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


RESULTS
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.


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.
Navarathna
Dhammika H M L P
DH
School of Biological Sciences, University of Nebraska, Lincoln, NE 68588, USA.
Hornby
Jacob M
JM
Hoerrmann
Natasha
N
Parkhurst
Anne M
AM
Duhamel
Gerald E
GE
Nickerson
Kenneth W
KW
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000737:chemistry / Q000187:drug effects* / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology*; D004195:Disease Models, Animal; D005204:Farnesol / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D051379:Mice; D008826:Microbial Sensitivity Tests; D016019:Survival Analysis; D014774:Virulence / Q000187:drug effects*
D000935:Antifungal Agents; D005204:Farnesol; D015725:Fluconazole