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JAC Advance Access published online on February 27, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn069
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Comparison of the dose-dependent activity and paradoxical effect of caspofungin and micafungin in a neutropenic murine model of invasive pulmonary aspergillosis

Russell E. Lewis1,2,*, Nathan D. Albert2 and Dimitrios P. Kontoyiannis1,2

1 The University of Houston College of Pharmacy, Texas Medical Center Campus, 1441 Moursund Street, Houston, TX 77030, USA 2 The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

Received 28 October 2007; returned 21 January 2008; revised 20 December 2007; accepted 30 January 2008

* Corresponding author. The University of Houston College of Pharmacy, Texas Medical Center Campus, 1441 Moursund Street, Houston, TX 77030, USA. Tel: +1-713-795-8326; Fax: +1-713-795-8383; E-mail: rlewis{at}uh.edu

Objectives: The safety and concentration-dependent pharmacodynamic characteristics of the echinocandins make them ideal candidates for dosage escalation in the treatment of aspergillosis. However, paradoxical attenuation of antifungal activity with increasing doses has been reported for some echinocandins in experimental models of invasive pulmonary aspergillosis (IPA).

Methods: We compared the activity of micafungin and caspofungin administered over a wide dosing range that encompasses clinical exposures (0.25–10 mg/kg) in a neutropenic murine model of IPA.

Results: Both echinocandins exhibited dose-dependent reductions in fungal burden; however, caspofungin displayed a relatively steeper dose–response curve with a modest paradoxical increase in fungal burden that was not seen in micafungin-treated animals. Equivalent activity was observed with both echinocandins at daily doses ranging from 4 to 10 mg/kg.

Conclusions: Both micafungin and caspofungin exhibit dose-dependent pharmacodynamic activity in vivo in the treatment of neutropenic IPA. Both echinocandins were equivalent at dosages ≥4 mg/kg day.

Key Words: Aspergillus , echinocandins , pharmacodynamics


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