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Antimicrobial Agents and Chemotherapy, December 2005, p. 5058-5068, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5058-5068.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Caspofungin in a Murine Model of Systemic Candidiasis: Importance of Persistence of Caspofungin in Tissues to Understanding Drug Activity

Arnold Louie,* Mark Deziel, Weiguo Liu, Michael F. Drusano, Tawanda Gumbo, and George L. Drusano

Emerging Infections and Pharmacodynamics Laboratory, Emerging Infections and Host Defense Section, Ordway Research Institute, Albany, New York 12208

Received 17 February 2005/ Returned for modification 23 April 2005/ Accepted 2 September 2005

Pharmacokinetic and pharmacodynamic studies were conducted in a murine model of systemic candidiasis to determine the pharmacodynamic parameter linked with caspofungin efficacy. Additional studies defined the importance of persistent tissue drug concentrations to treatment outcome. The pharmacokinetics of caspofungin were determined in the serum and kidneys of infected mice over 96 h. Population pharmacokinetic analysis demonstrated a serum terminal half-life (t1/2) for caspofungin of 20.2 h when only serum concentrations were considered, but the terminal t1/2 increased to 59.2 h when serum and kidney concentration-time data were comodeled. In dose-range studies, the dose-response effect was well described by an inhibitory sigmoid curve for the exposure-effect killing caused by the drug (r2 > 0.96; P << 0.001). In dose-fractionation studies, fungal counts in kidneys were not statistically different for total doses given as one, two, or four equally divided doses over 96 h, indicating that the area under the concentration-time curve/MIC is the pharmacodynamic parameter that predicts caspofungin efficacy in our infection model. In a separate study, mice infected with Candida albicans 24 h after serum concentrations of caspofungin fell below the MIC for the fungal isolate had significant reductions in fungal densities in their kidneys compared with the growth of fungi in the kidneys of untreated controls (P = 0.005). This in vivo biological assay demonstrates that therapeutic concentrations of caspofungin persist at the site of infection in kidney tissue well after serum concentrations fall below the MIC, underscoring the primacy of caspofungin levels in tissues on determining treatment outcome.

* Corresponding author. Mailing address: Emerging Infections and Pharmacodynamics Laboratory, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208. Phone: (518) 641-6434. Fax: (518) 641-6403. E-mail: alouie{at}ordwayresearch.org.

Antimicrobial Agents and Chemotherapy, December 2005, p. 5058-5068, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5058-5068.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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