Journal Article

Enhanced pathogenicity of <i>Candida albicans</i> pre-treated with subinhibitory concentrations of fluconazole in a mouse model of disseminated candidiasis

Dhammika H. M. L. P. Navarathna, Jacob M. Hornby, Natasha Hoerrmann, Anne M. Parkhurst, Gerald E. Duhamel and Kenneth W. Nickerson

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 56, issue 6, pages 1156-1159
Published in print December 2005 | ISSN: 0305-7453
Published online October 2005 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dki383
Enhanced pathogenicity of Candida albicans pre-treated with subinhibitory concentrations of fluconazole in a mouse model of disseminated candidiasis

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Objectives: To investigate the relative pathogenicity of Candida albicans treated with subinhibitory concentrations of fluconazole in a mouse model of disseminated candidiasis. Previous studies indicate that these cells secrete 10 times more farnesol than do untreated cells. In our usage, subinhibitory means a concentration which causes a prominent decrease in turbidity but still allows some cell growth.

Methods: C. albicans A72 cells were grown overnight in 0–5.0 μM fluconazole, washed, and inoculated in mice by tail vein injection. Groups of 15 or 16 mice were injected with 1.3 × 106 cells and mortality was recorded for 7 days post-inoculation. The levels of farnesol in control and treated C. albicans were determined by GC/MS.

Results: The MIC50 for strain A72 was 0.125 mg/L (0.4 μM). Mice administered C. albicans pre-treated with 0.5 to 1.0 μM fluconazole died 2.5 to 4 days earlier and had 2 to 4 times higher mortality rates than mice given untreated C. albicans. Fluconazole (0.5 to 1.0 μM) pre-treated cells were 4.2 to 8.5 times more lethal (P < 0.001) than untreated cells. The extracellular, membrane bound, and intracellular farnesol concentrations of cells pre-treated with 1.0 μM fluconazole were 12-, 2- and 6-times those of untreated cells.

Conclusions: The effects of fluconazole on C. albicans are very concentration-dependent. The enhanced pathogenicity of fluconazole pre-treated C. albicans in mice should be relevant to the therapeutic and prophylactic use of fluconazole. Further research is needed to explore whether farnesol production by C. albicans is a virulence factor.

Keywords: farnesol; virulence; candidaemia

Journal Article.  2757 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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