Enterococcus faecium is a Gram-positive bacterium increasingly identified as a critical nosocomial pathogen that poses significant treatment challenges due to its resistance to multiple antibiotics, particularly vancomycin-resistant E. faecium (VRE) strains. The urgent need for alternative therapeutic strategies has renewed interest in bacteriophage (phage) therapy, given phages specificity and bactericidal potential. This review explores the advancements in phage therapy against antibiotic-resistant E. faecium, including phage morphological diversity, genomic characteristics, and infection mechanisms. The efficacy of phage therapy in in vitro, ex vivo, and in vivo models and the compassionate use in clinical settings are evaluated, highlighting the promising outcomes of phage–antibiotic synergies and biofilm disruption. Key challenges and future research directions are discussed, with a focus on improving therapeutic efficacy and overcoming bacterial resistance. This review emphasizes the potential of phage therapy as a viable solution for managing multidrug-resistant E. faecium infections and underscores the importance of future investigations to enhance clinical applications.

Antibiotic resistance and biofilm tolerance narrow the treatment options for extended-spectrum β-lactamase-producing Escherichia coli. Bacteriophages are a proposed alternative, and some carry enzymes that degrade the biofilm matrix, but how enzyme architecture relates to antibiofilm performance is unclear. We isolated two lytic phages from hospital wastewater and characterized them genomically, structurally and phenotypically. F58V is a new species of the genus Phapecoctavirus; F63V is the proposed founding member of a new genus. Neither carries resistance or virulence genes, nor markers of a lysogenic lifestyle. F58V encodes a tail enzyme specific for colanic acid, present in all 51 non-redundant genomes of its genus and held under selection as strong as that acting on essential genes; F63V encodes a structurally different enzyme predicted to act on another sugar. Together the two phages infect 82% of a 50-strain panel enriched for multidrug-resistant isolates, with complementary ranges. Both prevented biofilm formation, however, against established biofilms, F58V reduced biomass or metabolic activity in three out of four clinical strains and F63V in one out of four. Our results show that phages preventing biofilms can act differentially against preformed biofilms, which parallels in part with their depolymerase architecture.