Pharmacology of Nystatin

Introduction/Overview

Nystatin represents a cornerstone antifungal agent within the polyene macrolide class, primarily employed for the management of superficial fungal infections caused by Candida species. Isolated in 1950 from the bacterium Streptomyces noursei, it was the first antifungal polyene discovered and introduced into clinical practice. Its discovery marked a significant advancement in medical mycology, providing a targeted therapeutic option for mucocutaneous candidiasis. The clinical relevance of nystatin remains substantial due to its efficacy, favorable safety profile when used topically or orally for local effect, and its role as a first-line agent for specific indications such as oropharyngeal candidiasis (thrush) and cutaneous candidal infections. Its importance is further underscored by its widespread use in immunocompromised populations, including patients with HIV/AIDS, those undergoing chemotherapy, and transplant recipients, who are at heightened risk for opportunistic fungal overgrowth.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the chemical classification of nystatin and its relationship to other polyene antifungals.
• Explain the detailed molecular mechanism of action by which nystatin exerts its fungicidal effect.
• Analyze the pharmacokinetic profile of nystatin, emphasizing its lack of systemic absorption and the implications for dosing and administration.
• Identify the approved clinical indications for nystatin and differentiate its use from systemic antifungal agents.
• Evaluate the adverse effect profile, drug interactions, and special population considerations associated with nystatin therapy.

Classification

Nystatin is definitively classified as a polyene macrolide antifungal antibiotic. This classification is based on its chemical structure, which features a large macrolide lactone ring with multiple conjugated double bonds—the defining “polyene” characteristic. The presence of these bonds is responsible for the drug’s typical yellow color and its affinity for sterol-containing membranes.

Chemical Classification and Structure

Chemically, nystatin is a tetraene polyene, containing four conjugated double bonds in its macrolide ring. It is structurally similar to amphotericin B, which is a heptaene (seven double bonds). The molecule is amphipathic, comprising a hydrophilic polyhydroxyl region and a hydrophobic polyene hydrocarbon chain. This amphipathic nature is fundamental to its mechanism of action. Nystatin is a mixture of closely related chemical compounds, primarily nystatin A1, along with minor components (nystatin A2 and A3). It is insoluble in water and most organic solvents but forms colloidal suspensions in aqueous media, which is the basis for its pharmaceutical formulations.

Mechanism of Action

The pharmacodynamic action of nystatin is exclusively fungicidal, with its activity spectrum primarily encompassing yeasts of the genus Candida, including C. albicans, C. tropicalis, and C. glabrata. It demonstrates negligible activity against bacteria, viruses, or protozoa. Its fungicidal effect is concentration-dependent and results from a specific interaction with fungal cell membrane components.

Molecular and Cellular Mechanisms

The primary molecular target of nystatin is ergosterol, the principal sterol component of fungal cell membranes. The drug’s mechanism proceeds through a sequence of specific interactions. Initially, the lipophilic polyene chain of nystatin inserts into the fungal plasma membrane, binding with high affinity to ergosterol molecules. This binding is highly selective; while nystatin can also bind to cholesterol, the predominant sterol in mammalian membranes, its affinity for ergosterol is significantly greater, which accounts for its selective toxicity.

Following binding, multiple nystatin-ergosterol complexes aggregate within the membrane. These aggregates reorganize to form transmembrane pores or channels. The architecture of these pores typically involves the hydrophilic hydroxyl-rich portions of approximately eight nystatin molecules lining an aqueous channel, with the polyene chains interacting with membrane lipids. The formation of these pores fundamentally compromises the integrity of the fungal cell membrane.

The functional consequence of pore formation is a rapid and unregulated efflux of vital intracellular components, particularly potassium (K⁺), magnesium (Mg²⁺), and other small molecules and ions. Concurrently, there is an uncontrolled influx of extracellular ions and water. This disruption of electrochemical gradients and osmotic balance leads to catastrophic cell damage. The net efflux of cations and the influx of water cause cellular swelling, loss of metabolic regulation, and ultimately, cell lysis and death. This mechanism is rapid and irreversible at therapeutic concentrations, classifying nystatin’s action as fungicidal rather than fungistatic.

Pharmacokinetics

The pharmacokinetic profile of nystatin is characterized by negligible systemic absorption, which dictates its therapeutic application solely to localized infections. This lack of absorption is a direct result of its physicochemical properties and its administration via non-parenteral routes.

Absorption

Nystatin is not absorbed to any clinically significant extent from intact skin, mucous membranes, or the gastrointestinal tract. When applied topically to the skin or vagina, systemic absorption is virtually undetectable. Following oral administration as a suspension or pastille for the treatment of oropharyngeal or intestinal candidiasis, the drug is not absorbed from the gastrointestinal lumen; it acts locally on luminal and mucosal fungi and is excreted unchanged in the feces. This property renders systemic toxicity exceedingly rare with standard topical or oral non-absorbable formulations.

