Pharmacodynamics Of Linezolid-Plus-Fosfomycin Against Vancomycin-Susceptible And -Resistant Enterococci In Vitro And In Vivo Of A Galleria mellonella Larval Infection Model

Objectives: To explore the in vitro and in vivo antibacterial activity of linezolid/fosfomycin combination against vancomycin-susceptible and -resistant enterococci (VSE and VRE), and provide a theoretical basis for the treatment of VRE. Methods: The checkerboard method and time-kill curve study were used to evaluate the efficacy of linezolid combined with fosfomycin against VSE and VRE. The transmission electron microscopy (TEM) was employed to observe the cell morphology of bacteria treated with each drug alone or in combination, which further elucidate the mechanism of action of antibiotic combination therapy. The Galleria mellonella infection model was constructed to demonstrate the in vivo efficacy of linezolid plus fosfomycin for VSE and VRE infection. Results: The fractional inhibitory concentration index (FICI) values of all strains suggested that linezolid showed synergy or additivity in combination with fosfomycin against five of the six strains. Time-kill experiments demonstrated that the combination of linezolid-fosfomycin at 1 xMIC or 2xMIC led to higher degree of bacterial killing without regrowth for all isolates tested than each monotherapy. TEM images showed that the combination treatment damaged the bacterial cell morphology more obviously than each drug alone. In the Galleria mellonella infection model, the enhanced survival rate of the combination treatment compared with linezolid monotherapy (P<0.05) was revealed. Conclusion: Our data manifested that the combination of linezolid and fosfomycin was a potential therapeutic regimen for VRE infection. The combination displayed excellent bacterial killing and inhibited amplification of fosfomycin-resistant subpopulations.