Concentration-dependent effects of caspofungin on the metabolic activity of Aspergillus species

被引:53
作者
Antachopoulos, Charalampos
Meletiadis, Joseph
Sein, Tin
Roilides, Emmanuel
Walsh, Thomas J.
机构
[1] NCI, Pediat Oncol Branch, CRC, Immunocompromised Host Sect, Bethesda, MD 20892 USA
[2] Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, Thessaloniki, Greece
关键词
D O I
10.1128/AAC.01160-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The minimum effective concentration (MEC) used to assess the in vitro antifungal activity of caspofungin against Aspergillus spp. is a qualitative endpoint requiring microscopic examination of hyphae. We therefore developed a tool for the quantitative assessment of caspofungin activity against Aspergillus spp. at clinically applicable concentrations. Susceptibility to caspofungin (0.008 to 8 mu g/ml) was studied for 9 A. fumigatus, 8 A. flavus, and 12 A. terreus isolates based on the Clinical and Laboratory Standards Institute M38-A protocol. After 48 h of incubation, the MEC was defined microscopically, and metabolic activity assessed with a modified XTT assay, using 100 mu g of the tetrazolium salt XTT/ml and 6.25 mu M menadione. A significant reduction in metabolic activity was demonstrated at the MEC (0.25 to 0.5 mu g/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 to 100% agreement with microscopic MEC). Fungal metabolism tended to reach the lowest levels (median, 17 to 38% of control) one to two dilutions higher than the MEC, at the minimum metabolic activity concentration (MMC). For 5 of 9 A. fumigatus isolates, 6 of 12 A. terreus isolates, and I of 8 A. flavus isolates, a paradoxical increase in metabolism was observed at concentrations greater than the MMC. Sigmoid (E-max) 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 endpoints for in vitro studies of caspofungin against Aspergillus spp.
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页码:881 / 887
页数:7
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