Nystatin

Description

Nystatin was found in the mycelium of Streptomyces noursei in 1950 and produced on an industrial scale by Squibb & Sons Co. in 1954. This antibiotic was used orally and topically as the first clinically applied polyene macrolide with antifungal properties. Nystatin shows activity against Candida and filamentous fungi and is used to treat Candida infections of the mouth, digestive organs, and vagina. The application of nystatin in combination with gentamicin and vancomycin to sterilize the gut in perioperation of bone-marrow transplantation has been developed recently.

Chemical properties

This substance is a yellow or yellow-brown powder with a unique smell and the ability to absorb moisture. It dissolves to a small extent in water, methanol, and ethanol, but cannot dissolve in acetone, ether, or chloroform. It is not stable when exposed to air, light, heat, water, acid, or alkali.

Originator

Mycostatin,Squibb,US,1954

The Uses of Nystatin

Polyene antifungal antibiotic complex containing 3 biologically active components, A1, A2, A3. Increases the permeability of the cell membrane of sensitive fungi by binding to sterols. Cell culture tested. Growth promotant. Nystatin A1 is shown.

The Uses of Nystatin

Nystatin is polyene antifungal containing a conjugated tetraene and a diene, isolated as a complex of three components A1, A2 and A3 from Streptomyces noursei and first reported in 1950. Nystatin, like most polyene antifungals, binds to sterols in the fungal cell membrane leading to formation of ion channels in the wall, ion imbalance and cell death. Nystatin is an established bioprobe and widely-used antifungal reagent with over 4,000 literature citations.

Indications

Nystatin is available in oral formulations for the treatment and/or prevention of oral candidiasis (a.k.a. thrush), intestinal candidiasis, and anal candidiasis. It is indicated topically for the treatment of vulvovaginal candidiasis and other cutaneous candida infections. A combination product containing nystatin alongside neomycin, gramicidin D, and triamcinolone is indicated in the treatment of corticosteroid-responsive dermatoses caused by bacterial or candidal infections and for pruritus ani/vulvae. It is also available in combination with metronidazole for the treatment of mixed infections due to Trichomonas vaginalis and Candida albicans.
Nystatin is also sometimes used off-label for the prevention of invasive candidiasis in low birth weight neonates, though it is generally reserved as a second-line option after fluconazole.

Background

Nystatin is a polyene antifungal drug that has broad-spectrum fungicidal and fungistatic activity against a number of yeasts and fungi, most notably Candida species. It is one of the most effective antifungal agents synthesized by bacteria, in this case a strain of Streptomyces noursei, and is closely related to amphotericin B, differing only slightly in structure. Nystatin has a greater antifungal activity than amphotericin B - parenterally administered nystatin, however, is associated with significant toxicity and is not available in a formulation appropriate for systemic use. As it undergoes very little absorption following oral or topical administration, nystatin's efficacy is limited to the treatment/prevention of cutaneous, mucocutaneous, and gastrointestinal fungal infections.

Indications

Nystatin (Mycostatin) is a polyene antifungal drug with a ring structure similar to that of amphotericin B and a mechanism of action identical to that of amphotericin B. Too toxic for systemic use, nystatin is limited to the topical treatment of superficial infections caused by C. albicans. Infections commonly treated by this drug include oral candidiasis (thrush), mild esophageal candidiasis, and vaginitis.

Definition

ChEBI: A polyene macrolide antibiotic; part of the nystatin complex produced by several Streptococcus species. The keto-form of nystatin A1.

Manufacturing Process

A typical isolation and recovery procedure for nystatin is described in US Patent 2,797,183 and is shown in the following diagram:

brand name

Barstatin 100 (Barlan); Candex (Bayer); Korostatin (Holland Rantos); Mycostatin (Bristol-Myers Squibb); Mycostatin (Westwood-Squibb).

Therapeutic Function

Antifungal

General Description

Nystatin (Mycostatin) is a polyene antibiotic that was first isolated in 1951 from a strain of the actinomycete Streptomyces noursei by Hazen and Brown.33 It occurs as a yellow to light tan powder. Nystatin is very slightly soluble in water and sparingly soluble in organic solvents. The compound is unstable to moisture, heat, and light. The aglycone portion of nystatin is called nystatinolide. The complete structure of nystatin has been determined by chemical degradation and x-ray crystallography.35 Nystatin is not absorbed systemically when administered by the oral route. It is nearly insoluble under all conditions. It is also too toxic to be administered parenterally. Hence, it is used only as a topical agent. Nystatin is a valuable agent for the treatment of local and gastrointestinal monilial infections caused by C. albicans and other Candida species. For the treatment of cutaneous and mucocutaneous candidiasis, it is supplied as a cream, an ointment, and a powder. Vaginal tablets are available for the control of vaginal candidiasis. Oral tablets and troches are used in the treatment of gastrointestinal and oral candidiasis. Combinations of nystatin with tetracycline can be used to prevent monilial overgrowth caused by the destruction of bacterial microflora of the intestine during tetracycline therapy.

