Polyene Antifungals: Amphotericin B and Nystatin

Introduction/Overview

Polyene antifungals represent a historically significant class of agents employed in the management of invasive and superficial fungal infections. Amphotericin B (AmB) and nystatin (NYS) are the most widely recognized representatives, each exhibiting a distinctive spectrum of activity, pharmacokinetic profile, and safety considerations. Their continued use in clinical practice underscores the enduring challenge of treating fungal pathogens, particularly in immunocompromised populations. A comprehensive understanding of their pharmacologic properties is essential for clinicians, pharmacists, and students engaged in infectious disease management, antimicrobial stewardship, and pharmacy practice.

Learning Objectives

• Describe the chemical classification and structural characteristics of amphotericin B and nystatin.
• Explain the mechanisms of fungal cell membrane disruption and host interaction.
• Summarize pharmacokinetic parameters influencing dosing and therapeutic monitoring.
• Identify approved therapeutic indications and common off‑label uses for each agent.
• Recognize major adverse effects, drug interactions, and special population considerations.

Classification

Drug Classes and Categories

Polyene antifungals are defined by a linear arrangement of conjugated double bonds, conferring a characteristic orange–yellow pigment and the capacity to bind ergosterol in fungal cell membranes. Within this class, amphotericin B and nystatin are categorized as follows:

• Amphotericin B – a broad–spectrum polyene with potent activity against systemic fungal pathogens.
• Nystatin – a topical or oral formulation primarily reserved for mucocutaneous Candida infections.

Chemical Classification

Both agents are produced by Streptomyces species and share a macrolide backbone comprising a 40‑membered ring with multiple hydroxyl groups and a carboxyl side chain. The polyene moiety is responsible for the antifungal activity, while the side chain contributes to water solubility and pharmacokinetic properties. Structural differences, particularly in the side chain and overall polarity, account for the divergent clinical applications and safety profiles of the two drugs.

Mechanism of Action

Pharmacodynamics

Amphotericin B exhibits fungicidal activity by binding specifically to ergosterol, an essential component of fungal cell membranes. This interaction yields the formation of transmembrane pores, permitting leakage of ions, small molecules, and ultimately leading to cell death. The binding affinity is considerably higher for fungal ergosterol compared to mammalian cholesterol, which explains the selective toxicity. In addition to pore formation, amphotericin B may induce reactive oxygen species generation, contributing to fungicidal effects.

Nystatin operates through a comparable mechanism, forming complexes with ergosterol and creating membrane pores. However, its activity is largely confined to the gastrointestinal tract and mucous membranes due to poor systemic absorption. Consequently, nystatin is considered fungistatic against many systemic pathogens, but fungicidal against superficial Candida species.

Receptor Interactions and Cellular Effects

While the primary target is ergosterol, polyenes may also interact with other membrane components, including sphingolipids, potentially amplifying their disruptive effects. The pore formation leads to ionic imbalance, depletion of ATP, and disruption of mitochondrial function. Moreover, the polyene–ergosterol complexes can provoke lipid peroxidation, further compromising membrane integrity. These multifaceted interactions collectively culminate in fungal cell lysis or growth inhibition.

Pharmacokinetics

Absorption

Amphotericin B is administered intravenously owing to its poor oral bioavailability (<1%). The drug exists in two clinically relevant formulations: conventional deoxycholate salt and lipid complex preparations. The deoxycholate formulation exhibits extensive tissue binding, particularly to the liver and spleen, whereas lipid formulations demonstrate a more favorable distribution profile, with reduced plasma protein binding and enhanced cellular uptake by phagocytes.

Nystatin, by contrast, is formulated for oral or topical use. Oral nystatin is poorly absorbed from the gastrointestinal tract, resulting in minimal systemic exposure. Topical preparations are intended for direct mucocutaneous contact, with absorption limited to the superficial epithelium.

Distribution

Amphotericin B demonstrates a large apparent volume of distribution (V_ss ≈ 50–200 L), reflecting extensive tissue penetration. In the deoxycholate formulation, significant sequestration occurs in the reticuloendothelial system, particularly in the liver and spleen. Lipid formulations show improved penetration into the central nervous system and pulmonary tissues, attributed to altered pharmacokinetics and reduced binding to plasma proteins.

