Liposomal amphotericin B-the past

Abstract

The discovery of amphotericin B, a polyene antifungal compound, in the 1950s, and the formulation of this compound in a liposomal drug delivery system, has resulted in decades of use in systemic fungal infections. The use of liposomal amphotericin B formulation is referenced in many international guidelines for the treatment of fungal infections such as Aspergillus and cryptococcal disease and Candida infections, as well as other less common infections such as visceral leishmaniasis. With the development of liposomal amphotericin B, an improved therapeutic index could be achieved that allowed the attainment of higher drug concentrations in both the plasma and tissue while simultaneously lowering the toxicity compared with amphotericin B deoxycholate. In over 30 years of experience with this drug, a vast amount of information has been collected on preclinical and clinical efficacy against a wide variety of pathogens, as well as evidence on its toxicity. This article explores the history and nature of the liposomal formulation, the key clinical studies that developed the pharmacokinetic, safety and efficacy profile of the liposomal formulation, and the available microbiological data.

Figure 1.

Mechanistic elements of liposomal AMB (AmBisome). The liposomes are rendered as spheres, with AMB as black dots (representing membrane-spanning aggregates of AMB as formed channels), and cholesterol or ergosterol as symbols as indicated. (A) The liposome has a relatively low propensity to transfer drug to a mammalian membrane; (B) the liposome formulation is able to pass through the fungal cell wall and bind to the fungal membrane surface (C); the latter may be facilitated by the complementary charged surfaces of the liposome and membrane; (D) driven by the presence of ergosterol and reflecting the ability of AMB to bind to ergosterol in preference to cholesterol, the liposome delivers the drug to the fungal membrane and is degraded. The structures of any transition states between AMB in the liposome bound to cholesterol and AMB in the fungal membrane bound to ergosterol are not known. AMB, amphotericin B.