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Effect of protein binding in the activity of voriconazole and anidulafungin alone or combined against Aspergillus sp. using a time-kill methodology

Abstract number: P1669

Cafini F., Sevillano D., Alou L., González N., Torrico M., Mir N., Prieto J.

Objectives: To study the effect of the presence of physiological concentrations of human albumin and 75% human serum by concentrations similar to the Cmax obtained in serum after steady-state doses of voriconazole (VOR) (400/200 mg) and anidulafungin (ANF) (200/100 mg) against two Aspergillus fumigatus (MIC VOR = 1 and MEC ANF=0.015 and 0.12 mg/L) and two Aspergillus flavus (MIC VOR = 1 mg/L and MIC ANF= 0.03 and 0.12 mg/L) strains.

Methods: Killing curves were performed with a final inoculum of approximately 105 spore/ml, and a final VOR and ANF concentration of 2.08 and 8.6 mg/l, respectively (Cmax) in different media: a) RPMI broth (Cmax); b) RPMI broth with 75% human serum (Cmax-S), and c) RPMI broth with 3.75 g/dL human albumin (Cmax-Alb). In parallel, killing curves with VOR or ANF concentrations (0.87 and 0.086 mg/L, respectively) corresponding to free-drug (CmaxF) were performed in RPMI broth considering 58%, and 99% protein binding for VOR for ANF, respectively. Control growth curves were performed in all media tested without antibiotics. Cultures were incubated at 35°C. At each time point (6, 10, 24 and 48 h) the metabolic activity was assessed using an XTT assay. All experiments were performed in triplicate.

Results: A rapid decrease in the cellular viability was observed for all strains in VOR and VOR plus ANF curves independently of the presence of human serum or albumin in the medium. In ANF curves, cellular viability (%) at 48 h was:

Conclusions: Synergism could not be demonstrated due to the high activity showed by VOR. Theoretical extrapolation of active drug from total drug by using the protein binding rate seems a non accurate method to study antifungal activity considering the implications of protein binding.

Strain/MEC (mg/L)CmaxCmax-SCmax-AlbCmaxF
A. fumigatus 5/0.01542.4450.5545.57100.00
A. fumigatus 8/0.1240.0035.0070.49100.00
A. flavus 9/0.12100.0064.91100.0098.28
A. flavus 10/0.0387.0659.877.3292.78

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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