EVREA-Phage: management of intestinal vancomycin resistant Enterococcus faecium through phage therapy

Enterococcus faecium is a versatile Gram-positive bacterium adaptable to a wide variety of environments. It is considered a commensal bacterium of the human gastrointestinal tract although it can become an opportunistic pathogen with potentially fatal outcomes. Vancomycin-resistant E. faecium (VREfm) are of great concern, within health care settings with infections rising steadily over the last decade and strains carrying additional resistance to last-resort antibiotics such as linezolid, daptomycin and tigecycline. Colonization of immunosuppressed patients with VREfm is linked to high mortality when compared to non-colonized patients. Currently no effective treatment strategy exists to eradicate VRE colonization and in this context, bacteriophages show great potential as therapeutic tools without known severe[RC1] [AFMM2] adverse events once the phages are sufficiently purified. The aim of the EVREA-Phage project, publicly funded under DZIF support, is the isolation and characterization of potential phage candidates, determining their potential for therapeutic application towards eradicating intestinal VREfm without disrupting the normal gut microbiota. Phages were isolated from multiple waste water and fecal samples, purified and characterized regarding morphology, in vitro lytic potential and host range against an extensive panel of clade A1 E. faecium strains, mainly represented by internationally relevant clones such as ST80, ST117 and ST203. Through EVREA-Phage a broad VREfm host range phage cocktail has been selected, promising candidates were selected for kinetics, sequencing, phage synergism, phage-antibiotic activity, eliciting of refractory behavior over time and the effect on other gut commensal bacteria. This translational project will include subsequent preclinical investigation in an in vitro intestinal model assay taking place at the University Hospital Bonn and an in vivo mouse model at the Helmholtz Centre for Infection Research in Braunschweig allowing for a thorough corroboration of the best candidates to finally produce an efficient cocktail against VRE strains and for pharmaceutical purification before later human application.