Although not a new therapy, fecal microbiota transplantation (FMT) has been widely used in recent times for treating recurrent or refractory Clostridioides difficile infection, showing an overall cure rate of 94% that outpaces the 31% cured with standard antibiotic therapy.

The potential of fecal bacteriotherapy has also been investigated in the context of Crohn’s disease, ulcerative colitis, irritable bowel syndrome, obesity, cirrhosis and even neurological and behavioral conditions. However, large-scale studies are needed to understand how best to utilize this therapy and any safety issues that may arise in its wake.

Indeed, restoring the gut microbiota through fecal transplants is not always free of adverse reactions.

A new study concerns the transfer of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli from a single donor to two highly compromised elderly patients.

The first patient had cirrhosis secondary to a hepatitis C virus infection and received 15 FMT capsules five times over 3 weeks to treat refractory hepatic encephalopathy. Seventeen days after receiving the final FMT dose, adverse events in the form of fever and cough appeared, together with blood cultures that were positive for ESBL-producing E. coli. The infection was eventually resolved with antibiotics.

A new study concerns the transfer of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli from a single donor to two highly compromised elderly patients

The second patient had therapy-related myelodysplastic syndrome and was enrolled in an independent clinical trial in which he received 15 oral FMT capsules on day 4 and on day 3 before allogeneic hematopoietic cell transplantation. The use of FMT in oncology is being studied as a means of preventing or treating post-transplantation complications and for enhancing the efficacy of newer immunotherapies. The patient died from severe sepsis 10 days after receiving the final FMT dose. An analysis of blood cultures revealed the presence of ESBL-producing E. coli.

While fecal samples from both patients were negative for ESBL-producing organisms before FMT, culture analyses showed that the donor capsules and blood isolates from the patients shared antimicrobial resistance patterns of ESBL-producing E. coli.

The same donor provided stool samples for a further 20 individuals, but none developed bacteremia. Even so, the fecal samples of 9 out of 19 recipients contained bacteria that grew on an ESBL selective medium. It should be acknowledged that the study did not mention whether the fecal transplants provided any benefit to the other patients.

These findings led the Food and Drug Administration (FDA) to issue an alert regarding the potential risk of serious or life-threatening infections associated with the use of FMT. More recently, the FDA has warned about infections caused by enteropathogenic Escherichia coli and Shigatoxin-producing E. coli that have occurred following investigational use of FMT.

The data highlight the need to include screening for ESBL-producing organisms in the donor screening protocol for FMT. Another recent paper highlights that specific attention should also be paid to handling and storing stool samples intended for FMT, to standardize the entire fecal transplant production process.

These findings led the Food and Drug Administration (FDA) to issue an alert regarding the potential risk of serious or life-threatening infections associated with the use of FMT

That live microorganisms should be avoided in highly compromised patients is also supported by a second study showing that a Lactobacillus rhamnosus GG probiotic administered in an intensive care unit resulted in bacteremia in six young patients.

To sum up, although the benefits of FMT may outweigh the risks when treating C. difficile-associated diarrhea, proper screening of donor samples is required, and especially in the context of patients at heightened risk of bacterial translocation, such as those described in the study. In the light of current data, scientists suggest that ESBL-producing organisms should be included in the 2018 FDA donor screening protocol for FMT.

Same can be said about SARS-CoV-2: a prolonged presence of viral RNA has been described in patients. Even though the FMT program has been put on hold in many places, once the COVID-19 pandemics is over it will be safe to look for this viral RNA and exclude positive patients as donors, despite the absence of knowledge about the risk of contamination via the fecal route.

 

References:

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van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013; 368(5):407-15. doi: 10.1056/NEJMoa1205037.

Sokol H, Landman C, Seksik P, et al. Fecal microbiota transplantation to maintain remission in Crohn’s disease: a pilot randomized controlled study. Microbiome. 2020; 8(1):12. doi: 10.1186/s40168-020-0792-5.

Dang X, Xu M, Zhou D, et al. Assessing the efficacy and safety of fecal microbiota transplantation and probiotic VSL#3 for active ulcerative colitis: A systematic review and meta-analysis. PLoS One. 2020; 15(3):e0228846. doi: 10.1371/journal.pone.0228846.

Xu D, Chen VL, Steiner CA, et al. Efficacy of fecal microbiota transplantation in irritable bowel syndrome: A systematic review and meta-analysis. Am J Gastroenterol. 2019; 114(7):1043-50. doi: 10.14309/ajg.0000000000000198.

Yu EW, Gao L, Stastka P, et al. Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial. PLoS Med. 2020; 17(3):e1003051. doi: 10.1371/journal.pmed.1003051.

Woodhouse CA, Patel VC, Goldenberg S, et al. PROFIT, a PROspective, randomised placebo controlled feasibility trial of Faecal microbiota Transplantation in cirrhosis: study protocol for a single-blinded trial. BMJ Open. 2019; 9:e023518. doi: 10.1136/bmjopen-2018-023518.

DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019; 381(21):2043-50. doi: 10.1056/NEJMoa1910437.

U.S. Food & Drug Administration. Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms. Silver Spring, MD. 2019. Available from https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse.

Burz SD, Abraham AL, Fonseca F, et al. A guide for ex vivo handling and storage of stool samples intended for fecal microbiota transplantation. Sci Rep. 2019; 9:8897. doi: 10.1038/s41598-019-45173-4.

Yelin I, Flett KB, Merakou C, et al. Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients. Nat Med. 2019; 25(11):1728-32. doi: 10.1038/s41591-019-0626-9.

Wu Y, Guo C, Tang L, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020 Mar 19. doi: 10.1016/S2468-1253(20)30083-2.

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