Antifungal

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 cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.<ref name=":112">Template:Cite journal</ref>

Routes of administration

Ocular

Indicated when the fungal infection is located in the eye. There is currently only one ocular antifungal available: natamycin. However, various other antifungal agents could be compounded in this formulation.<ref>Template:Cite book</ref>

Intrathecal

Used occasionally when there's an infection of the central nervous system and other systemic options cannot reach the concentration required in that region for therapeutic benefit. Example(s): amphotericin B.<ref name=":03">Template:Cite journal</ref>

Vaginal

This may be used to treat some fungal infections of the vaginal region. An example of a condition they are sometimes used for is candida vulvovaginitis which is treated with intravaginal Clotrimazole.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Topical

Template:Main articles This is sometimes indicated when there's a fungal infection on the skin. An example is tinea pedis; this is sometimes treated with topical terbinafine.<ref>Template:Cite journal</ref>

Oral

If the antifungal has good bioavailability, this is a common route to handle a fungal infection. An example is the use of ketoconazole to treat coccidioidomycosis.<ref name=":13">Template:Cite book</ref>

Intravenous

Like the oral route, this will reach the bloodstream and distribute throughout the body. However, it is faster and a good option if the drug has poor bioavailability. An example of this is IV amphotericin B for the treatment of coccidioidomycosis.<ref name=":13" />

Classes

The available classes of antifungal drugs are still limited but as of 2021 novel classes of antifungals are being developed and are undergoing various stages of clinical trials to assess performance.<ref>Template:Cite journal</ref>

Polyenes

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A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. This changes the transition temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. (In ordinary circumstances membrane sterols increase the packing of the phospholipid bilayer making the plasma membrane more dense.) As a result, the cell's contents including monovalent ions (K⁺, Na⁺, H⁺, and Cl⁻) and small organic molecules leak, which is regarded as one of the primary ways a cell dies.<ref name=baginski>Template:Cite journal</ref> Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing the risk of human toxicity. Amphotericin B is nephrotoxic when given intravenously. As a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.Template:Citation needed

• Amphotericin B
• Candicidin
• Filipin – 35 carbons, binds to cholesterol (toxic)
• Hamycin
• Natamycin – 33 carbons, binds well to ergosterol
• Nystatin
• Rimocidin

Azoles

Azole antifungals inhibit the conversion of lanosterol to ergosterol by inhibiting lanosterol 14α-demethylase.<ref name=sheehan>Template:Cite journal</ref> These compounds have a five-membered ring containing two or three nitrogen atoms.<ref name=":0">Template:Citation</ref> The imidazole antifungals contain a 1,3-diazole (imidazole) ring (two nitrogen atoms), whereas the triazole antifungals have a ring with three nitrogen atoms.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":0" />

Imidazoles

• Bifonazole
• Butoconazole
• Clotrimazole
• Econazole
• Fenticonazole
• Isoconazole
• Ketoconazole
• Luliconazole
• Miconazole
• Omoconazole
• Oxiconazole
• Sertaconazole
• Sulconazole
• Tioconazole

Triazoles

• Albaconazole
• Cyproconazole
• Efinaconazole
• Epoxiconazole
• Fluconazole
• Isavuconazole
• Itraconazole
• Posaconazole
• Propiconazole
• Ravuconazole
• Terconazole
• Voriconazole

Thiazoles

• Abafungin

Allylamines

Allylamines<ref>Template:Cite journal</ref> inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include butenafine, naftifine, and terbinafine.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Echinocandins

Echinocandins inhibit the creation of glucan in the fungal cell wall by inhibiting 1,3-Beta-glucan synthase:

• Anidulafungin
• Caspofungin
• Micafungin

Echinocandins are administered intravenously, particularly for the treatment of resistant Candida species.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

Triterpenoids

• Ibrexafungerp

Others

• Acrisorcin
• Amorolfine – a morpholine derivative used topically in dermatophytosis<ref>Template:Cite journal</ref>
• Aurones – possess antifungal properties<ref>Template:Cite journal</ref>
• Benzoic acid – has antifungal properties, such as in Whitfield's ointment, Friar's Balsam, and Balsam of Peru<ref>Template:Cite book</ref>
• Carbol fuchsin (Castellani's paint)
• Ciclopirox (ciclopirox olamine) – a hydroxypyridone antifungal that interferes with active membrane transport, cell membrane integrity, and fungal respiratory processes. It is most useful against tinea versicolour.<ref>{{#invoke:citation/CS1|citation

