Antifungal

Antifungal
Drug class
Other namesAntimycotic medication

An antifungal, is a type of medicine used to treat a fungal infection.[1] Conditions for which an antifungal may be given are many and include athlete's foot, ringworm, candidiasis, aspergillosis, cryptococcosis, and histoplasmosis, among others.[2] An antifungal may be applied in cream form for local infections of the skin, mouth, eye and vagina, or taken by mouth or given by injection into a vein for deeper fungal infections.[2] The choice and method of administration of antifungal is generally determined by which fungal infection is diagnosed.[2] An antifungal may be given to prevent fungal infection in people who have a weakened immune system; are taking medicines that suppress the immune system such as steroids, cancer treatments or medicines needed after organ transplant, have a condition that causes immunodeficiency such as HIV/AIDS, or have a medical device such as an artificial joint or heart valve, or in someone who has a long stay in intensive care.[2][3]

When taken by mouth, antifungals can be toxic.[4] Types include triazoles such as fluconazole, which is absorbed well after being taken by mouth and can reach the brain and bladder.[2] Imidazoles include clotrimazole, econazole and ketoconazole, and echinocandins are generally used for candidadiasis and aspergillosis.[2] The polyene antifungals include amphotericin B and nystatin.[2]

Several require a prescription, and some are available to buy over the counter (OTC).

The first effective antifungal to be approved was amphotericin B.[5][6]

Types of antifungal

Types of antifungal include triazoles, imidazoles, echinocandins and polyene antifungals.[2]

Of the clinically employed azole antifungals, only a handful are used systemically.[7] These include ketoconazole, itraconazole, fluconazole, fosfluconazole, voriconazole, posaconazole, and isavuconazole.[7][8] Examples of non-azole systemic antifungals include griseofulvin and terbinafine.[2]

Classes

Polyenes

Main article: Polyene antimycotic
Amphotericin B has also been used for treatment of cutaneous leishmaniasis[9]

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.[10] 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.

Azoles

Azoles inhibit conversion of lanosterol to ergosterol by inhibition of lanosterol 14α-demethylase.[11]

Imidazoles

Triazoles

Thiazoles

Allylamines

Allylamines[12] inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include butenafine, naftifine, and terbinafine.[13][14][15]

Echinocandins

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

Echinocandins are administered intravenously, particularly for the treatment of resistant Candida species.[16][17]

Triterpenoids

Others

Side effects

Apart from side effects like altered estrogen levels and liver damage, many antifungal medicines can cause allergic reactions in people.[32] For example, the azole group of drugs is known to have caused anaphylaxis.

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.[33] Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4,[33] causing increased concentration when administering, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, tricyclic antidepressants, macrolides and SSRIs.

Before oral antifungal therapies are used to treat nail disease, a confirmation of the fungal infection should be made.[34] Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.[34] The side effects of oral treatment are significant and people without an infection should not take these drugs.[34]

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.

History

The first effective antifungal to be approved was amphotericin B.[5]

