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JAC Advance Access published online on October 20, 2005
Journal of Antimicrobial Chemotherapy, 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
Received June 24, 2005
Revised September 22, 2005
Accepted September 23, 2005

Brief report

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

Dhammika H. M. L. P. Navarathna 1, Jacob M. Hornby 2, Natasha Hoerrmann 2, Anne M. Parkhurst 3, Gerald E. Duhamel 4, and Kenneth W. Nickerson 5*

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

* To whom correspondence should be addressed.
Kenneth W. Nickerson, E-mail: knickerson1{at}unl.edu


  Abstract

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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