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• Clioquinol
• Coal tar
• Copper(II) sulfate<ref>Template:Cite journal</ref>
• Crystal violet – a triarylmethane dye. It has antibacterial, antifungal, and anthelmintic properties and was formerly important as a topical antiseptic.<ref name=docampo>Template:Cite journal</ref>
• Chlorhexidine is a topical antibacterial and antifungal. It is commonly used in hospitals as an antiseptic. It is much more strongly antibacterial than antifungal, requiring at least a 10 times higher concentration to kill yeast compared to gram negative bacteria<ref>Template:Cite book</ref>
• Chlorophetanol
• Diiodohydroxyquinoline (Iodoquinol)
• Flucytosine (5-fluorocytosine) – an antimetabolite pyrimidine analog<ref>Template:Cite journal</ref>
• Fumagillin
• Griseofulvin – binds to microtubules and inhibits mitosis<ref>Template:Cite journal</ref>
• Haloprogin – discontinued due to the emergence of antifungals with fewer side effects<ref>{{#invoke:citation/CS1|citation

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• Miltefosine works by damaging fungal cell membranes <ref name="BrilhanteCaetano2015">Template:Cite journal</ref>
• Nikkomycin – blocks formation of chitin present in the cell wall of fungus.
• Orotomide (F901318) – pyrimidine synthesis inhibitor<ref name=oliver>Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Piroctone olamine
• Pentanenitrile
• Potassium iodide – preferred treatment for lymphocutaneous sporotrichosis and subcutaneous zygomycosis (basidiobolomycosis). The mode of action is obscure.<ref>Template:Cite book</ref>
• Potassium permanganate - for use only on thicker, more insensitive skin such as the soles of the feet.
• Selenium disulfide
• Sodium thiosulfate
• Sulfur
• Tolnaftate – a thiocarbamate antifungal, which inhibits fungal squalene epoxidase (similar mechanism to allylamines like terbinafine)Template:Medical citation needed
• Triacetin – hydrolysed to acetic acid by fungal esterases<ref>Template:Cite book</ref>
• Undecylenic acid – an unsaturated fatty acid derived from natural castor oil; fungistatic, antibacterial, antiviral, and inhibits Candida morphogenesisTemplate:Citation needed
• Zinc pyrithione

Side effects

Incidents of liver injury or failure among modern antifungal medicines are very low to non-existent. However, some can cause allergic reactions in people.<ref name="pmid27927037">Template:Cite journal</ref>

There are also many drug interactions. Patients must read in detail the enclosed data sheet(s) of any medicine. For example, the azole antifungals such as ketoconazole or itraconazole can be both substrates and inhibitors of the P-glycoprotein, which (among other functions) excretes toxins and drugs into the intestines.<ref name=doctorfungus/> Azole antifungals are also both substrates and inhibitors of the cytochrome P450 family CYP3A4,<ref name=doctorfungus>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> causing increased concentration when administering, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, tricyclic antidepressants, macrolides and SSRIs.<ref>Template:Cite journal</ref>

Before oral antifungal therapies are used to treat nail disease, a confirmation of the fungal infection should be made.<ref name="AADfive">{{#invoke:citation/CS1|citation |CitationClass=web }}, which cites

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• Template:Cite journal</ref> Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.<ref name="AADfive"/> The side effects of oral treatment are significant and people without an infection should not take these drugs.<ref name="AADfive"/>

Azoles are the group of antifungals which act on the cell membrane of fungi. They inhibit the enzyme 14-alpha-sterol demethylase, a microsomal CYP, which is required for the biosynthesis of ergosterol for the cytoplasmic membrane. This leads to the accumulation of 14-alpha-methylsterols resulting in impairment of function of certain membrane-bound enzymes and disruption of close packing of acyl chains of phospholipids, thus inhibiting growth of the fungi. Some azoles directly increase permeability of the fungal cell membrane.<ref>Template:Citation</ref>

Resistance

Antifungal resistance is a subset of antimicrobial resistance, that specifically applies to fungi that have become resistant to antifungals. Resistance to antifungals can arise naturally, for example by genetic mutation or through aneuploidy. Extended use of antifungals leads to the development of antifungal resistance through various mechanisms.<ref name=":112"/>

Some fungi (e.g. Candida krusei and fluconazole) exhibit intrinsic resistance to certain antifungal drugs or classes, whereas some species develop antifungal resistance to external pressures. Antifungal resistance is a One Health concern, driven by multiple extrinsic factors, including extensive fungicidal use, overuse of clinical antifungals, environmental change and host factors.<ref name=":112"/>

Like resistance to antibacterials, antifungal resistance can be driven by antifungal use in agriculture. Currently there is no regulation on the use of similar antifungal classes in agriculture and the clinic.<ref name=":112"/><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

The emergence of Candida auris as a potential human pathogen that sometimes exhibits multi-class antifungal drug resistance is concerning and has been associated with several outbreaks globally. The WHO has released a priority fungal pathogen list, including pathogens with antifungal resistance.<ref name="WHO">Template:Cite book</ref>

External links

• Antifungal Drugs – Detailed information on antifungals from the Fungal Guide written by R. Thomas and K. Barber
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