Tobramycin population pharmacokinetics in neonates*

Objective: To establish a tobramycin dosing schedule for neonates of various gestational ages.Methods: This was a retrospective study with prospective validation. A retrospective study in 470 neonates, with suspected speticemia in the first week of life, was performed. All patients received tobramycin according to the following scheme: neonates with a gestational age of less than 28 weeks received 3.5 mg/kg every 24 hours, neonates from 28 to 36 weeks received 2.5 mg/kg every 18 hours, neonates older than 36 weeks received 2.5 mg/kg every 12 hours. Trough and peak tobramycin serum levels were determined before drug administration and 30 minutes after the fourth dose. Tobramycin data were analyzed according to a one-compartment open model with use of NONMEM population pharmacokinetic software. Individual empirical Bayes estimates were generated on the basis of the population estimates and used to calculate predicted peak and trough levels for different doses and dosing intervals. To establish an optimal dosing regimen, target trough levels were set at below 2 mg/L and target peak levels were set above 5 to 10 mg/L. The dosing regimen was prospectively evaluated in 23 patients.Results: Of the 470 patients, 19.1% of measured peak and 32.8% of measured trough tobramycin serum levels were outside the desired therapeutic range, and 48.8% of neonates with a gestational age of less than 28 weeks had an aberrant trough level. With use of population estimates, the following dosing regimen was recommended: gestational age below 32 weeks, 4 mg/kg every 48 hours; gestational age between 32 and 37 weeks, 4 mg/kg every 36 hours, gestational age above 37 weeks, 4 mg/kg every 24 hours. With this dosing schedule, predicted peak levels were higher than 5 mg/L in 95.1% of the neonates. Predicted trough levels were higher than 2 mg/L in 1.9% of the neonates and higher than 1 mg/L in 7.6%. Prospectively measured peak levels were higher than 5 mg/L in all but one infant. Measured trough levels were higher than 2 mg/L in three patients and marginally higher than 1 mg/L in four patients.Conclusions: With the use of this proposed schedule, taking into account differences in gestational ages, predicted peak levels will be therapeutic, whereas predicted trough levels will minimize toxicity.