Pharmacodynamics of linezolid-plus-fosfomycin against vancomycin-susceptible and -resistant enterococci in vitro and in vivo of a Galleria mellonella larval infection model

Abstract

25Objective: To explore the in vitro and in vivo antibacterial activity of 26 linezolid/fosfomycin combination against vancomycin-susceptible and -resistant 27 enterococci (VSE and VRE), providing theoretical basis for the treatment of VRE. 28Methods: The checkerboard method and time-kill curve study were used to evaluate 29 the synergistic effect of linezolid combined with fosfomycin against VSE and VRE. 30The transmission electron microscopy (TEM) was employed to observe the bacterial 31 cell morphology followed by each drug alone and in combination, elucidating the 32 possible result of antibiotic combination therapy. The Galleria mellonella infection 33 model was constructed to demonstrate the in vivo efficacy of linezolid plus 34 fosfomycin for VSE and VRE infection.35 Results: The fractional inhibitory concentration index (FICI) values of all strains 36 suggested that linezolid showed synergy or additivity in combination with fosfomycin 37 against five of the six strains. Time-kill experiments demonstrated that the 38 combination of linezolid-fosfomycin at 1MIC or 2MIC led to higher degree of 39 bacterial killing without regrowth for all isolates tested than each monotherapy. TEM 40 imaging showed that the combination treatment damaged the bacterial cell 41 morphology more obviously than each drug alone. In the Galleria mellonella infection 42 model, the enhanced survival rate of the combination treatment was revealed 43 compared to linezolid monotherapy (P<0.05). 44 Conclusions: Our data manifest that the combination of linezolid and fosfomycin may 45 be a possible therapeutic regimen for VRE infection. The combination displays 46 excellent bacterial killing and inhibits amplification of fosfomycin-resistant 47 subpopulations.48

Factorial design and post-antibiotic sub-MIC effects of linezolid combined with fosfomycin against vancomycin-resistant enterococci

“…The synergistic effect of linezolid combined with fosfomycin against Staphylococcus aureus and enterococci has been reported previously (14,33,34). We chose different types of enterococci in the present study; however, the results of FICI for the 2-drug combination are similar to those of Qi et al (14). The results all suggested that the 2-drug combination has a synergistic or an additive effect against VREs, including vancomycin low-level resistant strains.…”

“…In recent years, potential treatment options have included linezolid and fosfomycin (3,31,32). The synergistic effect of linezolid combined with fosfomycin against Staphylococcus aureus and enterococci has been reported previously (14,33,34). We chose different types of enterococci in the present study; however, the results of FICI for the 2-drug combination are similar to those of Qi et al (14).…”

“…Due to its uncommon cross-resistance, fosfomycin is often used in combination with other drugs for severe infections to avoid the selection of resistant mutants (13). Qi et al (14) suggested linezolid in combination with fosfomycin as a potential treatment for VRE infection. In a study of the synergistic combination of linezolid and fosfomycin, Jiang et al (15) showed that the combination effectively inhibits the selection of enterococcal-resistant mutants by closing each other's mutant selection window.…”