The objective is to investigate the ocular pathogenesis of bacterial keratitis with the goal of limiting by chemotherapy the bacterial and host factors that produce stromal damage. Bacterial keratitis often results in irreversible scarring of the cornea, blindness, and the need for a corneal transplant. The incidence of bacterial keratitis has been rising, in large part because of the increased use of contact lenses. Therapy of bacterial keratitis often requires a minimum of seven days in the hospital; in most cases, drug therapy includes topical administration of an aminoglycoside and a cephalosporin. Although this therapy ultimately results in bacterial death, it does not generally prevent corneal scarring. Scarring involves an ill-defined sequence of cellular events initiated by the infectious process. The investigator's overall goal is to understand the nature of the events that initiate the irreversible stromal damage, both the mechanisms due to the bacteria and those due to the host response, and to apply this knowledge to the development of therapeutic strategies. These studies would employ novel drug delivery methods (iontophoresis and collagen shields) capable of delivering large amounts of antibiotic in a short time, as well as two rabbit models of Pseudomonas aeruginosa keratitis, one of the most destructive and rapidly spreading ocular infections. The immediate goals are to test the optimal delivery (timing and dose) of antibiotics and inhibitors of inflammation, separately and in combination, for efficacy in minimizing corneal scarring. In addition, bacterial virulence factors would be tested to determine their role in producing corneal damage. Using Pseudomonas mutants deficient in virulence factors in corneas of leukopenic rabbits, the investigator and his coworkers would define a keratitis with minimal corneal damage.
The specific aims are to: 1) Determine the contribution of bacterial virulence factors (alkaline protease and exotoxin A) produced during keratitis to the process of irreversible corneal scarring; 2) Determine if steroids (dexamethasone or prednisolone) plus antibiotics (ciprofloxacin or tobramycin) can reduce irreversible corneal scarring; 3) Determine if other agents such as nonsteroidal anti-inflammatory drugs (flurbiprofen or chelators), which reduce PMN infiltrates, can be used in combination with antibiotics to reduce irreversible corneal scarring; and 4) Determine if protease inhibitors (tripeptides and anti-collagenase antibodies) plus antibiotics can reduce the irreversible corneal scarring produced by Pseudomonas keratitis. Patients with bacterial keratitis would reap significant benefits from the development of a specific therapeutic regimen that minimizes corneal scarring.
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