Dose Optimization of Combined Linezolid and Fosfomycin against by Using an Pharmacokinetic/Pharmacodynamic Model.

The rapid spread of antibiotic resistance among has prompted considerable interest in determining the dosage regimen of linezolid combined with fosfomycin. A checkerboard assay was employed to evaluate whether linezolid combined with fosfomycin had a synergistic effect on isolates from the hospital, including three drug-resistant strains (MIC of linezolid [MIC], ≥8 mg/L; MIC of fosfomycin [MIC], ≥256 mg/L). The static time-kill assay, dynamic pharmacokinetic (PK)/pharmacodynamic (PD) model, and semimechanistic PK/PD model were used to explore and predict effective combined dosage regimens. The checkerboard assay and static time-kill assay demonstrated that linezolid combined with fosfomycin has a synergistic effect on drug-resistant and sensitive . In the PK/PD model, the dosage regimen of linezolid (8 mg/L or 12 mg/L, steady-state concentration) combined with fosfomycin (6 g or 8 g) via a 0.5-h infusion every 8 h effectively suppressed bacterial growth at 24 h with a 3 log CFU/mL decrease compared with the initial inocula against two resistant and one sensitive isolates. The semimechanistic PK/PD model predicted that linezolid (more than 16 mg/L) combined with fosfomycin (6 g or 10 g) via a 0.5-h infusion every 8 h was required to achieve a 4 log CFU/mL decrease at 24 h against isolates (MIC ≥ 8 mg/L and MIC ≥ 256 mg/L). According to the prediction of the semimechanical PK/PD model, the effect of the combination was driven by linezolid, with fosfomycin enhancing the effect. Our study is the first to explore the synergistic effects of these two drugs from a qualitative and quantitative perspective and provides a simulation tool for future studies. In this study, we found that linezolid combined with fosfomycin could kill and that the administered dose was significantly lower after the combination treatment, which could reduce adverse effects and the development of drug resistance. The potential mechanism of the two-drug combination against was revealed from a quantitative perspective, which is an important step toward dose optimization in simulated humans. We hope that our research will help build a better relationship between clinicians and patients as we work together to address the challenges of antibiotic resistance in the 21st century.