Distribution

Due to its lack of absorption, nystatin does not achieve measurable concentrations in plasma, tissues, or body fluids following topical, vaginal, or oral administration for local effect. Its distribution is confined to the site of application—the skin, oral mucosa, vaginal mucosa, or gastrointestinal lumen. Any distribution is local and superficial, limited by the drug’s inability to penetrate beyond the outermost layers of the stratum corneum or mucosal surfaces.

Metabolism

As nystatin is not absorbed systemically, it does not undergo hepatic metabolism via cytochrome P450 or other enzymatic systems. The drug remains in its active form at the site of application until it is physically removed or inactivated by local factors. There is no known active or inactive metabolic pathway of clinical relevance.

Excretion

The route of elimination is entirely dependent on the formulation. For topical, oral, and vaginal products, the unabsorbed drug is eliminated in the feces following oral administration or is simply shed with exfoliated skin cells or mucosal turnover. In the rare instance of intravenous administration of a lipid-complexed formulation (not commercially available in most regions), excretion occurs primarily via the biliary route into the feces, with minimal renal excretion.

Half-life and Dosing Considerations

Since systemic concentrations are not achieved, a conventional elimination half-life (t_1/2) is not defined for nystatin. Its effective duration of action at the site of application is relatively short, necessitating frequent dosing to maintain therapeutic concentrations against replicating fungi. Dosing schedules for oral suspension are typically four to five times daily, as the drug is quickly cleared from the oral cavity by swallowing and salivary flow. Topical applications are generally recommended two to four times daily. The lack of absorption negates concerns regarding accumulation with repeated dosing, but adherence to the prescribed frequency is critical for clinical efficacy.

Therapeutic Uses/Clinical Applications

The therapeutic utility of nystatin is restricted to the treatment of localized candidal infections, a direct consequence of its pharmacokinetic limitations. It is not effective for systemic fungal infections such as candidemia or invasive aspergillosis.

Approved Indications

Oropharyngeal Candidiasis (Thrush): This is the most common indication for nystatin. The oral suspension (100,000 units/mL) is swished and swallowed or, in infants, applied to the oral mucosa. Pastilles or lozenges are also used. Treatment typically continues for several days after symptoms resolve to prevent recurrence.

Cutaneous Candidiasis: Nystatin is formulated in creams, ointments, and powders (often 100,000 units/g) for the treatment of candidal intertrigo, diaper dermatitis complicated by Candida, and other superficial skin infections caused by susceptible Candida species.

Vulvovaginal Candidiasis: Intravaginal tablets or creams are used for uncomplicated vaginal yeast infections. Treatment courses are usually short (e.g., 7-14 days).

Intestinal Candidiasis: Although its diagnostic criteria are controversial, oral nystatin suspension is sometimes used to treat suspected or documented overgrowth of Candida in the gastrointestinal tract, particularly in immunocompromised patients.

Prophylaxis: In high-risk immunocompromised patients (e.g., those undergoing intensive chemotherapy or hematopoietic stem cell transplantation), oral nystatin may be used prophylactically to prevent oropharyngeal or gastrointestinal candidiasis, though fluconazole is often preferred for its systemic activity.

Off-Label Uses

Angular Cheilitis: Topical nystatin cream, often combined with a topical corticosteroid or antibacterial agent, is commonly used for inflammatory fissuring at the corners of the mouth when candidal infection is a contributing factor.

Candidal Paronychia: Topical nystatin may be employed as part of the management of this nail fold infection.

Esophageal Candidiasis: While systemic azoles (e.g., fluconazole) are first-line, oral nystatin suspension has been used as a non-absorbable alternative for mild cases, with the instruction to swallow slowly to coat the esophagus, though its efficacy is considered inferior.

Adverse Effects

The adverse effect profile of nystatin is generally mild and localized, reflecting its lack of systemic absorption. Serious adverse reactions are exceptionally rare.

Common Side Effects

Most adverse effects are related to the route of administration and are typically irritant in nature. With the oral suspension, nausea, vomiting, mild abdominal pain, and diarrhea are occasionally reported, likely due to local gastrointestinal irritation. A unpleasant taste is a frequent complaint. Topical application can sometimes cause contact dermatitis, manifested as localized irritation, burning, stinging, pruritus, or erythema. Vaginal formulations may cause local irritation, burning, itching, or a rash.

Serious/Rare Adverse Reactions

Severe hypersensitivity reactions, including anaphylaxis, are documented but are extremely rare. Stevens-Johnson syndrome and other severe cutaneous adverse reactions have been reported anecdotally. Systemic toxicity is not expected with standard formulations. If a significant amount of a topical preparation is ingested, gastrointestinal distress would be the anticipated consequence, but systemic effects would not occur due to lack of absorption.