See also

References

  1. ↑ Lampiris, Henry W.; Maddix, Daniel S. (2020). "48. Antifungal agents". In Katzung, Bertram G.; Trevor, Anthony J. (eds.). Basic and Clinical Pharmacology (15th ed.). New York: McGraw-Hill. pp. 887–896. ISBN 978-1-260-45231-0. Archived from the original on 2021-10-10. Retrieved 2021-11-18.
  2. 1 2 3 4 5 6 7 8 9 "5.3 Fungal infection". British National Formulary (BNF) (82 ed.). London: BMJ Group and the Pharmaceutical Press. September 2021 – March 2022. pp. 635–647. ISBN 978-0-85711-413-6.{{cite book}}: CS1 maint: date format (link)
  3. ↑ Seagle, Emma E.; Williams, Samantha L.; Chiller, Tom L. (2021). "Recent trends in the epidemiology of fungal infections". In Ostrosky-Zeichner, Luis (ed.). Fungal Infections, An Issue of Infectious Disease Clinics of North America. Philadelphia: Elsevier. pp. 237–238. ISBN 978-0-323-81294-8. Archived from the original on 2021-09-03. Retrieved 2021-11-19.
  4. ↑ Ritter, James M.; Flower, Rod; Henderson, Graeme; Loke, Yoon Kong; Rang, Humphrey P. (2020). "54. Antifungal drugs". Rang & Dale's Pharmacology (9th ed.). Elsevier. pp. 690–695. ISBN 978-0-7020-7448-6. Archived from the original on 2021-08-28. Retrieved 2021-11-18.
  5. 1 2 Ostrosky-Zeichner, Luis; Casadevall, Arturo; Galgiani, John N.; Odds, Frank C.; Rex, John H. (September 2010). "An insight into the antifungal pipeline: selected new molecules and beyond". Nature Reviews Drug Discovery. 9 (9): 719–727. doi:10.1038/nrd3074. ISSN 1474-1784. Archived from the original on 2021-11-18. Retrieved 2021-11-18.
  6. ↑ Di Mambro, Tomas; Guerriero, Ilaria; Aurisicchio, Luigi; Magnani, Mauro; Marra, Emanuele (2019). "The Yin and Yang of Current Antifungal Therapeutic Strategies: How Can We Harness Our Natural Defenses?". Frontiers in Pharmacology. 10: 80. doi:10.3389/fphar.2019.00080. ISSN 1663-9812. Archived from the original on 2020-09-04. Retrieved 2021-11-18.
  7. 1 2 Benitez, Lydia L.; Carver, Peggy L. (2019). "Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents". Drugs. 79 (8): 833–853. doi:10.1007/s40265-019-01127-8. ISSN 0012-6667. PMID 31093949. S2CID 155093431.
  8. ↑ Chang, Chia-Hsuin; Young-Xu, Yinong; Kurth, Tobias; Orav, John E.; Chan, Arnold K. (2007). "The Safety of Oral Antifungal Treatments for Superficial Dermatophytosis and Onychomycosis: A Meta-analysis". The American Journal of Medicine. 120 (9): 791–798.e3. doi:10.1016/j.amjmed.2007.03.021. ISSN 0002-9343. PMID 17765049.
  9. ↑ Goyonlo, Vahid Mashayekhi; Vosoughi, Elham; Kiafar, Bita; Nahidi, Yalda; Momenzadeh, Akram; Taheri, Ahmad Reza (November 2014). "Efficacy of intralesional amphotericin B for the treatment of cutaneous leishmaniasis". Indian Journal of Dermatology. 59 (6): 631. doi:10.4103/0019-5154.143571. ISSN 1998-3611. Retrieved 16 November 2023.
  10. ↑ Baginski M, Czub J (June 2009). "Amphotericin B and its new derivatives - mode of action". Current Drug Metabolism. 10 (5): 459–69. doi:10.2174/138920009788898019. PMID 19689243.
  11. ↑ Sheehan DJ, Hitchcock CA, Sibley CM (January 1999). "Current and emerging azole antifungal agents". Clinical Microbiology Reviews. 12 (1): 40–79. doi:10.1128/cmr.12.1.40. PMC 88906. PMID 9880474.
  12. ↑ Ameen M (March 2010). "Epidemiology of superficial fungal infections". Clinics in Dermatology. Elsevier Inc. 28 (2): 197–201. doi:10.1016/j.clindermatol.2009.12.005. PMID 20347663.
  13. ↑ "As Fungal Infections Expand, so Does Market | GEN Magazine Articles | GEN". GEN. 15 February 2012. Archived from the original on 2015-09-06. Retrieved 2015-10-17.
  14. ↑ "Research and Markets: Global Antifungal Therapeutics (Polyenes, Azoles, Echinocandins, Allylamines) Market:Trends and Opportunities (2014-2019) | Business Wire". www.businesswire.com. 28 August 2014. Archived from the original on 2016-03-04. Retrieved 2015-10-17.
  15. ↑ "Tinea Cruris". nurse-practitioners-and-physician-assistants.advanceweb.com. Archived from the original on 2017-09-01. Retrieved 2015-10-17.
  16. ↑ "Echinocandins for the treatment of systemic fungal infection | Canadian Antimicrobial Resistance Alliance (CARA)" (PDF). Archived (PDF) from the original on 2021-10-09. Retrieved 2021-11-08.
