Population pharmacokinetics and dosing regimen optimization of ceftazidime in plasma and cerebrospinal fluid of neonatal sepsis patients.

INTRODUCTION

Ceftazidime is a mainstay in the treatment of neonatal sepsis. However, the lack of pharmacokinetic (PK) data regarding its blood-cerebrospinal fluid (CSF) penetration in neonates hinders accurate exposure assessment and dose optimization for patients with concomitant central nervous system infections.

METHODS

A population PK (PPK) model was established using plasma and CSF samples from 69 neonates using NLME software. Model predictive performance was validated using goodness-of-fit plots, bootstrapping, visual predictive checks, and normalized prediction distribution errors. Monte Carlo simulations were employed to optimize dosing regimens, targeting a probability of target attainment (PTA) ≥90%.

RESULTS

A two-compartment plasma-CSF model was developed, with body weight and estimated glomerular filtration rate identified as significant covariates for ceftazidime clearance. Simulations indicated that a 50 mg/kg q8h regimen (30-min infusion) achieved ≥90% PTAs for bloodstream infections (MIC ≤ 4 mg/L) in neonates weighing 2-5 kg with an estimated glomerular filtration rate of 15-60 mL/min/1.73 m². Achieving similar PTAs in the CSF for MIC = 4 mg/L requires a 4-h extended infusion. For higher CSF MICs (MIC = 8 mg/L), 150 mg/kg/d or less cannot achieve the desired pharmacodynamic targets (PTAs < 90%), regardless of infusion modality.

CONCLUSIONS

This study developed a PPK model of ceftazidime in plasma and CSF. The dosing regimen of 50 mg/kg q8h (30-min infusion) is suitable for treating most cases of neonatal sepsis caused by susceptible Enterobacterales in neonates with normal body weight and renal function. For CSF infections with MICs up to 4 mg/L, extended infusion is recommended. Precise dosing should be tailored to the developmental maturity, renal function, and pathogen susceptibility.