Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system.
The central nervous system (CNS) distribution and antifungal efficacy of all 4 approved formulations of amphotericin B (AmB) were investigated in a rabbit model of hematogenous Candida albicans meningoencephalitis. Treatment with AmB deoxycholate (1 mg/kg/day) or liposomal AmB (5 mg/kg/day) yielded the highest peak plasma concentration (C(max)), area under concentration versus time curve from zero to 24 h (AUC(0-24)), and time during dosing level tau Ttau>minimum inhibitory complex (MIC) values and led to complete eradication of C. albicans from brain tissue (P<.05 vs. untreated controls). By comparison, AmB colloidal dispersion and AmB lipid complex (5 mg/kg/day each) were only partially effective (not significant vs. untreated controls). There was a strong correlation of C(max), AUC(0-24), C(max)/MIC, AUC(0-24)/MIC, and Ttau>MIC with clearance of C. albicans from brain tissue (P</=.0002). Although pharmacodynamic parameters derived from the MIC of free AmB were highly predictive of antifungal efficacy, parameters derived from MICs of individual formulations were not predictive. AmB deoxycholate and liposomal AmB had the greatest antifungal efficacy. This activity was concentration and time dependent.
Groll
A H
AH
Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Giri
N
N
Petraitis
V
V
Petraitiene
R
R
Candelario
M
M
Bacher
J S
JS
Piscitelli
S C
SC
Walsh
T J
TJ
D000666:Amphotericin B / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D020314:Central Nervous System Fungal Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D008055:Lipids / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D016896:Treatment Outcome
D000935:Antifungal Agents; D008055:Lipids; D000666:Amphotericin B