Synergistic activity of fosfomycin combined with old and new oxazolidinones (linezolid, contezolid, delpazolid, and sutezolid) against bloodstream isolates of vancomycin-resistant Enterococcus faecium

Purpose: Current treatment options for infections caused by vancomycin-resistant (VR) Enterococcus faecium remain limited and often suboptimal. This study investigates the in vitro activity of combination therapies involving fosfomycin and oxazolidinones (linezolid, contezolid, delpazolid, and sutezolid) against five vanA and five vanB E. faecium isolates obtained from blood cultures. Methods: The synergistic activity of fosfomycin combined with each oxazolidinone was assessed using checkerboard and time-kill assays. Results: Synergistic interactions were demonstrated with all fosfomycin–oxazolidinone combinations, although the effect was more consistent with delpazolid. In some cases (one for contezolid, three for linezolid, four for sutezolid), the interaction was additive rather than synergistic. Synergy was mainly driven by a significant reduction in fosfomycin minimum inhibitory concentration (MIC), up to 16-fold, while decreases in oxazolidinone MIC were modest. Time-kill assays performed on representative isolates Ef-3 (vanB) and Ef-10 (vanA) confirmed the synergistic interactions, showing a reduction in viable cell counts after 24 h. Conclusion: Our findings provide preclinical evidence supporting the use of fosfomycin in combination with novel oxazolidinones as a promising therapeutic strategy against VR E. faecium infections.