Treatment with topical azithromycin 1% ophthalmic solution (AzaSite, InSite Vision) using a frequent dosing regimen was effective in reducing colony counts of azithromycin-resistant Pseudomonas aeruginosa in an animal model of keratitis.
"Historically, the rabbit keratitis model has performed well in validating clinical performance, so these results suggest clinical studies may be warranted to determine the role of azithromycin for the treatment of bacterial keratitis," said Francis S. Mah, MD, assistant professor of ophthalmology, and co-medical director, The Charles T. Campbell Eye Microbiology Laboratory, University of Pittsburgh Medical Center. "Clearly, azithromycin may not be the drug of choice for known Pseudomonas infection, but with aggressive dosing, it may be an effective treatment."
Azithromycin is a widely used macrolide antibiotic with a reasonably broad spectrum of action. However, P aeruginosa represents one of the gaps in its coverage. Even so, patients found to have P aeruginosa infections after enrollment in the phase 3 clinical study of azithromycin 1% ophthalmic solution for bacterial conjunctivitis were successfully treated.
"Breakpoints are defined based on antimicrobial concentrations achieved in the serum. However, those values may be irrelevant to the treatment of ocular infections with topical antibiotics that are able to deliver much higher concentrations safely to the target site," he explained.
The preclinical keratitis study was performed using an established New Zealand White rabbit keratitis model. A total of 24 animals were included in two identically designed trials.
Keratitis was induced by injecting a broth containing approximately 1,000 CFU of an azithromycin-resistant (MIC = 24 μg/ml) P aeruginosa ocular isolate into the stroma of both eyes. In each trial, 12 rabbits were randomly divided into four treatment groups of three animals each to receive bilateral treatment with: 1) azithromycin 1% every 0.5 hour; 2) azithromycin 1% every 1 hour; 3) azithromycin 1% every 2 hours; or 4) saline every 0.5 hour. In all animals, the assigned treatment was started 16 hours post-bacterial inoculation and continued for 8 hours.
One hour after receiving the last dose, the rabbits were euthanized and the corneas processed for assay of viable bacterial counts. The colony counts from both eyes of each animal were averaged and transformed into Log10 values. Statistically significant differences between groups were evaluated using mean ± SD values.
The results from one trial showed that animals treated with the most frequent azithromycin dosing regimen (every 0.5 hour) had a Log10 mean ± SD corneal colony count of 2.2 ± 2.0 CFU/ml. That value was significantly lower than the Log10 mean corneal colony count of P aeruginosa in the saline-treated control group (5.3 ± 0.5 CFU/ml) but also significantly lower than in animals treated with azithromycin every hour (4.7 ± 0.4 CFU/ml) or every 2 hours (5.1 ± 0.5 CFU/ml). There were no significant differences in pairwise comparisons of Log10 mean corneal colony counts between the latter three treatment groups.