Pharmacokinetic and pharmacodynamic strategies to optimize antifungal therapy, prevent resistance and minimize treatment failure

Abstract

Invasive fungal diseases (IFDs) present significant challenges in clinical practice due to high morbidity and mortality rates, compounded by antifungal resistance, diagnostic limitations and pharmacokinetic (PK) and pharmacodynamic (PD) complexities. The main antifungal classes, triazoles, polyenes, echinocandins and pyrimidine analogues, are essential for managing IFDs but are increasingly undermined by resistance due to genetic mutations, efflux pump over-expression and biofilm formation. Some fungal pathogens, such as Candidozyma auris, can resist multiple antifungal classes by deploying a combination of mechanisms. PK/PD indices, including Cmax/minimum inhibitory concentration (MIC), AUC/MIC and percentage of time (%T) > MIC, are essential for optimizing antifungal therapy and improving the likelihood of adequate efficacy, while potentially limiting resistance selection through improved exposure. However, achieving these targets is often hindered by factors such as physiological variability, drug–drug interactions and inadequate tissue penetration, particularly in difficult-to-treat infections like fungal meningitis. Newer antifungal agents, including rezafungin, with its once-weekly dosing, and ibrexafungerp, the first-in-class oral triterpenoid, offer potentially useful additions to current therapy, although clinical experience and resistance-related outcome data remain limited for newer agents. These drugs feature enhanced PK/PD profiles and activity against resistant strains. Furthermore, therapeutic drug monitoring and advanced modelling techniques, such as Monte Carlo simulations, are vital for tailoring treatment regimens to individual patients. This review highlights the importance of integrating PK/PD principles, novel antifungal therapies and stewardship strategies to optimize antifungal exposure and support patient management in IFDs. These approaches may help reduce treatment failure and resistance selection, although direct clinical evidence for prevention of acquired resistance remains limited.