Antifungal Pharmacodynamics

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´╗┐Antifungal Pharmacodynamics
The pharmacodynamics of antifungal compounds involve relationships among drug concentrations, time, and antimicrobial effects in vitro and in vivo. Beyond better understanding of a drug's mode of action, characterization of these relationships has important implications for setting susceptibility breakpoints, establishing rational dosing regimens, and facilitating drug development. Important advances have been made in the experimental investigation of pharmacokinetics and pharmacodynamics of antifungal drugs; however, much remains to be learned about specific pathogens and specific sites of infection. Increased incorporation of pharmacokinetic and pharmacodynamic principles in experimental and clinical studies with antifungal agents is an important objective that will benefit the treatment and prophylaxis of life-threatening invasive fungal infections in immunocompromised patients.

Pharmacodynamics of antifungal compounds involve characterizing relationships among drug concentrations, time, and antimicrobial effects. These relationships can be investigated in vitro, in discriminative animal infection models that incorporate pharmacokinetic measurement, and in human infections.

Common in vitro methods of assessing the dynamics of antifungal drugs include time-kill assays, the study of persistent effects such as postantifungal and subinhibitory effects, in vitro models, and various techniques to assess cell vitality. These methods provide important information on the mode and time course of the intrinsic activity of a drug or drug combination against specific pathogens. However, standing alone, they generally have no predictive value for responses in vivo and must be followed by carefully designed pharmacodynamic animal infection models that correlate dosage, drug concentrations at the infected site or in blood, and in vitro susceptibility of the organism with end points of antifungal efficacy.

In contrast to the clinical setting, such models provide a high degree of control of covariates and true outcome measurements, and correct for interspecies differences in drug metabolism and elimination. The latter is a major impediment to the translation of results from conventional animal studies to clinical research. They provide important insights into a drug's dose-response relationship and are highly useful for setting susceptibility breakpoints, guiding rational dosing regimens, and facilitating drug develop-ment. Given the surge in invasive fungal infec-tions and their high morbidity and mortality, it is increasingly important to incorporate pharmaco-kinetic and pharmacodynamic principles in experimental and clinical studies with antifungal agents.

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