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.

• Authors: Jodi Lestner, Laura McEntee, Adam Johnson, Joanne Livermore, Sarah Whalley, Julie Schwartz, John R Perfect, Thomas Harrison, William Hope
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 61 Issue 6 (06 2017) ISSN: 1098-6596 [Electronic] United States
• PMID: 28320715 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Lestner et al.

Chemical References

• Antifungal Agents
• liposomal amphotericin B
• Amphotericin B

Topics

• AIDS-Related Opportunistic Infections (drug therapy, microbiology)
• Amphotericin B (pharmacokinetics, therapeutic use)
• Animals
• Antifungal Agents (pharmacokinetics, therapeutic use)
• Brain (microbiology)
• Cryptococcus neoformans (drug effects)
• Dose-Response Relationship, Drug
• Immunocompromised Host
• Meningitis, Cryptococcal (drug therapy, microbiology)
• Meningoencephalitis (drug therapy, microbiology)
• Mice
• Microbial Sensitivity Tests
• Rabbits