<p>Pharmacodynamics Of Linezolid-Plus-Fosfomycin Against Vancomycin-Susceptible And -Resistant Enterococci In Vitro And In Vivo Of A <em>Galleria mellonella</em> Larval Infection Model</p>

Abstract

ObjectivesTo explore the in vitro and in vivo antibacterial activity of linezolid/fosfomycin combination against vancomycin-susceptible and -resistant enterococci (VSE and VRE), and provide a theoretical basis for the treatment of VRE.MethodsThe checkerboard method and time-kill curve study were used to evaluate the efficacy of linezolid combined with fosfomycin against VSE and VRE. The transmission electron microscopy (TEM) was employed to observe the cell morphology of bacteria treated with each drug alone or in combination, which further elucidate the mechanism of action of antibiotic combination therapy. The Galleria mellonella infection model was constructed to demonstrate the in vivo efficacy of linezolid plus fosfomycin for VSE and VRE infection.ResultsThe fractional inhibitory concentration index (FICI) values of all strains suggested that linezolid showed synergy or additivity in combination with fosfomycin against five of the six strains. Time-kill experiments demonstrated that the combination of linezolid-fosfomycin at 1×MIC or 2×MIC led to higher degree of bacterial killing without regrowth for all isolates tested than each monotherapy. TEM images showed that the combination treatment damaged the bacterial cell morphology more obviously than each drug alone. In the Galleria mellonella infection model, the enhanced survival rate of the combination treatment compared with linezolid monotherapy (P<0.05) was revealed.ConclusionOur data manifested that the combination of linezolid and fosfomycin was a potential therapeutic regimen for VRE infection. The combination displayed excellent bacterial killing and inhibited amplification of fosfomycin-resistant subpopulations.

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

“…In this study, the FICI values of 43 strains indicated that linezolid-fosfomycin combination showed synergistic or additive effect on 69.8% of the tested strains and no antagonistic effects was observed. Consistent with this experiment, the synergistic antibacterial activity of the linezolid-fosfomycin combination against Staphylococcus aureus and Enterococcus was also confirmed in vitro time-killing curve ( Chai et al, 2016 ; Chen et al, 2018 ; Qi et al, 2019 ). However, research on the combination to prevent resistance was still lacking.…”

“…Fosfomycin, due to its unique mechanism of action, has a synergistic effect with a variety of antibiotics and is not easy to produce cross-resistance ( Falagas et al, 2016 ). The previous study of our group confirmed that linezolid combined with fosfomycin has an in vitro synergistic effect on Enterococcus and Staphylococcus aureus ( Chen et al, 2018 ; Qi et al, 2019 ). However, the ability of the combination to prevent enterococcus resistance remains to be studied.…”

“…Checkerboard assay was used for the synergy testing. Tests were performed on 96-well plates according to our previous study ( Qi et al, 2019 ), the two drugs were diluted with Mueller-Hinton Broth into a series of concentrations based on the MICs for each tested isolate. In brief, linezolid ranging between 1/64 × MIC and 2 × MIC was dispensed in each column.…”

Alternatives to Fight Vancomycin-Resistant Staphylococci and Enterococci

“…Combinations of vancomycin with oritavancin have also been tested but have not shown better results than individual treatments with the antibiotics [ 66 ]. The combination of linezolid with fosfomycin is promising, as it has been shown that synergy is possible between these two molecules in the G. mellonella larvae model [ 67 ]. The authors supposed that fosfomycin, by acting on cell wall synthesis via MurA inhibition, promotes linezolid penetration, showing increased activity on both VRE [ 67 ] and MRSA ( Figure 1 ) [ 68 , 69 ].…”

“…The combination of linezolid with fosfomycin is promising, as it has been shown that synergy is possible between these two molecules in the G. mellonella larvae model [ 67 ]. The authors supposed that fosfomycin, by acting on cell wall synthesis via MurA inhibition, promotes linezolid penetration, showing increased activity on both VRE [ 67 ] and MRSA ( Figure 1 ) [ 68 , 69 ]. In addition, an activity on biofilms of vancomycin resistant E. faecium has been demonstrated with this combination [ 69 ].…”