Antimicrobial Resistant Organism Decolonization After Microbiome Perturbation

Reconstituting the perturbed microbiome is a novel therapeutic modality with the potential to decrease ARO colonization and infection and combat AMR without additional pressure for selection of further antimicrobial resistance. No trial has yet assessed the potential of a therapeutic microbial consortium for ARO decolonization and infection prevention after antibiotic treatment.

The investigational product, Microbial Ecosystem Therapeutic-2 (MET-2), is a defined microbial community derived from healthy donor stool. MET capsules are orally administered mixtures of bacterial strains cultured from the stool of a healthy donor. This study is designed to determine if a trial of administration of MET-2 after antibiotic treatment for bloodstream infections is feasible. Stool and plasma biomarkers to assess the effects of the intervention will also be evaluated.

• MET-2 (Drug): Microbial Ecosystem Therapeutics (MET) is a defined microbial community derived from healthy donor stool. MET capsules are orally administered mixtures of pure cultures of human-derived bacterial strains.
• Placebo (Drug): Microcrystalline Cellulose

Primary outcomes

• Recruitment rate overall and by study site [1.5 years]: Defined by the numbers of eligible, consented, and randomized patients
• Adherence to MET-2/placebo for the treatment duration [30 days]: Defined as >80% of loading dose (16/20 pills) + >75% of daily doses (18/24 pills) for the maintenance period, as determined by returned unused capsules

Secondary outcomes

• Change in microbiome composition after intervention [180 days]: Assessment of gut microbiome composition in pre- and post-randomization stool samples using bacterial culture and culture-independent (sequencing) assays.
• Number of biomarker samples collected, by sample type and timepoint [30 days]: Successful adherence to biomarker sample collection is defined as >80% of participants having samples suitable for analysis at 30 days post-intervention
• Concentration of potential biomarkers in pre- and post-randomization blood and urine samples [180 days]: Microbial-derived metabolites (short chain fatty acids and bile acids in blood, and 3-indoxyl sulfate in urine), markers of intestinal permeability (soluble CD14, LPS, LPS-binding protein, ZO-1, intestinal fatty acid protein), immune cell profiles (CD8 T lymphocytes, CD4 T lymphocytes, T regulatory cells, B lymphocytes, Th17 cells, Th1 cells).

Other outcomes

• Adverse events [180 days]: Frequency and grade
• 90- and 180-day infection rate [180 days]: Infection will be defined as either isolation of a pathogenic species from any sterile site OR the initiation of a therapeutic course of antimicrobials with or without isolation of a pathogenic species from a sterile or non-sterile site
• ARO colonization by culture at 30 and 90 days post-intervention [90 days]: Defined as any positive result for ARO from any site
• Determine 90- and 180-day recurrence/re-infection rates (with the same organism) in each treatment arm [180 days]
• AMR gene complement by sequencing at 30 and 90 days post-intervention [90 days]
• 90- and 180-day all-cause mortality [180 days]
• ICU and hospital lengths of stay [180 days]
• C. difficile carriage at days 30 and 90 [90 days]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Adult (≥18 years old) inpatient not admitted to the ICU or equivalent (step-up and step-down units are eligible)
2. Positive blood culture with an ARO:

   * AmpC beta-lactamase producing species: Enterobacter cloacae, Citrobacter spp., Klebsiella aerogenes, Serratia spp., Morganella morganii, Hafnia alvei OR
   * ESBL-producing gram-negative bacilli
3. Currently receiving treatment for the bloodstream infection

Exclusion Criteria:

1. Inability to swallow oral MET-2 or placebo capsule
2. Recipient of small bowel transplant
3. Inflammatory bowel disease, short bowel syndrome, diverting/non-diverting ileo/colostomy
4. Use of >3 days over-the-counter or prescription probiotics (not including food additives) within 10 days of enrolment
5. Receipt of fecal microbiota transplant (FMT) within 3 months of enrolment
6. Absolute neutrophil count <0.5x109/L
7. Death expected within 72 hours of enrolment
8. Planned continuation of non-prophylaxis antimicrobial therapy active against the bloodstream isolate for >42 days
9. Known pregnancy, planning to become pregnant during the study period, or breastfeeding
10. Any other reason in view of the site investigator or treating team

• Bryan Coburn, MD, PhD, Principal investigator, University Health Network, Toronto