Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia*

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Abstract
Objective: To determine the steady-state plasma pharmacokinetic variables and epithelial lining fluid concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Design: Prospective, open-label study. Setting: An intensive care unit and research ward in a university hospital. Patients: Sixteen critically ill adult patients with ventilator-associated pneumonia. Interventions: All subjects received 1-hr intravenous infusions of linezolid 600 mg twice daily. After 2 days of therapy, the steady-state plasma pharmacokinetic variables and epithelial lining fluid concentrations of linezolid were determined by high-performance liquid chromatography. Measurements and Main Results: The mean ± sd linezolid peak and trough concentrations were 17.7 ± 4.0 mg/L and 2.4 ± 1.2 mg/L in plasma and 14.4 ± 5.6 mg/L and 2.6 ± 1.7 mg/L in epithelial lining fluid, respectively, showing a mean linezolid percentage penetration in epithelial lining fluid of approximately 100%. The mean ± sd area under concentration-time curve during the observational period (AUC0–12) was 77.3 ± 23.7 mg·hr/L, corresponding to a mean AUC0–24 of 154.6 mg·hr/L. Conclusions: Our study shows satisfactory results, with linezolid concentrations exceeding the susceptibility breakpoint for Gram-positive bacteria in both plasma and epithelial lining fluid. This suggests that a dosage of 600 mg administered intravenously twice daily to critically ill patients with Gram-positive ventilator-associated pneumonia would achieve success against organisms with minimum inhibitory concentrations as high as 2–4 mg/L in both plasma and epithelial lining fluid.

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