Comparison of Ophthalmic Gatifloxacin 0.3% and Ciprofloxacin 0.3% in Healing of Corneal Ulcers Associated With Pseudomonas Keratitis in Rabbits

Abstract

Abstract: : Purpose:Ocular infections with the Gram negative pathogen Pseudomonas aeruginosa require very aggressive therapy. We evaluated gatifloxacin, a novel 4th generation fluoroquinolone being developed for the treatment of ocular bacterial infections, versus ciprofloxacin in a corneal ulcer model of Pseudomonas keratitis in rabbits. Methods:Corneal ulceration was surgically induced by topical application of heptanol in the right eye of anesthetized New Zealand White rabbits (N=40). The resulting 6.5 mm defect was immediately inoculated with a 100 µl suspension of 10₆ CFU of Pseudomonas aeruginosa. All study animals received systemic analgesics. Study medication (gatifloxacin ophthalmic solution 0.3% [GF] or ciprofloxacin HCl 0.3% [CF]) was administered beginning 24 hr post-inoculation and lasting 22 days. GF dosing frequency varied among 4 treatment groups, with initial frequencies of 16-48 doses/day for 2-7 days and maintenance dosing of 3-4 doses/day for the rest of the study. Total doses received by each group in the first 48 hr post-inoculation and the rest of the study, respectively, were: 1) GF 32 and 76; 2) GF 64 and 57; 3) GF 64 and 76; 4) GF 64 and 136, and 5) CF 60 and 76. The CF regimen was based on labeled dosing for corneal ulcers. Infection severity was assessed daily. Ophthalmologic examinations were performed pre- and post-inoculation, then weekly. Results:All eyes showed evidence of infection by 48 hr post-inoculation, with 36/40 exhibiting moderate to severe keratitis (grade 3 to 5 on a 1-5 scale). All eyes developed secondary cicatricial keratitis, and all showed signs of corneal healing (corneal vascularization, cellular infiltration) by day 15. There were no significant differences in the rates or magnitudes of corneal healing among the treatment groups, although the 2 groups receiving 64 doses of gatifloxacin in the first 48 hr tended to have smaller fluorescein retention area scores than those receiving CF or other GF regimens. No eyes tested positive for P. aeruginosa at the end of the study. No evidence of corneal precipitates was found following dosing with gatifloxacin. Conclusion:Ophthalmic gatifloxacin 0.3% is at least as effective as ciprofloxacin at healing corneal ulcers infected with the challenging Gram negative ocular pathogen Pseudomonas aeruginosa, even when gatifloxacin is given on less-frequent dosing regimens. Trends favored gatifloxacin in fluorescein retention area scores. Gatifloxacin did not form corneal precipitates even when dosed as frequently as 48 times/day.

Keywords: 449 keratitis • 316 animal model • 390 drug toxicity/drug effects