In Vitro Activity And Post-antibiotic Effects Of Linezolid In Combination With Fosfomycin Against Clinical Isolates Of Staphylococcus Aureus

Objective Linezolid combination therapy is recommended for the treatment S.aureus infections.However,the optimal regimen for S.aureus is unknown.This study was to investigate the in vitro activity,post-antibiotic effect(PAE)and post-antibiotic sub-MIC effect(PA-SME)of linezolid alone and combined with fosfomycin against S.aureus strains.Methods(1)A broth microdilution and checkerboard methods were applied to assess the synergism effect between linezolid and fosfomycin against 11 clinical isolates of Staphylococcus aureus(5 MSSA,5 MRSA and ATCC 25923),and then the Fractional inhibitoryconcentration index(FICI)was used to assessed results.(2)MRSA(No.36),MSSA(No.8)and ATCC 25923 were used in this study.Time-kill method was performed to assess linezolid alone and in combination with fosfomcyin.(3)Determined PAE and PA-SME of linezolid alone and in combination with fosfomcyin against S.aureus by plate colony counting in different concentrations anddifferent time points.Results(1)The MICs of linezolid againstS.aureus ATCC 25923 and 10 clinical strains were from 1 to 4 mg/L,while that of fosfomycin were 2 mg/L.The MBCs of linezolid were almost the same or lower than the fosfomycin.In addition,the results of MBC/MIC ratios indicated that these strains were not tolerant to linezolid and fosfomycin.The results of checkerboard method indicated synergism between linezolid and fosfomycin for all tested strains except No.24,14 and 55 strains.(2)In our time-kill studies,neither linezolid nor fosfomycin alone at 1 x MIC has poor effect on the S.aureus death.However,the antibacterial activity of the two drugs combined significantly increased,and with the increase of fosfomycin concentration increased.In addition,4 x MIC of linezolid combined with 4 x MIC of fosfomycin exhibited the best synergistic effect.(3)Linezolid alone and in combination with fosfomycin can produce significant PAE and PA-SME,and with the gradual extension of drug concentrations,showing a significant concentration-dependent.Additionally,although no statistically differences were found,the PAE also showed an increase as the exposure time of antibiotic was increased(P > 0.05).Conclusion(1)The combination between linezolid and fosfomycin against 11 S.aureuspresented synergistic action in vitro.No antagonism was found with any combination.(2)The combination has good antibacterial activity against MSSA and MRSA,and 4 x MIC of linezolid combined with 4 x MIC of fosfomycin exhibited the best synergistic effect by the results of time-kill studies.(3)Linezolid alone and in combination with fosfomycin can produce significant PAE and PA-SME,and with the increase in drug concentrations and contact time,showing a concentration and time dependent manner.