In vitro and in vivo Antibacterial Activity of Linezolid Plus Fosfomycin Against Staphylococcus aureus with Resistance to One Drug

Na Xie,1 Lifang Jiang,1 Mingtao Chen,1 Guijun Zhang,1 Yanyan Liu,2 Jiabin Li,2 Xiaohui Huang1 1Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Xiaohui HuangDepartment of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, Anhui Province, 230032, People’s Republic of ChinaTel +86 138 5518 3138Email math2088@163.comJiabin LiDepartment of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Jixi Road, 218#, Hefei, Anhui Province, 230032, People’s Republic of ChinaFax +86 551 62922713Email lijiabin@ahmu.edu.cnObjective: The purpose of this study is to assess the in vitro/vivo activities of linezolid plus fosfomycin against Staphylococcus aureus (S. aureus) isolates with varying susceptibility to the study drugs.Methods: The increasing concentration stepwise method was used to induce S. aureus resistant strains. The in vitro antibacterial activity of linezolid combined with fosfomycin against S. aureus in vitro was studied by time-kill curve and PAE. The transmission electron microscopy (TEM) was employed to observe the cell morphology of bacteria treated with drug, and the changes of cell wall thickness were recorded. The Galleria mellonella infection model was established to demonstrate the in vivo efficacy of linezolid and fosfomycin against S. aureus with varying susceptibility.Results: The antibiotic combination showed excellent synergistic or additive effects on the original and the linezolid-resistant strain, but showed indifferent effect for fosfomycin-resistant strain. TEM images showed that fosfomycin alone and in combined could reduce the cell wall thickness of the strains resistant to linezolid and cell lysis, while linezolid increases the cell wall thickness of the strains resistant to fosfomycin. In the Galleria mellonella infection model, the survival rate of the antibiotic combined was improved compared with that of the single drug. There was a good correlation between in vivo efficacy and in vitro susceptibility.Conclusion: The type of interaction expressed in the test combination was highly dependent on fosfomycin resistance.Keywords: linezolid, fosfomycin, interaction, resistant, Staphylococcus aureus, Galleria mellonella