Pharmacometric validation and optimization of antibiotic dosing in neonates with perinatal asphyxia and premature neonates

Neonatal sepsis remains a clinical challenge for neonates of all gestational ages, necessitating safe and effective antibiotic dosing strategies. However, dosing optimization is especially complicated in neonates presenting with altered pharmacokinetics (PK), such as neonates with perinatal asphyxia or extreme prematurity. This thesis explores antibiotic PK in these vulnerable populations, validating and refining dosing guidelines to improve clinical implementation.
The first part focuses on validation studies. A liquid chromatography-tandem mass spectrometry (LC-MS) assay was developed and validated for seven antibiotics, ensuring accuracy and clinical applicability. Additionally, external validation of a gentamicin PK model in neonates undergoing therapeutic hypothermia confirmed its predictive performance and supported model-informed precision dosing (MIPD). A comparative study of simplified versus complex amikacin dosing regimens demonstrated both achieved therapeutic targets, allowing clinicians to choose based on clinical resources.
In the second part, ceftazidime and vancomycin PK models were developed for neonates with perinatal asphyxia undergoing therapeutic hypothermia. Ceftazidime clearance varied based on postnatal age and temperature, warranting phase-specific dosing adjustments. Vancomycin clearance was lower than in non-asphyxiated neonates, requiring a reduced dosing regimen compared to current guidelines to prevent overexposure and the associated risk of nephrotoxicity.
In conclusion, this thesis enhances neonatal antibiotic dosing strategies through pharmacometric research, highlighting altered PK in neonates with perinatal asphyxia and proposing optimized dosing regimens. The findings emphasize the critical role of external validation and MIPD in improving neonatal antibiotic therapy.