Intravenous penetration of fluconazole during endophthalmitis

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A recent article by Akler et al. summarized 27 cases of fluconazole-treated candidal endophthalmitis reported in the English language literature [1]. Fluconazole was the sole therapy in 14 patients, and a favorable outcome was obtained in 15 of 16 eyes, including five infections that were complicated by vitreitis; however, ocular penetration of fluconazole was not evaluated. Although the high vitreous penetration of fluconazole is generally considered to be responsible for the favorable clinical outcome, data on vitreous fluconazole concentrations in humans have been reported only twice [2]. We have assessed fluconazole penetration into the vitreous humor of a patient with endophthalmitis.

A 27-year-old male heroin addict, weighing 78 kg, having normal renal function, was hospitalized in August 1994 for blurred vision in the left eye. Ocular examination revealed chorioretinal lesions compatible with candidal endophthalmitis and vitreitis. Angiography confirmed the diagnosis, but direct examination and mycologic cultures of the vitreous humor remained negative. Treatment consisted of four intravitreous injections of amphotericin B at 48-h intervals and fluconazole 200 mg twice-daily intravenously for 1 month and then orally for 2 months. Vitrectomy was performed in the third week because of severe vitreitis. Two vitreous samples (days 4 and 11) and one serum sample (day 7) were obtained about 3 h after the previous dose. Fluconazole concentrations were measured by reverse-phase liquid chromatography with absorbance detection at 260 nm, either by direct injection of the vitreous humor samples or after liquid–liquid extraction in the case of the plasma samples. The vitreous fluconazole concentrations on days 4 and 11 were 10.4 and 11.9 mg/L, respectively, while the plasma concentration on day 7 was 15.0 mg/L. The retina of the infected eye became detached in the fifth week. The infection resolved completely and no relapse had occurred after more than 10 months of follow-up.

In samples taken 3 h after drug administration, the vitreous fluconazole concentration was 69–79% of that measured in plasma. These results are very similar to those reported earlier [2]. Since the fluconazole elimination half-life is about 30 h, the steady state should have been attained by day 5 of treatment. Theoretically, if fluconazole penetration into vitreous humor were accomplished solely by passive diffusion, its vitreous concentration at steady state would be equal to that of the free fraction in plasma (89% in humans with normal renal function). The difference from the measured values is small and probably not significant. Therefore, fluconazole-protein binding may be a major factor controlling drug penetration into vitreous humor. This possibility is important because fluconazole-protein binding has been shown to depend on the α1-acid glycoprotein level and to be increased from 11% in normal subjects to 22% in chronic renal failure patients treated by hemodialysis [3], and this enhanced protein binding could result in lower fluconazole penetration into the eye. Although no relationship has been established between the fluconazole concentration in body fluids and in vivo antifungal activity, indirect arguments suggest that such a relationship does exist for other azole compounds, such as ketoconazole [4] and itraconazole [5].

Finally, available pharmacokinetic data in humans are not adequate to define an optimal dosage schedule for fluconazole in endophthalmitis. However, owing to its long half-life and high bioavailability, once-daily administration by the oral or intravenous route should be equally effective in treating candidal endophthalmitis. Because the fluconazole levels achieved in the vitreous humor are proportional to the dose in the 200- to 400-mg range (data on other dosages have not been reported), it is possible that higher doses would produce higher vitreous levels and better efficacy.

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