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R. A. Rebong, B. E. Goldhagen, W. J. Steinbach, N. A. Afshari; Calcineurin Inhibitors Enhance the Antifungal Treatment of Aspergillus Keratitis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5721.
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© ARVO (1962-2015); The Authors (2016-present)
To establish the ability of the calcineurin-inhibitor FK506 to work synergistically with voriconazole, amphotericin B, and polyhexamethylene biguanide (PHMB) against Aspergillus fumigatus in order to provide better topical eye drop treatments for Aspergillus keratitis.
Broth susceptibility testing was carried out using each of the four antifungal agents individually and in combination (FK506 with voriconazole, amphotericin B, or PHMB) against wild type Aspergillus fumigatus. FK506 was used at concentrations between 0.01 ug/ml to 0.08 ug/ml, voriconazole between 0.125 ug/ml to 1 ug/ml, amphotericin B between 2 ug/ml to 64 ug/ml, and PHMB between 0.3 ug/ml to 30 ug/ml. Fungal growth was compared against controls and across the varying drug concentrations and combinations.
Among the concentrations tested, FK506 inhibited fungal growth starting at 0.02 ug/ml, voriconazole inhibited growth starting at 0.25 ug/ml and eliminated growth starting at 1 ug/ml, amphotericin B inhibited growth starting at 64 ug/ml, and PHMB eliminated growth starting at 3 ug/ml. When FK506 was added to voriconazole, amphotericin B, or PHMB, fungal growth inhibition was enhanced and/or occurred at lower concentrations than when voriconazole, amphotericin B, or PHMB was used individually. Fungal growth inhibition was enhanced at 0.25 ug/ml voriconazole with the addition of at least 0.02 ug/ml FK506. Fungal growth inhibition occurred starting at 8 ug/ml amphotericin B with the addition of 0.08 ug/ml FK506. Fungal growth inhibition occurred starting at 0.5 ug/ml PHMB with the addition of at least 0.01 ug/ml FK506.
PHMB, not traditionally used as an antifungal, is shown here to be very effective in inhibiting Aspergillus growth. The calcineurin-inhibitor FK506 can enhance the effectiveness of the more traditional antifungals voriconazole and amphotericin B as well as of PHMB against Aspergillus. These findings have implications for developing improved topical eye drop treatments for Aspergillus keratitis.
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