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Antifungal
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<h2 id="routes-of-administration">Routes of administration</h2> <h3>Ocular</h3> <p>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.<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a> </p> <h3>Intrathecal</h3> <p>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.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p> <h3>Vaginal</h3> <p>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<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p> <h3>Topical</h3> <p class="note">Main article: Topical antifungal drugs</p> <p>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.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> </p> <h3>Oral</h3> <p>If the antifungal has good <a href="/facts/Bioavailability/9l6na9MV">bioavailability</a>, this is a common route to handle a fungal infection. An example is the use of ketoconazole to treat coccidioidomycosis.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p> <h3>Intravenous</h3> <p>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.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p> <h2 id="classes">Classes</h2> <p>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.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h3>Polyenes</h3> <p class="note">Main article: <a href="/facts/Polyene_antimycotic/3YQ5tTDm">Polyene antimycotic</a></p> <p>A <a href="/facts/Polyene/gnf4zsEs">polyene</a> is a molecule with multiple <a href="/facts/Conjugated_system/Ddx9qzox">conjugated double bonds</a>. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals <a href="/facts/Amphiphilic/FkmYh9JI">amphiphilic</a>. The <a href="/facts/Polyene_antimycotic/3YQ5tTDm">polyene antimycotics</a> bind with <a href="/facts/Sterol/QrVlPnWn">sterols</a> in the fungal <a href="/facts/Cell_membrane/vAXSD0DT">cell membrane</a>, principally <a href="/facts/Ergosterol/Xt5FV1ut">ergosterol</a>. 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.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> Animal cells contain <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> 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 <a href="/facts/Nephrotoxic/QaWn5pwB">nephrotoxic</a> when given <a href="/facts/Intravenously/AwwuD3Nu">intravenously</a>. 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. </p> <ul><li><a href="/facts/Amphotericin_B/c2H3NmRQ">Amphotericin B</a></li> <li><a href="/facts/Candicidin/GxTxzLbv">Candicidin</a></li> <li><a href="/facts/Filipin/KtIU3jG9">Filipin</a> – 35 carbons, binds to cholesterol (toxic)</li> <li><a href="/facts/Hamycin/uf2qH6SX">Hamycin</a></li> <li><a href="/facts/Natamycin/VLjNtCxo">Natamycin</a> – 33 carbons, binds well to ergosterol</li> <li><a href="/facts/Nystatin/povtrmq3">Nystatin</a></li> <li>Rimocidin</li></ul> <h3>Azoles</h3> <p><a href="/facts/Azole/Nj3CWSM2">Azole</a> antifungals inhibit the conversion of <a href="/facts/Lanosterol/nmuMgCK3">lanosterol</a> to <a href="/facts/Ergosterol/Xt5FV1ut">ergosterol</a> by inhibiting <a href="/facts/Lanosterol_14%CE%B1-demethylase/c6LnqX35">lanosterol 14α-demethylase</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> These compounds have a five-membered ring containing two or three nitrogen atoms.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> The imidazole antifungals contain a 1,3-diazole (<a href="/facts/Imidazole/5MybM6Hh">imidazole</a>) ring (two nitrogen atoms), whereas the triazole antifungals have a ring with three nitrogen atoms.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p> <h4>Imidazoles</h4> <ul><li><a href="/facts/Bifonazole/GoRjU3vU">Bifonazole</a></li> <li><a href="/facts/Butoconazole/p168a00l">Butoconazole</a></li> <li><a href="/facts/Clotrimazole/SRY1jAW9">Clotrimazole</a></li> <li><a href="/facts/Econazole/RYM36pr1">Econazole</a></li> <li><a href="/facts/Fenticonazole/QC51kBgk">Fenticonazole</a></li> <li><a href="/facts/Isoconazole/kvz6gV5x">Isoconazole</a></li> <li><a href="/facts/Ketoconazole/UQcvnER5">Ketoconazole</a></li> <li><a href="/facts/Luliconazole/xuDvHsVr">Luliconazole</a></li> <li><a href="/facts/Miconazole/PjA5UgFB">Miconazole</a></li> <li><a href="/facts/Omoconazole/wnkdLgo3">Omoconazole</a></li> <li><a href="/facts/Oxiconazole/K9n41AaX">Oxiconazole</a></li> <li><a href="/facts/Sertaconazole/m8cHLtC7">Sertaconazole</a></li> <li><a href="/facts/Sulconazole/zC8TTIpV">Sulconazole</a></li> <li><a href="/facts/Tioconazole/LHQ7UtRQ">Tioconazole</a></li></ul> <h4>Triazoles</h4> <ul><li><a href="/facts/Albaconazole/KS4m3DXg">Albaconazole</a></li> <li><a href="/facts/Cyproconazole/ufae18yY">Cyproconazole</a></li> <li><a href="/facts/Efinaconazole/IhqJrzsf">Efinaconazole</a></li> <li><a href="/facts/Epoxiconazole/n7rgzfeu">Epoxiconazole</a></li> <li><a href="/facts/Fluconazole/UYpk9mKl">Fluconazole</a></li> <li><a href="/facts/Isavuconazole/0Gzdhck7">Isavuconazole</a></li> <li><a href="/facts/Itraconazole/x7IeB92o">Itraconazole</a></li> <li><a href="/facts/Posaconazole/6vFoI0tH">Posaconazole</a></li> <li><a