The triazoles have revolutionized the treatment of invasive and allergic fungal diseases. Fluconazole, itraconazole, voriconazole and posaconazole are available for clinical use. Isavuconazole and ravuconazole are in development. The triazoles have broad spectrum antifungal activity. The pharmacokinetics and pharmacodynamics (PK-PD) of the triazoles have been extensively investigated in murine models of disseminated candidiasis. The PD parameter that optimally links drug exposure with the observed antifungal effect is the ratio of the area under the concentration-time curve (AUC) to MIC (AUC:MIC). There is increasing information on the magnitude of the AUC:MIC that is required for optimal antifungal effect. PK-PD principles have been used to define in vitro susceptibility breakpoints. The triazoles are fungistatic against Candida spp. Their mode of action against Aspergillus spp. is less well defined, although they clearly exhibit dose-dependant decrement in fungal burden in laboratory animal models of invasive pulmonary aspergillosis. The triazoles accumulate in tissues and this is important for an understanding of their antifungal effect. In humans, the triazoles are characterized by complicated pharmacokinetic properties. Both itraconazole and voriconazole exhibit nonlinear pharmacokinetics. The triazoles all exhibit clinically relevant exposure-response relationships. Recent work from our laboratory suggests that itraconazole exhibits clinically relevant concentration-toxicity relationships. Higher concentrations of voriconazole are associated with a progressively higher probability of hepatotoxicity, photopsia and central nervous system toxicity. Because of the significant pharmacokinetic variability and clinically relevant drug exposure-response relationships, therapeutic drug monitoring (TDM) is frequently used. A strong argument can be made for the routine monitoring of itraconazole and voriconazole. There may also be grounds to consider monitoring posaconazole levels. TDM should be considered for all patients receiving triazoles who have refractory disease. Furthermore, TDM should be considered when compliance, drug interactions and variable pharmacokinetics result in uncertainty about resultant drug exposures. An understanding of the PK-PD relationships of the triazoles has been instrumental in optimising their clinical efficacy.
Full conference title:
19th European Congress of Clinical Microbiology and Infectious Diseases
- ECCMID 19th (2009)