Multi-Donor Fecal Microbial Transplantation for Critically Ill Patients: Rationale and Standard Operating Procedure

Abstract

Patients in the intensive care unit often lose a considerable fraction of their gut microbiome due to exposure to broad-spectrum antibiotics and other reasons. Dysbiosis often results in prolonged diarrhea and increase occurrence of multi-drug resistant pathogens in the colon with clinical consequences not yet well understood. Restoring the microbiome by fecal microbial transplantation (FMT) is a plausible therapeutic possibility, so far only documented in case reports and case series using very heterogeneous methodologies. Before FMT with critically ill patients can be tested in randomized controlled trials, there is a burning need to describe a standardized operating procedure (SOP) of the whole process, respecting the specifics of the critically ill population, such as the risk of the disrupted intestinal barrier and time-critical nature of the procedure. We describe the SOP that has been developed for experimental use in critically ill patients by a multidisciplinary team of intensivists, gastroenterologists, and microbiologists based on feedback from regulatory authority (State Institute for Drug Control of the Czech Republic). The hallmarks of these SOPs are multi-donor freshly frozen transplants guaranteed for 2 months consisting of seven aliquots from seven unrelated healthy donors and administered by a rectal tube. In this paper we discuss the rationale for this SOP and the process of its development in detail and release the full proposed SOP is in the form of an online appendix.

Assessment of Faecal Microbiota Transplant Stability in Deep Freeze Conditions: A 12-month Ex Vivo Viability Analysis

“…2013). The selection and assessment of donors were performed as previously described [20]. The donors were provided with a sterile faecal collector container (FECONTAINER, Excretas Ltd., The Netherlands) and were instructed to bring the stool as soon as possible but no later than within 3 hours after defecation.…”

“…The donors were provided with a sterile faecal collector container (FECONTAINER, Excretas Ltd., The Netherlands) and were instructed to bring the stool as soon as possible but no later than within 3 hours after defecation. The donor stool was processed according to published standard operating procedures [20]. Of the 9 donors, two donated twice and two donated three times, yielding a total of 15 processed faecal samples.…”

“…There is a degree of variability in standard operating procedures for processing and storing frozen samples across institutions [10][11][12][13][14] and legislative frameworks [15][16][17][18], although these protocols generally agree on basic points, which include timely processing, the use of cryoprotectants, and adherence to a storage temperature of -80°C [19]. Based on these principles, we developed a detailed standard operating procedure for the selection and examination of donors and their stool, the process of processing the donor's stool, the method of preservation, the process of thawing, and preparation for administration [20]. The approval process of these SOPs by the State Institute of Drug Control (SÚKL) unveiled the lack of data on the stability of the graft during cold storage.…”

The central role of the gut in intensive care

“…FMT should be done 48 h after the last antibiotic to maximize engraftment. Due to safety concerns, new studies should only include hemodynamically stable patients without perforated viscous or immunoparalysis [ 12 ].…”

“…Illness and drugs can disrupt the GM balance. In the intensive care unit (ICU), patients are subjected to antibiotics, gastrointestinal transit changes, nutritional changes, and sepsis [ 4 ], collectively leading to a GM imbalance, namely dysbiosis, whose most common symptom is diarrhea [ 12 ]. Ninety percent of the intestinal microflora is lost within 6 h of ICU admission [ 13 ].…”