Single-Dose Pharmacodynamics of Amphotericin B against Aspergillus Species in an In Vitro Pharmacokinetic/Pharmacodynamic Model

Abstract

Conventional MIC testing of amphotericin B results in narrow MIC ranges challenging the detection of resistant strains. In order to discern amphotericin B pharmacodynamics, the in vitro activity of amphotericin B was studied against Aspergillus isolates with the same MICs by using a new in vitro pharmacokinetic/pharmacodynamic (PK/PD) model that simulates amphotericin B human plasma levels. Clinical isolates of Aspergillus fumigatus, A. terreus, and A. flavus with 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 with C max values 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 against A. fumigatus with amphotericin B with a C max of >2.4 mg/liter. At the lower C max values 0.6 and 1.2 mg/liter, significant growth delays of 34 and 52 h were observed, respectively (P < 0.001). For A. flavus, there was no complete inhibition but a progressive growth delay of 1 to 50 h at an amphotericin B C max of 0.6 to 4.8 mg/liter (P < 0.001). For A. terreus, the growth delay was modest (up to 8 h) at all C max s (P < 0.05). The C max (95% confidence interval) associated with 50% activity for A. fumigatus was 0.60 (0.49 to 0.72) mg/liter, which was significantly lower than for A. A mphotericin B (AMB) is an antifungal drug of major importance in the treatment of invasive aspergillosis (1). It is a highly lipophilic and amphoteric molecule that interacts with fungal cell membrane, forming pores and disrupting its integrity (2). Due to its unique mechanism of action, it demonstrates a wide range of pharmacodynamic effects and broad spectrum of antifungal activity. However, conventional MIC testing of amphotericin B resulted in narrow MIC ranges within one to two 2-fold dilutions challenging the detection of resistant strains (3-5). Efforts to develop in vitro assays that separate susceptible and resistant strains using richer media or gradient drug concentrations strips were unsuccessful (3, 5). Species-specific epidemiological cutoff values (ECV) have been proposed for amphotericin B and Aspergillus spp. based on Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology, with the Aspergillus terreus ECV being one dilution higher than the A. fumigatus and A. flavus ECV (6).In addition to inhibitory activity captured by the MIC, amphotericin B exerts a range of different pharmacodynamic effects such as postantifungal effect and concentration-dependent killing (7). All of these effects are usually determined after fungal exposure to constant drug concentrations (2). However, in vivo, fungus is exposed to nonconstant amphotericin B concentrations as the drug undergoes metabolism, distribution, and excretion. In particular, its plasma levels follow a triphasic time-concentration profile characterized by the alpha-phase observed within the first 4 ...

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