title: In vitro pharmacodynamics of amphotericin B, itraconazole, and voriconazole against Aspergillus, Fusarium, and Scedosporium spp.
abstract: We compared the in vitro pharmacodynamics of amphotericin B, itraconazole, and voriconazole against Aspergillus, Fusarium, and Scedosporium species with a combination of two non-culture-based techniques: the tetrazolium salt 2,3-bis-(2-methoxy-4-nitro-5-[(sulfenylamino)carbonyl]-2H-tetrazolium-hydroxide) (XTT) colorimetric reduction assay, and fluorescent microscopy with the cellular morbidity dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC) to directly visualize hyphal damage. Amphotericin B exhibited species-specific concentration-dependent activity, with 50% effective concentrations (EC(50)s) ranging from 0.10 to 0.12 mg/ml for A. fumigatus, 0.36 to 0.53 mg/ml for A. terreus, 0.27 to > or = 32 mg/ml for F. solani, 0.41 to 0.55 mg/ml for F. oxysporum, and 0.97 and 0.65 mg/ml for S. apiospermum and S. prolificans, respectively. Similarly, itraconazole inhibited the growth of A. fumigatus and A. terreus isolates with MICs of <1 mg/ml (EC(50) 0.03 to 0.85 mg/ml) and S. apiospermum, but was not active against Fusarium species or S. prolificans. Voriconazole effectively inhibited the growth of Aspergillus, Fusarium, and S. apiospermum (EC(50) 0.10 to 3.3 mg/ml) but had minimal activity against a multidrug-resistant isolate of F. solani or S. prolificans. Hyphal damage visualized by DiBAC staining was observed more frequently with voriconazole and amphotericin B versus itraconazole. These data highlight the species-specific differences in antifungal pharmacodynamics between mold-active agents that could be relevant for the development of in vitro susceptibility breakpoints and antifungal dosing in vivo.
authors.affiliation: University of Houston College of Pharmacy, 1441 Moursund St. #423, Houston, TX 77030, USA. rlewis@uh.edu
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: Michael E
authors.initials: ME
authors.lastname: Klepser
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects*; D003124:Colorimetry; D005453:Fluorescence; D005670:Fusarium / Q000187:drug effects*; D017964:Itraconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000494:pharmacology*; D021681:Scedosporium / Q000187:drug effects*; D013045:Species Specificity; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; D000666:Amphotericin B; D065819:Voriconazole
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