Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis.
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.
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom jlestner@liverpool.ac.uk.
Jodi
J
Lestner
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Laura
L
McEntee
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Adam
A
Johnson
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Joanne
J
Livermore
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Sarah
S
Whalley
Charles River Laboratories, Davis, California, USA.
Julie
J
Schwartz
Department of Medicine, Duke University, Durham, North Carolina, USA.
John R
JR
Perfect
Research Centre for Infection and Immunity, St. George's University of London, London, United Kingdom.
Thomas
T
Harrison
Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
William
W
Hope
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000382:microbiology; D000666:Amphotericin B / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001921:Brain / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016867:Immunocompromised Host; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology; D008590:Meningoencephalitis / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011817:Rabbits
D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B
Cryptococcus neoformans; cryptococcal meningitis; liposomal amphotericin B; meningoencephalitis; pharmacodynamics; pharmacokinetics