Population Pharmacokinetics of Intravenous Linezolid in Premature Infants

Abstract

Background: The emergence of coagulase-negative staphylococci with reduced vancomycin susceptibility in some neonatal intensive care units has resulted in an increase of linezolid use. Linezolid pharmacokinetics (PK) and safety in premature infants still need to be better established.

Methods: This was a retrospective PK study. All infants who received intravenous linezolid and had linezolid plasma concentrations per standard of care were included. Linezolid concentrations were measured by high performance liquid chromatography. A population PK model was developed using nonlinear mixed effects modeling. Optimal dosing was determined based on achievement of the surrogate pharmacodynamics target for efficacy: a ratio of the area under the concentration-time curve to minimum inhibitory concentration >80. We assessed the occurrence of thrombocytopenia and lactic acidosis in relation with drug exposure.

Results: A total of 78 plasma concentrations were collected from 26 infants, with a median postnatal age (PNA) of 24 days (8-88) and weight of 1423 g (810-3256). A 1-compartment model described linezolid data well. The final model included PNA and weight on clearance and weight on volume of distribution. Considering an MIC90 of 1 mg/L, all infants reached an area under the concentration-time curve/minimum inhibitory concentration > 80. Although thrombocytopenia and hyperlactatemia occurred frequently, they were not sustained and were not considered related to linezolid.

Conclusion: and was well tolerated in critically ill premature infants. PNA was the main determinant of clearance.