Pharmacokinetic evaluation of linezolid in patients with major thermal injuries

Abstract

To evaluate the pharmacokinetics of linezolid following its administration in patients with major thermal injuries and in a group of healthy volunteers. In an open-label, multicentre design with two parallel groups, a group of patients with major thermal injuries (>20% body area) and a group of age-, sex- and weight-matched healthy volunteers, subjects received a single 600 mg intravenous dose of linezolid. Serial blood and urine collections were made and the concentrations of linezolid in these samples were determined by HPLC. Non-compartmental analyses were used to describe the pharmacokinetic disposition of linezolid. C_max concentrations and the volume of distribution at steady state (V_ss) were not statistically different (P > 0.05) between the two groups of subjects. In contrast, values describing clearance [elimination rate constant (k_el), t_1/2 and mean residence time (MRT)] were significantly different (P < 0.05) in patients with thermal injuries compared with volunteers, which lead to an approximate reduction by half in AUC_0–∞ from 98.1 mg·h/L (volunteers) to 42.5 mg·h/L (patients). Although renal clearance was similar in the two groups (24.7 ± 23 versus 30.6 ± 14.3 mL/min; P = 0.156), non-renal clearance was substantially increased (323 ± 191 versus 80.4 ± 27.5 mL/min) in the patients with thermal injuries, though this difference did not achieve statistical significance (P = 0.063). The pharmacokinetics of linezolid are altered in patients with major thermal injuries, mainly as a result of increased non-renal clearance. These changes are of sufficient magnitude that linezolid concentrations may be sub-therapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.