ObjectivesLinezolid combination therapy is recommended for the treatment of Staphylococcus aureus (S. aureus) infections. However, the optimal regimen of the combination therapy for S. aureus is unknown. The objective of this study was to investigate the antibacterial activity, post-antibiotic effect (PAE), and post-antibiotic subminimum inhibitory concentration (MIC) effect (PA-SME) of linezolid alone and in combination with fosfomycin against eleven clinical isolates of S. aureus.MethodsThe synergistic effects and antibacterial activity of linezolid and fosfomycin were assessed by checkerboard and time-kill assays. To determine the PAE and PA-SME, S. aureus strains in the logarithmic phase of growth were exposed for 1, 2, and 3 hours to the antibiotics, alone and in combination. Recovery periods of test strains were evaluated using viable counting after dilution.ResultsSynergistic effects were observed for eight strains and no antagonism was found with any combination. Moreover, linezolid combined with fosfomycin at 4x MIC showed the best synergistic antibacterial effect, and this effect was retained after 24 hours. In addition, both the antibiotics alone and in combination showed increased PAE and PA-SME values in a concentration- and time-dependent manner.ConclusionLinezolid combined with fosfomycin exerted a good antibacterial effect against S. aureus, and the combinations have significant PAE and PA-SME.

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ObjectivesTo 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.MethodsThe 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.ResultsThe 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×MIC or 2×MIC 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.ConclusionOur 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.

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