Optimising the meropenem dosing regimen in neonates: A dual-centre cohort study

To characterise meropenem pharmacokinetics in neonates and identify dosing regimens that optimize target attainment against common pathogens.

This retrospective dual-centre cohort study analysed opportunistic meropenem plasma concentrations measured using a validated HPLC-MS/MS method. Neonates with severe renal impairment were excluded. A population pharmacokinetic model was developed and externally validated. Monte Carlo simulations were used to evaluate the probability of target attainment and cumulative fraction of response (CFR) for traditional simple/prolonged-infusion (TSPI) and optimised two-step administration therapy (OTAT) regimens.

The analysis included 114 neonates. A one-compartment model with first-order elimination best described the data. Body weight at admission (WT) was a significant covariate for both clearance (CL) and volume of distribution (V_d), while congenital heart disease (CHD) was a significant covariate for clearance. Typical CL and V_d were 0.175 L/h and 0.403 L, respectively. External validation showed satisfactory predictive performance. For the aggressive target (100% f T > MIC), TSPI often required high doses (≥ 30 mg/kg every 8 h). All evaluated OTAT regimens (20 mg/kg per dose every 8-12 h) were predicted to achieve CFR ≥ 90% for both targets across the evaluated pathogens. Simulated steady-state peak concentrations increased with the bolus fraction; therefore, the 5 mg/kg bolus followed by infusion of the remaining 15 mg/kg was selected as the preferred OTAT regimen to limit unnecessary peak exposure.

WT and CHD significantly influence meropenem pharmacokinetics in neonates. The 5 + 15 mg/kg OTAT regimen may provide a model-informed alternative to empirical dose escalation. Prospective clinical evaluation is warranted.