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JAC Advance Access originally published online on October 20, 2005
Journal of Antimicrobial Chemotherapy 2005 56(6):1156-1159; doi:10.1093/jac/dki383
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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@oxfordjournals.org

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

Dhammika H. M. L. P. Navarathna1,2, Jacob M. Hornby3, Natasha Hoerrmann3, Anne M. Parkhurst4, Gerald E. Duhamel2 and Kenneth W. Nickerson1,*

1 School of Biological Sciences, University of Nebraska, Lincoln, NE 68588, USA; 2 Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, NE 68583, USA; 3 Division of Natural Sciences, Lewis-Clark State College, Lewiston, ID 83501, USA; 4 Department of Statistics, University of Nebraska, Lincoln, NE 68583, USA

Received 24 June 2005; returned 5 August 2005; revised 22 September 2005; accepted 23 September 2005

* Corresponding author. Tel: +1-402-472-2253; Fax: +1-402-472-8722; E-mail: knickerson1{at}unl.edu

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 x 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


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