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Antifungal

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Not to be confused withAntifungal protein.

Antifungal
Drug class
Canesten (clotrimazole) antifungal cream
Synonymsantimycotic medication
Legal status
In Wikidata

Anantifungal medication,also known as anantimycotic medication,is apharmaceuticalfungicideorfungistaticused to treat and preventmycosissuch asathlete's foot,ringworm,candidiasis(thrush), serious systemic infections such ascryptococcalmeningitis,and others. Such drugs are usually obtained by a doctor'sprescription,but a few are availableover the counter(OTC). The evolution ofantifungal resistanceis a growing threat to health globally.[1]

Routes of administration[edit]

Ocular[edit]

Indicated when the fungal infection is located in the eye. There is currently only one ocular antifungal available. This is Natamycin. However, various other antifungal agents could be compounded in this formulation.[2]

Intrathecal[edit]

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.[3]

Vaginal[edit]

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[4]

Topical[edit]

Main article:Topical antifungal drugs

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.[5]

Oral[edit]

If the antifungal has goodbioavailability,this is a common route to handle a fungal infection. An example is the use of ketoconazole to treat coccidioidomycosis.[6]

Intravenous[edit]

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.[6]

Classes[edit]

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.[7]

Polyenes[edit]

Main article:Polyene antimycotic

Apolyeneis a molecule with multipleconjugated double bonds.A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungalsamphiphilic.Thepolyene antimycoticsbind withsterolsin the fungalcell membrane,principallyergosterol.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.[8]Animal cells containcholesterolinstead 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 isnephrotoxicwhen givenintravenously.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.[citation needed]

Azoles[edit]

Azoleantifungals inhibit conversion oflanosteroltoergosterolby inhibition oflanosterol 14α-demethylase.[9]These compounds have a five-membered ring containing two or three nitrogen atoms.[10]The imidazole antifungals contain a 1,3-diazole (imidazole) ring (two nitrogen atoms), whereas the triazole antifungals have a ring with three nitrogen atoms.[11][10]

Imidazoles[edit]

Triazoles[edit]

Thiazoles[edit]

Allylamines[edit]

Allylamines[12]inhibitsqualene epoxidase,another enzyme required forergosterolsynthesis. Examples includebutenafine,naftifine,andterbinafine.[13][14][15]

Echinocandins[edit]

Echinocandinsinhibit the creation ofglucanin the fungalcell wallbyinhibiting1,3-Beta-glucan synthase:

Echinocandins are administered intravenously, particularly for the treatment of resistantCandidaspecies.[16][17]

Triterpenoids[edit]

Others[edit]

Side effects[edit]

Incidents of liver injury or failure among modern antifungal medicines are very low to non-existent. However, some can cause allergic reactions in people.[33]

There are also manydrug interactions.Patients must read in detail the enclosed data sheet(s) of any medicine. For example, the azole antifungals such as ketoconazole oritraconazolecan be both substrates and inhibitors of theP-glycoprotein,which (among other functions) excretes toxins and drugs into the intestines.[34]Azole antifungals also are both substrates and inhibitors of thecytochrome P450familyCYP3A4,[34]causing increased concentration when administering, for example,calcium channel blockers,immunosuppressants,chemotherapeutic drugs,benzodiazepines,tricyclic antidepressants,macrolidesandSSRIs.[35]

Before oral antifungal therapies are used to treatnail disease,a confirmation of the fungal infection should be made.[36]Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.[36]The side effects of oral treatment are significant and people without an infection should not take these drugs.[36]

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 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.[citation needed]

Resistance[edit]

Antifungal resistance is a subset ofantimicrobial resistance,that specifically applies to fungi that have become resistant to antifungals. Resistance to antifungals can arise naturally, for example by genetic mutation or throughaneuploidy.Extended use of antifungals leads to development of antifungal resistance through various mechanisms.[1]

Some fungi (e.g.Candida kruseiandfluconazole) exhibit intrinsic resistance to certain antifungal drugs or classes, whereas some species develop antifungal resistance to external pressures. Antifungal resistance is aOne Healthconcern, driven by multiple extrinsic factors, including extensive fungicidal use, overuse of clinical antifungals,environmental changeand host factors.[1]

Unlike 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.[1][37]

The emergence ofCandida aurisas 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.[38]

References[edit]

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External links[edit]

  • Antifungal Drugs– Detailed information on antifungals from the Fungal Guide written by R. Thomas and K. Barber
  • "Clotrimazole".Clotrimazole (Canesten).Bayer Philippines.
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