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G. M. Comer, J. B. Miller, N. W. Khan, G. Scott, V. M. Elner, D. N. Zacks; Intraocular Toxicity of Daptomycin: A Broad-spectrum Antibiotic for Drug-resistant, Gram-positive Infections. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3558.
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Daptomycin is a broad-spectrum antibiotic for Gram-positive bacteria, including those with vancomycin resistance. The rapid and complete bactericidal activity, long half-life, minimal resistance, and lack of cell-wall lysis with bacterial death compare favorably to vancomycin. If safety and efficacy are established in animal models, daptomycin may change the endophthalmitis treatment paradigm. This study evaluated the intraocular ocular safety of daptomycin in a pigmented rabbit model.
Twelve, male, adult Dutch belted rabbits (2.2-2.5 kilograms) were divided into four groups of three rabbits. Both eyes of all rabbits underwent dilated indirect ophthalmoscopy and electroretinography (ERG) at baseline. The right eye then received 0.05 milliliters (ml) of daptomycin diluted with 0.9% sodium chloride for a total of 75, 188, 375, and 750 micrograms (mcg) of daptomycin in the three rabbits of each group respectively. All left eyes received 0.05 ml of 0.9% sodium chloride control. After 14 days, both eyes of all rabbits underwent repeat dilated indirect ophthalmoscopy and ERG. The animals were sacrificed, and the eyes were enucleated for histopathology.
An escalating dose-toxicity relationship was observed with 188 mcg of daptomycin being the maximum safely administered dose. All control eyes were normal and unchanged from baseline with ophthalmoscopy, electroretinography, and histopathology. On ophthalmoscopy, the exam was uniformly normal in the 75 and 188 mcg doses, while the 375 and 750 mcg doses induced cataracts in some rabbits. ERG demonstrated no scotopic or photopic depression with the 75 or 188 mcg doses, moderate depression with 375 mcg, and severe depression with the 750 mcg dose. Histopathology revealed severe inner and outer layer cellular disruption in the 750 mcg dose of daptomycin. The other doses and control eyes revealed mild inner layer vacuolization, mild inflammation, and retinal detachment with relative preservation of the cellular layers.
Up to 188 mcg of intravitreal daptomycin appears safe in the Dutch belted rabbit eye. Given the roughly 1.5 ml volume of the rabbit vitreous, this translates to a 125 mcg/ml concentration. In calcium-supplemented broth, the minimum inhibitory concentration (MIC90) and minimum bactericidal concentration (MBC90) of daptomycin extend from <1 mcg/ml for assorted Gram-positive isolates to 8 mcg/ml for some enterococci, which generally represents the most difficult genera to eradicate. Thus, the largest safe concentration in a Dutch belted rabbit is approximately 15 times the largest MIC90 and MBC90.
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