Tamara van Donge

Chapter 11 232 optimal and individualized dosing of antibiotic treatment. The growth of the pathogen needs to be inhibited by the antibiotic agent and is dependent on the minimal inhibitory concentration (MIC) breakpoint. An increase in MIC breakpoints should ultimately result in dose adjustments to ensure efficacious exposure. This requires that dosing guidelines should be regularly updated and amended. With a limited pipeline of new antibiotics, relying on proper use and understanding the link between antibiotic exposure PK and microbiological response (PD) is a key issue concerning dosing optimization of the presently available antibiotics ( Chapter 3 ). 9,10 Pharmacometric modeling and simulation has the ability to provide valuable insights in the dose-concentration-effect relationship. 11 Dosing regimen acceptability Figure 1: Paradox of identifying the optimal amoxicillin dosing regimen in the neonatal population. The above mentioned strategy was applied in Chapter 4 , where efficacious and safe amoxicillin exposures were modelled for current neonatal dosing regimens given a range of assumptions for MIC breakpoints, targeted % f T>MIC and the potential for neurotoxicity. 12 The exposure of amoxicillin was simulated by applying a Pop-PK model which included gestational age (GA), weight and postnatal age (PNA) as covariates on the clearance of amoxicillin. 13 Amoxicillin PK profiles were obtained by attributing each dosing regimen to each patient of an international neonatal cohort (n=1063). This study showed that at low PKPD targets (<70% f T>MIC) and MICs (≤1 mg/L) all regimens performed well, and regimen selection could primarily be driven by avoidance of high and potentially neurotoxic concentrations and by simplicity of dosing regimens for readiness of implementation. In contrast, at high PKPD targets (70% f T>MIC or greater) or MICs (>2 mg/L) none of the regimens are expected to result in probability of target attainment (PTA) ≥90%, indicating that amoxicillin may not