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JAC Advance Access published online on May 25, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki178
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received February 7, 2005
Revised April 25, 2005
Accepted April 27, 2005

Original article

Efficacy of Abelcet and caspofungin, alone or in combination, against CNS aspergillosis in a murine model

Jackie Imai 1, Gaurav Singh 1, Belkys Fernandez 1, Karl V. Clemons 2*, and David A. Stevens 2

1 California Institute for Medical Research, San Jose, CA 95128, USA
2 California Institute for Medical Research, San Jose, CA 95128, USA; Department of Medicine, Division of Infectious Diseases, Santa Clara Valley Medical Center, San Jose, CA 95128, USA; Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA 94305, USA

* To whom correspondence should be addressed.
Karl V. Clemons, E-mail: clemons{at}cimr.org


  Abstract

Objectives: Currently, few options exist to treat central nervous system (CNS) aspergillosis, which is usually fatal. We tested the efficacy of Abelcet and caspofungin, alone and in combination for treatment of this disease.

Methods: Male CD-1 mice were immunosuppressed with 200 mg/kg cyclophosphamide 2 days prior to infection and every 5 days thereafter. In the first study, mice were infected intracerebrally with 2.1 x 106 conidia/mouse of Aspergillus fumigatus; 10 days of once daily therapy began one day later. Groups of 10 received 0.8, 4, or 8 mg/kg of Abelcet, intravenously (iv), or caspofungin, intraperitoneally, 0.8 mg/kg of conventional amphotericin B (AmB) iv, or no treatment. In a second study, mice were challenged with 6.4 x 106 conidia and given no treatment, 8 mg/kg of Abelcet or caspofungin, alone or in combination. On day 14, cfu were determined in survivors by plating of organ homogenates.

Results: In the first study, mice given any regimen of Abelcet or caspofungin had a survival rate ≥80% whereas untreated had 90% mortality. All drug regimens prolonged survival (P ≤ 0.0008) and reduced cfu (P ≤ 0.0001-0.003) recovered from the brains and kidneys compared with untreated. Abelcet showed an apparent dose-related reduction of cfu in the brains. Abelcet at 4 or 8 mg/kg were equivalent to AmB in reducing cfu from both organs (P > 0.05); AmB was superior to 0.8 mg/kg of Abelcet in the brain only (P < 0.02). Abelcet at 8 mg/kg or AmB at 0.8 mg/kg were superior to all regimens of caspofungin in reducing cfu (P ≤ 0.05-0.001). In the second study, Abelcet alone significantly prolonged survival and reduced cfu in the organs versus the controls. Caspofungin did not significantly prolong survival or reduce cfu in comparison with the controls. In combination, Abelcet and caspofungin were equivalent to Abelcet alone.

Conclusions: Abelcet proved to be efficacious, but not curative, in the treatment of CNS aspergillosis and was equivalent overall to conventional AmB. Caspofungin was not as effective against the larger inoculum, but did not enhance or interfere with the efficacy of Abelcet. Since Abelcet displayed dose-responsive efficacy, it is possible higher doses could produce superior results, yet not show toxicity.

Keywords: Aspergillus fumigatus; antifungal combination therapy; echinocandins.
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