Nystatin’s distribution is largely confined to the gastrointestinal tract and mucous membranes, with negligible systemic distribution. Topical formulations remain localized to the application site, achieving high local concentrations without systemic exposure.

Metabolism

Amphotericin B undergoes limited metabolism, with a minor contribution from hepatic enzymes. The primary elimination pathway is renal excretion of unchanged drug and small metabolites. Lipid formulations may involve additional metabolism of the lipid carrier, potentially influencing clearance rates.

Nystatin is minimally metabolized, with the majority of the drug excreted unchanged in feces. The negligible systemic absorption results in an essentially negligible metabolic profile.

Excretion

Renal excretion accounts for approximately 20–30 % of amphotericin B clearance. The remainder is eliminated via biliary excretion or sequestration within tissues. The elimination half‑life of conventional amphotericin B is 20–30 h, whereas lipid formulations exhibit a longer half‑life (up to 48–72 h) due to sustained release from lipid carriers.

Nystatin is excreted predominantly via the fecal route, with minimal renal elimination. The negligible systemic exposure renders renal clearance largely irrelevant for dosing considerations.

Half‑Life and Dosing Considerations

For conventional amphotericin B, a daily dose of 0.5–1.0 mg/kg is often employed, with adjustments based on renal function and clinical response. Lipid formulations may allow higher dosing (1.0–1.5 mg/kg) with reduced toxicity. Monitoring of serum creatinine and electrolytes is recommended to detect nephrotoxicity and hypokalemia. Dose adjustments are generally based on renal function, as the drug is renally excreted to a limited extent.

Nystatin dosing for oral preparations typically involves 25–50 mg/kg/day divided into multiple administrations, while topical use may require 0.5–2 % solutions applied four times daily. The low systemic absorption reduces the need for therapeutic drug monitoring.

Therapeutic Uses/Clinical Applications

Approved Indications

Amphotericin B is indicated for life‑threatening invasive fungal infections, including cryptococcal meningitis, systemic candidiasis, invasive aspergillosis, and zygomycosis. Lipid formulations are preferred for patients with renal impairment or those at high risk of nephrotoxicity. Nystatin is approved for oral candidiasis, esophageal candidiasis, and superficial cutaneous Candida infections. Topical nystatin is also utilized for diaper dermatitis and oral thrush in infants.

Off‑Label Uses

Amphotericin B is frequently employed off‑label for infections caused by rare or emerging fungal species, such as Scedosporium and Lomentospora species. Its role in prophylaxis for high‑risk transplant recipients or patients undergoing hematopoietic stem cell transplantation is well documented. Nystatin may be used off‑label as an adjunctive therapy in patients with invasive candidiasis who are intolerant to azoles, or in combination with systemic therapy to eradicate mucosal reservoirs.

Adverse Effects

Common Side Effects

Amphotericin B is associated with infusion‑related reactions, including fever, chills, rigors, and hypotension, predominantly with the deoxycholate formulation. Nephrotoxicity remains a significant concern, presenting as acute tubular necrosis, reduced glomerular filtration rate, and electrolyte disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia. Other effects include anemia, thrombocytopenia, and fatigue. Lipid formulations reduce the incidence of infusion reactions and nephrotoxicity but may still cause hepatotoxicity and infusion site reactions.

Nystatin’s adverse effect profile is generally mild, with local irritation, burning, or itching at the site of application. Oral administration may cause dyspepsia or nausea, although systemic absorption is minimal. Rare systemic side effects include allergic reactions, such as urticaria or anaphylaxis, particularly in patients with hypersensitivity to macrolide antibiotics.

Serious or Rare Adverse Reactions

Amphotericin B may precipitate severe renal failure, especially in patients with pre‑existing kidney disease or those receiving concomitant nephrotoxic agents. Delayed-onset nephrotoxicity can occur weeks after completion of therapy. Lipid formulations can cause hepatic dysfunction, characterized by elevated transaminases and bilirubin. Infusion reactions may become life‑threatening if not promptly managed.

