Mold-active Azoles: Development, Validation and Implementation of strategies for Safe and Effective Dosing (M-ADVISED)

Infections, including severe bacterial infections and invasive fungal infections, are a major cause of morbidity and mortality in critically ill patients and other patient populations (i.e. patients with hematological malignancies). Therapeutic exposure to antibacterial or antifungal drugs at the site of infection (or in plasma as a surrogate matrix) is crucial for successful treatment of severe bacterial and fungal infections. However, it has been shown that critically ill patients are at risk of subtherapeutic exposure to antimicrobial drugs, mainly due to pathophysiological changes (i.e. augmented renal clearance, fluid shifts and hypoalbuminemia) that alter pharmacokinetics (PK) of commonly used antibiotic and antifungal agents (i.e. beta-lactams and azoles). In order to overcome suboptimal exposure to antimicrobials different dose optimization strategies have been developed, including personalized and covariate-based dosing regimens. Population PK (popPK) analysis is a widely applied method to guide individualized dosing strategies as it allows for a better understanding of covariates impacting PK variability in a specific patient population. Simulations based on popPK modeling can lead to different dosing strategies aiming to optimize (in silico) target attainment. These effective dosing solutions might include 1) higher doses for a broad population, 2) stratified dosing based on specific patient characteristics (e.g. renal function) or 3) model-informed precision dosing (MIPD) based on both patient characteristics (a priori information) and monitored concentrations (a posteriori information). The impact of these optimized dosing strategies, including MIPD, on pharmacokinetic-pharmacodynamic target attainment and clinical outcomes should be further scrutinized. Therefore, the major objective of this PhD research is to formulate effective dosing strategies for different antibacterial (i.e. ceftriaxone, meropenem and amikacin) and antifungal (i.e. voriconazole) drugs and to evaluate their impact on clinically relevant outcomes in special patient populations. Additionally, this PhD thesis aims to document the exposure and target attainment to isavuconazole in a real-life clinical setting, to identify covariates that may influence isavuconazole concentrations in different patient populations and to evaluate the impact of extracorporeal membrane oxygenation on the PK of isavuconazole.