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Antimicrobial Agents and Chemotherapy, October 2008, p. 3497-3503, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00478-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vivo Pharmacodynamic Target Investigation for Micafungin against Candida albicans and C. glabrata in a Neutropenic Murine Candidiasis Model

D. R. Andes,^1,2* D. J. Diekema,³ M. A. Pfaller,³ K. Marchillo,¹ and J. Bohrmueller¹

Department of Medicine,¹ Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin,² Department of Pathology, University of Iowa, Iowa City, Iowa³

Received 10 April 2008/ Returned for modification 16 June 2008/ Accepted 7 July 2008

Previous studies using in vivo candidiasis models have demonstrated that the concentration-associated pharmacodynamic indices, the maximum concentration of a drug in serum/MIC and 24-h area under the curve (AUC)/MIC, are associated with echinocandin treatment efficacy. The current investigations used a neutropenic murine model of disseminated Candida albicans and C. glabrata infection to identify the 24-h AUC/MIC index target associated with a stasis and killing endpoint for the echinocandin, micafungin. The kinetics after intraperitoneal micafungin dosing were determined in neutropenic infected mice. Peak levels and AUC values were linear over the 16-fold dose range studied. The serum drug elimination half-life ranged from 7.5 to 16 h. Treatment studies were conducted with 4 C. albicans and 10 C. glabrata isolates with micafungin MICs varying from 0.008 to 0.25 µg/ml to determine whether similar 24-h AUC/MIC ratios were associated with efficacy. The free drug AUC/MICs associated with stasis and killing (1-log) endpoints were near 10 and 20, respectively. The micafungin exposures associated with efficacy were similar for the two Candida species. Furthermore, the free drug micafungin exposures required to produce stasis and killing endpoints were similar to those recently reported for another echinocandin, anidulafungin, against the identical Candida isolates in this model.

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* Corresponding author. Mailing address: Department of Medicine, University of Wisconsin, 600 Highland Ave., H4/572, Madison, WI 53792. Phone: (608) 263-1545. Fax: (608) 263-4464. E-mail: dra{at}medicine.wisc.edu

Published ahead of print on 14 July 2008.

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Antimicrobial Agents and Chemotherapy, October 2008, p. 3497-3503, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00478-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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