Tamara van Donge

Key components for antibiotic dose optimization 51 3 Table 2: Challenges to overcome the burden of sepsis and the opportunities to improve diagnostic tools, measurement techniques and implementation of modeling and simulation techniques. Challenges; what is missing? Opportunities • Uniform sepsis definitions for all age groups across pediatric age range • Identification of biomarkers (e.g. presepsin or cystatin C) with accurate thresholds • Diagnostic tools to identify pathogen and infection • Use of microdialysis to measure drug concentrations at target site • Adequate descriptors of drug concentration at target site • Apply kill-curves approach for describing changing antibacterial activity • Understanding PK/PD relationships and parameters which can characterize dynamic process of antibacterial activity • Multidisciplinary collaboration and communication between research groups and physicians • Reliable measurements for GFR in pediatric population (augmented renal clearance) • Implementation of modeling and simulation strategies in clinical settings (e.g. for individual dose optimization) • Straightforward applications of model-based approaches • Development of understandable time-saving software tools for individualized dosing • Implementation of adjusted dosing guidelines in clinical practice Moreover, today the MIC-based approach is well-established and may offer a thorough understanding of why a specific dosing regimen achieves clinical success. 32 Nonetheless, antibacterial activity is a dynamic process and since MIC is a one-point threshold value, the MIC can only provide an approximation on the antibacterial effect. 43 Drug dosing is currently being adjusted for patients with impaired kidney function (risk for toxicity), whereas for patients with augmented renal clearance (elevated drug clearance) no dose adjustments are being recommended. 44 Furthermore, it has been shown that equations to estimate the glomerular filtration rate (GFR) in patients less than 17 years old are not appropriate. 44 Finally, an understanding of pharmacometric modelling and simulation can provide insights in the dose-concentration-effect relationship. 45 Unfortunately, the modeling and simulation strategy is still underutilized, although it has been shown that mechanistic modeling such as physiological based pharmacokinetic (PBPK) models have good predictive value and enable extrapolation by using information about the drug and the physiology. 46,47 Nonetheless, it is surprising that despite the fact that modeling and simulation is frequently reported in the literature, the results and adjusted dosing recommendations are not yet implemented in daily clinical practice. 28