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To evaluate the penetration of commercially available levofloxacin 0.5%, ofloxacin 0.3%, and ciprofloxacin 0.3% topical ophthalmic solutions in human corneal stromal and aqueous humor tissues.A total of 67 patients scheduled to undergo penetrating keratoplasty for treatment of stromal scar or dystrophy, keratoconus, pellucid marginal degeneration, or endothelial disease were enrolled in this prospective, double-blind, 3-center study. To be considered for inclusion, patients had to have an intact corneal epithelium and minimal or no corneal edema (pachymetry < 650 μm). After informed consent was obtained, patients were randomized to receive 1 drop of levofloxacin 0.5%, ofloxacin 0.3%, or ciprofloxacin 0.3% topical ophthalmic solution at approximately 15 and 10 minutes before surgery. Approximately 0.1 mL of aqueous fluid was aspirated by paracentesis through the trephination wound at the onset of surgery, followed by excision of the affected cornea and removal of its epithelium. Specimens were stored frozen at −70°C until assayed by high-performance liquid chromatography.All 3 fluoroquinolones were well tolerated. A total of 65 corneas and 59 aqueous fluid samples were obtained and assayed. The mean ± standard deviation corneal concentrations of ciprofloxacin, ofloxacin, and levofloxacin following a 2-drop administration were 9.92 ± 10.99 μg/g (n = 18), 10.77 ± 5.90 μg/g (n = 23), and 18.23 ± 20.51 μg/g (n = 24), respectively. Although corneal stromal levels were highest in the levofloxacin group, the high degree of interpatient variability prevented demonstration of statistically significant differences when compared with ofloxacin (P = 0.377). In contrast, levofloxacin concentrations were approximately twice as high as ciprofloxacin, and this difference reached statistical significance (P = 0.014). The corresponding aqueous humor concentrations of ciprofloxacin, ofloxacin, and levofloxacin were 0.135 ± 0.231 μg/mL (n = 15), 0.135 ± 0.111 μg/mL (n = 20), and 0.372 ± 0.546 μg/mL (n = 24, P < 0.001 versus ciprofloxacin and ofloxacin).The topical administration of all 3 agents was well tolerated in patients undergoing penetrating keratoplasty. Two drops of levofloxacin 0.5% solution results in a 1.7- to 2.7-fold greater penetration into human corneal stromal and aqueous humor tissues than ofloxacin 0.3% or ciprofloxacin 0.3%. The mean intracorneal concentrations of all three agents following 2 drops exceeds the MIC90 for the majority of pathogens causing bacterial keratitis. Topical levofloxacin appears to offer pharmacokinetic and pharmacodynamic advantages over ofloxacin and ciprofloxacin in terms of enhanced transcorneal penetration; however, clinical comparative trials are needed to confirm these relative advantages.