Synergistic Combination of Linezolid and Fosfomycin Closing Each Other's Mutant Selection Window to Prevent Enterococcal Resistance.

Lifang Jiang,Xiaohui Huang,Na Xie,Shuaishuai Wang,Mingtao Chen,Jun Mao,Yanyan Liu,Jiabin Li

doi:10.3389/fmicb.2020.605962

Abstract

Enterococci, the main pathogens associated with nosocomial infections, are resistant to many common antibacterial drugs including β-lactams, aminoglycosides, etc. Combination therapy is considered an effective way to prevent bacterial resistance. Preliminary studies in our group have shown that linezolid combined with fosfomycin has synergistic or additive antibacterial activity against enterococci, while the ability of the combination to prevent resistance remains unknown. In this study, we determined mutant prevention concentration (MPC) and mutant selection window (MSW) of linezolid, fosfomycin alone and in combination including different proportions for five clinical isolates of Enterococcus and characterized the resistance mechanism for resistant mutants. The results indicated that different proportions of linezolid combined with fosfomycin had presented different MPCs and MSWs. Compared with linezolid or fosfomycin alone, the combination can restrict the enrichment of resistant mutants at a lower concentration. A rough positive correlation between the selection index (SI) of the two agents in combination and the fractional inhibitory concentration index (FICI) of the combination displayed that the smaller FICI of linezolid and fosfomycin, the more probable their MSWs were to close each other. Mutations in ribosomal proteins (L3 and L4) were the mechanisms for linezolid resistant mutants. Among the fosfomycin-resistant mutants, only two strains have detected the MurA gene mutation related to fosfomycin resistance. In conclusion, the synergistic combination of linezolid and fosfomycin closing each other’s MSW could effectively suppress the selection of enterococcus resistant mutants, suggesting that the combination may be an alternative for preventing enterococcal resistance. In this study, the resistance mechanism of fosfomycin remains to be further studied.

Highlights

Enterococci are one of prominent causes of hospital acquired infection, especially in urinary tract, soft tissue, and deviceassociated infections (Fiore et al, 2019; García-Solache and Rice, 2019)
For the five selected isolates with different fractional inhibitory concentration index (FICI) values, their MIC99% alone, mutant prevention concentration (MPC) alone of the two antimicrobial agents were listed on Table 1
For the five tested isolates, the MPCs of linezolid used alone ranged from 8.0 to 25.6 mg/L, while MPC/minimum inhibitory concentration (MIC) ratio was in the range of 3–6

Summary

Introduction

Enterococci are one of prominent causes of hospital acquired infection, especially in urinary tract, soft tissue, and deviceassociated infections (Fiore et al, 2019; García-Solache and Rice, 2019). Enterococcus faecalis and Enterococcus faecium are the main pathogenic bacteria of enterococcal infections (Gilmore et al, 2013). Both the two species shown intrinsic resistance to common antibiotics historically used as front-line agents, making enterococcal infection to be a serious threat to public health (Mercuro et al, 2018; Torres et al, 2018; Haghi et al, 2019). Clinical studies shown that patients treated with antibacterial combination therapy can obtain good clinical effect and lower mortality rates (Falagas et al, 2014; Ni et al, 2015). There are few researches about combinations that can effectively prevent enterococcal resistance

Methods

Results

Conclusion