Treatment of exogenous Candida endophthalmitis in rabbits with oral fluconazole

Abstract

We investigated the efficacy of oral fluconazole, alone or in combination with oral flucytosine (5FC), in treating Candida endophthalmitis using a rabbit model. Albino rabbits were infected with an intravitreal inoculation of 1,000 CFU of susceptible Candida albicans and randomized 5 days later to receive treatment with oral fluconazole alone (80 mg/kg of body weight per day), a combination of fluconazole and 5FC (100 mg/kg/12 h), or no treatment. The treatment effect was assessed at 2 and 4 weeks after therapy by funduscopy, quantitative vitreous culture, and histopathology. Intravitreal levels of fluconazole, 2 to 24 h after the first dose, were measured to be >10 times the MIC of the drug for C. albicans. Among rabbits treated with fluconazole for 2 weeks, 67% had a >90% reduction in fungal load (P < 0.05) and 33% were sterile. After 4 weeks, all had a >99% reduction in fungal load (P < 0.05) and 75% were sterile (P ‫؍‬ 0.01). This treatment effect was unchanged 4 weeks after discontinuation of fluconazole. Among rabbits treated with fluconazole and 5FC for 2 weeks, 67% died during therapy. Among the surviving rabbits, 75% had a >90% reduction in fungal load (P < 0.05) and 25% were sterile. We conclude that oral fluconazole may be useful for treatment of Candida endophthalmitis. Addition of 5FC was associated with high toxicity and minimal additional antifungal effect in our rabbit model. Intraocular fungal infection can result from an exogenous inoculation of the microorganism, as in posttraumatic or postoperative endophthalmitis, or from an endogenous source, as in patients with fungemia. Fungal endophthalmitis accounts for 12% of all cases of infectious endophthalmitis and is a leading cause of endogenous infectious endophthalmitis (29). The most common cause of fungal endophthalmitis is Candida albicans.Traditionally, the commonly used therapy for fungal endophthalmitis consists of intravenous amphotericin B, used alone or in combination with vitrectomy and intravitreal injection of amphotericin B (1, 8, 14-16, 20, 22, 23). Although intravenous amphotericin B therapy is often effective for treatment of chorioretinitis associated with fungal endophthalmitis, treatment failure can occur in eyes with advanced endophthalmitis with marked vitreous infiltrates due to the poor penetration of the drug into the vitreous (8). In addition, systemic administration of the drug requires prolonged hospitalization and is associated with unpleasant and potentially dangerous side effects. Treatment efficacy for advanced endophthalmitis may be enhanced by combining systemic amphotericin B therapy with vitrectomy and intravitreal amphotericin B injections, but such procedures are associated with potential morbidity.For these reasons, the current advocated treatment for fungal endophthalmitis is controversial, and the therapy often is individualized on the basis of the severity of the endophthalmitis (8). In patients with endogenous Candida endophthalmitis without evidence of systemic infection, vitrectomy alone or vitrectomy...

Experimental models in antifungal chemotherapy

“…Intravenous inoculation with C. albicans also induces endophthalmitis in rabbits [48], furthermore exogenous endophthalmitis can be produced [82]. Anaesthetized rabbits are inoculated over the marginal ear vein with lo6 Candida cells grown overnight on Sabouraud glucose agar at 37 " C .…”

“…For exogenous Candida endophthalmitis, the following method is used [82]. In anaesthetized mycoses 41, 1-30 (1998) rabbits, mydriasis is achieved with phenylephrine and tropicamide ophthalmic solutions.…”

Pros and Cons of Extrapolating Animal Data on Antifungal Pharmacodynamics to Humans

“…Because of clinical experience, amphotericin is still considered a first-line agent for Candida endophthalmitis, but amphotericin distribution into the vitreous is minimal and probably inflammation-dependent. Intravenous and oral fluconazole produces adequate vitreal concentrations in rabbit models and has been used successfully as an alternative to amphotericin in susceptible Candida endophthalmitis [19][20][21][22]. Similarly, adequate voriconazole penetration into the vitreous of 38% plasma concentration after oral administration is supported by human data [23].…”

Editorial Response: Treatment Options for Candidal Endophthalmitis

“…However, in another study den and the inflammatory debris; it also may facilitate drug of rabbits with exogenous candidal endophthalmitis candidal diffusion within the eye. Often, a combination of treatment endophthalmitis [7], treatment with high dosages of fluconazole modalities is used. The decision as to which treatments to use for 4 weeks eradicated infection from most eyes even if treatis not an easy one: amphotericin B, given systemically, is ment was begun 5 days after infection.…”