Polyenes

Polyenes are a class of fungicidal agents that consist of 2 primary drugs in current use, namely, nystatin and amphotericin B. Both these drugs exert their effects by binding to ergosterol (a critical component of fungal cell membranes) and creating pores in the membrane, leading to the leakage of intracellular components and ultimately cell lysis. Both nystatin and amphotericin B have a broad spectrum of antifungal activity, little to no oral absorption, and significant toxicity (especially nephrotoxicity) when used parenterally. Nystatin is too toxic to be administered intravenously; thus, it is only used to treat fungal infections of the skin, mucous membranes, and GI lumen. Amphotericin B is administered via IV, intrathecal, or intraperitoneal routes, or using aerosols to treat serious, life-threatening fungal infections. Secondary resistance to nystatin and amphotericin B is rare but emerging.

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Classification

Polyenes are one of the original classes of antifungal medications. There are 2 primary polyenes that are currently used:

  • Nystatin:
    • “Topical” use only (skin, mucous membranes, and GI lumen)
    • Too toxic for parenteral use
  • Amphotericin B:
    • Several nonoral routes of administration, including the IV route
    • Highly effective, but significant toxicity compared with other antifungal agents
    • Available as 2 primary formulations:
      • Liposomal amphotericin B (more commonly used due to better tolerability)
      • Amphotericin B deoxycholate

Chemistry and Pharmacodynamics

Chemical structure

Nystatin and amphotericin B have very similar chemical structures, including:

  • A large lactone ring
  • Multiple hydroxyl (-OH) groups on 1 side of the ring
  • Polyene structure on the other side of the ring:
    • Polyunsaturated organic compounds containing at least 3 alternating double and single carbon-carbon bonds (known as conjugated double bonds)
    • Contains a mycosamine group:
      • Binding site for ergosterol
      • Removal of mycosamine group results in the loss of antifungal properties.

Mechanism of action

Polyenes exert their effects by creating pores in the fungal cell membrane through binding to ergosterol; however, the exact mechanism of action is unclear.

  • Ergosterol: a critical component of fungal cell membranes (the equivalent of cholesterol in human cell membranes)
  • Polyenes bind to ergosterol and create artificial pores in the cell, resulting in:
    • Leakage of intracellular components (including H+, K+, Cl, and Na+) → destabilizes the cell → cell lysis and death
    • ↑ Production of free radicals and oxidative damage within the cell
  • Considered fungicidal
  • Other effects of amphotericin B (mechanism is not fully understood):
    • Immunomodulatory effects: ability to alter the transcription of cytokines, chemokines, and prostaglandins
    • Upregulates the genes involved in angiogenesis
    • Induces accumulation of NO
Antifungal agents and mechanisms of action

Antifungal agents and mechanisms of action

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Amphotericin B preparations: deoxycholate versus liposomal

  • Amphotericin B deoxycholate:
    • Conventional preparation in which amphotericin B is in a colloidal suspension
    • High toxicity: Amphotericin can bind to mammalian cholesterol and create similar pores in cells in humans.
  • Liposomal amphotericin B:
    • Developed to reduce toxicity
    • Liposomal amphotericin B preparation:
      • Packaged within lipid drug-delivery vehicles
      • Binds to lipids with an affinity that is in between that of fungal ergosterol and human cholesterol
    • Effects:
      • Less nonspecific binding to human cell membranes → ↓ toxicity without reduced efficacy
      • Larger doses can be administered.
    • Significantly more expensive than amphotericin deoxycholate

Pharmacokinetics

Nystatin

Nystatin is only used topically and as an oral suspension (administered with instructions to “swish and swallow”).

  • Absorption:
    • Not absorbed through mucous membranes or intact skin
    • Oral suspensions are poorly absorbed.
  • Excretion (oral suspension only): fecal, as unchanged drug

Amphotericin B

  • Absorption: poor oral absorption
    • Oral amphotericin is only effective on fungi present within the lumen of the GI tract (it is no longer used to treat these infections).
    • IV administration is required for systemic infections.
  • Distribution:
    • Protein binding > 90%, primarily bound to lipoproteins
    • Widely distributed in most tissues, including:
      • Pleural, peritoneal, pericardial, and synovial fluids
      • Liver, spleen, and bile
      • Aqueous humor
    • Only 2% of drug in the serum reaches the CSF. Intrathecal therapy may be required when used to treat fungal meningitis.
    • Crosses the placenta, but considered relatively safe in all trimesters of pregnancy (Category B: no evidence of risk in studies)
  • Metabolism and excretion: 
    • No metabolites have been identified.
    • Elimination is unclear: Only 5% of an administered dose is accounted for in urine and fecal excretion.
    • Half-life: approximately 15 days
    • No dosing adjustments required in hepatic or renal impairment

