Penetration of topical and oral ofloxacin into the aqueous and vitreous humor of inflamed rabbit eyes,☆☆

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Abstract

Purpose: This study aimed to investigate the penetration of topical and oral ofloxacin into aqueous humor and vitreous humor in post-traumatic endophthalmitis model in rabbits. Methods: A standardized intraocular infection after penetrating injury was made in the right eyes of 16 rabbits. Intraocular infection was induced by intravitreal injection of a suspension of Staphylococcus aureus. The intact left eyes were maintained as controls. The animals were divided randomly into two groups. (1) In the topical group, two drops of ofloxacin 0.3% eyedrops were instilled to both eyes every 30 min for 4 h. (2) In the topical-oral group, two doses of 25 mg/kg of ofloxacin at 12-h intervals were given orally, then the protocol of the first group was applied. Aqueous and vitreous humor samples were taken 30 min after the last drop. Ofloxacin concentrations were measured by using HPLC. Results: Mean aqueous levels of ofloxacin in control eyes were: 3.25±2.55 μg/ml in topical group, 4.58±5.39 μg/ml in topical-oral group. Mean aqueous levels in inflamed eyes were: 5.21±4.55 μg/ml in topical group, 10.34±8.88 μg/ml in topical-oral group. Mean vitreous levels of ofloxacin in control eyes were: 0.17±0.07 μg/ml in topical group, 1.30±1.23 μg/ml in topical-oral group. Mean vitreous levels in inflamed eyes were: 0.35±0.22 μg/ml in topical group, 3.48±2.69 μg/ml in topical-oral group. There was no significant difference among the groups (P>0.05), however. Conclusions: The result of this study suggests that oral supplementation of ofloxacin to topical instillation increased the ocular levels of ofloxacin in the post-traumatic endophthalmitis model. Mean drug concentrations in aqueous and vitreous humors were above the 90% minimum inhibitory concentrations (MIC90) for most of the common microorganisms causing endophthalmitis in all eyes, except in the vitreous humors of the intact eyes instilled topically.

Introduction

Endophthalmitis is one of the most serious complications of intraocular procedures and penetrating ocular trauma. Although intravitreal antibiotics are the most important component of therapy in eradicating endophthalmitis, intravenous broad-spectrum antibiotics are commonly given to patients with penetrating ocular trauma to prevent post-traumatic endophthalmitis and are be used also as an adjunct to intravitreal antibiotics (Monk and Campoli-Richards, 1987, Osato et al., 1989, Todd and Faulds, 1991, Davis, 1996). Recent studies have shown that penetrating eye trauma and inflammation affects the ocular pharmacokinetics of certain antibiotics given intravenously, resulting in higher concentrations in traumatized (Alfaro et al., 1996) and inflamed eyes (Martin et al., 1990, Mounier et al., 1992, Meredith et al., 1995).

Ofloxacin is a fluorinated 4-quinolone antibiotic and is active against a wide spectrum of gram-positive and gram-negative organisms including various species of Staphylococcus, Streptococcus, and Pseudomonas (Auckenthaler et al., 1986, Osato et al., 1989, Todd and Faulds, 1991). It is among the fluoroquinolones considered promising for the treatment of ocular infections and shows nearly 100% bioavailability after oral administration (Monk and Campoli-Richards, 1987, Todd and Faulds, 1991). It was reported that ofloxacin penetrates the corneal and the blood-aqueous barriers and can achieve therapeutic aqueous humor levels above the minimum inhibitory concentration for many bacteria cultured in endophthalmitis in both topical and systemic administrations (Von Gunten et al., 1994, Donnenfeld et al., 1997). But higher concentrations of the antibiotic are required to inhibit Streptococcus pneumonia and Pseudomonas aeruginosa (Auckenthaler et al., 1986, Osato et al., 1989, Todd and Faulds, 1991).

Although there are several studies related to the penetration of ofloxacin into aqueous humor after topical or systemic administration (Yokota et al., 1986, Giamarellou et al., 1993, Von Gunten et al., 1994, Verbraeken et al., 1996, Başcı et al., 1997, Donnenfeld et al., 1997, Fiscella et al., 1997, Çekiç et al., 1998, Öztürk et al., 1999a), reports on penetration of systemic ofloxacin into aqueous humor and vitreous humor in inflamed eyes are limited (Mounier et al., 1992, Gatti and Panozzo, 1995, Öztürk et al., 1999a). Furthermore there are no data on penetration of topical or topical and systemic administration of ofloxacin in inflamed eyes. The purpose of the present study was to determine the aqueous and vitreous humors ofloxacin concentrations following topical instillation and oral medication in normal and inflamed eyes, and to compare the intraocular ofloxacin concentrations provided by two routes together and topical route alone.

Section snippets

Materials and methods

A total of 16 mixed-gender New Zealand white rabbits weighing between 2 and 3 kg were used in accordance with the ARVO Resolution on the Use of Animals in Research. The rabbits were anaesthetised with intramuscular injection of a 50/50 mixture of xylazine hydrochloride (10 mg/kg) and ketamine hydrochloride (30 mg/kg). To further reduce discomfort, the eyes were anaesthetised using one to two drops of a oxybuprocaine (Benoxinate®, Thilo). A standardized posterior penetrating ocular trauma was

Results

The mean concentrations of ofloxacin in the aqueous and vitreous humor are listed in Table 1. The aqueous levels of ofloxacin were above the 90% minimum inhibitory concentrations (MIC90) for most of the common microorganisms causing endophthalmitis in all eyes but the vitreous levels only in the inflamed eyes of the rabbits treated both topically and orally.

In the intact eyes, oral ofloxacin supplementation increased both the aqueous and vitreous levels of ofloxacin. In the inflamed eyes, drug

Discussion

Broad-spectrum, intravenous antibiotics are commonly suggested and administered as an adjunct to intravitreal antibiotics for treatment of endophthalmitis and for prophylaxis in penetrating ocular injuries (Martin et al., 1990, Meredith et al., 1995, Alfaro et al., 1996, Davis, 1996). The combination of systemic ofloxacin and topical ofloxacin was proposed as a single-drug therapy with broad-spectrum coverage for penetrating injury, surgical prophylaxis, and, possibly, the treatment of

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    Presented at the First Combined International Symposium on Ocular Immunology and Inflammation, Amsterdam, The Netherlands, June 27–July 1, 1998

    ☆☆

    Proprietary interest: none

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