Amphotericin B, an antifungal drug used to treat systemic fungal infections, was developed in the 1950s and approved for medical use in the late 1950s. Its history is marked by its effectiveness against a wide range of fungal pathogens, but also by the discovery of notable nephrotoxicity and infusion-related reactions, which led to careful dosing and monitoring guidelines. Amphotericin B, a polyene antifungal that binds to ergosterol in fungal cell membranes, was approved in the United States in 1958 and remains a key therapy for severe fungal infections, often in combination with other antifungals. Its development featured extensive clinical testing and formulation improvements, including lipid-based preparations that reduced toxicity and allowed safer administration.
BRAND NAMES
Fungizone – the conventional deoxycholate formulation.
AmBisome – a liposomal formulation designed to reduce toxicity.
Abelcet – an amphotericin B lipid complex formulation.
Amphotec – an amphotericin B colloidal dispersion.
MECHANISM OF ACTION
Amphotericin B is a polyene antifungal that binds to ergosterol, an essential component of fungal cell membranes. This binding creates pores in the membrane, increasing permeability and causing leakage of intracellular ions and molecules. The resulting cell death makes Amphotericin B effective against a wide range of systemic fungal infections. Its action is largely fungicidal, although it can also have some fungistatic effects depending on the organism and concentration.
PHARMACOKINETICS
Absorption
Amphotericin B has very poor oral absorption and is therefore administered intravenously for systemic infections. Oral formulations are only effective for localized gastrointestinal fungal infections. Because of its low absorption from the gut, it is not suitable for treating systemic infections orally.
Distribution
Amphotericin B (AmB) has a very high, large apparent volume of distribution, typically reported around 4 L/kg for the conventional deoxycholate formulation, indicating extensive distribution into tissues rather than remaining in plasma. It exhibits slow elimination and accumulates in tissues like the liver, spleen, and lungs.
Metabolism
Amphotericin B undergoes minimal metabolism in the body. Most of the drug remains in its active form, which contributes to its prolonged antifungal activity. Its limited metabolism reduces the formation of toxic metabolites, but the drug’s persistence in tissues also plays a role in its nephrotoxicity and infusion-related side effects.
Elimination
Amphotericin B is slowly eliminated from the body, primarily through biliary excretion into the feces and to a lesser extent via the urine. Its long tissue half-life can range from several days to weeks, which allows sustained antifungal activity but also contributes to cumulative toxicity, particularly in the kidneys.
PHARMACODYNAMICS
Amphotericin B exerts its antifungal effects by binding to ergosterol in fungal cell membranes, creating pores that disrupt membrane integrity and cause leakage of intracellular contents. This leads to fungicidal activity against a broad spectrum of fungi, including Candida, Aspergillus, and Cryptococcus species. The drug’s activity is concentration-dependent, and its prolonged tissue persistence supports sustained antifungal effects, though it also contributes to dose-related toxicities.
ADMINISTRATION
Amphotericin B is usually given intravenously for systemic infections, with slow infusion to reduce side effects. Lipid formulations allow higher doses with less toxicity, while oral or topical forms are used only for localized infections.
DOSAGE AND STRENGTH
Amphotericin B dosing depends on the formulation and infection severity. Conventional IV doses are 0.3–1 mg/kg/day, while lipid-based forms like AmBisome allow 3–5 mg/kg/day with less toxicity. Doses are adjusted for weight, kidney function, and infection type.
DRUG INTERACTIONS
Amphotericin B can increase kidney damage with nephrotoxic drugs and heart risks with drugs that alter potassium or magnesium. Monitoring is advised with other antifungals.
FOOD INTERACTIONS
Amphotericin B has no significant food interactions. Its absorption and effectiveness are not affected by meals, so it can be administered with or without food.
CONTRAINDICATIONS
Amphotericin B is contraindicated in patients with known hypersensitivity. Caution is needed in severe kidney disease, electrolyte imbalances, liver dysfunction, heart disease, or bone marrow suppression. During pregnancy, liposomal forms are preferred, and concurrent use with other nephrotoxic drugs requires careful monitoring.
SIDE EFFECTS
Nephrotoxicity: Acute kidney injury, electrolyte imbalances (hypokalemia, hypomagnesemia)
Infusion-related reactions: Fever, chills, rigors, hypotension
Hematologic effects: Anemia, leukopenia, thrombocytopenia
Hepatic effects: Elevated liver enzymes
Gastrointestinal: Nausea, vomiting
Cardiac: Arrhythmias (rare, usually secondary to electrolyte disturbances)
Thrombophlebitis: At the infusion site
TOXICITY
Amphotericin B can cause kidney damage, electrolyte imbalances, infusion reactions (fever, chills, hypotension), anemia, liver enzyme rise, and rarely arrhythmias. Risk increases with prolonged use, so kidney function and electrolytes must be monitored.
