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P. Karicherla, J. A. Hobden; Nona-D-Arginine Therapy for Pseudomonas aeruginosa Keratitis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):726.
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Exotoxin A, an important virulence factor in P. aeruginosa corneal disease, relies on a host protease (furin) for activation. Furin may also activate a number of other host processes detrimental to corneal tissue. This study determined the efficacy of nona-D-arginine (D9R), a potent inhibitor of furin, as a possible therapy for P. aeruginosa keratitis when administered alone and in combination with the antibiotic ciprofloxacin.
Right eyes of NIH Swiss black mice were scarified using a 21G needle and infected with 1X 106 colony forming units (CFU) of P. aeruginosa PAO1. At time 0 and hourly for 5 hours (total of six drops/infected eye), corneas received a 5µl drop of either phosphate buffered saline (PBS, pH 7.4), 10µM D9R (N=40) or100 µM D9R (N=15). At 16 hours post infection (PI) and then hourly for 5 hours, eyes treated with D9R or PBS then received a 5µl drop of either ciprofloxacin (N=20) or deionized water (N=20). At 24 hours PI, eyes were evaluated for pathology and scored on a scale of 0 (normal eye) to +4 (corneal perforation). Mice were then sacrificed and eyes were harvested for histopathology (N=6) or CFU determination (N=15).
Eyes treated with a combination of either 10 or 100 µM D9R (0-5hours PI) and ciprofloxacin (16-21 hours PI) had significantly less pathology (p<0.01) than PBS-treated eyes or eyes treated with ciprofloxacin alone. There was significant reduction (p<0.0001) in log10 CFU in eyes treated with ciprofloxacin, with or without prior treatment with D9R, when compared to PBS-treated eyes. Eyes treated with 10 or 100 µM D9R (0-5hours PI) alone had significantly less (p< 0.001) pathology than PBS-treated eyes; however there were no significant differences in CFU between these three groups (p>0.100).
Administration of 10 or 100 µM D9R effectively reduced the pathology associated with P. aeruginosa keratitis. In addition, combination therapy of D9R and ciprofloxacin was significantly more effective in treating P. aeruginosa keratitis than treatment with antibiotic alone by reducing the pathology as well as eradicating viable bacteria from the eye.
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