Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis

Abstract

Cryptococcal 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.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

“…14 Clearance of infection was as rapid in the 1-week amphotericin B groups as it was in the 2-week amphotericin B groups, and, as expected, the shorter regimens had fewer side effects, with, in particular, less anemia. Our results with 1 week of amphotericin B-flucytosine lend further support to the concept of prolonged efficacy after an initial loading of brain compartments with amphotericin B, 13,21 as was also recently shown with the use of a single high dose of liposomal amphotericin B. 22 Of note, we implemented full preemptive management and monitoring of amphotericin B toxic effects.…”

Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

“…Animal studies have produced estimates indicating that the cerebral concentrations of DAmB at which the suppression of growth is half-maximal are 0.02 mg/liter in mice and 0.154 mg/liter in rabbits ( 34 ). AmB exposure above the level required to optimize antifungal activity appears to contribute only to toxicity ( 34 , 36 ). Our simulations suggested that the optimal plasma AUC value in humans lies somewhere between 10 and 15 mg · h/liter, though the information required to extrapolate this to cerebral DAmB concentrations is not currently available.…”

Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial

“…that increasing L-AmB dosing from the currently recommended 3-4 mg/kg may lead to improved outcomes and that very shortcourse regimens may be as effective as daily therapy [17,19]. The concept of single-or intermittent-dose L-AmB therapy has been tested in prophylaxis for hematology patients, with single doses of up to 15 mg/kg given without significant toxicities [20][21][22], and is established in treatment of visceral leishmaniasis where single doses of 10 mg/kg are routinely given and have been shown to be efficacious [23].…”