Activity Of Linezolid Combined With Fosfomycin In Vitro And In A Murine Model Of Peritonitis Due To Clinical Isolates Of Vancomycin-Resistant-Enterococci

Objective The aim of this study was to investigate the in vitro and in vivo efficacies of linezolid plus fosfomycin against clinical vancomycin-resistant-enterococci isolate.Methods One VRE(N1809)and one vancomycin-susceptible-enterococci(N859)were tested.ATCC 29212 and ATCC 51299 were control strains.In vitro,the sensitivity of linezolid(LIN)alone and combined with fosfomycin(FOS)to four experimental strains was analyzed by checkerboard method and time-kill experiment,and the minimum inhibitory concentration(MIC),fractional inhibitory concentration index(FICI)and time-kill curve was obtained.In addition,the plate colony count method was used to determine the PAE value and bacterial recovery growth curve of three strains of tested exposed to different concentrations of linezolid and fosfomycin alone or combination,which were used to evaluate the post-antibiotic effect(PAE).In vivo,a clinically isolated vancomycin-resistant enterococci(N1809)was selected to establish a mouse model of peritonitis by intraperitoneal injection of a mixed bacterial suspension.After 2 hours of infection,treatment was started in the control group and the treatment group.The treatment cycle was 25 hours.The mortality of mice in different groups was counted and all mice were sacrificed after the end of treatment.The peritoneal fluid(PF),liver tissue and spleen tissue were collected and homogenized for bacterial count.The therapeutic effect was evaluated and statistical analysis was performed.Results The checkerboard studies showed additive effect for N1809 and Synergistic effects for N859.No antagonism was observed.Linezolid in combination with fosfomycin at 1x MIC and above in the kill curve was bacteriostatic and produced a additive effect for all test strains.In addition,both the antibiotics combination showed increased PAE values compared with LIN and FOS monotherapies and have a concentration and time-dependent manner for N1809(VRE)and N859(VSE).In the animal model,the survival rate at 25 h post-inoculation was similar and no death occurred in the combination group and the linezolid monotherapy group compared with FOS group and the control group.However,LIN in combination with FOS significantly decreased the number of viable bacteria in the different infection sites,and there was a statistical difference(P < 0.05).Conclusion The present study indicated linezolid in combination with fosfomycin showed good efficacy against vancomycin-resistant-enterococci in terms of checkerboard,time-kill,the post-antibiotic effect experiments and animal experiment results in bacterial killing and survival rate.This combination might be considered as therapeutic options to treat deep-seated or severe VRE infection such as peritonitis.