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Topical fluoroquinolones are broad spectrum, bactericidal agents with activity against both Gram positive and Gram negative corneal pathogens. Single drug administration with topical fluoroquinolones has been effectively used in treatment of bacterial ulcerative keratitis. The drugs are safe, but a white crystalline deposit, that in most cases spontaneously dissolved, has been reported1–4 with ciprofloxacin 0.3% and norfloxacin 0.3%. Up to now this side effect has not been described with ofloxacin 0.3%. We present two children with severe vernal conjunctivitis who developed corneal deposits after use of ofloxacin 0.3% eye drops.
Material and methods
A 6 year old boy with vernal keratoconjunctivitis (VKC) developed a painful right eye while on holiday. His ophthalmologist diagnosed a corneal ulcer and prescribed ofloxacin eye drops followed by ofloxacin ointment four times a day for 3 weeks, associated with prednisolone drops. As the inflammation in the right eye persisted, the child was referred to our department. Slit lamp examination revealed mild VKC and a corneal ulcer with a dense, white, sharply demarcated crystalline deposit (Fig 1). All topical treatment was discontinued, but since the deposit did not spontaneously disappear and inflammation persisted, corneal scraping was performed 7 days later to remove the deposit. The sample was analysed by low contrast microscopy.
A 4 year old boy was referred for severe bilateral VKC with a corneal erosion in the right eye. One month before referral the child had had a corneal erosion in the right eye caused by the rubbing of a giant papilla on his upper eyelid. After an initial good response to terramycin ointment with fluorometholone and emadine, an increase in symptoms was observed. A topical treatment with ofloxacin ointment and patching was initiated, but the inflammation persisted. On administration to our department we observed a corneal ulcer associated with a white round crystalline deposit in the right eye. Ofloxacin treatment was discontinued, but the deposit did not dissolve and inflammation persisted. Twelve days after the discontinuation of the topical treatment a corneal scraping of the deposit was performed in combination with a subtarsal injection of corticosteroids in both eyes.
The corneal scraping was analysed by microscopy. To that end, pefloxacin was added as internal standard and the minute tissue sample was extracted with an acid (formic acid, pH 3.0) mixture of water/acetonitrile (60/40). An aliquot was injected onto a 1 mm × 15 cm Inertsil ODS C18 column (5 μm), eluted isocratically (40 μl/min) with 90/10 water/acetonitrile pH 3.0. Detection was performed using a Q-TOF mass spectrometer (Micromass, Manchester, UK) in the MS/MS mode. The retention time data and the full scan product ion spectrum (major diagnostic ions m/z 362.1, 318.1, and 264.1) unequivocally disclosed that ofloxacin was present in the deposit. After removal of the deposit the ulcer epithelialised rapidly.
Topical ofloxacin 0.3% has been used in the treatment of patients with bacterial keratitis,1 in an animal model of keratitis5 and has been tested in an in vitro tear model.6,7 So far no reports of corneal deposits have been made. There is only one case report in which deposits are described after the combined use of cyclosporin and ofloxacin8; however, the authors attributed the deposit to the use of cyclosporin, although they did not conduct an analysis on the corneal deposits.
We report for the first time two children who demonstrate corneal deposits of ofloxacin adherent to a corneal erosion caused by VKC. Analysis of a corneal deposit proved the presence of ofloxacin while treatment had been discontinued for 7 days, indicative of ofloxacin depot formation by precipitation.
The exact factors contributing to the formation of the fluoroquinolone precipitate are unknown, but pH solubility profiles are of importance. Ofloxacin, like the other fluoroquinolones, exhibits pH dependent solubility. In the in vitro tear model7 tear drug concentration of ofloxacin remained below solubility at all pH values tested (pH 6.4–7.2).
One could argue that VKC associated ulcers occur in a different “microenvironment” compared to bacterial ulcers. Mast cell activation leads to the release of different mediators and inflammatory cells, such as histamine, serotonin, heparin, prostaglandins, protease, tryptase and eosinophils, all of which can contribute to a “microenvironment” potentially promoting ofloxacin precipitation in one way or the other. It would be interesting to find out whether there are significant changes, pH or other, in the tears of children with VKC.
In conclusion, we can say that ofloxacin does not seem to form corneal deposits when used in the treatment of bacterial ulcers, contrary to ciprofloxacin or norfloxacin. However, clinicians should be aware that deposits can occur after the use of ofloxacin in VKC associated ulcers.
This work was supported in part by grant GOA99–120501.99 (Bijzonder OnderzoeksFonds). Ilse Claerhout is a research assistant of the Flemish Fund for Scientific Research (FWO-Vlaanderen), Belgium