Penetration of Prulifloxacin in human aqueous humour following oral administration

Abstract

Editor, Endophthalmitis is one of the most serious sight-threatening complications secondary to intraocular procedures and penetrating intraocular trauma. Consequently, intraocular drug penetration capacity is warranted to prevent or treat this complication in the best way possible. Only a few drugs can penetrate in the eye after oral administration, and they rarely reach significant concentrations. Over the past 10 years, several studies have indicated that fluoroquinolone antibiotics achieve significant intraocular concentrations after oral administration, even in non-inflamed eyes (Cekic et al. 1999; Donnenfeld et al. 1997; Fiscella et al. 1999; Garcia-Saenz et al. 2001; Hariprasad et al.2003). We studied aqueous penetration after systemic administration of prulifloxacin (PFUX), a fourth-generation quinolone with a broad spectrum of activity. After systemic administration, PFUX is rapidly absorbed, reaches Tmax at 1 hr after being administered, has a long elimination half-life and is well distributed in tissues, often achieving concentrations that exceed serum concentrations. PFUX is generally administered in one 600-mg daily dose although a double dose can also be administered (a 600-mg tablet every 12 hr): it is rapidly metabolized into its active metabolite ulifloxacin (UFX). We studied forty patients selected among those referred for cataract surgery: they were randomly divided into two groups: the first group (20 patients) received a single oral dose of 600 mg PFUX at 7 a.m. on the day of surgery; the second group (20 patients) received two oral doses of 600 mg PFUX, the first one at 7 p.m. the day before surgery and the second at 7 a.m. on the day of surgery. Immediately before surgery, aqueous humour was aspirated by paracentesis using an insulin syringe, promptly transferred to a pretared Eppendorf vial and immediately stored at −20°C. As PFUX is rapidly metabolized into UFX, we determined its intraocular concentration through high-performance liquid chromatography (HPLC-UV) that uses a reversed-phase column as described previously (Pellegrino et al. 2008). Our study showed that PFUX penetrates into the aqueous humour after systemic administration: in the first group, mean UFX concentration was 0.03822 ± 0.022 μg/ml, and in the second group, it was 0.06255 ± 0.029 μm/ml. Moreover, UFX concentration increases linearly following the systemic dose, and it is constant without significant variations during the time of the examination (Fig. 1). Aqueous humour concentration of patients receiving a single and double oral dose of prulifloxacin. Our study showed that UFX reaches efficient therapeutic intraocular levels only for some pathogen infections: in fact, after a single dose, mean UFX concentration in the aqueous humour reaches MIC90 for Escherichia coli (0.025), Klebsiella oxytoca (0.025), Shigella sp. (0.025), Proteus mirabilis (0.025) and Morganella morganii (0.025), while after a double systemic dose of PFUX, mean UFX concentration reaches MIC90 also for Klebsiella pneumoniae (0.05) and Haemophilus influenzae (0.05). The Endophthalmitis Vitrectomy Study (EVS 1995) revealed that gram-positive bacteria cause 94.2% of cases of postoperative endophthalmitis, most commonly Staphylococcus epidermidis and Staphylococcus aureus. Gram-negative pathogens accounted for 5.9% of confirmed-growth isolates, and the most common pathogen involved is Proteus mirabilis (Han et al. 1996). Then, systemic administration of PFUX is efficient for only a limited number of intraocular postoperative infections, because it cannot reach clinically significant concentrations against the majority of gram-positive pathogens. However, the administration of 600 mg twice a day of PFUX ensured therapeutic aqueous concentrations against certain important pathogens, particularly Proteus mirabilis and Haemophilus influenzae, the major player in endophthalmitis after filtering surgery. We believe that because endophthalmitis is one of the most serious sight-threatening complications, this information is significant: it is useful to know the intraocular penetration capacity of each drug following systemic administration because it can potentially be used as a prophylaxis or as a therapy against infections.