Nystatin, sold under the brandname Mycostatin among others, is an

antifungal medication An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypt ...

. It is used to treat '' Candida'' infections of the skin including

diaper rash Irritant diaper dermatitis (IDD, also called a diaper/nappy rash) is a generic term applied to skin rash in the diaper nappy area that are caused by various skin disorders and/or irritants. Generic irritant diaper/nappy dermatitis is characteriz ...

, thrush,

esophageal candidiasis Esophageal candidiasis is an opportunistic infection of the esophagus by ''Candida albicans''. The disease usually occurs in patients in immunocompromised states, including post-chemotherapy and in AIDS. However, it can also occur in patients wi ...

, and vaginal yeast infections. It may also be used to prevent candidiasis in those who are at high risk. Nystatin may be used by mouth, in the vagina, or applied to the skin. Common side effects when applied to the skin include burning, itching, and a rash. Common side effects when taken by mouth include vomiting and diarrhea. During

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

use in the vagina is safe while other formulations have not been studied in this group. It works by disrupting the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

of the fungal cells. Nystatin was discovered in 1950 by Rachel Fuller Brown and Elizabeth Lee Hazen. It was the first polyene macrolide antifungal. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...

. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. It is made from the bacterium '' Streptomyces noursei''. In 2020, it was the 227th most commonly prescribed medication in the United States, with more than 2million prescriptions.

Medical uses

Skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

vaginal In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hyme ...

mouth In animal anatomy, the mouth, also known as the oral cavity, or in Latin cavum oris, is the opening through which many animals take in food and issue vocal sounds. It is also the cavity lying at the upper end of the alimentary canal, bounded on ...

, and esophageal '' Candida'' infections usually respond well to treatment with nystatin. Infections of nails or hyperkeratinized skin do not respond well. It is available in many forms. When given parenterally, its activity is reduced due to presence of plasma. Oral nystatin is often used as a preventive treatment in people who are at risk for fungal infections, such as

AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...

patients with a low CD4⁺ count and people receiving

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

. It has been investigated for use in patients after liver transplantation, but

fluconazole Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to prevent ...

was found to be much more effective for preventing colonization, invasive infection, and death. It is effective in treating oral candidiasis in elderly people who wear dentures. It is also used in very low birth-weight (less than 1500 g or 3 lb 5oz o) infants to prevent invasive fungal infections, although fluconazole is the preferred treatment. It has been found to reduce the rate of invasive fungal infections and also reduce deaths when used in these babies. Liposomal nystatin is not commercially available, but investigational use has shown greater ''in vitro'' activity than colloidal formulations of

amphotericin B Amphotericin B is an antifungal medication used for serious mycosis, fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candida infections, candidiasis, coccidioidomy ...

, and demonstrated effectiveness against some amphotericin B-resistant forms of fungi. It offers an intriguing possibility for difficult-to-treat systemic infections, such as invasive aspergillosis, or infections that demonstrate resistance to amphotericin B. ''

Cryptococcus ''Cryptococcus'' is a genus of fungi in the family Cryptococcaceae that includes both yeasts and filamentous species. The filamentous, sexual forms or teleomorphs were formerly classified in the genus ''Filobasidiella'', while ''Cryptococcus'' ...

'' is also sensitive to nystatin. Additionally, liposomal nystatin appears to cause fewer cases of and less severe nephrotoxicity than observed with amphotericin B. In the UK, its license for treating neonatal oral thrush is restricted to those over the age of one month. It is prescribed in 'units', with doses varying from 100,000 units (for oral infections) to 1 million (for intestinal ones). As it is not absorbed from the gut, it is fairly safe for oral use and does not have problems of drug interactions. On occasion, serum levels of the drug can be identified from oral, vaginal, or cutaneous administration, and lead to toxicity.

Adverse effects

Bitter taste and nausea are more common than most other adverse effects. The oral suspension form produces a number of adverse effects including but not limited to: #Diarrhea #Abdominal pain #Rarely, tachycardia, bronchospasm, facial swelling, muscle aches Both the oral suspension and the topical form can cause: #Hypersensitivity reactions, including

Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...

in some cases #Rash, itching, burning and acute generalized

exanthem An exanthem is a widespread rash occurring on the outside of the body and usually occurring in children. An exanthem can be caused by toxins, drugs, or microorganisms, or can result from autoimmune disease. The term exanthem is from the Greek ...

atous

pustulosis Pustulosis is highly inflammatory skin condition resulting in large fluid-filled blister-like areas - pustules. Pustulosis typically occurs on the palms of the hands and/or the soles of the feet. The skin of these areas peels and flakes ( exfoliates ...

