Mechanism of Action (Pharmacodynamics)
Unlike azoles or allylamines, which inhibit sterol synthesis, amphotericin B targets pre-formed molecules. Its affinity for fungal membrane ergosterol is 500 times greater than for human cholesterol.
By binding to ergosterol, the drug exerts a dual damaging effect:
- Pore formation (primary mechanism) — disrupts membrane integrity, causing leakage of intracellular contents.
- Free radical generation (secondary mechanism) — toxic radicals further destabilize the membrane.
Depending on the drug concentration and the susceptibility of the specific pathogen, its action can be either fungistatic or fungicidal.
Pharmacokinetics and Formulations
For systemic infections, the drug is administered intravenously. The duration of action following an infusion is 4–6 hours. It is eliminated by the kidneys. The initial half-life ($t_{1/2}$) is 24–48 hours; however, with chronic administration, the drug accumulates in tissues, extending the $t_{1/2}$ up to 15 days. For infections caused by Coccidioides, intrathecal administration may be used.
Formulations:
- Powder in vials for IV administration.
- Powder for inhalation.
- Topical ointment.
Indications and Combination Therapy
The drug is used for severe systemic mycoses. To enhance efficacy and reduce toxicity, it is often combined with the antimetabolite flucytosine.
Mechanism of synergy: Amphotericin B damages the fungal plasma membrane, facilitating the intracellular uptake of flucytosine. This provides several clinical advantages:
- Lower dose of amphotericin B (reduced adverse effects).
- Shorter overall course duration.
- Prevention of resistance (which develops rapidly to flucytosine monotherapy).
Key indications for combination: cryptococcal meningoencephalitis and endocarditis, aspergillosis, and central nervous system or urinary tract candidiasis.
Polyene antibiotics are also used for the etiotropic treatment of dysbiosis (overgrowth of Candida species) induced by broad-spectrum antibiotic therapy.
Adverse Effects (IV Administration)
The toxicity of conventional amphotericin B (deoxycholate) is high. Adverse reactions are divided into immediate and delayed (organ-specific).
- Acute reactions ("Cytokine storm"): Immune cells release TNF-$\alpha$ and IL-1. Manifests as chills, fever, and hypotension during the first hours of infusion. Management: slower infusion rate, premedication with NSAIDs (e.g., paracetamol) or glucocorticoids (hydrocortisone).
- Nephrotoxicity (hallmark effect): Vasoconstriction of renal afferent arterioles leads to ischemia and proximal tubular injury. Clinical findings: hypokalemia, hypomagnesemia, acidosis, and cylindruria. Requires potassium and magnesium supplementation.
- Hematologic toxicity: Thrombocytopenia and anemia. Anemia is secondary to decreased erythropoietin synthesis by damaged kidneys (treated with recombinant erythropoietin).
- Neurotoxicity: Headache, tremor, convulsions, polyneuropathy, paresis, and visual disturbances (diplopia).
- Other: Dyspepsia, infusion-site reactions (thrombophlebitis), and allergic reactions.
Lipid Formulations: Toxicity-Reduction Strategies
To protect normal host tissues (especially renal proximal tubules), the active drug is incorporated into lipid carriers, such as liposomes. Drug release occurs primarily upon direct contact with the fungal cell.
Examples: Liposomal amphotericin B, lipid complex, and colloidal dispersion.
Their clinical efficacy is comparable to standard amphotericin B, but toxicity is significantly lower. The main disadvantage is high cost. Indications: Severe systemic mycoses in patients with renal impairment.
Clinical Prescription Examples
Depending on the site of infection, the drug can be administered systemically, via inhalation, or topically.
Intravenous Infusion:
- Amphotericin B IV infusion based on patient body weight (administered on alternate days), reconstituted in an appropriate sterile diluent.
Inhalation:
- Amphotericin B powder for inhalation dissolved in sterile water for injection.
Topical (Ointment):
- Apply a thin layer to affected skin areas.