facilities through transplantation, [leading to] spread and transmission.”
Once available, donor MDRO culture results should promptly be shared with transplant centers to trigger treatment and infection control response, she said.
“This highlights the importance of regional collaboration of public health authorities to detect resistance, protect patients, and prevent spread through MDROs,” she said.
The question of whether organs from infected donors should be rejected by receiving facilities was raised at the EIS meeting. Bardossy put the risk in perspective with the critical shortage of organs.
“In 2017, 18 people a day died waiting for an organ transplant,” she said. “In contrast, suspected infections happen to 1% to 2% of cases. From those suspected infections, less than 1% of the cases is transmission-confirmed, and mortality is low. Clinicians may evaluate whether they want to reject the organ or not. It is up to the facilities.”
Moderating the EIS session was Denise Cardo, MD, director of the CDC DHQP.
“Sometimes, people say, ‘Test all the donors to see if they have infections,’” Cardo said. “I think the most important piece here is the communication after detection, not only for the patient and the recipient to be treated, but also for avoiding further transmission. Patients move from one transmission center to another, and that can be a problem.”
While initial communication is critical, another point to remember in preventing transmission is that recipients of organs with MDROs may remain colonized for prolonged periods as they go in and out of hospitals, Bardossy added.
- FDA. MedWatch Alert: Fecal microbiota for transplantation: Safety communication — Risk of serious adverse reactions due to transmission of multidrug-resistant organisms. June 18, 2019. Available at: https://bit.ly/2XDJrAK.
- Bardossy AC, Annambhotla P, Basavaraju S, et al. Transmission of OXA-23-producing carbapenem-resistant Acinetobacter baumannii through lung transplantation. Presented at 68th Annual EIS Conference, April 29-May 2, 2019.
Multidrug-resistant organisms are infecting new patients via transplantation, putting recipients at risk of infections and threatening to spur larger hospital outbreaks. Two recently reported incidents underscore the threat, with one described in an alert by the FDA about fecal microbiota transplantation to treat Clostridioides difficile infections.
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