Serious systemic reactions to nystatin are exceedingly uncommon, but hypersensitivity reactions can manifest as anaphylactic shock. In patients with underlying respiratory conditions, systemic absorption of topical formulations may theoretically precipitate bronchospasm, although evidence is limited.

Black Box Warnings

Amphotericin B carries a black box warning for nephrotoxicity and infusion‑related reactions. The use of the deoxycholate formulation is contraindicated in patients with severe renal impairment or known hypersensitivity. Lipid formulations, while safer, still require monitoring for hepatic dysfunction and potential hypersensitivity.

Drug Interactions

Major Drug–Drug Interactions

Amphotericin B may potentiate the nephrotoxic effects of other renally excreted drugs, such as aminoglycosides, cisplatin, and certain antiretrovirals (e.g., tenofovir). Concomitant use with nephrotoxic agents should be avoided or closely monitored. Amphotericin B can reduce the absorption of oral azoles by binding to their lipid carriers, potentially diminishing antifungal efficacy.

Nystatin has a relatively low interaction potential due to minimal systemic absorption. However, concurrent use with other topical antifungals or corticosteroids may alter local skin barrier function, potentially affecting efficacy or increasing the risk of skin irritation.

Contraindications

Amphotericin B is contraindicated in patients with known hypersensitivity to the drug, severe hepatic impairment (for lipid formulations), or uncontrolled renal failure (for deoxycholate). Nystatin is contraindicated in patients with known allergy to macrolide antibiotics or those with severe systemic disease requiring high systemic antifungal exposure.

Special Considerations

Use in Pregnancy/Lactation

Amphotericin B is classified as pregnancy category C; however, it is considered relatively safe due to limited placental transfer. The risk of fetal exposure is low, but monitoring for potential teratogenicity is prudent. Lactation remains acceptable; the drug is excreted minimally in breast milk, and adverse effects on the infant are unlikely.

Nystatin is generally regarded as safe during pregnancy and lactation, with minimal systemic absorption. It is classified as category B, indicating no evidence of risk in humans. Nonetheless, topical use should be limited to areas where the infant is directly exposed, and caregivers should monitor for local irritation.

Pediatric/Geriatric Considerations

In pediatrics, amphotericin B dosing is weight-based, with careful monitoring of renal function and electrolytes. Pediatric patients may exhibit increased sensitivity to nephrotoxicity. Geriatric patients often have reduced renal clearance, necessitating lower doses and more frequent monitoring.

Nystatin dosing in children mirrors adult recommendations, adjusted for weight. Topical formulations are generally well tolerated, but infants may develop diaper dermatitis if the drug is applied to large skin areas. Geriatric patients may have altered skin barrier function, potentially increasing local irritation risk.

Renal/Hepatic Impairment

Renal impairment significantly increases the risk of amphotericin B nephrotoxicity. In patients with creatinine clearance <30 mL/min, lipid formulations are preferred, and dose adjustments should be considered. Hepatic impairment may necessitate alternative therapies, as both formulations are metabolized hepatically to some extent.

Nystatin is largely unaffected by renal or hepatic dysfunction due to negligible systemic absorption. Local application remains effective regardless of organ function.

Summary/Key Points

• Amphotericin B is a broad‑spectrum, fungicidal polyene, best suited for invasive fungal infections; its use is limited by nephrotoxicity and infusion reactions.
• Nystatin is a topical or oral agent with fungistatic activity against superficial Candida, characterized by a favorable safety profile.
• The deoxycholate formulation of amphotericin B exhibits higher toxicity; lipid complexes reduce renal damage and improve pharmacokinetics.
• Monitoring of renal function, electrolytes, and hepatic enzymes is essential during amphotericin B therapy.
• Drug interactions, especially with other nephrotoxic agents, can exacerbate toxicity; careful medication reconciliation is required.
• In pregnancy, amphotericin B is relatively safe with minimal fetal exposure; nystatin is well tolerated in both pregnancy and lactation.
• Special populations (pediatrics, geriatrics, renal/hepatic impairment) require dose adjustments and vigilant monitoring to mitigate adverse effects.

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