Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in anIn VitroPharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum

Abstract

ABSTRACTAlthough conventional amphotericin B was for many years the drug of choice and remains an important agent against invasive aspergillosis, reliable susceptibility breakpoints are lacking. Three clinicalAspergillusisolates (Aspergillus fumigatus,Aspergillus flavus, andAspergillus terreus) were tested in anin vitropharmacokinetic-pharmacodynamic model simulating the biphasic 24-h time-concentration profile of free amphotericin B concentrations in human serum with free peak concentrations (fCmax) of 0.1, 0.3, 0.6, 1.2, and 2.4 mg/liter administered once daily. Drug concentrations were measured with a bioassay, and fungal growth was monitored for 72 h with galactomannan production. ThefCmax/MIC corresponding to half-maximal activity (P50) was determined for each species, and the percentage of target attainment was calculated for different MICs for the standard (1 mg/kg of body weight) and a lower (0.6-mg/kg) dose of amphotericin B with Monte Carlo simulation analysis. ThefCmax/MICs (95% confidence intervals) corresponding toP50were 0.145 (0.133 to 0.158), 0.371 (0.283 to 0.486), and 0.41 (0.292 to 0.522) forA. fumigatus,A. flavus, andA. terreus, respectively. The median percentages ofP50attainment were ≥88%, 47%, and 0% forA. fumigatusisolates with MICs of ≤0.5, 1, and ≥2 mg/liter, respectively, and ≥81%, 24%, and 0% and ≥75%, 15%, and 0% forA. flavusandA. terreusisolates with MICs of ≤0.25, 0.5, and ≥1 mg/liter, respectively. The lower dose of 0.6 mg/kg would retain efficacy forA. fumigatus,A. flavus, andA. terreusisolates with MICs of ≤0.25, ≤0.125, and ≤0.125 mg/liter, respectively. The susceptibility, intermediate susceptibility, and resistance breakpoints of ≤0.5, 1, and ≥2 mg/liter forA. fumigatusand ≤0.25, 0.5, and ≥1 mg/liter forA. flavusandA. terreuswere determined for conventional amphotericin B with a pharmacokinetic-pharmacodynamic model simulating free-drug serum concentrations.