Comparative Efficacy and Distribution of Lipid Formulations of Amphotericin B in ExperimentalCandida albicansInfection of the Central Nervous System

Abstract

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.

Nanoparticle transport across the blood brain barrier

“…Groll and colleagues 41 23 Recently, the authors studied the efficacy of AmBisome, micafungin (MICA), caspofungin (CAS), amphotericin B, voriconazole (VCZ), given alone or in combination, after administration in immune-suppressed mice, infected intracerebrally with Aspergillus fumigates. In the first study, the brain infection was significantly reduced by Ambisome treatment if compared with fluconazole and amphotericine B treatments.…”

Antifungal Pharmacokinetics and Pharmacodynamics

“…One potentially relevant PK/PD difference is penetration into certain tissues, such as the CNS. For example, LAmB is composed of small unilamellar particles (liposomes) that exhibit high serum and CNS concentrations in comparison with other lipid preparations (Groll et al 2000). The relevance of this PK difference was found to be important in a CNS-invasive candidiasis model, whereby the difference in drug concentration in brain parenchyma was closely related to treatment efficacy in favor of LAmB over the other formulations (Groll et al 2000).…”

“…For example, LAmB is composed of small unilamellar particles (liposomes) that exhibit high serum and CNS concentrations in comparison with other lipid preparations (Groll et al 2000). The relevance of this PK difference was found to be important in a CNS-invasive candidiasis model, whereby the difference in drug concentration in brain parenchyma was closely related to treatment efficacy in favor of LAmB over the other formulations (Groll et al 2000). Conversely, both ABLC and ABCD achieve much higherconcentrations in the intracellular space and in organs of the reticuloendothelial system (Janknegt et al 1992).…”

Difficulties in antifungal therapy with amphotericin B and the continuous search for new formulations: A literature review

“…Existing studies classify polyenes -AmB -as concentration-dependent compounds (Groll et al, 2000). However, these studies show conflicting results such as the observation of similar antifungal action in the early hours or persistence after 24 h of administration, which may reflect a slow diffusion in vivo in tissues.…”