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C. Onyewu, J. Heitman, N.A. Afshari; The Efficacy of Cyclosporine A and Fluconazole in Combination for the Treatment of Candida albicans Murine Keratomycosis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):300.
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To test the in vivo efficacy of combining ophthalmic preparations of the calcineurin inhibitor cyclosporine A (CsA) and the ergosterol biosynthesis inhibitor fluconazole for treatment of Candida albicans keratomycosis.
The right corneas of 90 immunosuppressed BALB/c mice were scarred by a 28.5–gauge needle and immediately inoculated with a suspension of ∼106 wild–type (n=52) or calcineurin mutant (n=38) C. albicans cells. A clinical ocular grading scale of 0 (clear cornea) to 4 (severe infection) was predetermined to rank corneal infection. Animals were divided into four drug treatment groups, receiving no drug (n=31), 2% CsA only (n=10), 0.2% fluconazole only (n=35), or 2% CsA and 0.2% fluconazole (n=14) daily for 4 or 6 days. Topical treatment was begun two days after infection when at least one animal in each treatment group reached a grade ≥3 infection. Treated animals received 5 µl of 2% CsA one to two times per day and/or 5 µl of 0.2% fluconazole one to two times per day. The infected eye of each animal was examined and scored daily using a conventional slit–lamp. The eyes were enucleated at day 4 or 6 of treatment.
By day three of treatment, the majority of wild–type C. albicans infections in animals receiving combination therapy with topical fluconazole and CsA had completely resolved to a grade 0 (n=11/14). Contrastingly, animals receiving no treatment (n=15/18) or monotherapy with either fluconazole (n=6/12) or CsA (n=7/8) for wild–type infections still had visible signs of infection up to the last day of treatment. There was no significant difference observed between the disease score of untreated animals and animals treated with CsA alone. Animals infected with a C. albicans mutant strain lacking the calcineurin B gene developed mild infections (n=15) that were rapidly cleared with fluconazole treatment. A C. albicans calcineurin mutant strain for which the wild–type calcineurin B gene was reintroduced was also used to infect animals (n=15). The infection caused by this complemented mutant strain mimicked the wild–type infections, and did not easily resolve with fluconazole treatment.
In a murine model of C. albicans keratomycosis, the protein phosphatase calcineurin that is targeted by cyclosporine A was found to contribute to pathogenicity, and combination therapy with ophthalmic preparations of fluconazole and cyclosporine A effectively resolved the wild–type infection more rapidly than monotherapy with either drug.
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