Amphotericin B

Introduction

Amphotericin B is a polyene antifungal medication used primarily for serious fungal infections. It is derived from the bacterium Streptomyces nodosus, and it was first discovered in the 1950s. Amphotericin B is known for its broad-spectrum antifungal activity and is often considered the drug of choice for severe systemic fungal infections, despite its significant toxicity profile.

Chemical Structure and Properties

Amphotericin B is a complex macrolide with a large lactone ring and multiple conjugated double bonds, which are responsible for its characteristic yellow color. The molecule contains both hydrophilic and hydrophobic regions, allowing it to interact with fungal cell membranes. Its chemical formula is C47H73NO17, and it has a molecular weight of approximately 924.09 g/mol.

The structure of Amphotericin B includes a polyene macrolide ring, a mycosamine sugar, and a carboxyl group. The polyene region interacts with ergosterol, a key component of fungal cell membranes, disrupting membrane integrity and leading to cell death.

Mechanism of Action

Amphotericin B exerts its antifungal effects by binding to ergosterol in the fungal cell membrane. This binding creates pores in the membrane, increasing its permeability and causing leakage of essential intracellular components. The loss of cellular ions and other molecules ultimately leads to cell death. Amphotericin B's selectivity for ergosterol over cholesterol, the primary sterol in mammalian cell membranes, accounts for its antifungal specificity, although it can still cause significant toxicity in human cells.

Clinical Uses

Amphotericin B is used to treat a variety of serious fungal infections, including:

It is often reserved for severe infections or cases where other antifungal agents have failed due to its toxicity profile. Amphotericin B is available in several formulations, including conventional deoxycholate, lipid complex, and liposomal preparations, each with varying degrees of efficacy and toxicity.

Formulations

Conventional Amphotericin B

The conventional formulation, Amphotericin B deoxycholate, is the oldest and most widely used form. It is administered intravenously and is associated with significant nephrotoxicity, infusion-related reactions, and electrolyte imbalances.

Lipid-Based Formulations

To reduce toxicity, several lipid-based formulations have been developed:

**Amphotericin B lipid complex (ABLC)**: This formulation combines Amphotericin B with lipids, reducing nephrotoxicity and infusion-related reactions.
**Liposomal Amphotericin B (L-AmB)**: Encapsulating Amphotericin B in liposomes further reduces toxicity and allows for higher dosing.
**Amphotericin B colloidal dispersion (ABCD)**: This formulation disperses Amphotericin B in a colloidal suspension, offering a different toxicity profile.

Pharmacokinetics

Amphotericin B is poorly absorbed from the gastrointestinal tract and must be administered intravenously for systemic infections. It has a large volume of distribution and is extensively bound to plasma proteins. The drug is slowly metabolized and excreted, with a half-life ranging from 15 days to several weeks, depending on the formulation.

Toxicity and Side Effects

The use of Amphotericin B is limited by its significant toxicity profile. Common adverse effects include:

**Nephrotoxicity**: Renal impairment is the most significant toxicity, often requiring dose adjustments and monitoring of renal function.
**Infusion-related reactions**: Fever, chills, rigors, and hypotension are common during administration.
**Electrolyte imbalances**: Hypokalemia and hypomagnesemia are frequent due to renal tubular damage.
**Hematologic effects**: Anemia and leukopenia can occur with prolonged use.

Resistance

Fungal resistance to Amphotericin B is relatively rare but can occur. Mechanisms of resistance include alterations in ergosterol biosynthesis, reducing the drug's binding affinity, and changes in membrane composition that decrease permeability.

Research and Development

Ongoing research aims to develop new formulations and derivatives of Amphotericin B with improved efficacy and reduced toxicity. Efforts include the synthesis of novel analogs, combination therapies with other antifungal agents, and the exploration of new delivery systems.