Synergistic activity of fosfomycin and chloramphenicol against vancomycin-resistant Enterococcus faecium (VREfm) isolates from bloodstream infections

•Vancomycin-resistant enterococci (VRE) antibiotic options are limited.•Fosfomycin maintains good efficacy against VRE but clinical experience is limited. VRE susceptibility to chloramphenicol is ≥ 90%.•We tested the combination of chloramphenicol + fosfomycin (CAF+FOS) against 10 VRE strains from bloodstream infections.•CAF+FOS combination determined a synergic effect observed for 50% of the isolates and an additive effect for the remaining 50%.•The survival of G. mellonella larvae infected with a lethal dose of a VRE strain was significantly higher with antibiotic combination. Vancomycin-resistant Enterococcus faecium (VREfm) infections are increasing. Current anti-VREfm options (linezolid and daptomycin) are suboptimal. Fosfomycin maintains good efficacy against VREfm and chloramphenicol is active against ≥ 90% of VREfm. We tested chloramphenicol + fosfomycin (CAF+FOS) against 10 VREfm isolated from blood. MICs were 64 to 512 µg/mL for fosfomycin and 8 to 16 µg/mL for chloramphenicol. The combination decreased both MICs, with a synergic effect in 50% of the isolates and an additive effect in the remaining 50%. Time-kill assays performed on fractional inhibitory concentration index ≤ 0.5 strains confirmed the synergism. The antibiotic combination at ¼ of minimum inhibitory concentrations (MICs) caused a ≥ 2 log10 reduction compared to the two antibiotics alone. Finally, we provided a proof of concept of the in vitro efficacy of CAF+FOS in G. mellonella. The survival of G. mellonella larvae treated with the combination was significantly higher. The activity of fosfomycin and chloramphenicol against VREfm increases when they are used in combination.