Biochem/physiol Actions

Potency: ≥3000 units/mg (anhydrous).

Pharmacology

Nystatin is stereoisomeric 33-[(3-amino-3,6-dideoxy-β-D-mannopyranosyl) oxy]-1,3,4,7,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo [33.3.1] nonatriaconta-19,21,25,27,29,31-hexaen-36-carboxylic acid (35.1.2). Nystatin was isolated in 1949 from the products of the vital activity of the actinomycete Streptomyces noursei, and it was the first antifungal antibiotic to be discovered. This polyene antibiotic is structurally similar to amphotericin B. It has a broad spectrum of activity. The mechanism of antifungal activity is similar to the mechanism of action of amphotericin B. It is used for preventing and treating candida infections of the skin and mucous membranes. In terms of preventative action, it is used for preventing the development of candidomycosis during prolonged treatment with penicillin drugs and antibiotics of other group, especially during oral use of tetracycline antibiotics, levomecytin, and others. Synonyms of this drug are biofanal, moronal, nicporil, fazigin, candex, and others.

Pharmacokinetics

Nystatin is an antifungal that is both fungistatic and fungicidal in vitro against a wide variety of yeasts and yeast-like fungi. It exerts its antifungal effects via disruption of the fungal cell membrane. Resistance to nystatin is minimal in Candida albicans, but tends to develop in other species of Candida. Nystatin carries no significant activity against bacteria, protozoa, or viruses. It carries significant systemic toxicity and is currently unavailable in a formula appropriate for systemic use - its efficacy is currently restricted, therefore, to topical, oral, and gastrointestinal infections.

Clinical Use

Nystatin, the first clinically useful polyene antifungal antibiotic, is a conjugated tetraene isolated from cultures of the bacterium Streptomyces noursei in 1951. Nystatin is an effective topical antifungal against a wide variety of organisms and is available in a variety of creams and ointments. Nystatin is too toxic to be used systemically, but because very little drug is absorbed following oral administration, it may be administered by mouth to treat fungal infections of the mouth and gastrointestinal tract.

Safety Profile

Poison by intraperitoneal and intravenous routes. Moderately toxic by subcutaneous route. Mildly toxic by ingestion. An experimental teratogen. Mutation data reported. An antibiotic. When heated to decomposition it emits toxic fumes of NOx.

Veterinary Drugs and Treatments

Orally administered nystatin is used primarily for the treatment of oral or gastrointestinal tract Candida infections in dogs, cats, and birds; it has been used less commonly in other species for the same indications.

Absorption

Systemic absorption of nystatin is minimal following oral administration, and no detectable plasma concentrations are attained following topical or vaginal administration.

Metabolism

Because nystatin undergoes little-to-no systemic absorption it is not metabolized to any appreciable extent.

Metabolism

No significant gastrointestinal absorption.

Toxicity

The oral LD50 in rats is 10 g/kg. There have been no reports of serious toxic effects following overdosage of nystatin - doses in excess of five million units daily have resulted in nausea and gastrointestinal upset with no other associated effects.

Side Effects

Common Side effects of Nystatin include:

Diarrhea

Nausea

Stomach pain or upset

Vomiting

Contact dermatitis

Stevens-Johnson syndrome

Hypersensitivity reactions

Skin irritation or redness

Mouth irritation

Rash

Hives

Allergic reaction

Slow heart rate

Bronchospasm

Facial swelling

Muscle pain

Purification Methods

Nystatin is a light yellow powder with the following solubilities at ~28o: MeOH (1.1%), ethylene glycol (0.9%), H2O (0.4%), CCl4 (0.12%), EtOH (0.12%), CHCl3 (0.05%) and *C6H6 (0.03%). It has been precipitated from MeOH solution by addition of H2O. Aqueous suspensions of this macrolide antifungal antibiotic are stable at 100o/10minutes at pH 7.0 but decompose rapidly at pH <2 and >9, and in the presence of light and O2. [Birch et al. Tetrahedron Lett 1491, 1485 1964, Weiss et al. Antibiot Chemother 7 374 1957.] It may contain a mixture of components A1, A2 and A3. [Beilstein 18 III/IV 7480.]