Polyenes are one of the original classes of antifungal medications. There are 2 primary polyenes that are currently used:
- “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
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
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
- Less nonspecific binding to human cell membranes → ↓ toxicity without reduced efficacy
- Larger doses can be administered.
- Significantly more expensive than amphotericin deoxycholate
Nystatin is only used topically and as an oral suspension (administered with instructions to “swish and swallow”).
- Not absorbed through mucous membranes or intact skin
- Oral suspensions are poorly absorbed.
- Excretion (oral suspension only): fecal, as unchanged drug
- 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.
- 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
Nystatin is used for susceptible Candida species that cause fungal infections in:
- Mucous membranes
- Oral cavity (oral suspension given as “swish and swallow”)
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
- Leishmania spp.
- Endemic mycoses:
- Black and brown molds
Organisms with intrinsic resistance to amphotericin B:
- A. terreus
- C. lusitaniae
- Scedosporium spp.
- Some Fusarium spp.
Adverse Events and Contraindications
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
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.
- Near-universal effects during administration:
- Fever and chills
- Myalgias and muscle spasms
- Normal saline infusion
- With/without corticosteroids
- A test dose may be administered before starting therapy to gauge the severity of reactions and tolerability.
- 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
- Renal tubular acidosis
- Anemia: due to ↓ erythropoietin production
- Consider ↓ dose or switching agents
- Sodium loading via normal saline infusion given with amphotericin B
- Dialysis may be required.
- Hepatic toxicity:
- ↑ Transaminases
- Acute hepatic failure (rare)
- Cardiac toxicity:
- Heart failure due to direct myocardial toxicity
- Cardiac arrest
- Hypersensitivity reactions/anaphylaxis
- After transthecal therapy:
- 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
|Drug class (examples)||Mechanism of action||Clinical 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|
|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:|
|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|
|Terbinafine||Inhibits the squalene epoxidase enzyme → blocks the production of squalene epoxide, which is a precursor to ergosterol and a critical component of the cell membrane|
|Flucytosine||A pyrimidine analog with metabolites:|
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