Concentration-dependent effects of caspofungin on the metabolic activity of Aspergillus species
Author:
Antachopoulos C, Meletiadis J, Sein T, Roilides E, Walsh TJ
Date: 21 December 2006
Abstract:
The minimum effective concentration (MEC) used for assessment of in vitro antifungal activity of caspofungin against Aspergillus spp. is a qualitative end point requiring microscopic examination of hyphae. We therefore developed a tool for quantitative assessment of caspofungin activity against Aspergillus spp. at clinically applicable concentrations. Susceptibility to caspofungin (0.008-8 microg/ml) was studied for 9 A. fumigatus, 8 A. flavus and 12 A. terreus isolates based on CLSI M38-A protocol. After 48 h incubation, the MEC was defined microscopically and metabolic activity assessed with a modified XTT assay, using 100 microg/ml of the tetrazolium salt XTT and 6.25 microM menadione. A significant reduction in metabolic activity was demonstrated at the MEC (0.25-0.5 microg/ml) for all Aspergillus spp. and was more pronounced for A. flavus (median metabolic activity: 25% of control) compared to A. fumigatus and A. terreus (median metabolism: 42% and 53% respectively), allowing determination of MEC with the XTT assay (93-100% agreement with microscopic MEC). Fungal metabolism tended to reach lowest levels (median: 17-38% of control) 1 to 2 dilutions higher than the MEC, at the MMC (minimum metabolic activity concentration). For 5/9 of A. fumigatus, 6/12 of A. terreus and 1/8 of A. flavus isolates, a paradoxical increase in metabolism was observed at concentrations > MMC. The sigmoid (Emax) or bell-shaped models described accurately (median R(2): 0.97) the concentration-dependent metabolic changes in the absence or presence, respectively, of paradoxical response. Assessment of metabolic activity may provide useful quantitative end points for in vitro studies of caspofungin against Aspergillus spp
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