Abstract
ABSTRACTCryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2 weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAMB) is unknown. The pharmacodynamics of LAMB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAMB in the plasma and brains of mice were measured using high-performance liquid chromatography (HPLC). Histopathological changes were determined. The penetration of LAMB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brains of mice, with near-maximal efficacy achieved with LAMB at 10 to 20 mg/kg/day. The terminal elimination half-life in the brain was 133 h. The pharmacodynamics of a single dose of 20 mg/kg was the same as that of 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAMB at 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative area under the concentration-time curve, 2,500 mg · h/liter). Amphotericin B was visible in the intra- and perivascular spaces, the leptomeninges, and the choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggests that abbreviated induction regimens of LAMB are possible for cryptococcal meningoencephalitis.
Highlights
Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients
We recently demonstrated that an abbreviated course of DAMB (3 days) may be as effective as 2 weeks of therapy [13] and that short courses of DAMB are associated with rapid clearance of the cerebrospinal fluid (CSF) in patients with cryptococcal meningitis [14]
Liposomal amphotericin B was well tolerated in mice with no observed toxicity following rapid intravenous (i.v.) injection
Summary
Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. The prolonged mean residence time of amphotericin B in the brain suggests that abbreviated induction regimens of LAMB are possible for cryptococcal meningoencephalitis. The best current therapy cannot be administered to patients in many countries where the prevalence of cryptococcal meningitis is the highest In these cases, the only alternative agent is fluconazole, but even with the use of high doses (800 to 1,200 mg/day), the fungicidal activity in CSF. We recently demonstrated that an abbreviated course of DAMB (3 days) may be as effective as 2 weeks of therapy [13] and that short courses of DAMB (in combination with fluconazole) are associated with rapid clearance of the CSF in patients with cryptococcal meningitis [14].
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