Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system.

Abstract

Progress in the treatment of systemic mycoses in immunocompromised patients has been greatly impeded by the paucity of new, effective antifungal compounds. The need for such compounds, particularly agents that effectively penetrate the blood-brain barrier, has become even more important with the advent of AIDS, in which there is a 6V0-8V0 frequency of cryptococcosis of the CNS [1-3]. Cryptococcal meningoencephalitis in other populations of patients will generally respond to a treatment course of amphotericin B and flucytosine [4]. Courses of similar duration in patients with AIDS who have cryptococcal meningoencephalitis are, however, associated with a recurrence rate of ^O^o or with persistence of infection. Moreover, the toxicity of flucytosine in patients with AIDS often precludes an extended treatment course with this compound [2]. The need for extended and, perhaps, lifelong therapy with amphotericin B to prevent relapse of cryptococcosis of the CNS has recently been recognized [1, 3]. Fluconazole is a new triazole antifungal agent that has unique pharmacokinetic and pharmacological properties. The bioavailability after oral administration in humans is 80^0 [5]. Fluconazole has been shown to be effective in treating cryptococcal meningitis in animal models [6, 7] and has been proposed as a therapeutic alternative to long-term therapy with amphotericin B in patients with AIDS who have cryptococcal meningoencephalitis [8]. For human and subhuman primates, no pharmacokinetic data exist, however, that examine simultaneous sequential CSF and plasma levels of fluconazole to document and characterize penetration of this drug into the CSF. The current study was performed to evaluate CSF penetration of fluconazole by using a subhuman primate model that reliably predicts CSF penetration and pharmacokinetics of drugs in humans and has been demonstrated to serve as a valid substitute for human experimentation [9, 10].