Determination of Tissue Penetration and Pharmacokinetics of Linezolid in Patients with Diabetic Foot Infections Using In Vivo Microdialysis

Abstract

Staphylococcus aureus and other Gram-positive organisms, including methicillin-resistant S. aureus , continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of in vivo microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ± standard deviations (SD) for the maximum concentration in serum ( C _max ), the volume of distribution at terminal phase ( V _z ), and the half-life ( t _1/2 ) for linezolid in plasma were 11.99 ± 3.67 μg/ml, 0.71 ± 0.25 liters/kg of body weight, and 4.71 ± 1.23 h, respectively. Mean protein binding was 14.78% (range, 3.85 to 32.03%). The mean areas under the concentration-time curves from 0 to 12 h for the free, unbound fraction of linezolid ( f AUC _0–12 values) ± SD for plasma, wound tissue, and thigh tissue were 51.24 ± 12.72, 82.76 ± 59.01, and 92.52 ± 60.44 μg · h/ml, respectively. Tissue penetration ratios (tissue f AUC to plasma f AUC) were similar for thigh (1.42; range, 1.08 to 2.23) and wound (1.27; range, 0.86 to 2.26) tissues ( P = 0.648). With the currently approved dosing regimen, linezolid penetrated well into both healthy thigh tissue and infected wound tissue in these diabetic patients.