Indications

Nystatin

Nystatin is used for susceptible Candida species that cause fungal infections in:

  • Skin
  • Mucous membranes
  • Oral cavity (oral suspension given as “swish and swallow”)

Amphotericin B

Owing to its toxicity and the availability of less toxic agents, amphotericin B should be used only for individuals with severe, life-threatening, invasive fungal infections, or those unable to tolerate alternative agents.

Spectrum of activity:

Amphotericin B is active against:

  • Most Candida spp.
  • Most Aspergillus spp.
  • Cryptococcal meningitis
  • Mucormycosis
  • Leishmania spp.
  • Endemic mycoses:
    • Blastomycosis
    • Histoplasmosis
    • Coccidioidomycosis
    • Sporotrichosis
  • Black and brown molds

Resistance:

Organisms with intrinsic resistance to amphotericin B:

  • A. terreus
  • C. lusitaniae
  • Scedosporium spp.
  • Some Fusarium spp.

Adverse Events and Contraindications

Nystatin

Topical and oral nystatin have very few adverse effects. The only contraindication is a known allergy.

  • Topical: contact dermatitis
  • Oral: nausea, vomiting, and/or diarrhea (1%‒10% of individuals)
  • Contraindication: hypersensitivities

Amphotericin B

Therapy with amphotericin B is often limited by its toxicity, especially drug-induced renal impairment. Adverse events can be divided into immediate infusion-related reactions and effects due to cumulative toxicity.

Infusion-related toxicity:

  • Near-universal effects during administration:
    • Fever and chills
    • Myalgias and muscle spasms
    • Nausea/vomiting
    • Headache
    • Hypotension
  • Management:
    • Pretreatment:
      • Normal saline infusion
      • Antipyretics
      • Antihistamines
      • With/without corticosteroids
    • A test dose may be administered before starting therapy to gauge the severity of reactions and tolerability.

Cumulative toxicity:

  • Nephrotoxicity:
    • Most clinically significant reaction
    • Some degree of renal impairment is noted in up to 80% of individuals:
      • Deoxycholate is more toxic than liposomal preparations.
      • Severe renal failure due to amphotericin B alone is uncommon.
    • The degree of azotemia is variable (typically stabilizes during therapy).
    • May be:
      • Reversible, when due to ↓ prerenal perfusion
      • Permanent, when due to renal tubular injury
    • Presentation:
      • Oliguria/anuria
      • Renal tubular acidosis
      • Hypokalemia
      • Hypomagnesemia
      • Anemia: due to ↓ erythropoietin production
    • Management:
      • Consider ↓ dose or switching agents
      • Sodium loading via normal saline infusion given with amphotericin B
      • Dialysis may be required.
  • Hepatic toxicity:
    • ↑ Transaminases 
    • Hepatitis
    • Acute hepatic failure (rare)
  • Cardiac toxicity:
    • Heart failure due to direct myocardial toxicity
    • Cardiac arrest
    • Arrhythmias
  • Hypersensitivity reactions/anaphylaxis
  • After transthecal therapy:
    • Seizures
    • Chemical arachnoiditis may lead to serious neurologic sequelae.

Contraindications and Precautions:

  • Hypersensitivity (the only absolute contraindication)
  • CKD or concurrent use with other nephrotoxic medications

Mechanisms of Resistance

Secondary resistance to amphotericin B is rare but emerging. The primary mechanisms of resistance include:

  • ↓ Ergosterol content in the cell membrane through:
    • Alterations in the ergosterol synthesis pathway
    • Use of sterol intermediates
  • Changes in cell wall structure
  • Exposure of certain yeasts to subinhibitory concentrations of fluconazole can induce resistance to oxidative stress, leading to some resistance against amphotericin B.

