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JAC Advance Access published online on September 4, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn361
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Published by Oxford University Press 2008 on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Anticandidal effects of voriconazole and caspofungin, singly and in combination, against Candida glabrata, extracellularly and intracellularly in granulocyte-macrophage colony stimulating factor (GM-CSF)-activated human monocytes

Aldona L. Baltch1,2,*, Lawrence H. Bopp1, Raymond P. Smith1,2, William J. Ritz1,2 and Phyllis B. Michelsen1,2

1 Stratton Veterans Affairs Medical Center, Albany, NY 12208, USA 2 Albany Medical College, Albany, NY 12208, USA

Received 19 May 2008; returned 3 July 2008; revised 30 July 2008; accepted 7 August 2008

* Correspondence address. Infectious Disease Research (111D), Stratton VA Medical Center, 113 Holland Avenue, Albany, NY 12208, USA. Tel: +1-518-626-6416; Fax: +1-518-626-6564; E-mail: aldona.baltch{at}med.va.gov

Objectives: The antifungal effects of voriconazole and caspofungin, singly and in combination, were determined against Candida glabrata in time–kill curves in broth, in human monocyte-derived macrophages (MDMs) and in MDMs activated by granulocyte-macrophage colony-stimulating factor (GM-CSF).

Methods: Three strains of fluconazole-resistant C. glabrata were evaluated. For intracellular studies, MDM monolayers, with or without GM-CSF activation, were infected with C. glabrata and treated with voriconazole and caspofungin at 2.5x and 5x MIC, respectively, or at 1x MIC. Extracellular studies in broth were performed using drug concentrations from 0.1 to 10x MIC. Viable yeast were enumerated at 0, 24 and 48 h.

Results: Significantly greater killing of C. glabrata occurred with the drug combination than with either single drug, both intracellularly and extracellularly (P < 0.01). For voriconazole, the antifungal activity in MDM activated by GM-CSF was greater than that in unactivated MDM, regardless of antibiotic concentration or time of exposure. However, for caspofungin and for the two-drug combination, enhanced activity in GM-CSF-activated MDM depended on the drug concentration and time of exposure.

Conclusions: Our data suggest that combinations of voriconazole and caspofungin may be efficacious for the treatment of serious C. glabrata infections. With single-drug therapy, especially voriconazole, GM-CSF activation of monocytes could be considered.

Key Words: phagocytes , drug combinations , human monocytes , Candida spp.


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