The Post-Antibiotic Sub-MIC Effect Of Linezolid Combined With Fosfomycin On Staphylococcus Aureus In Different Doses,Intervals And Sequences

Objective: Staphylococcus aureus(S.aureus)was used as the tested strain to determine the MIC,bactericidal curve,and PAE of linezolid(LNZ)and fosfomycin(FOS),and then conduct the related PA-SME study according to the measured MIC and PAE.From the perspective of PA-SME,to explore the dosage combination,administration interval,and administration sequence of linezolid combined with fosfomycin to have better antibacterial activity in vitro,and to provide a basis for rational clinical use of linezolid and fosfomycin in the treatment of MRSA infection.Methods: MIC and combined sensitivity of linezolid and fosfomycin were determined by the broth dilution method.The time-bactericidal curve of linezolid combined with fosfomycin and the MIC changes after drug treatment were determined by the agar plate culture.Three strains with good synergistic effects were selected for the determination of PAE in vitro.Linezolid and fosfomycin alone and combined PA-SME were determined by different administration sequence,interval,and dose.Results: Among the 10 strains of Staphylococcus aureus,linezolid combined with fosfomycin had a synergistic effect on 7 strains of Staphylococcus aureus,an additive effect on 3 strains of Staphylococcus aureus,and no antagonistic effect occurred.PAE results showed that the average PAE value of linezolid alone was 2.5 ± 0.25 h,the average PAE value of fosfomycin alone was 1.58 ± 0.29 h,and the average PAE value of linezolid combined with fosfomycin to the three strains of S.aureus was 2.89± 0.07 h.The results of PA-SME with different subinhibitory concentrations showed that the average PA-SME value of linezolid alone against the three strains of S.aureus was 0.1,0.2,and 0.3 MIC,respectively.At 2.92 ± 0.44 h,3.51 ± 0.62 h,4.04 ±0.55 h,the average PA-SME value of fosfomycin alone against the three strains of S.aureus was 0.1,0.2,0.3 MIC,respectively: At 1.42 ± 0.2 h,1.71 ± 0.42 h,1.85± 0.45 h,the average PA-SME values of linezolid combined with fosfomycin against the three strains of S.aureus were 0.1,0.2,0.3 MIC,respectively: 5.13 ± 0.27 h,6.3± 0.5 h,7.03 ± 0.4 h.The PA-SME obtained by adding subinhibitory concentration(sub-MIC)at the early stage of PAE was longer than that obtained at the late stage,and the difference was statistically significant(P < 0.05).When the administration sequence of linezolid and fosfomycin was changed,the combination of PA-SME was also affected.Both PAE and PA-SME have synergistic effects and concentration dependence.Conclusions: The combination of linezolid and fosfomycin showed a synergistic antibacterial effect in MIC,combined drug sensitivity,and bactericidal curve tests.Moreover,the combination of Fosfomycin and Fosfomycin had a protective effect on the drug resistance of the two drugs.The results of PAE and PA-SME showed that the combination of two drugs had weak synergistic PAE and good synergistic PA-SME.In this study,the PA-SME of linezolid and fosfomycin was studied by different dose,sequence,and interval,and the results suggested that the clinical administration regimen could be optimized by appropriately reducing the dose of the two drugs and extending the interval.