Pharmacodynamic Effects of Simulated Standard Doses of Antifungal Drugs against Aspergillus Species in a New In Vitro Pharmacokinetic/Pharmacodynamic Model

摘要

In conventional ΜΙC tests, fungi are exposed to constant drug concentrations, whereas in vivo, fungi are exposed to changing drug concentrations. Therefore, we developed a new in vitro pharmacokinetic/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 of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus with 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 with Aspergillus conidia 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. fumigatus but not A. flavus and A. terreus, whose growth was delayed for 7.53 and 22.8 h, respectively. Voriconazole partially inhibited A. 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 but A. terreus. The new model simulated human pharmacokinetics of antifungal drugs and revealed important pharmacodynamic differences in their activity.