Polyenes

Definition and Clinical Relevance
Polyenes are a class of broad-spectrum antifungal agents characterized by the presence of multiple conjugated double bonds in their chemical structure. They are natural macrocyclic polyene macrolides derived from Streptomyces species and exert their fungicidal or fungistatic effects by binding to ergosterol, a crucial component of fungal cell membranes. This interaction disrupts membrane integrity, leading to leakage of cellular contents, cell death, and organism clearance.

Polyenes are primarily used for the treatment of systemic, mucocutaneous, and superficial fungal infections, including life-threatening invasive mycoses caused by Candida, Aspergillus, Cryptococcus, and other pathogenic fungi. Some polyenes are also applied topically for dermatomycoses or used in oral suspensions for oropharyngeal candidiasis.

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1. Chemical Classification of Polyenes

Polyenes are named for their conjugated carbon-carbon double bond chains. Based on the number of conjugated double bonds, they are classified as:

• Tetraenes – 4 double bonds (e.g., nystatin)

• Pentaenes – 5 double bonds (e.g., amphotericin B)

• Hexaenes – 6 double bonds (rare or investigational)

The number of double bonds influences the compound’s antifungal potency and mammalian toxicity—more double bonds generally correlate with greater selectivity for fungal sterols over cholesterol, reducing toxicity.

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2. Mechanism of Action

Polyenes exhibit their antifungal effect primarily by binding to ergosterol, a sterol component of fungal cell membranes (analogous to cholesterol in human cells).

Key mechanisms:

• Ergosterol binding: Polyenes insert into the fungal lipid bilayer and bind to ergosterol.

• Pore formation: This interaction leads to the formation of aqueous transmembrane pores, increasing membrane permeability.

• Cell leakage: Ions (K⁺, Mg²⁺), small molecules, and intracellular contents leak out.

• Fungal cell death: This results in fungicidal activity against susceptible fungi.

Polyenes have minimal activity against bacteria (which lack sterols) and selectivity for fungi over mammalian cells due to their higher affinity for ergosterol than for cholesterol.

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3. Spectrum of Antifungal Activity

Polyenes are broad-spectrum agents effective against many pathogenic fungi:

Sensitive Organisms:

• Candida species (including C. albicans, C. tropicalis, C. krusei)

• Aspergillus species

• Cryptococcus neoformans

• Histoplasma capsulatum

• Blastomyces dermatitidis

• Coccidioides immitis

• Paracoccidioides brasiliensis

• Zygomycetes (e.g., Mucor, Rhizopus)

Resistant Organisms:

• Candida auris (variable susceptibility)

• Certain strains of Fusarium, Scedosporium, and Pseudallescheria

• Fungi with low ergosterol content or altered sterols

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4. Therapeutic Indications

Polyenes are used both systemically and topically depending on the agent and indication.

A. Systemic Therapy (Amphotericin B and its derivatives):

• Invasive candidiasis

• Cryptococcal meningitis

• Pulmonary aspergillosis

• Mucormycosis

• Disseminated histoplasmosis

• Febrile neutropenia (empirical antifungal therapy)

B. Topical or Oral Non-absorbable Therapy (Nystatin, Natamycin):

• Oral thrush (oropharyngeal candidiasis)

• Vaginal candidiasis

• Cutaneous candidiasis

• Diaper rash (fungal)

• Fungal keratitis (natamycin ophthalmic suspension)

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5. Generic Drug Names and Common Brand Examples

Generic Name	Formulations	Common Brands
Amphotericin B	IV deoxycholate, lipid complex, liposomal	Fungizone, AmBisome, Abelcet
Nystatin	Topical cream, ointment, oral suspension	Mycostatin, Nystop
Natamycin	5% ophthalmic suspension	Natacyn

Note:

• Liposomal amphotericin B and lipid complex forms offer reduced nephrotoxicity and are preferred for systemic infections.

