Single-Dose Pharmacodynamics of Amphotericin B against Aspergillus Species in anIn VitroPharmacokinetic/Pharmacodynamic Model

Abstract

ABSTRACTConventional MIC testing of amphotericin B results in narrow MIC ranges challenging the detection of resistant strains. In order to discern amphotericin B pharmacodynamics, thein vitroactivity of amphotericin B was studied againstAspergillusisolates with the same MICs by using a newin vitropharmacokinetic/pharmacodynamic (PK/PD) model that simulates amphotericin B human plasma levels. Clinical isolates ofAspergillus fumigatus,A. terreus, andA. flavuswith the same Clinical and Laboratory Standards Institute modal MICs of 1 mg/liter were exposed to amphotericin B concentrations following the plasma concentration-time profile after single-bolus administration withCmaxvalues of 0.6, 1.2, 2.4, and 4.8 mg/liter. Fungal growth was monitored for up to 72 h based on galactomannan production. Complete growth inhibition was observed only againstA. fumigatuswith amphotericin B with aCmaxof ≥2.4 mg/liter. At the lowerCmaxvalues 0.6 and 1.2 mg/liter, significant growth delays of 34 and 52 h were observed, respectively (P< 0.001). ForA. flavus, there was no complete inhibition but a progressive growth delay of 1 to 50 h at an amphotericin BCmaxof 0.6 to 4.8 mg/liter (P< 0.001). ForA. terreus, the growth delay was modest (up to 8 h) at allCmaxs (P< 0.05). TheCmax(95% confidence interval) associated with 50% activity forA. fumigatuswas 0.60 (0.49 to 0.72) mg/liter, which was significantly lower than forA. flavus3.06 (2.46 to 3.80) mg/liter and forA. terreus7.90 (5.20 to 12.29) mg/liter (P< 0.001). A differentialin vitroactivity of amphotericin B was found amongAspergillusspecies despite the same MIC in the orderA. fumigatus>A. flavus>A. terreusin thein vitroPK/PD model, possibly reflecting the different concentration- and time-dependent inhibitory/killing activities amphotericin B exerted against these species.