Novel lytic phages improve the antibiofilm activity of dalbavancin, daptomycin, and fosfomycin against vancomycin-resistant enterococci
Abstract
Periprosthetic joint infections (PJI) caused by Enterococcus spp., especially vancomycin-resistant strains (VRE), are challenging to treat due to biofilm tolerance and limited antibiotic options. Bacteriophages offer a promising adjunct through targeted and biofilm-disrupting activity. This study evaluated two novel lytic phages, alone and combined with last-line antibiotics, for their ability to eradicate VRE biofilms in vitro. Two novel lytic phages, CUB-FM (E. faecium) and CUB-FS (E. faecalis), were isolated from hospital sewage and characterized via whole-genome sequencing and transmission electron microscopy. Antibiofilm efficacy of phages alone and in combination with dalbavancin, daptomycin, and fosfomycin was assessed against biofilm-embedded VRE strains using isothermal microcalorimetry. Synergy was defined as a combined effect exceeding the sum of individual activities. Genomic analysis confirmed both phages as strictly lytic and free of lysogeny, virulence, or resistance genes. TEM classified CUB-FM within Salasmaviridae and CUB-FS within Herelleviridae. Both exhibited dose-dependent antibiofilm activity, with optimal efficacy at 10¹² (CUB-FM) and 10⁸ PFU/mL (CUB-FS). While antibiotic monotherapies showed limited antibiofilm effects, phage-antibiotic combinations markedly enhanced activity. CUB-FM with dalbavancin achieved the strongest suppression against E. faecium (tMax22.3 h vs. 5.2 h control, P E. faecalis biofilms. Daptomycin-phage combinations produced…
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