Black Box Warnings

Nystatin does not carry any black box warnings from regulatory agencies such as the U.S. Food and Drug Administration (FDA). Its safety profile is considered favorable for its approved indications.

Drug Interactions

Given its pharmacokinetic profile, nystatin has a very low potential for clinically significant pharmacokinetic drug interactions. It does not induce or inhibit hepatic cytochrome P450 enzymes and is not a substrate for them.

Major Drug-Drug Interactions

No major pharmacokinetic interactions have been established. However, a potential pharmacodynamic interaction exists with other agents that can cause gastrointestinal irritation. Concurrent use with other drugs known to cause nausea or diarrhea might have additive gastrointestinal effects when nystatin suspension is used orally.

Contraindications

The primary contraindication to nystatin therapy is a documented history of hypersensitivity to nystatin or any component of its formulation. There are no other absolute contraindications based on its mechanism or effects. Its use for trivial or unconfirmed fungal infections should be discouraged to prevent unnecessary exposure and potential development of resistance, though this is less common with polyenes than with azoles.

Special Considerations

Use in Pregnancy and Lactation

Nystatin is generally categorized as Pregnancy Category C in older classification systems, or its equivalent, indicating that risk cannot be ruled out due to a lack of well-controlled human studies. However, because systemic absorption is negligible, the potential for fetal exposure following topical, vaginal, or oral administration is considered minimal. Consequently, it is widely regarded as safe for use during pregnancy for treating symptomatic candidiasis, particularly vulvovaginal infections. Similarly, during lactation, the lack of systemic absorption means nystatin is not excreted into breast milk in significant quantities, making its use compatible with breastfeeding. Topical application to the nipples should be wiped clean before nursing to avoid infant ingestion.

Pediatric Considerations

Nystatin is extensively used and considered safe in pediatric populations, including neonates, for the treatment of oral thrush and candidal diaper dermatitis. Dosing is typically based on weight or age for oral suspension (e.g., 100,000 units four times daily for infants). Care should be taken with topical applications over large body surface areas in infants, as the theoretical risk of increased absorption through immature skin exists, though clinical problems are not reported with standard use. The bitter taste of the suspension can make administration challenging.

Geriatric Considerations

No specific dosage adjustments are required in elderly patients. The same considerations regarding lack of absorption and local tolerability apply. Elderly patients, particularly those with dentures or receiving broad-spectrum antibiotics, may be at increased risk for oropharyngeal candidiasis and are appropriate candidates for nystatin therapy. Adherence to the frequent dosing schedule should be assessed.

Renal and Hepatic Impairment

As nystatin is not absorbed systemically, its pharmacokinetics are not altered by renal or hepatic dysfunction. No dosage adjustment is necessary for patients with any degree of renal impairment (including end-stage renal disease) or hepatic impairment. This characteristic makes nystatin a particularly useful agent in patients with multi-organ failure who develop superficial candidiasis and in whom systemic antifungal agents might require dose modification or pose additional risks.

Summary/Key Points

• Nystatin is a polyene macrolide antifungal agent with a fungicidal mechanism of action based on selective binding to ergosterol in fungal cell membranes, leading to pore formation, ion leakage, and cell death.
• Its pharmacokinetic profile is defined by negligible systemic absorption from the gastrointestinal tract, skin, and mucous membranes, confining its therapeutic use to localized candidal infections.
• Primary clinical indications include oropharyngeal candidiasis (thrush), cutaneous candidiasis, and vulvovaginal candidiasis. It is not effective for systemic fungal infections.
• The adverse effect profile is favorable and consists primarily of local irritation, gastrointestinal upset (with oral suspension), and unpleasant taste. Serious systemic toxicity is exceptionally rare.
• Nystatin has minimal potential for drug-drug interactions and does not require dosage adjustment in renal or hepatic impairment, pregnancy, lactation, or in pediatric or geriatric populations, due to its lack of systemic exposure.

Clinical Pearls

• For oral thrush in infants, applying the suspension directly to the affected mucosal areas with a swab or dropper is often more effective than placing it in the mouth for swallowing.
• Patients using the oral suspension should be instructed to swish the medication in the mouth for as long as possible before swallowing to maximize mucosal contact time.
• Treatment should be continued for at least 48 hours after clinical resolution of symptoms to prevent immediate relapse, as nystatin has no residual prophylactic effect.
• While resistance to nystatin among Candida species remains uncommon, clinical failure may occur and is more often related to inadequate dosing frequency, poor adherence, or severe host immunosuppression rather than true microbial resistance.
• Topical nystatin is often combined with a topical corticosteroid (e.g., triamcinolone) and an antibacterial (e.g., neomycin) in compounded formulations for inflammatory skin conditions where infection, inflammation, and bacterial overgrowth coexist.

References

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