The long-range goals of this proposal are to study the factors which determine the intraocular penetration of antibiotics in order to improve the efficacy of treatment of bacterial and fungal ocular infections. We intend to examine three areas: (1) Liposome-intercalated amphotericin B (lip-AMB). We have developed a liposome formulation of amphotericin B (AMB) which is markedly less toxic than AMB. We will use a rabbit model of hematogenous Candida endophthalmitis to compare iv with intravitreal AMB given either as AMB or as lip-AMB with respect to intraocular levels and antifungal efficacy. Those routes which seem best in the rabbit model will be compared in cynomolgus monkeys. (2) We will study the ability of corneal iontophoresis to produce clinically useful intraocular concentrations of antibiotics. We will apply selected regimens to determine the influence of the bath (concentration, diluent), the current (intensity, duration) and the state of the eye (phakic or aphakic; normal or infected; sector iridectomy) upon intraocular levels. We will examine the most promising regimens in cynomolgus monkeys to determine the applicability of the findings to the primate eye. (3) Efficacy of antibiotics in vitreous humor. We will measure a number of variables in the vitreous humor which might influence the efficacy of B-lactam and aminoglycoside antibiotics (bacterial counts, growth rates, PO2, PH, DNA content). We will administer graded doses of antibiotics intravitreally to rabbits with endophthalmitis to determine the relation between antibiotic concentration and bactericidal activity. We will establish an in vitro model simulating the conditions in the vitreous humor to determine whether antibiotics in this situation behave as they do in vivo.
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