Intraocular penetration of systemically administered antifungal agents

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...

Section: Discussionsupporting

confidence: 80%

Treatment of exogenous Candida endophthalmitis in rabbits with oral fluconazole

Park

D’Amico

Paton

et al. 1995

“…Sixteen hours after single-dose administration, drug concentrations in the aqueous after both D-AMB and ABLC treatment were significantly lower than those after L-AMB treatment. Similar drug levels have been reported in patients treated with D-AMB for fungal endophthalmitis (7,20).…”

Section: Discussionsupporting

confidence: 66%

Ocular Distribution of Intravenously Administered Lipid Formulations of Amphotericin B in a Rabbit Model

Goldblum¹,

Rohrer²,

Frueh³

et al. 2002

Little is known about the ocular penetration of amphotericin B (AMB) and its lipid formulations, the current drug of choice in fungal endophthalmitis. The ocular distribution of AMB lipid complex (ABLC), liposomal AMB (L-AMB), and AMB deoxycholate (D-AMB) was studied in a rabbit model. D-AMB (1 mg/kg of body weight/day), ABLC (5 mg/kg/day), or L-AMB (5 mg/kg/day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 consecutive days after induction of unilateral uveitis by intravitreal injection of endotoxin. AMB concentrations in aqueous humor, vitreous humor, and plasma were determined by high-pressure liquid chromatography 16 h after administration of a single dose or 24 h after the last of seven doses. After single-dose administration, L-AMB achieved at least eightfold-higher AMB concentrations in the aqueous of inflamed eyes than ABLC or D-AMB (1.21 ؎ 0.58 g/ml versus 0.14 ؎ 0.04 and 0.11 ؎ 0.09 g/ml, respectively). At that time point no drug was detectable in the vitreous. After 7 days of treatment, the concentration of AMB in the vitreous was higher after treatment with L-AMB (0.47 ؎ 0.21 g/ml) than after treatment with ABLC (0.27 ؎ 0.18 g/ml) and D-AMB (0.16 ؎ 0.04 g/ml). Similarly, AMB concentration in the aqueous was higher after repeated doses of L-AMB (0.73 ؎ 0.43 g/ml) than after repeated doses of ABLC (0.03 ؎ 0.02 g/ml) or D-AMB (0.13 ؎ 0.06 g/ml). No AMB was detected in noninflamed eyes. Following systemic administration, AMB distribution to the eye is inflammation dependent and occurs sequentially, first to the aqueous and then to the vitreous. Compared to D-AMB and ABLC, L-AMB reaches higher drug concentrations in both ocular compartments.Fungal endophthalmitis is a sight-threatening infection that is often difficult to treat. Intravenous amphotericin B (AMB), with or without additional 5-flucytosine, is considered the treatment of choice for severe systemic fungal infections and is often used as adjuvant treatment for intraocular infections caused by a wide range of fungi (24). The usefulness of this polyene, however, is limited by a number of adverse reactions (26), particularly its dose-limiting nephrotoxicity (12, 23). Renal insufficiency in association with azotemia, renal tubular acidosis, and impaired urinary concentrating capacity resulting in electrolyte imbalance often leads to dose reduction or premature discontinuation of the drug (5, 10). The lipid formulations of AMB now available for clinical use may offer therapeutic advantages. Due to their reduced nephrotoxicity and different pharmacodynamic properties, higher doses of the parent compound may be delivered to infected tissues (3, 17, 29).The exact mechanism responsible for the reduced toxicity of the lipid formulations is not yet known. A recent publication suggests that it may be related to lower concentrations of free AMB found in plasma after administration of lipid-associated AMB. The exposure to free and protein-bound AMB in subjects treated with liposomal AMB (L-AMB) was found to be approximat...

“…Although inflammation seems to be an important factor in ocular penetration of ketoconazole, we found measurable amounts of ketoconazole in all ocular sites tested, even in uninflamed eyes. Recently, O'Day et al (27) reported detectable amounts of ketoconazole in the aqueous humor and vitreous body from a patient undergoing therapeutic vitrectomy for fungal endophthalmitis. We measured ketoconazole in the aqueous humor of two patients and found levels in this fluid which were approximately onequarter of the concentrations found in simultaneous serunm samples (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis

Savani¹,

Perfect²,

Cobo³

et al. 1987

198

We studied the penetration of three azole compounds, ketoconazole, itraconazole, and fluconazole, into the ocular tissues and fluids of rabbits in the presence and absence of ocular inflammation. Drug concentrations were compared with those found in serum and cerebrospinal fluid. The rank order of penetration into eye tissue was fluconazole > ketoconazole > itraconazole. Fluconazole penetrated freely into both inflamed and uninflamed eyes. The presence of inflammation improved penetration of all three compounds into ocular fluids and tissues. Penetration of these azoles into the anterior chamber of uninflamed eyes and into the cerebrospinal fluid was similar. All three azole compounds reduced the number of yeasts found in the eye in hematogenous Candida albicans endophthalmitis in rabbits when therapy was initiated within 24 h of inoculation. However, only ketoconazole significantly reduced yeast counts in the eye when therapy was postponed for 7 days.The incidence of ocular fungal infections has increased (10, 11, 26) due to a number of factors: increased prevalence of immunosuppression associated with organ transplantation and malignancies; prolonged recovery from complex surgical procedures; and increasing use of antibiotics, immunosuppressive agents, intravenous catheters, and hyperalimentation fluids. Endogenous Candida endophthalmitis (ECE) also occurs in heroin addicts