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.

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.

PURPOSE. CD36 is a Class B scavenger receptor that is constitu- tively expressed in the corneal epithelium and has been impli- cated in many homeostatic functions, including the homeosta- sis of the epidermal barrier. The aim of this study is to determine (1) whether CD36 is required for the maintenance of the corneal epithelial barrier to infection, and (2) whether CD36-deficient mice present with an increased susceptibility to bacterial keratitis. METHODS. The corneas of CD36- /- , TSP1- /- , TLR2- /- , and C57BL/6 WT mice were screened via slit lamp microscopy or ex vivo analysis. The epithelial tight junctions and mucin layer were assessed via LC-biotin and Rose Bengal staining, respec- tively. Bacterial quantification was performed on corneal but- tons and GFP-expressing Staphylococcus aureus was used to study bacterial binding. RESULTS. CD36-/- mice develop spontaneous corneal defects that increased in frequency and severity with age. The mild corneal defects were characterized by a disruption in epithelial tight junctions and the mucin layer, an infiltrate of macro- phages, and increased bacterial binding. Bacterial quantifica- tion revealed high levels of Staphylococcus xylosus in the corneas of CD36-/- mice with severe defects, but not in wild-type controls. CONCLUSIONS. CD36 -/- mice develop spontaneous bacterial keratitis independent of TLR2 and TSP1. The authors conclude that CD36 is a critical component of the corneal epithelial barrier, and in the absence of CD36 the barrier breaks down, allowing bacteria to bind to the corneal epithelium and result- ing in spontaneous keratitis. This is the first report of sponta- neous bacterial keratitis in mice. (Invest Ophthalmol Vis Sci. 2011;52:256–263) DOI:10.1167/iovs.10-5566

Purpose: To describe the microbiology results of corneal scrapings and morphology results of corneal ulcers over a one year period at the St John Eye Hospital with the following objectives: (i) to describe the positive culture results (ii) to describe the commonest causative organisms (iii) to describe resistance patterns to antibiotics (iv) to correlate the positive culture results with the clinical characteristics of the ulcer. Methods: A retrospective cross sectional review of patient medical records and microbiology reports of patients who presented with corneal ulcers at the St John Eye Hospital between October 2007 and October 2008. One hundred and fifty one (151) corneal scrapings submitted to the National Health Laboratory Services (NHLS) for microbiology, culture and sensitivity testing were analyzed. The following information was extracted from the microbiology reports and patient medical records: patient demographics, microbial isolations, antibiotic sensitivity and resistance, and corneal ulcer morphology (central versus peripheral). Results: Of the 151 patients who had corneal scrapings, 63(42%) were female and 88(58%) were male. The median age was 39.6(range 1-95; SD 19.3). An organism was identified in 78(52%) of the samples. Of the 93 pathogens isolated, 78(83.9%) were gram positive, 10(10.8%) were gram negative, and 5(5.4%) were fungi. Mixed isolates were found in 15 of the 151 corneal scrapings. The most common gram positive isolates were Staphylococcus aureus 23(29.5%), coagulase negative Staphylococcus 18(23.1%), and Streptococcus pneumoniae 16(20.5%). The two most commonly isolated gram negative organisms were Pseudomonas aeruginosa 3(30%) and Haemophilus influenza 3(30%). A total of 5 fungi were isolated from the 151 corneal scrapings with Fusarium 3(60%) being the most common fungus isolated. Antibiotic resistance patterns were as follows: Gram positive isolates (73) consistently showed 100% sensitivity to vancomycin. A small number of gram positive organisms showed in vitro resistance to the second generation fluoroquinolone ciprofloxacin. This was, however only a small number of gram positive isolates and therefore the P value (P<0.001) remained significant. Overall the gram positives isolates showed a 95.3% sensitivity to ciprofloxacin. Both second and fourth generation fluoroquinolones, ciprofloxacin and moxifloxacin respectively, showed equivalent (100%) in vitro activity against the gram negative isolates. All gram negative isolates showed 100% laboratory susceptibility to the aminoglycosides, gentamicin and amikacin. Inpatient medical records were available for 56 of the 151 corneal ulcer scrapings. Of the 56 inpatient records reviewed 42(75%) were central ulcers. Streptococcus pneumoniae 10(23.8%) was the most common organism isolated in central corneal ulcers, while staphylococcus aureus 4(28.6%) was the most common organism isolated in peripheral corneal ulcers. Conclusion: Compared with previous reports from the St John Eye Hospital, the spectrum of causative organisms has remained unchanged over the past 25 years. The organisms commonly responsible for microbial keratitis at the hospital are significantly susceptibility to the antibiotics currently being used as therapy.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg in partial fuifillment of the requirements for the degree of Master of Medicine in Ophthalmology, / This dissertation describes the causation and management of bacterial keratitis at St John Eye Hospital. [Abbreviated Abstract. Open document to view full version] / AC2017

Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / "May 1998." Typescript. Vita. Includes bibliographical references (leaves 71-76). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / Typescript. Vita. Includes bibliographical references (leaves: 71-76). Also available on the Internet.

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Microbial keratitis is the most serious, and only potentially blinding complication of contact lens wear. To further understand and reduce the risk of this disease, incidence rates and risk factors have been estimated in numerous studies. Since these studies were conducted, new lens types have been introduced designed to reduce the risk of infection. It was hypothesised that the issues of contact lens related hypoxia and poor lens hygiene could be addressed by the introduction of silicone hydrogel and daily disposable lenses respectively. This thesis describes the incidence of and risk factors for contact lens related microbial keratitis in Australia and New Zealand. The incidence of infection was determined by capturing all cases of contact lens related presumed microbial keratitis in a 12-month surveillance study, and by estimating the number of lens wearers using a population-based phone survey. Characteristics of the cases and controls were compared to estimate risk factors. In Australia, rates of infection with daily and overnight wear of hydrogel lenses were similar to previously published reports (1.9 [95%CI]:1.8-2.0] and 19.5 [95%CI:14.6-29.5] per 10,000 wearers respectively). Compared to the incidence of infection with hydrogel lenses, silicone hydrogel lenses had a higher rate in daily wear (11.9 [95%CI: 10.0-14.6]), and a similar rate in extended wear (19.5 [95%CI:14.6-29.5]). Daily disposable lenses had a similar rate of infection to daily wear of hydrogel lenses (2.0 [95%CI:1.7-2.4]), but appeared to reduce the incidence of severe or vision loss keratitis (0.5 [95%CI: 0.5-0.6] and 0.0 [95%CI: 0.0-0.0] respectively). Conducting the study in New Zealand confirmed the increase in incidence for overnight use of lenses, irrespective of lens type. Comparison of the incidence rates in New Zealand and Australia show that the rates in the two countries are comparable, bar an unexplained lower rate of infection for extended wear of soft hydrogel lenses in New Zealand. Risk factors for infection were overnight use of lenses, from occasional overnight to extended wear use, poor lens case hygiene, smoking, high socio-economic status and less than 6 months experience in current lens type. Amongst daily wearers, Internet or mail order purchasing of lenses was also associated with a higher risk of infection. This study is unique in terms of the study design and sample size, and the wide scope of risk factors considered. The determination of these incidence rates of infection and identification of risk factors is of extreme value to lens wearers and lens care practitioners around the world, particularly as the strongest and most prevalent risk factors are modifiable.