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

Abstract

BackgroundAntimicrobial drug resistance, including vancomycin-resistant enterococci (VRE), has long been an inescapable clinical problem. If vancomycin loose its therapeutic relevance, a regimen of linezolid combined with fosfomycin may provide an alternative option.MethodsIn this study, the in vitro antimicrobial effect of linezolid combined with fosfomycin on several different types of VRE was investigated using a checkerboard method and time-kill assays. Based on the results of the 24 h time-kill assays, a 22 factorial design was then adopted. Finally, the post-antibiotic effect (PAE), post-antibiotic sub-minimum inhibitory concentration effect (PASME), and single sub-minimum inhibitory concentration effect (SME) of a combination of the two drugs on three selected strains was examined.ResultsThe checkerboard method and factorial design analysis showed that linezolid combined with fosfomycin not only had synergistic and additive effects but also had an interactive effect on VREs. The time-kill assays showed that 1× minimum inhibitory concentration (MIC) of linezolid combined with 1× MIC or 1/4× MIC of fosfomycin had no statistically significant difference in the bactericidal effect against VRE at 24 h (P>0.05). The combination of the two drugs did not significantly extend the PAE or the SME; however, in relation to 1/4× MIC, the combination of the two drugs significantly prolonged the duration of the PASME compared to that of a single drug on VREs (P<0.05; with values of 1.97±0.01, 4.32±0.18, and 1.74±0.13 h, respectively).ConclusionsOur results showed that when linezolid is selected for the treatment of VRE infections, sub-inhibitory concentrations of fosfomycin can be administered at multiple intervals to improve the therapeutic effect.