External Evaluation of a Plasma and Cerebrospinal Fluid Population Pharmacokinetics Model of Meropenem in Infants.

Abstract

Objective: Meropenem is commonly used to treat bloodstream and central nervous system (CNS) infections in preterm and term infants; however, the optimal dosage of meropenem in infants <3 months is not known, and its cerebrospinal fluid (CSF) pharmacokinetics (PK) are not well established in this age group.

Methods: We externally evaluated a previously developed meropenem population PK model using opportunistic plasma and CSF PK samples collected in infants and children <2 years of age who received intravenous meropenem per standard of care. We evaluated model performance, and simulated age-dependent dosing regimens (20 and 40 mg/kg every 8 hours [12 hours if gestational age <32 weeks and postnatal age <2 weeks]) to estimate the reduction in CSF bacterial burden.

Results: Clinical and PK data from 10 children were used to externally evaluate the NeoMero model; model predictive performance was satisfactory with the addition of NeoMero (n = 167) data. Visual predictive check of combined data showed reasonable concordance between predictions and observed concentrations for plasma and CSF. Dosing simulations adjusted for population minimum inhibitory concentration distributions for Pseudomonas aeruginosa estimated that a 20 mg/kg intravenous bolus dose reduced CSF bacterial burden by a weighted mean 5.13 (SD 1.51) log colony forming unit (CFU), while a 40 mg/kg intravenous bolus dose resulted in a weighted mean 5.48 (SD 1.14) log CFU reduction in CSF.

Conclusions: The original NeoMero model performed reasonably well, and the proposed dosing regimens, that is, 20 or 40 mg/kg every 8 hours (12 hours if gestational age <32 weeks and postnatal age <2 weeks), depending on target MIC are estimated to achieve substantial bacterial killing in the CNS.