Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS

We studied fluconazole penetration in the brain in five patients who had a deep cerebral tumor whose removal required the excision of healthy brain tissue. Plasma and brain samples were simultaneously obtained after oral ingestion of 400 mg of fluconazole daily for 4 days (90% of steady state). Fluconazole penetration in healthy cerebral parenchyma was determined. Plasma and brain samples were assayed by high-pressure liquid chromatography. Concentrations in plasma and brain tissue were 13.5 ؎ 5.5 g/ml and 17.6 ؎ 6.6 g/g, respectively. The average ratio of concentrations in the brain and plasma (four patients) was 1.33 (range, 0.70 to 2.39). Despite the lack of data concerning the penetration of fluconazole in brain abscesses, these results should permit the use of a daily dose of 400 mg of fluconazole in prospective clinical studies that evaluate the effectiveness of this drug in the treatment of brain abscesses due to susceptible species of fungi.Fluconazole, a triazole compound, is a systemic antifungal synthetic agent. Its fungistatic action is the inhibition of fungal cytochrome P-450 sterol C-14 alpha demethylation (18). During recent years, an increase in the rate of central nervous system fungal infections mainly due to an increased prevalence of immunosuppressed states (e.g., AIDS, malignancies, and organ transplantation) has been reported. Treatment by fluconazole of invasive infections due to various fungi has been a significant advance in antimicrobial chemotherapy (1,19,21). Its efficacy in treating cryptococcal and coccidioidal meningitis (2,3,5,14,22,23) is well established in clinical studies.In acute AIDS-associated cryptococcal meningitis fluconazole was shown to be as effective as amphotericin B (23) and more so in preventing relapse (3,22). However, use of fluconazole for treatment of this disease remains controversial (6,20,24), and the optimal dose remains uncertain. The incidence of cryptococcal intracerebral lesions is unknown and probably underestimated (6,8,11,27). Inadequate control of these lesions is perhaps one of the risk factors for failure or relapse of cryptococcal meningitis. Actually, therapeutic failures and relapses may occur when using amphotericin B or fluconazole (400 mg/day), and higher doses of fluconazole as salvage therapy have been proposed (2).While the penetration of fluconazole in human cerebrospinal fluid is known to be good (60 to 80% of levels in serum) (10, 25), data regarding its penetration in brain tissue other than in animals are lacking (17,26). The objective of this research was to study the penetration of fluconazole in human brain tissue and to determine the ratio of concentrations in the brain and plasma at steady state. MATERIALS AND METHODSObtaining brain tissue samples from patients with cryptococcal meningitis is not acceptable in light of current diagnostic and therapeutic strategies. Obtaining tissue samples from healthy volunteers is not conceivable. We therefore decided to study the penetration of fluconazole in the healthy cerebral parenchyma...

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Fluconazole penetration in cerebral parenchyma in humans at steady state

Thaler

Bernard

Tod

et al. 1995

“…Although there are anecdotal clinical reports of cases of fungal endophthalmitis that have failed therapy with fluconazole alone (31), the dose of fluconazole that has been used clinically for endophthalmitis thus far is much lower than the doses that were used in this and other animal studies, as well as in patients with cryptococcal meningitis (4,17). In addition, these cases may represent advanced infection which may have failed the more traditional therapy with systemically administered amphotericin B with or without vitrectomy and intravitreal amphotericin B.…”

Section: Discussionmentioning

confidence: 89%

Treatment of exogenous Candida endophthalmitis in rabbits with oral fluconazole

Park

D’Amico

Paton

et al. 1995

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...

“…When individuals with AIDS and meningeal cryptococcosis are treated with either amphotericin B or fluconazole alone, only 40 to 50% have sterile cerebrospinal fluid (CSF) after 2 weeks (1,2,26,48). Although the combination of either amphotericin B or fluconazole with flucytosine results in a modest improvement in treatment success, more than 25% of subjects fail therapy (1,25,26,33,50).…”

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Phase I Evaluation of the Safety and Pharmacokinetics of Murine-Derived Anticryptococcal Antibody 18B7 in Subjects with Treated Cryptococcal Meningitis

Larsen

Pappas

Perfect

et al. 2005

214

151

A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drugassociated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.