Mechanism of action

and

natamycin Natamycin, also known as pimaricin, is an antifungal medication used to treat fungal infections around the eye. This includes infections of the eyelids, conjunctiva, and cornea. It is used as eyedrops. Natamycin is also used in the food indust ...

, nystatin is an

ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...

. It binds to

ergosterol Ergosterol (ergosta-5,7,22-trien-3β-ol) is a sterol found in cell membranes of fungi and protozoa, serving many of the same functions that cholesterol serves in animal cells. Because many fungi and protozoa cannot survive without ergosterol, the ...

, a major component of the fungal

. When present in sufficient concentrations, it forms pores in the membrane that lead to K⁺ leakage, acidification, and death of the fungus. Ergosterol is a

sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the go ...

unique to fungi, so the drug does not have such catastrophic effects on animals or plants. However, many of the systemic/toxic effects of nystatin in humans are attributable to its binding to mammalian sterols, namely

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

. This is the effect that accounts for the

nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...

observed when high serum levels of nystatin are achieved. Nystatin also impacts cell membrane potential and transport by lipid peroxidation. Conjugated double bonds in nystatin's structure steal

electron density In quantum chemistry, electron density or electronic density is the measure of the probability of an electron being present at an infinitesimal element of space surrounding any given point. It is a scalar quantity depending upon three spatial va ...

from ergosterol in fungal cell membranes. Lipid peroxidation alters the

hydrophilicity A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...

of the interior of

channels Channel, channels, channeling, etc., may refer to: Geography * Channel (geography), in physical geography, a landform consisting of the outline (banks) of the path of a narrow body of water. Australia * Channel Country, region of outback Austral ...

in the membrane, which is necessary to transport ions and

polar Polar may refer to: Geography Polar may refer to: * Geographical pole, either of two fixed points on the surface of a rotating body or planet, at 90 degrees from the equator, based on the axis around which a body rotates * Polar climate, the c ...

molecules. Disruption of membrane transport from nystatin results in rapid cell death. Lipid peroxidation by nystatin also contributes significantly to K⁺ leakage due to structural modifications of the membrane.

Biosynthesis

Nystatin A₁ (or referred to as nystatin) is biosynthesized by a bacterial strain, '' Streptomyces noursei''. The structure of this active compound is characterized as a polyene macrolide with a deoxysugar D-

mycosamine D-Mycosamine is an amino sugar found in several polyene antimycotics. Structural analogs of these agents lacking this monosaccharide component do not exhibit substantial antifungal An antifungal medication, also known as an antimycotic medicat ...

, an

aminoglycoside Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...

. The genomic sequence of nystatin reveals the presence of the polyketide loading module (nysA), six polyketide syntheses modules (nysB, nysC, nysI, nysJ, and nysK) and two thioesterase modules (nysK and nysE). It is evident that the biosynthesis of the macrolide functionality follows the

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

I pathway. Following the biosynthesis of the macrolide, the compound undergoes post-synthetic modifications, which are aided by the following enzymes: GDP-mannose dehydratase (nysIII), P450 monooxygenase (nysL and nysN), aminotransferase (nysDII), and glycosyltransferase (nysDI). The biosynthetic pathway is thought to proceed as shown to yield nystatin. File:L-5.gif, Loading to 5 File:Mod6-12.jpg, Modules 6-12 File:M13-18.gif, Modules 13 -18 File:Completed nystatin biosynthesis.jpg, Completed molecule The melting point of nystatin is 44 - 46 °C.

History

Elizabeth Lee Hazen Rachel Fuller Brown 1950s

Like many other antifungals and antibiotics, nystatin has

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

l origin. It was isolated from '' Streptomyces noursei'' in 1950 by Elizabeth Lee Hazen and Rachel Fuller Brown, who were doing research for the Division of Laboratories and Research of the New York State Department of Health. Hazen found a promising micro-organism in the soil of a friend's dairy farm. She named it ''Streptomyces noursei'', after Jessie Nourse, the wife of the farm's owner. Hazen and Brown named nystatin after the

New York New York most commonly refers to: * New York City, the most populous city in the United States, located in the state of New York * New York (state), a state in the northeastern United States New York may also refer to: Film and television * '' ...

State Health Department in 1954. The two discoverers patented the drug, and then donated the $13 million in profits to a foundation to fund similar research.

