Increasing the ability of antibiotics to control S. aureus keratitis

Microbial keratitis is a major cause of avoidable visual impairment worldwide with S. aureus a leading cause of this disease in humans. Recently S. aureus isolated from eye infections have exhibited resistance to many antibiotics with those isolates from more severe infections exhibiting higher rates of antibiotic resistance. New therapies are therefore needed to ensure adequate treatment for these infections. In microbial keratitis the hosts' immune response is responsible for significant disease pathology so development of a therapy which also targets the immune response would be beneficial. The fimbrolides produced by Delisea pulchra are potential candidates as they are both growth inhibitory and immunomodulatory in vitro. The antibiotic susceptibility of clinical S. aureus isolates from ocular infections was determined using the CDS method and similarity of these isolates determined by PFGE and PCR-ribotyping. In addition the effect of fimbrolides on bacterial growth alone or in combination with antibiotics and the immune response to bacterial stimulation in PMNs and HCE cells was determined. Fimbrolides were then topically applied to S. aureus corneal infections and the effect of these compounds on disease progression determined by assessing corneal pathology, bacterial numbers and PMNs recovered from infected corneas. A larger proportion of keratitis isolates exhibited resistance to antibiotics than conjunctivitis isolates. Keratitis isolates were also related within a geographical region. The fimbrolides inhibited bacterial growth and modulated the immune response to bacterial stimulation in vitro. These compounds also exhibited synergy with conventional antimicrobials. In combination with ciprofloxacin the fimbrolides reduced the clinical score and numbers of bacteria recovered from ciprofloxacin-resistant or ciprofloxacin-sensitive S. aureus corneal infections.This thesis has identified that S. aureus isolates which produce the worst disease pathology in the eye are related and also exhibit higher rates of resistance to antibiotics indicating novel therapies to treat these infections are needed. This thesis demonstrated that fimbrolides inhibit S. aureus growth, exhibit synergy with antibiotics and modulate the immune response in vitro. In combination with ciprofloxacin the fimbrolides also improved disease pathology in keratitis, illustrating the potential of fimbrolides to be used as an adjunct therapy in the treatment of S. aureus keratitis