The fundamental thesis of this application is that the final damage to the eye from endophthalmitis is a result of two contributing sets of events: 1) microbial infection consisting of bacterial replication with the release of bacterial products such as toxins and cell wall components; and 2) the host response to infection including the inflammatory response which may in an exaggerated form contribute to tissue damage. We will pursue lines of investigation to examine aspects of both sets of factors. Bacterial infections created by Bacillus spp. and gram-negative bacteria will be examined in a quantitative fashion to test the ability of bacterial cell walls and various products of the bacteria such as endotoxin, necrotic exotoxin, and cereolysin to induce intraocular inflammation alone and in combination. We have identified a bactericidal effect in the vitreous induced by infection with S. epidermidis and by inflammation created by heat-killed S. epidermidis. We will attempt to further characterize this effect, identify whether it is cellular mediated alone or the result of an elaborated factor, and isolate this factor if appropriate. We will examine strategies to enhance bacterial killing in the vitreous by defining the pharmacokinetics of the current antibiotics of choice for intravitreal injection, and testing the synergistic effects of antibiotic combinations and surgery. We will search for successful strategies to modulate the inflammatory response to infection including examining the potential role of agents to block specific factors which create inflammation of unusual severity after infection with certain bacteria.
