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

Abstract

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. C. albicans A72 cells were grown overnight in 0-5.0 microM fluconazole, washed, and inoculated in mice by tail vein injection. Groups of 15 or 16 mice were injected with 1.3 x 10(6) 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. The MIC50 for strain A72 was 0.125 mg/L (0.4 microM). Mice administered C. albicans pre-treated with 0.5 to 1.0 microM 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 microM) 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 muM fluconazole were 12-, 2- and 6-times those of untreated cells. 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.