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Antimicrobial Agents and Chemotherapy, March 2007, p. 881-887, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01160-06

Concentration-Dependent Effects of Caspofungin on the Metabolic Activity of Aspergillus Species{triangledown}

Charalampos Antachopoulos,1 Joseph Meletiadis,1 Tin Sein,1 Emmanuel Roilides,1,2 and Thomas J. Walsh1*

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland,1 Third Department of Pediatrics, Aristotle University, Hippokration Hospital, Thessaloniki, Greece2

Received 15 September 2006/ Returned for modification 4 November 2006/ Accepted 27 November 2006

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 µg/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 µg of the tetrazolium salt XTT/ml and 6.25 µM menadione. A significant reduction in metabolic activity was demonstrated at the MEC (0.25 to 0.5 µg/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 1 of 8 A. flavus isolates, a paradoxical increase in metabolism was observed at concentrations greater than the MMC. Sigmoid (Emax) or bell-shaped models described accurately (median R2 = 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.

* Corresponding author. Mailing address: Pediatric Oncology Branch, National Cancer Institute, CRC, Rm. 1-5750, MSC 1100, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 480-2308. E-mail: walsht{at}mail.nih.gov.

{triangledown} Published ahead of print on 4 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 881-887, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01160-06




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