Comparison of Antifungal Medications

Table: Comparison of antifungal medications
Drug class (examples)Mechanism of actionClinical relevance
Azoles (Fluconazole, Voriconazole)Inhibits the production of ergosterol (a critical component of the fungal cell membrane) by blocking the lanosterol 14-α-demethylase enzyme
  • Widely used antifungals with a relatively broad spectrum of activity
  • Many drug-to-drug interactions due to effects on the CYP450 system
  • Hepatotoxicity
  • Overall less toxic than amphotericin B
Polyenes (Amphotericin B, Nystatin)Binds to ergosterol in the fungal cell membrane creating artificial pores in the membrane → results in leakage of cellular components and leads to cell lysis (death)Amphotericin B:
  • Reserved for life-threatening fungal infections
  • Broad spectrum of activity
  • Relatively ↑ toxicity (especially nephrotoxicity)
  • Overall less toxic than amphotericin B

Nystatin:
  • Topical use only: skin, mucous membranes, GI lumen
Echinocandins (Caspofungin, Micafungin, Anidulafungin)Inhibits β-glucan synthase (the enzyme synthesizing β-glucan and an important structural component of the fungal cell wall) → weakened cell wall → cell lysis
  • Treats Candida and Aspergillus infections in critically ill and neutropenic patients
  • Minimal toxicity
  • Minimal drug-to-drug interactions
Griseofulvin
  • Binds to the keratin in newly forming skin, making the human cells resistant to invasion → over time the new, uninfected hair/skin/nail structures replace the old, infected structures
  • Inhibits the assembly of microtubules in dermatophytes → inhibits fungal cell replication
  • Treats dermatophyte infections of the hair, skin, and nails
  • Oral medication only (not topically active)
  • Affects the CYP450 system (more drug-to-drug interactions)
  • Largely replaced by newer agents (e.g., terbinafine)
TerbinafineInhibits the squalene epoxidase enzyme → blocks the production of squalene epoxide, which is a precursor to ergosterol and a critical component of the cell membrane
  • Treats dermatophyte infections of the hair, skin, and nails
  • Agent of choice for onychomycosis
  • Relatively low toxicity
FlucytosineA pyrimidine analog with metabolites:
  • Competing with uracil and disrupting RNA synthesis
  • Irreversibly inhibiting thymidylate synthase → fungus is unable to synthesize or correct DNA
  • Always used in combination with other agents due to:
    • Positive synergistic effects
    • ↑ Resistance with monotherapy
  • Major indications:
    • Cryptococcal meningitis
    • Chromoblastomycosis
  • Toxicity: myelosuppression

References

  1. Sheppard, D., Lampiris, H.W. (2012). Antifungal Agents. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic and Clinical Pharmacology, 12th Ed., pp. 849‒853.
  2. Drew, R. H. (2020). Pharmacology of amphotericin B. In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/pharmacology-of-amphotericin-b
  3. Nivoix, Y., Ledoux, M., Herbrecht, R. (2020). Antifungal therapy: New and evolving therapies. Seminars in Respiratory and Critical Care Medicine. 41, 158–174. Retrieved July 21, 2021, from https://www.medscape.com/viewarticle/924712_3 
  4. Noor, A. (2021). Amphotericin B. In StatPearls. Retrieved July 21, 2021 from https://www.statpearls.com/articlelibrary/viewarticle/17480/ 
  5. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved July 21, 2021, from:
  6. Kauffman, C.A. (2021). Management of candidemia and invasive candidiasis in adults. In Baron, E.L. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/management-of-candidemia-and-invasive-candidiasis-in-adults 
  7. Cox, G.M., Perfect, J.R. (2020). Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/cryptococcus-neoformans-treatment-of-meningoencephalitis-and-disseminated-infection-in-hiv-seronegative-patients 
  8. Cox, G.M. (2021). Mucormycosis (zygomycosis). In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/mucormycosis-zygomycosis 
  9. Patterson, T.F. (2021). Treatment and prevention of invasive aspergillosis. In Bond, S. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/treatment-and-prevention-of-invasive-aspergillosis 
  10. Kauffman, C.A. (2020). Diagnosis and treatment of pulmonary histoplasmosis. In Bogorodskaya, M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-pulmonary-histoplasmosis 
  11. Bradsher, R.W. (2020). Treatment of blastomycosis. In Bogorodskaya. M. (Ed.), UpToDate. Retrieved July 21, 2021, from https://www.uptodate.com/contents/treatment-of-blastomycosis

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