Pharmacodynamics of Linezolid Plus Fosfomycin Against Vancomycin–Resistant Enterococcus faecium in a Hollow Fiber Infection Model

Abstract

The optimal therapy for severe infections caused by vancomycin-resistant Enterococcus faecium (VREfm) remains unclear, but the combination of linezolid and fosfomycin may be a good choice. The 24-h static-concentration time-kill study (SCTK) was used to preliminarily explore the pharmacodynamics of linezolid combined with fosfomycin against three clinical isolates. Subsequently, a hollow-fibre infection model (HFIM) was used for the first time to further investigate the pharmacodynamic activity of the co-administration regimen against selected isolates over 72 h. To further quantify the relationship between fosfomycin resistance and bacterial virulence in VREfm, the Galleria mellonella infection model and virulence genes expression experiments were also performed. The results of SCTK showed that the combination of linezolid and fosfomycin had additive effect on all strains. In the HFIM, the dosage regimen of linezolid (12 mg/L, steady-state concentration) combined with fosfomycin (8 g administered intravenously every 8 h as a 1 h infusion) not only produced a sustained bactericidal effect of 3∼4 log10 CFU/mL over 72 h, but also completely eradicated the resistant subpopulations. The expression of virulence genes was down-regulated to at least 0.222-fold in fosfomycin-resistant strains compared with baseline isolate, while survival rates of G. mellonella was increased (G. mellonella survival ≥45% at 72 h). For severe infections caused by VREfm, neither linezolid nor fosfomycin monotherapy regimens inhibited amplification of the resistant subpopulations, and the development of fosfomycin resistance was at the expense of the virulence of VREfm. The combination of linezolid with fosfomycin produced a sustained bactericidal effect and completely eradicated the resistant subpopulations. Linezolid plus Fosfomycin is a promising combination for therapy of severe infections caused by VREfm.

Assessing the Emergence of Resistance in vitro and Invivo: Linezolid Combined with Fosfomycin Against Fosfomycin-Sensitive and Resistant Enterococcus

“… 56 Wang et al further found that the downregulation of the virulence of fosfomycin was concentration-dependent on the fosfomycin-resistant mutants obtained from the hollow fiber model. 24 Subsequently, RT-qPCR revealed that the overall virulence factor of the mutant decreased, with cylA and esp showing a decreasing trend on average, while asaL showed a slightly increasing trend at NO.24. A similar situation was found in previous studies of daptomycin-resistant methicillin-resistant Staphylococcus aureus and artificially induced Streptococcus that acquired daptomycin resistance.…”

“… 23 Thus, the difference in treatment may be related to this hypothesis, as shown by Wang’s study; VRE virulence gene expression (especially acm ) and mortality of G. mellonella decreased with an increase in fosfomycin resistance, and virulence of the strain presumably decreased with an increase in fosfomycin resistance. 24 In addition, competition of Enterococcus strains to acquire fosfomycin resistance has not been reported yet. Studies on Enterococcus have mostly focused on in vitro rather than in vivo competition.…”

The Application of Hollow Fiber Cartridge in Biomedicine

“…Fosfomycin resistance develops readily in vitro but less so in vivo. This discordance, at least partly, can be attributed to the function of the immune system in vivo and the lower likelihood that fosfomycin was selected in acidic environments [ 28 ]. At present, the temperature, sampling, and pump flow of the whole system can be controlled through computer to improve the experimental efficiency [ 9 ].…”

“…An increasing number of reports on the isolation of resistant pathogens combined with a weak antibiotic pipeline suggests that optimization of antibiotic therapy should be aimed at the suppression of resistance [ 37 ]. However, previous studies are limited by the continuous antibiotic concentration of more than 24 h, which is difficult to guide clinical rational drug use, and it is more difficult to explain the development of drug resistance from a quantitative perspective [ 28 ]. As an in vitro model, HFIM can determine when and at what dosage bacteria develop resistance and study the mechanism of resistance by related genetic testing techniques.…”

Fosfomycin Enhances the Inhibition Ability of Linezolid Against Biofilms of Vancomycin-Resistant Enterococcus faecium in vitro

“… 13 , 14 We also got the conclusion that, for VRE strains, neither linezolid nor fosfomycin monotherapy inhibited amplification of the resistant sub-populations, and the development of fosfomycin resistance was at the expense of the virulence of VRE fm . 15 Fosfomycin plus linezolid or tigecycline showed synergism on VRE in time-kill studies of approximately 10% and 30%, respectively. 16 The combination of oritavancin and fosfomycin increased drug susceptibility and showed a synergistic effect in 80% of isolates and an additive effect in the remaining isolates.…”