Other uses

It is also used in cellular biology as an inhibitor of the

lipid raft The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial. ...

caveolae In biology, caveolae ( Latin for "little caves"; singular, caveola), which are a special type of lipid raft, are small (50–100 nanometer) invaginations of the plasma membrane in the cells of many vertebrates. They are the most abundant surface ...

endocytosis pathway on mammalian cells, at concentrations around 3 μg/ml. In certain cases, nystatin has been used to prevent the spread of mold on objects such as works of art. For example, it was applied to wood panel paintings damaged as a result of the Arno River Flood of 1966 in Florence, Italy. Nystatin is also used as a tool by scientists performing "perforated" patch-clamp electrophysiologic recordings of cells. When loaded in the recording pipette, it allows for measurement of electrical currents without washing out the intracellular contents, because it forms pores in the cell membrane that are permeable to only monovalent

ions An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

Formulations

* An oral suspension form is used for the prophylaxis or treatment of oropharyngeal thrush, a superficial candidal infection of the mouth and pharynx. * A tablet form is preferred for candidal infections in the intestines. * Nystatin is available as a topical cream and can be used for superficial candidal infections of the skin. * Additionally, a liposomal formulation of nystatin was investigated in the 1980s and into the early 21st century. The liposomal form was intended to resolve problems arising from the poor solubility of the parent molecule and the associated systemic toxicity of the free drug. *Nystatin pastilles have been shown to be more effective in treating oral candidiasis than nystatin suspensions. Due to its

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

profile when high levels in the serum are obtained, no injectable formulations of this drug are currently on the US market. However, injectable formulations have been investigated in the past.

Brand names

The original brandname was Fungicidin *Nyamyc *Pedi-Dri *Pediaderm AF Complete *Candistatin *Nyaderm *Bio-Statin *PMS-Nystatin *Nystan (oral tablets, topical

ointment A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

, and

pessaries A pessary is a prosthetic device inserted into the vagina for structural and pharmaceutical purposes. It is most commonly used to treat Stress incontinence, stress urinary incontinence to stop urinary leakage and to treat pelvic organ prolapse to ...

, formerly from

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

) *Infestat *Nystalocal from Medinova AG *Nystamont *Nystop (topical powder,

Paddock A paddock is a small enclosure for horses. In the United Kingdom, this term also applies to a field for a general automobile racing competition, particularly Formula 1. Description In Canada and the United States of America, a paddock is a small ...

) *Nystex *Mykinac *Nysert (vaginal suppositories,

Procter & Gamble The Procter & Gamble Company (P&G) is an American multinational consumer goods corporation headquartered in Cincinnati, Ohio, founded in 1837 by William Procter and James Gamble. It specializes in a wide range of personal health/consumer hea ...

) *Nystaform (topical cream, and ointment and cream combined with iodochlorhydroxyquine and

hydrocortisone Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, ...

; formerly

Bayer Bayer AG (, commonly pronounced ; ) is a German multinational corporation, multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of busi ...

now Typharm Ltd) *Nilstat (vaginal tablet, oral drops, Lederle) *Korostatin (vaginal tablets, Holland Rantos) *Mycostatin (vaginal tablets, topical powder, suspension

) *Mycolog-II (topical ointment, combined with

triamcinolone Triamcinolone is a glucocorticoid used to treat certain skin diseases, allergies, and rheumatic disorders among others. It is also used to prevent worsening of asthma and COPD. It can be taken in various ways including by mouth, injection i ...

; Apothecon) *Mytrex (topical ointment, combined with triamcinolone) *Mykacet (topical ointment, combined with triamcinolone) *Myco-Triacet II (topical ointment, combined with triamcinolone) *Flagystatin II (cream, combined with metronidazole) *Timodine (cream, combined with

and

dimethicone Polydimethylsiloxane (PDMS), also known as dimethylpolysiloxane or dimethicone, belongs to a group of polymeric organosilicon compounds that are commonly referred to as silicones. PDMS is the most widely used silicon-based organic polymer, as i ...

) *Nistatina (oral tablets, Antibiotice Iaşi) *Nidoflor (cream, combined with neomycin sulfate and

triamcinolone acetonide Triamcinolone acetonide, sold under the brand name Kenalog among others, is a synthetic corticosteroid medication used topically to treat various skin conditions, to relieve the discomfort of mouth sores, and by injection into joints to trea ...

) *Stamicin (oral tablets, Antibiotice Iaşi) *Lystin *Animax (veterinary topical ointment or cream; combined with neomycin sulfate,

thiostrepton Thiostrepton is a natural cyclic oligopeptide antibiotic of the thiopeptide class, derived from several strains of streptomycetes, such as ''Streptomyces azureus'' and ''Streptomyces laurentii''. Thiostrepton is a natural product of the ribosom ...

and

) *Nyata (topical powder)

References

External links

* {{portal bar, Medicine Antifungals World Health Organization essential medicines Wikipedia medicine articles ready to translate Polyketides Lactones Polyenes Hemiketals Lactols Vicinal diols Secondary alcohols Amines Carboxylic acids Conjugated dienes Acetals