Polyene antifungals
Polyene antifungals are a class of antifungal agents originally derived from Streptomyces species in the 1950s, notable for their effectiveness in treating deep-seated fungal infections. These drugs are characterized by their unique macrolide ring structure, which features alternating conjugated double bonds. The primary mechanism of action for polyenes involves disrupting fungal cell membranes by inserting into them and forming channels, leading to the leakage of vital intracellular components and ultimately cell death. Importantly, polyenes are selective for ergosterol, a lipid found in fungal cells, sparing mammalian cells that contain cholesterol.
Three key polyene antifungals include Nystatin, Amphotericin B, and Natamycin, each with distinct applications and side effects. Nystatin is commonly used for mild oral candidiasis but is not suitable for systemic infections due to its poor absorption. Amphotericin B is a potent injectable option for serious systemic infections, albeit with significant potential side effects, prompting the development of lipid-based formulations to reduce renal toxicity. Natamycin is primarily used in ophthalmic applications for treating fungal infections of the eye. While healthy individuals can typically fend off fungal infections, those with compromised immune systems face a heightened risk, making the use of polyene antifungals critical in such vulnerable populations.
Polyene antifungals
Definition
Polyene antifungals, which were derived from Streptomyces species in the 1950s, were the first antifungal agents available to reliably treat deep-seated fungal infections. The polyenes were named for the alternating conjugated double bonds that are part of their macrolide ring structure.
Mechanism of Action
Polyene antifungals are membrane disruptors. They function by inserting themselves into sterol-containing cell membranes and by then forming channels. Important intracellular components such as calcium, sodium, and potassium cations can then leak, leading to cell death. Polyenes have a much higher affinity for ergosterol, the predominant lipid in fungal cells, than they do for cholesterol, which is more prevalent in mammalian cell membranes. Polyenes have no significant activity in bacterial, viral, or protozoan infections, but they work against yeast and yeastlike fungi.
Drugs in This Class
Three drugs are available in this class, and they have very different uses. Nystatin (Mycostatin) is considered first-line therapy for mild oral candidiasis (thrush) and is given as either a suspension or a lozenge. The lozenges should be allowed to dissolve slowly and the suspension should be held in the mouth for as long as possible before swallowing to allow adequate contact time with the infected area. The drug is not absorbed orally, so it cannot be used to treat systemic infections; a tablet is available, however, to treat fungal infections of the gastrointestinal tract. In this case, the drug does not need to enter the bloodstream and is already available at the site of action. The most common adverse effects of nystatin are rash, nausea, vomiting, diarrhea, and gastrointestinal upset. Nystatin is too toxic to be formulated for systemic use.
Amphotericin B (Fungizone) is a broad-spectrum injectable agent that must be used with caution. It has serious adverse effects that include infusion reactions (fever, chills, and hypotension), low potassium levels, and renal toxicity. Even with this side effect profile, amphotericin B is the drug of choice for a number of life-threatening systemic fungal infections, including those involving Candida species, Cryptococcus neoformans, and Aspergillus species. Because of poor water solubility, the drug has been formulated as a complex with deoxycholic acid. This allows the drug to be formulated as a solution for intravenous administration but does nothing to limit toxicity.
Formulation development has focused on limiting the kidney toxicity of the drug. Three available lipid-based formulations lead to selective delivery of the drug to organs in the reticuloendothelial system (liver, spleen, and lung). This protects the kidney from the drug. In cases in which the fungal infection is primarily in the liver or related organs, the lipid formulation will take the drug directly to the site of the infection. Two of the formulations are drug-lipid complexes (Abelcet and Amphotec), while the other is a liposome (AmBisome). These formulations, however, are not more effective than the conventional product and cost significantly more.
Natamycin (pimaricin) is active against yeasts and molds. It is available as an ophthalmic suspension for treatment of fungal infections of the eye.
Impact
Healthy persons can generally easily fight fungal infections, but in those persons with impaired immune systems, these infections can become life-threatening. Fungal infections are most serious in persons with acquired immunodeficiency syndrome (AIDS) or in persons who have undergone organ transplant or chemotherapy.
Bibliography
Allen, L. V., N. G. Popovich, and H. C. Ansel. “Novel Dosage Forms and Drug Delivery Technologies.” In Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. 9th ed. Baltimore: Lippincott Williams & Wilkins, 2011.
"Clinical Treatment of Fungal Diseases: Antifungals." Centers for Disease Control, 24 Oct. 2024, www.cdc.gov/fungal/hcp/clinical-care/index.html#. Accessed 4 Feb. 2025.
Griffith, R. K. “Antifungal Drugs.” In Foye’s Principles of Medicinal Chemistry, edited by Thomas L. Lemke et al. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2008.
Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. “Antifungal Agents.” In Medical Microbiology. 6th ed. Philadelphia: Mosby/Elsevier, 2009.
Webster, John, and Weber, Roland. Introduction to Fungi. New York: Cambridge University Press, 2007.