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JAC Advance Access originally published online on June 7, 2006
Journal of Antimicrobial Chemotherapy 2006 58(2):466-469; doi:10.1093/jac/dkl236
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© The Author 2006. 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

Efficacy of Abelcet alone, or in combination therapy, against experimental central nervous system aspergillosis

Karl V. Clemons1–,3,*, Rachana Parmar1, Marife Martinez1 and David A. Stevens1–,3

1 California Institute for Medical Research San Jose, CA 95128, USA 2 Department of Medicine, Division of Infectious Diseases, Santa Clara Valley Medical Center San Jose, CA 95128–2699, USA 3 Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University Stanford, CA 94305, USA

Received 3 November 2005; returned 15 December 2006; revised 2 May 2006; accepted 14 May 2006

*Correspondence address. Division of Infectious Diseases, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128, USA. Tel: +1-408-998-4557; Fax: +1-408-998-2723; E-mail: clemons{at}cimr.org

Background: CNS aspergillosis is the most frequent and devastating manifestation of dissemination and mortality is high.

Methods: Cyclophosphamide-suppressed CD-1 mice were infected intracerebrally with conidia of Aspergillus fumigatus and treated for 10 days with suboptimal doses of Abelcet (4 mg/kg) plus micafungin (1 mg/kg), caspofungin (1 mg/kg), itraconazole (100 mg/kg) or voriconazole (40 mg/kg) and compared with monotherapy. Other groups included conventional amphotericin B (1 mg/kg), Abelcet at 10 or 12 mg/kg or 5% dextrose water (diluent control).

Results: All controls died and all treatment regimens significantly prolonged survival. No monotherapy regimen was superior to another. All dosages of Abelcet and conventional amphotericin B tested were equivalent. Significant enhancement of survival over the respective monotherapies was found only with the combination of Abelcet and voriconazole. Other combinations were not better than Abelcet alone. Recovery of cfu from the brains and kidneys of survivors showed that no regimen was curative. Abelcet and voriconazole showed significantly enhanced efficacy in reducing brain infection. Other combinations showed lower cfu, but no significant enhancement over either drug alone. Dose-escalation of Abelcet alone did not increase reduction of cfu. Recovery from the kidneys showed non-significant reduction of cfu by combinations compared with monotherapies.

Conclusions: Each of the drugs tested had significant efficacy against CNS aspergillosis and Abelcet in combination with voriconazole had enhanced efficacy. Additional studies are warranted.

Keywords: murine models , antifungal therapies , echinocandins , azoles , fungi


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