Population Pharmacokinetics and Pharmacodynamic Target Attainment of Meropenem in Critically Ill Young Children

Objective: This study aims to describe the population pharmacokinetics and pharmacodynamic target attainment of meropenem in critically ill children.

Methods: The study involved a retrospective medical record review from a 189-bed, freestanding children's tertiary care teaching hospital of patients ages 1 to 9 years who received meropenem with concurrent therapeutic drug monitoring.

Results: There were 9 patients ages 1 to 9 years (mean age, 3.1 ± 2.9 years) with a mean weight of 17.1 ± 11.9 kg who met the inclusion/exclusion criteria and were included in the pharmacokinetic analysis. Meropenem concentrations were best described by a 2-compartment model with first-order elimination, with an R² and bias of 0.91 and 13.2 mg/L, respectively, for the observed versus population predicted concentrations, and an R², bias, and imprecision of 1, 0.0675, and 1 mg/L, respectively, for the observed versus individual predicted concentrations. The mean total body drug clearance for the population was 6.99 ± 2.5 mL/min/kg, and V_c was 0.57 ± 0.47 L/kg. The calculated population estimate for the total volume of distribution was 0.78 ± 0.73 L/kg. Standard 0.5-hour meropenem infusions did not provide for appropriate pharmacodynamic exposures of 40% free time > minimum inhibitory concentration (40% fT > MIC) for Gram-negative organisms with susceptible MICs. Dosage regimens employing prolonged and continuous infusion regimens did provide appropriate pharmacodynamic exposures of 40% fT > MIC for Gram-negative organisms up to the break point for Pseudomonas aeruginosa of 4 mg/L.

Conclusion: These data suggest the reference dosage regimens for meropenem (20-40 mg/kg per dose every 8 hours) do not meet an appropriate pharmacodynamic target attainment in critically ill children ages 1 to 9 years. Based on these data, only the 3- to 4-hour prolonged infusion and 24-hour continuous infusion regimens were able to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 40% fT > MIC. Dosage regimens of 120 and 160 mg/kg/day as continuous infusion regimens may be necessary to achieve an optimal probability of target attainment against all susceptible Gram-negative bacteria in critically ill children for 80% fT > MIC. Based on these findings, confirmation with a larger, prospective investigation in critically ill children is warranted.