  17. ↑ Cappelletty D, Eiselstein-McKitrick K (March 2007). "The echinocandins". Pharmacotherapy. 27 (3): 369–88. doi:10.1592/phco.27.3.369. PMID 17316149. S2CID 32016049.
  18. ↑ Polak, Annemarie (1983). "Antifungal activity in vitro of Ro 14-4767/002, a phenylpropyl-morpholine". Medical Mycology. 21 (3): 205–213. doi:10.1080/00362178385380321. ISSN 1369-3786. PMID 6635894. Archived from the original on 2021-11-18. Retrieved 2021-11-08.
  19. ↑ Sutton CL, Taylor ZE, Farone MB, Handy ST (February 2017). "Antifungal activity of substituted aurones". Bioorganic & Medicinal Chemistry Letters. 27 (4): 901–903. doi:10.1016/j.bmcl.2017.01.012. PMID 28094180.
  20. ↑ Wilson G, Block B (2004). Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry. Philadelphia, Pa.: Lippincott Williams & Wilkins. ISBN 0-7817-3481-9. Archived from the original on 2021-11-18. Retrieved 2021-11-08.
  21. ↑ Long, Scott F. "Anti-Fungals". Southwestern Oklahoma State University. Archived from the original on 17 June 2008.
  22. ↑ Borkow G (August 2014). "Using Copper to Improve the Well-Being of the Skin". Current Chemical Biology. 8 (2): 89–102. doi:10.2174/2212796809666150227223857. PMC 4556990. PMID 26361585.
  23. ↑ Docampo R, Moreno SN (1990). "The metabolism and mode of action of gentian violet". Drug Metabolism Reviews. 22 (2–3): 161–78. doi:10.3109/03602539009041083. PMID 2272286.
  24. ↑ Vermes A, Guchelaar HJ, Dankert J (August 2000). "Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions". The Journal of Antimicrobial Chemotherapy. 46 (2): 171–9. doi:10.1093/jac/46.2.171. PMID 10933638.
  25. ↑ Olson, Jazmine M.; Troxell, Todd (2021). "Griseofulvin". StatPearls. StatPearls Publishing. PMID 30726008. Retrieved 22 June 2021.
  26. ↑ "Haloprogin". DrugBank. University of Alberta. November 6, 2006. Archived from the original on 2007-01-01. Retrieved 2007-02-17.
  27. ↑ Brilhante RS, Caetano EP, Lima RA, Castelo Branco DS, Serpa R, Oliveira JS, Monteiro AJ, Rocha MF, Cordeiro RA, Sidrim JJ (October 2015). "In vitro antifungal activity of miltefosine and levamisole: their impact on ergosterol biosynthesis and cell permeability of dimorphic fungi". Journal of Applied Microbiology. 119 (4): 962–9. doi:10.1111/jam.12891. PMID 26178247. S2CID 206011501.
  28. ↑ Oliver JD, Sibley GE, Beckmann N, Dobb KS, Slater MJ, McEntee L, du Pré S, Livermore J, Bromley MJ, Wiederhold NP, Hope WW, Kennedy AJ, Law D, Birch M (November 2016). "F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America. 113 (45): 12809–12814. doi:10.1073/pnas.1608304113. PMC 5111691. PMID 27791100.
  29. ↑ Hope WW, McEntee L, Livermore J, Whalley S, Johnson A, Farrington N, Kolamunnage-Dona R, Schwartz J, Kennedy A, Law D, Birch M, Rex JH (August 2017). "Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease". mBio. 8 (4): e01157-17. doi:10.1128/mBio.01157-17. PMC 5565967. PMID 28830945.
  30. ↑ "Systemic Therapy". Rook's Textbook of Dermatology. Vol. 4 (8th ed.). 2010. p. 74.48.
  31. ↑ Gendimenico, Gerard J. (2007). "Dermatotherapeutic Agents". Ullmann's Encyclopedia of Industrial Chemistry (7th ed.). doi:10.1002/14356007.a08_301.pub2. ISBN 978-3527306732.
  32. ↑ Kyriakidis I, Tragiannidis A, Munchen S, Groll AH (February 2017). "Clinical hepatotoxicity associated with antifungal agents". Expert Opinion on Drug Safety. 16 (2): 149–165. doi:10.1080/14740338.2017.1270264. PMID 27927037. S2CID 43198078.
  33. 1 2 doctorfungus > Antifungal Drug Interactions Archived 2010-06-19 at the Wayback Machine Archived June 19, 2010, at the Wayback Machine Content Director: Russell E. Lewis, Pharm. D. Retrieved on Jan 23, 2010
  34. 1 2 3 American Academy of Dermatology (February 2013). "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation. American Academy of Dermatology. Archived from the original on 2013-12-01. Retrieved 2013-12-05., which cites
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    • Mehregan DR, Gee SL (December 1999). "The cost effectiveness of testing for onychomycosis versus empiric treatment of onychodystrophies with oral antifungal agents". Cutis. 64 (6): 407–10. PMID 10626104.
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