Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics.
Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children ≥12 months;n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach.
Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (±sd) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 ± 1.1 h, 0.34 ± 0.15 liter/h/kg and 0.73 ± 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug.
Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.