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Infection - Microbial Keratitis

Microbial keratitis (MK) is a serious ophthalmic infection that can cause visual impairment and blindness72lens The market for MK is large as estimates for annual cases worldwide are about 1.5 to 2 million though this is likely an underestimate due to underreporting of cases 72,73. The MK infection is commonly caused by Pseudomonas aeruginosa and Staphylococcus aureus and is commonly treated by the fourth-generation fluoroquinolones 74–77. Moxifloxacin is a fourth-generation fluoroquinolone that has superior activity against Staphylococcus aureus as well as gram negative organisms compared to earlier fluoroquinolones such as ofloxacin and ciprofloxacin 78,79. Another option is to use combination therapy such as a mixture of vancomycin for gram-positive coverage and an aminoglycoside such as gentamycin for gram-negative coverage80,81. Studies have shown that 0.5% moxifloxacin was comparable to many of the combination therapies including cefazolin & tobramycin82, aminoglycoside & cephalosporin83, cefazolin/tobramycin, cefuroxime/gentamicin84. For this reason, moxifloxacin is often a first-line choice by ophthalmologists for the treatment and prevention of anterior ophthalmic infections. Also, aqueous humor penetration is highest for moxifloxacin followed by gatifloxacin and lowest for ciprofloxacin85. The aqueous humor penetration is important to achieve the minimum inhibitory concentration (MIC95) of the drug which is in the range from 0.047–0.094 for susceptible strains and from 1.5-12 μg/mL for resistant strains 86,87 of S. Aurelius. The MIC50 for Pseudomonas aeruginosa to moxifloxacin in keratitis isolates is 3.0 μg/mL 88. The frequency of drop instillation for MK could be as high as half-hourly drops or hourly drops for the first 24-72 hours including nights with even more frequent drops every 5 min for the first 30 min.89–91. Subsequently, the frequency decreases to once every 2 or 4 hours. The high frequency is required because drugs instilled as eye drops remain in contact with the epithelia for only about 5 min. due to the rapid tear drainage and only about 1-5% of the drug permeates into the eye during this time25,92,93. Furthermore, drug that diffuses into the cornea and aqueous humor is cleared via aqueous drainage resulting in an exponential decrease in concentration with time. To keep the aqueous humor concentrations at therapeutic values thus requires frequent eye drops. For example, three drop instillations (0, 15, 30 min) resulted in aqueous humor concentrations of 33.4 μg/g 94 which is sufficiently high for even the resistant strains. The total number of drops for this therapy though could be as high as about 100 over 1-week of treatment. While efficacious, the patients have difficulties in complying with this high frequency application of eye drops resulting in poor prognosis 95. Antibiotics are becoming less effective because of development of resistance in organisms 96 to second- and third generation and even the newer fourth-generation fluoroquinolones, such as moxifloxacin 88,97,98. There are many factors that could be leading to proliferation of resistant strains including decrease in concentration to below MIC for a period of time 99. Recent studies have suggested that fluoroquinolones may possess a mutant-prevention concentration (MPC) concentration that would require an organism to possess 2 mutations simultaneously for growth in the presence of the drug at concentrations above the MPC100. Achieving consistent concentrations above the MPC could reduce development of resistance. Any lack of compliance with the high frequency instillation could lead to lower concentrations for the period of noncompliance which could drive development of resistance. For example, instilling drops every 2 hours and every six hours results in maximum aqueous chamber levels of 2.28 ± 1.23 and 0.88 ± 0.88 μg/mL, respectively 87. These maximum concentrations are higher than MIC for susceptible strains but lower than MIC for resistant strains. Furthermore, the concentration in aqueous humor will decay in the time between successive drops to below the MIC due to the aqueous outflow which could be a factor in development of resistance. Thus, delivery via eye drops is sub optimal for treating infections and low bioavailability of eye drops could be a factor in the disease progression as well as development of antibiotic resistant strains. We, at Freya, have developed a vitamin E loaded contact lens that can release moxifloxacin for a period of 72 hours. We expect lens-based therapy to treat infection in less time compared to drops, which typically last about 7-days. Our lens will be placed on the eye continuously for 72 hours and after that another lens may be inserted on the eye for another 72 hours, if needed. The in vitro release from the lens and in vivo predictions based on a validated model are shown in Figure 6 and 7, respectively. Based on the validated model predictions, a single contact lens will replace about 72 eye drops and will eliminate the need for instilling eye drops at night. Furthermore, high, and consistent concentration may lead to faster healing and reduction in the possibility of development of resistance to antibiotics.