Implications of Evolving and Emerging Pharmacokinetic-Pharmacodynamic Research for Triazoles and Echinocandins

Abstract

Clinicians should be encouraged to use pharmacokinetic-pharmacodynamic (PK-PD) studies to optimize antifungal drug dosing in the absence of robust comparative effectiveness data or in cases where evidence of causality has not yet been firmly established. The purpose of this article is to review how new triazole and echinocandin PK-PD studies have contributed to our current understanding of antifungal selection and dose optimization against invasive fungal infections. Emerging infections such as C. auris and novel antifungal drugs such as rezafungin will also be highlighted. Future research endeavors are suggested where currently robust clinical outcomes data associated with PK-PD target attainment are lacking. Recent results from clinical fluconazole PK-PD studies may indicate that unique AUC24/MIC thresholds exist for specific Candida species. The inability of recent studies to confirm previous fluconazole AUC24/MIC clinical PK-PD targets of 11 to 400 may also be due to previously unrecognized PK variability in special patient populations such as those with augmented renal clearance. A free AUC24/MIC threshold of 25 appears to be conserved across the azole antifungal class in animal models of invasive candidiasis. Current therapeutic drug monitoring guidance with voriconazole, posaconazole, and itraconazole has been used to indirectly confirm pre-clinical AUC24/MIC PK-PD targets in invasive candidiasis and aspergillosis. Elucidation of the PK-PD targets in pre-clinical models has led to successful isavuconazole dose optimization in human studies and has contributed to dosing recommendations for the novel echinocandin rezafungin. PK-PD research will also be important in guiding antifungal selection against infections caused by emerging pathogens, such as Candida auris, and those caused by fungi for which reduced susceptibility is a growing concern, including Coccidioides species and azole-resistant Aspergillus fumigatus. PK-PD research may be used to inform treatment decisions for rare fungal infections, infections with rapidly changing epidemiology, in patient populations expected to have altered pharmacokinetics, for novel antifungal drugs or those with new formulations, and in cases where evidence of causality cannot be established from large randomized comparative studies. A number of animal models have been developed and more clinical PK-PD studies are being conducted. In the absence of clinical PK-PD outcome data in human studies, researchers have expanded the use of currently available therapeutic drug monitoring to gain insight into possible PK-PD targets.