The role of pharmacokinetics and pharmacodynamics (PK/PD) has gained increasing recognition as critical for selection and dosing of antimicrobial therapeutics, including antifungal agents. The study of antimicrobial PD provides insight into the link between drug pharmacokinetics, in vitro susceptibility, and treatment efficacy. PK/PD investigations have been valuable for defining antifungal dosing regimens to optimize therapy, guiding therapeutic drug monitoring, developing in vitro susceptibility breakpoints and defining clinical resistance. PD observations from animal model studies have proven useful for outcome predictions in triazole treatment of human infections. Similar investigations have been undertaken with compounds from the echinocandin class. Results from studies in rodent invasive candidiasis models have demonstrated concentration dependent killing and prolonged persistent growth suppression. Dose fractionation studies show optimal outcome with the echinocandins is achieved by providing large exposures and efficacy is maintained with very widely spaced dosing intervals. Investigations have also begun to define the PD target or dose level needed for efficacy against Candida spp. Results from these experiments demonstrate the impact of MIC, Candida spp., and protein binding. Clinical trial results have become available that now allow exploration of the predictive value of these experimental models. Analysis thus far suggests concordance between the animal model and clinical trials. These data should be used to refine susceptibility breakpoints and guide dosing regimen design for this class of antifungal compounds.
Full conference title:
17th International Society for Human and Animal Mycology
- ISHAM 17th (2009)