Pharmacodynamic Effects of Simulated Standard Doses of Antifungal Drugs against Aspergillus Species in a NewIn VitroPharmacokinetic/Pharmacodynamic Model

Abstract

ABSTRACTIn conventional ΜΙC tests, fungi are exposed to constant drug concentrations, whereasin vivo, fungi are exposed to changing drug concentrations. Therefore, we developed a newin vitropharmacokinetic/pharmacodynamic model where human plasma pharmacokinetics of standard doses of 1 mg/kg amphotericin B, 4 mg/kg voriconazole, and 1 mg/kg caspofungin were simulated and their pharmacodynamic characteristics were determined against three clinical isolates ofAspergillus fumigatus,Aspergillus flavus, andAspergillus terreuswith identical MICs (1 mg/liter for amphotericin B, 0.5 mg/liter for voriconazole) and minimum effective concentrations (0.5 mg/liter for caspofungin). This new model consists of an internal compartment (a 10-ml dialysis tube made out of a semipermeable cellulose membrane allowing the free diffusion of antifungals but not galactomannan) inoculated withAspergillusconidia and placed inside an external compartment (a 700-ml glass beaker) whose content is diluted after the addition of antifungal drugs by a peristaltic pump at the same rate as the clearance of the antifungal drugs in human plasma. Fungal growth was assessed by galactomannan production. Despite demonstrating the same MICs, amphotericin B completely inhibited (100%)A. fumigatusbut notA. flavusandA. terreus, whose growth was delayed for 7.53 and 22.8 h, respectively. Voriconazole partially inhibitedA. fumigatus(49.5%) and Α.flavus(27.9%) but not Α.terreus; it delayed their growth by 3.99 h (A. fumigatus) and 5.37 h (Α.terreus). Caspofungin did not alter galactomannan production in all of the species butA. terreus. The new model simulated human pharmacokinetics of antifungal drugs and revealed important pharmacodynamic differences in their activity.