Polyene antibiotics

Chemical structure and mechanism of action

Polyene molecules have a complex structure based on a polyunsaturated macrocyclic lactone ring. They are amphiphilic: consisting of lipophilic and hydrophilic parts.

The drugs exert their action at the level of the fungal cytoplasmic membrane:

1. The lipophilic part binds to ergosterol, the main structural sterol of the fungal membrane (a functional analogue of human cholesterol).
2. The hydrophilic regions of several molecules align to form a through-channel (pore) in the membrane.
3. Through the resulting openings, the cell rapidly loses low-molecular-weight substances and ions ($K^+$, $Mg^{2+}$).

The loss of intracellular contents leads to the death of the pathogen, thereby producing a fungicidal effect. The selectivity of action is explained by the fact that mammalian cell membranes contain cholesterol, for which polyenes have a significantly lower affinity.

Amphotericin B: the main systemic drug

This antibiotic has the highest affinity: its affinity for ergosterol is 500 times higher than its affinity for human cholesterol. In addition to forming pores, amphotericin B generates toxic free radicals, further destabilizing the membranes.

• Spectrum of activity: Administered intravenously by infusion as a life-saving measure for severe systemic mycoses (aspergillosis, cryptococcosis, blastomycosis, histoplasmosis, coccidioidomycosis, systemic candidiasis).
• Non-fungal activity: The drug is lethal to certain protozoa. It is used in visceral leishmaniasis and amoebic meningoencephalitis (caused by Naegleria fowleri).
• Pharmacokinetics: Not absorbed in the gastrointestinal tract, penetrates the blood-brain barrier poorly (intratecal administration is possible for Coccidioides infections). Excreted by the kidneys. With systematic use, the half-life increases from 24–48 hours to 15 days due to drug accumulation in tissues.

Toxicity and lipid formulations

Amphotericin B exhibits high toxicity. Adverse reactions are divided into immediate and delayed (organ-specific):

• "Cytokine storm": An acute reaction during the first hours of infusion (chills, fever, hypotension) due to the release of TNF-$\alpha$ and IL-1 by immune cells. Managed by reducing the infusion rate and premedication (paracetamol, NSAIDs, hydrocortisone).
• Nephrotoxicity: The main adverse effect. Constriction of afferent arterioles causes ischemia and damage to the proximal renal tubules. Manifests as hypokalemia, hypomagnesemia, and acidosis.
• Hematotoxicity: Thrombocytopenia and anemia (due to decreased renal erythropoietin synthesis).
• Neurotoxicity: Headache, seizures, tremor, polyneuropathy, visual disturbances.

To reduce toxicity, lipid formulations have been developed (liposomal Ambisome, lipid complex Abelcet, colloidal dispersion Amphocil). In these, the antibiotic is enclosed within a lipid carrier and is released only upon contact with the fungus. This reliably protects the patient's kidneys while maintaining full clinical efficacy, although the cost of such treatment is significantly higher.

Topical formulations

Due to high toxicity upon systemic administration and lack of absorption in the intestine, certain polyenes (nystatin, leворин [levorin]) are used exclusively topically. They are most active against yeast-like fungi of the genus Candida.

Indications for use:

• Treatment of superficial candidiasis of the skin, mucous membranes (oral cavity, pharynx, vagina), and intestines.
• Prophylaxis: Prevention of candidiasis development during prolonged broad-spectrum antibiotic therapy.

When taken orally, these drugs work exclusively within the gastrointestinal lumen. Potential adverse effects are limited to allergic reactions and dyspeptic disorders.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Pharmacokinetics of amphotericin B upon intravenous administration and mechanisms of its tissue accumulation.
• Pathogenesis of polyene nephrotoxicity: from glomerular ischemia to tubular injury.
• Mechanism of the "cytokine storm" during amphotericin B infusion and methods for its prevention.
• Non-fungal activity of amphotericin B: application in the treatment of severe protozoan infections.
• Comparative profile of polyenes with other antifungals (echinocandins and triazole derivatives).

Other topics in the section "Antifungal agents"

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