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

BACKGROUND: Antimicrobial 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. METHODS: In 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 2(2) 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. RESULTS: The 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). CONCLUSIONS: Our 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.