Optimisation of Neonatal Antimicrobial Therapy Using Pharmacokinetic-Pharmacodynamic Modelling

Bacterial infections, namely sepsis and meningitis, are among the major causes of morbidity and mortality during the neonatal period. In an era of increasing antimicrobial resistance, when few new types of antibiotics are being developed, antimicrobial therapy needs to be optimised to ensure that adequate doses are given. At the same time, since renal function is immature in neonates, the dosing regime needs to be designed to minimise toxicity. The studies described here aimed to address the following questions: what is the appropriate way to scale drug clearance in the paediatric population; how can treatment be individualised and optimised to help improve the therapeutic drug monitoring of gentamicin; what meropenem dose should be recommended for neonates and infants with sepsis or meningitis; and finally how can a modelling approach be used to facilitate the definition of neonatal sepsis. The above questions were addressed using distinct strategies. An extensive comparison of published models for scaling clearance was performed. Population pharmacokinetic models using data from large gentamicin and meropenem studies in neonates were developed, and then either implemented in provisional software, or used to make dose recommendations, respectively. Also, in a preliminary study, item response theory models were applied to pharmacodynamic data from neonates with sepsis. The use of allometric weight scaling with a postmenstrual age driven sigmoidal maturation function was recommended as a standard approach for scaling clearance. The population pharmacokinetic model developed using gentamicin data showed that specifically timed trough levels are not needed for therapeutic drug monitoring. The results of the meropenem study imply that the current recommended dosing regimen for neonates is appropriate for susceptible bacteria. Finally, the proof-of-concept study suggested that metabolic acidosis provided the most information about the sepsis status of neonates