Mycograb increases Candida sensitivity to fluconazole in vitro
Abstract number: 1733_1463
Nooney L., Al-Akeel R., Awad S., AlShami I., Matthews R., Burnie J.
Introduction: Hsp90 has been implicated in the development of anti-fungal drug resistance and has been shown to play an important role in the development and continuation of resistance. The role of hsp90 in resistance to fluconazole (FLC) is exerted through calcineurin. The blocking of either hsp90 or calcineurin results in enhanced drug activity or reversed drug resistance. We hypothesize that Mycograb, an inhibitor of hsp90, may act in a similar way to geldanamycin and delay or block the development of high level resistance to fluconazole in Candida.
Methods: Six isolates of Candida were exposed to FLC at a range of 0.03125 to 512ug/mL in the presence of 4, 8 and 16ug/mL Mycograb in a broth macrodilution assay. Colonies from each of the isolates that grew at the concentration just prior to culture sterilisation were also examined in the same assay.
Results: Five of the six isolates displayed increased sensitivity to FLC with the addition of 4, 8 or 16ug/mL Mycograb, the MIC-2 was reduced by one or more dilution. A fluconazole sensitive strain of Candida albicans was the most sensitive with a FLC MIC-2 of 2ug/mL before the addition of Mycograb and an MIC-2 of 0.5ug/mL in the presence of 8 and 16mg/mL Mycograb. Comparisons of CFU/mL between cultures with FLC only and those that contained Mycograb demonstrated additivity (>1 log reduction in CFU/mL) between fluconazole and Mycograb in four isolates and synergy, ≥2log reduction in CFU/mL, in a single isolate. Repetition of the assay using resistant colonies also showed that Mycograb increased sensitivity to FLC in four isolates. A fluconazole resistant strain of C. albicans was the most sensitive isolate to the activity of Mycograb with an MIC-2 of 16mg/mL and an MIC-2 of 0.03125ug/mL in the absence and presence of Mycograb respectively. Additivity was observed in two isolates and synergism in a single isolate. No antagonism was demonstrated.
Conclusion:Candida species exposed to fluconazole (FLC) in combination with Mycograb were found to have increased sensitivity to fluconazole in vitro. The MIC-2 to FLC in fluconazole sensitive and in fluconazole resistant sub-populations of Candida species was found to be reduced
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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