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6. Pharmacokinetics

Amphotericin B:

• Absorption: Not orally absorbed; administered IV for systemic use

• Distribution: Highly protein-bound; accumulates in tissues; minimal CSF penetration (except with high doses or intrathecal use)

• Metabolism: Not fully elucidated; very slow clearance

• Half-life: ~15 days (biphasic)

• Excretion: Slowly via kidneys and bile

Nystatin:

• Absorption: Not absorbed systemically; local action only

• Use: Oral, topical, or vaginal for mucocutaneous candidiasis

Natamycin:

• Absorption: Minimal systemic absorption from eye drops

• Use: Ophthalmic treatment only

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7. Adverse Effects

Amphotericin B (especially conventional form):

Infusion-related reactions:

• Fever, chills, rigors (commonly called "shake and bake")

• Hypotension

• Nausea, vomiting

• Thrombophlebitis

Organ toxicity:

• Nephrotoxicity (dose-limiting): direct tubular damage, decreased GFR, renal potassium and magnesium wasting

• Electrolyte imbalances: Hypokalemia, hypomagnesemia

• Anemia: Normochromic, normocytic due to reduced erythropoietin

Lipid formulations reduce these adverse effects but are more costly.

Nystatin:

• GI upset (with oral suspension)

• Skin irritation (with topical use)

• Very low systemic toxicity

Natamycin:

• Ocular irritation or redness

• Hypersensitivity reactions (rare)

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8. Contraindications

• Known hypersensitivity to polyenes or any formulation component

• Use of IV amphotericin B in patients with severe renal dysfunction (relative contraindication—requires risk-benefit assessment)

• Intrathecal administration (off-label; not routinely recommended due to neurotoxicity)

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9. Precautions and Monitoring

Amphotericin B (systemic use):

• Monitor renal function (serum creatinine, BUN)

• Monitor electrolytes, especially potassium and magnesium

• Hydration before administration may reduce nephrotoxicity

• Monitor liver enzymes and CBC

• Use lipid formulations in patients at high renal risk

Nystatin and Natamycin:

• Avoid contact with deep wounds or internal cavities

• Discontinue on signs of hypersensitivity

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10. Drug Interactions

Amphotericin B:

A. Nephrotoxicity-enhancing agents:

• Cyclosporine

• Aminoglycosides (e.g., gentamicin)

• Vancomycin

• NSAIDs

• Contrast media

B. Potassium-wasting agents:

• Corticosteroids

• Loop or thiazide diuretics

• Can increase risk of arrhythmias when hypokalemia is exacerbated

C. Digoxin:

• Hypokalemia increases digoxin toxicity risk

D. Flucytosine:

• Amphotericin B enhances flucytosine uptake in fungal cells; combination is synergistic but increases risk of bone marrow suppression

Nystatin / Natamycin:

• No significant systemic interactions due to lack of absorption

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11. Resistance Mechanisms

Though rare, resistance to polyenes may occur due to:

• Altered ergosterol synthesis

• Decreased ergosterol content in the fungal membrane

• Replacement of ergosterol with precursor sterols (e.g., in Candida lusitaniae)

Note: Resistance is less common compared to azoles or echinocandins.

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12. Clinical Considerations

• Amphotericin B remains the gold standard for many life-threatening fungal infections, particularly when rapid fungal clearance is necessary or when resistance to azoles or echinocandins is suspected.

• Nystatin is reserved for mucosal candidiasis, diaper rash, or vaginal candidiasis with a long history of safe topical use.

• Natamycin is the only FDA-approved agent for fungal eye infections and is first-line for fungal keratitis.

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13. Summary of Key Polyenes

Agent	Use	Form	Systemic Absorption
Amphotericin B	Systemic fungal infections	IV	Yes (IV only)
Liposomal AmB	Invasive mycoses with renal risk	IV	Yes
Nystatin	Mucocutaneous candidiasis	Oral, topical, vaginal	No
Natamycin	Fungal eye infections	Ophthalmic drops	No