Chemotherapy and pathogenic mechanisms of Staphylococcus aureus keratitis

Staphylococcus aureus is a leading cause of bacterial keratitis and endophthalmitis in the USA. These infections arise spontaneously or as a consequence of ocular surgical procedures. Despite prompt and effective antibiotic therapy, infections can result in blindness or loss in visual acuity. Emphasis in this research is on identifying bacterial virulence factors that mediate tissue damage and developing improved antibiotic therapy that can prevent or treat infection.;Research has demonstrated that alpha-toxin is produced by 75% of S. aureus and is responsible for tissue damaging reactions in keratitis. Mechanisms by which alpha-toxin deficient strains cause corneal damage were investigated. Analysis of mutants deficient in specific toxin genes and of purified toxins demonstrated that gamma-toxin is a corneal virulence factor. Furthermore, the prototype strain reportedly lacking alpha-toxin, indeed produces reduced, but significant, quantities of alpha-toxin. This is first evidence of S. aureus producing reduced amounts of alpha-toxin and that gamma-toxin is a corneal virulence factor.;Improvements in chemotherapy for Staphylococcus ocular infections are needed to overcome bacterial resistance and inefficient drug delivery. Frequency of post-surgical infections could be reduced by more effective prophylactic therapy. A new model for testing prophylactic therapy was developed and permitted studies quantifying prophylactic effectiveness of several antibiotics. Results demonstrated that the effectiveness of tobramycin could be improved by 3--4 orders of magnitude by the use of a penetrating enhancing agent. The effectiveness of various fluoroquinolone antibiotics was compared and moxifloxacin was found to be the most effective.;Research on two new anti-microbial agents for treatment of MRSA keratitis was undertaken. Lysostaphin, a zinc metaloproteinase, was tested as a therapy for both keratitis and endophthalmitis. Lysostaphin was the most effective therapy yet tested and resistance is very rare. Moxifloxacin (fourth generation fluoroquinolone), a broadspectrum antibiotic, was found to be effective against S. aureus with methicillin and fluoroquinolone resistance.;This research has identified new mechanisms of bacterial corneal pathogenesis and demonstrated therapies to prevent infection and to treat highly resistant S. aureus strains.