Pharmacokinetic/pharmacodynamic integration of linezolid alone and in combination with fosfomycin against methicillin-resistant Staphylococcus aureus in a neutropenic murine thigh infection model

• Linezolid–fosfomycin combination reduced the linezolid f AUC/MIC required for efficacy by 1.4–6.4-fold. • The combination synergistically narrowed the mutant selection window (MSW) of both drugs against MRSA. • At equivalent linezolid doses, the combination increased the % f T>MPC of linezolid by 1.7–4.8-fold compared with monotherapy. This study sought to compare the pharmacokinetic-pharmacodynamic (PK/PD) targets of linezolid against methicillin-resistant Staphylococcus aureus (MRSA) in monotherapy versus combination with fosfomycin. We assessed the antibacterial effect of linezolid plus fosfomycin, followed by determination of the mutant prevention concentrations (MPCs) under both individual and combined regimens. Next, using a neutropenic murine thigh infection model, we determined the pharmacokinetics of linezolid and evaluated its efficacy following administration as monotherapy or in combination with fosfomycin. PK/PD analysis was subsequently conducted using an E max model. Finally, we compared the % f T>MPC (the percentage of the dosing interval during which free drug concentrations exceeded the MPC) of linezolid between its monotherapy and combination therapy with fosfomycin. Combination therapy enhanced bactericidal activity against MRSA and reduced the MPCs of the agents, thereby narrowing the mutant selection window (MSW). Addition of fosfomycin significantly improved linezolid efficacy in the MRSA thigh infection model. For linezolid, the f AUC/MIC values required for stasis, 1-log 10 kill, and 2-log 10 kill were 18.01, 47.87, and 225.07, respectively. When administered together, fosfomycin reduced the required f AUC/MIC of linezolid by 1.4–6.4-fold. At equivalent linezolid doses, combination therapy increased linezolid % f T>MPC by 1.7–4.8-fold. Combined linezolid and fosfomycin therapy enhances in vivo anti-MRSA efficacy, reduces the risk of resistance emergence, and lowers the exposure requirements for linezolid.