Precision Modulation of Gut Microbiome Enteropathogen Colonization in Critical Illness

Phase 1b Randomized Controlled Trial Evaluating Medical Food Synbiotic KB-101+KB-102 for Safety and Dietary Management of Enteropathogen Colonization of the Gut Microbiome of Critically Ill Patients

Patients requiring life support therapies in intensive care units are at very high risk of hospital-acquired infections. An important source of these infections is the accumulation of pathogenic bacteria in the microbiome of their gut. We hypothesize that treatment with an enteral synbiotic (combination of probiotic and prebiotic), which has been specifically designed to combat pathogen colonization in the gastrointestinal tract, will be safe and effective to reduce pathogen levels in the gut, and potentially reduce infections.

We are conducting a phase 1b randomized, open-label, controlled trial to assess safety biological efficacy of enteral synbiotic therapy to reduce gastrointestinal enteropathogen colonization in adult critically ill patients.

Enteropathogen colonization of the gut microbiome in critically ill patients is associated with adverse outcomes. Observational studies have consistently reported that gut colonization with enteropathogens including Enterobacterales (e.g. Klebsiella spp., E. coli, Enterobacter spp., and others) and Enterococcus spp. (e.g. E. faecium) is associated with increased risks of hospital-acquired infections, death, organ dysfunction severity, prolongation of life support, and hospitalization. Mechanistically, gut enteropathogen colonization has been shown to contribute to adverse outcomes like hospital-acquired infections (HAI) through the gut's ability to serve as both a reservoir of HAI pathogens, as well as through pathological microbiome-immune interactions that suppress immune defences against HAI. Consequently, therapeutic strategies to reduce gut enteropathogen colonization have been identified as potentially impactful interventions to reduce hospital-acquired infections and adverse outcomes in patients with critical illness.

Prior clinical trials have employed diverse strategies to modulate the gut microbiome with the objective of reducing adverse outcomes, including large randomized controlled trials of probiotics, or opposing strategies such as digestive decontamination. However, outcomes have been heterogeneous owing to a number of crucial methodological limitations of both the interventions as well as study designs. First, despite proposed mechanisms involving microbiome modulation, none of the important trials have actually analyzed the microbiome to confirm whether their intervention favourably modified the microbiome (i.e. lack of confirmation of biological plausibility). Next, investigations of probiotics have suffered from a lack of rationalized designed for their intended mechanism. For example, the large RCT of probiotics in critically ill patients utilized Lactobacillus rhamnosus GG, yet the choice of this particular probiotic was not based on any prior mechanistic data demonstrating that this species could engraft in the ICU microbiome, nor whether it has the potential to displace enteropathogens from the gut. In fact, very few probiotic trials have ever even determined whether the probiotic strain could engraft into the ICU gut microbiome, nor have any trials determined whether interventions successfully decolonized enteropathogens.

To address these limitations, we will conduct a randomized controlled trial to assess both the safety and biological efficacy (microbiome engraftment and enteropathogen decolonization) of the synbiotic medical nutrition product in critically ill patients. In this phase 1b randomized controlled trial, 64 critically ill patients requiring mechanical ventilation will be randomly assigned to a 21-day course of enteral synbiotic or control (open label). Primary outcome will be safety and biological efficacy of synbiotic engraftment in the gut, with secondary outcome of gut enteropathogen colonization.

Inclusion Criteria:

• Adult (>18 years old) admitted to FMC ICU within 48h of admission
• Mechanically ventilated via endotracheal tube
• Expected duration of mechanical ventilation >72 hours from time of screening (as determined by attending ICU physician)

Exclusion Criteria:

• Goals of care designation that limits the use of life-sustaining interventions
• Life expectancy <72 hours (in the opinion of the attending ICU physician)
• Unable to receive enteral administration of medications
• Presence of ileus, discontinuous GI tract (including ileostomy), total or partial colectomy, bariatric surgery, inflammatory bowel disease, active graft-versus-host disease, cirrhosis with Child-Pugh Class C, or short bowel syndrome
• Acute immunosuppression including recent (within 30 days) cytotoxic chemotherapy; chronic systemic steroids (≥20 mg prednisone equivalent/day for >3 weeks); uncontrolled HIV infection (with CD4 count <400/μl); neutropenia (absolute neutrophil count <500/μL)
• Pregnancy or breastfeeding
• Concurrently taking pre-, pro-, synbiotic, or live biotherapeutic product, or other fermented food product and unwilling to discontinue these for the duration of the study
• Concurrently enrolled in another clinical trial of pre-, pro-, synbiotic, or live biotherapeutic product, antimicrobial, or immune modulator therapy
• History of lactose allergy (lactose intolerance not exclusionary)
• Unsuitable for inclusion in study in the opinion of the attending physician or investigator