Decreasing clinical burden of neonatal sepsis through pharmacometric optimization of antibiotic monitoring

In this thesis the personalized antimicrobial treatment and prophylaxis of neonatal sepsis were explored together with novel assessment methods for therapeutic drug monitoring (TDM). In Part I the development and validation of a highly sensitive bioanalytical method for the determination of amikacin and flucloxacillin concentrations in plasma and saliva are described and discussed. This method was used in Part II, which focusses on the pharmacokinetics (PK) of the aminoglycoside antibiotics amikacin and gentamicin in plasma and saliva. Additionally, the applicability of TDM of aminoglycosides based on saliva samples was evaluated. It was found that both gentamicin and amikacin were freely distributed in the saliva of neonates in quantifiable levels and that the salivary PK of both antibiotics could be described using a pharmacometric model. Moreover, TDM using saliva samples seemed plausible for both gentamicin and amikacin. In Part III the clinical efficacy of several current antibiotic dose regimes was evaluated. First, the effect of the antibiotic vancomycin on bacterial DNA loads (BDLs) was quantified using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model. An empirical PK-PD was developed, describing the vancomycin concentration dependent decrease in BDL of Coagulase-negative staphylococci. Second, it was assessed whether the dose of currently administered intrapartum antibiotics for early-onset sepsis prophylaxis resulted in adequate concentrations in the fetus and neonate. It was found that current intrapartum antibiotic doses indeed achieve concentrations in fetal plasma that are associated with antimicrobial effect. The results of this thesis may contribute to optimized antimicrobial treatment and prophylaxis of neonatal sepsis, thereby decreasing clinical burden.