href="/facts/Propiconazole/D1pPdf6y">Propiconazole</a></li> <li><a href="/facts/Ravuconazole/dWE7I6AR">Ravuconazole</a></li> <li><a href="/facts/Terconazole/baFIK6tM">Terconazole</a></li> <li><a href="/facts/Voriconazole/IvdczEq3">Voriconazole</a></li></ul> <h4>Thiazoles</h4> <ul><li><a href="/facts/Abafungin/0fqEw3sz">Abafungin</a></li></ul> <h3>Allylamines</h3> <p><a href="/facts/Allylamine/tnuE9nxj">Allylamines</a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> inhibit <a href="/facts/Squalene_epoxidase/DvT6qa8q">squalene epoxidase</a>, another enzyme required for <a href="/facts/Ergosterol/Xt5FV1ut">ergosterol</a> synthesis. Examples include <a href="/facts/Butenafine/LrjCcy7L">butenafine</a>, <a href="/facts/Naftifine/khTx1zIT">naftifine</a>, and <a href="/facts/Terbinafine/7qBCjoYW">terbinafine</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p> <h3>Echinocandins</h3> <p><a href="/facts/Echinocandin/4B7fJgPx">Echinocandins</a> inhibit the creation of <a href="/facts/Glucan/SGarVY1s">glucan</a> in the fungal <a href="/facts/Cell_wall/DYXJVrnw">cell wall</a> by <a href="/facts/Enzyme_inhibitor/MkFwGXHJ">inhibiting</a> <a href="/facts/1,3-Beta-glucan_synthase/kjmsQ478">1,3-Beta-glucan synthase</a>: </p> <ul><li><a href="/facts/Anidulafungin/ngTkhtQe">Anidulafungin</a></li> <li><a href="/facts/Caspofungin/coHmwgaI">Caspofungin</a></li> <li><a href="/facts/Micafungin/Rp6NulyQ">Micafungin</a></li></ul> <p>Echinocandins are administered intravenously, particularly for the treatment of resistant <i><a href="/facts/Candida_(fungus)/IIYvWvx5">Candida</a></i> species.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h3>Triterpenoids</h3> <ul><li><a href="/facts/Ibrexafungerp/V4ScRJGl">Ibrexafungerp</a></li></ul> <h3>Others</h3> <ul><li><a href="/facts/Acrisorcin/qXrcLbCa">Acrisorcin</a></li> <li><a href="/facts/Amorolfine/022MWvyR">Amorolfine</a> – a morpholine derivative used topically in dermatophytosis<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a></li> <li><a href="/facts/Aurone/8yhCgNeY">Aurones</a> – possess antifungal properties<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a></li> <li><a href="/facts/Benzoic_acid/7HrmrBYS">Benzoic acid</a> – has antifungal properties, such as in <a href="/facts/Whitfield%27s_ointment/n1RpYDhk">Whitfield's ointment</a>, <a href="/facts/Friar%27s_Balsam/t6pFB8ro">Friar's Balsam</a>, and <a href="/facts/Balsam_of_Peru/pW5UgJjG">Balsam of Peru</a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a></li> <li><a href="/facts/Carbol_fuchsin/V43KyCpV">Carbol fuchsin</a> (Castellani's paint)</li> <li><a href="/facts/Ciclopirox/5GrxTMm1">Ciclopirox</a> (ciclopirox olamine) – a hydroxypyridone antifungal that interferes with active membrane transport, cell membrane integrity, and fungal respiratory processes. It is most useful against <a href="/facts/Tinea_versicolour/y4wzgMrl">tinea versicolour</a>.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a></li> <li><a href="/facts/Clioquinol/f9rDIBo5">Clioquinol</a></li> <li><a href="/facts/Coal_tar/6lLDL4Ic">Coal tar</a></li> <li><a href="/facts/Copper(II)_sulfate/Ya6fPoQe">Copper(II) sulfate</a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></li> <li><a href="/facts/Crystal_violet/CgcGjkra">Crystal violet</a> – a <a href="/facts/Triarylmethane_dye/PnPvyEoF">triarylmethane dye</a>. It has antibacterial, antifungal, and <a href="/facts/Anthelmintic/2p02KN0X">anthelmintic</a> properties and was formerly important as a <a href="/facts/Topical/alFfLndS">topical</a> antiseptic.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a></li> <li><a href="/facts/Chlorhexidine/Gyv5LNxf">Chlorhexidine</a> 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<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a></li> <li><a href="/facts/Chlorophetanol/KXuc0zUK">Chlorophetanol</a></li> <li><a href="/facts/Diiodohydroxyquinoline/h044ftny">Diiodohydroxyquinoline</a> (Iodoquinol)</li> <li><a href="/facts/Flucytosine/z9l4g9pv">Flucytosine</a> (5-fluorocytosine) – an <a href="/facts/Antimetabolite/NICtB9BU">antimetabolite</a> pyrimidine analog<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a></li> <li><a href="/facts/Fumagillin/2Xf9EwDb">Fumagillin</a></li> <li><a href="/facts/Griseofulvin/Cqs6n8mc">Griseofulvin</a> – binds to <a href="/facts/Microtubule/ENL1TxSe">microtubules</a> and inhibits <a href="/facts/Mitosis/ExxrSUs8">mitosis</a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></li> <li><a href="/facts/Haloprogin/UdTqd8QN">Haloprogin</a> – discontinued due to the emergence of antifungals with fewer side effects<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a></li> <li><a href="/facts/Miltefosine/FpqMITAq">Miltefosine</a> works by damaging fungal cell membranes <a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a></li> <li><a href="/facts/Nikkomycin/b9GRG9Qq">Nikkomycin</a> – blocks formation of chitin present in the cell wall of fungus.</li> <li><a href="/facts/Orotomide/yhzoTp9e">Orotomide</a> (F901318) – pyrimidine synthesis inhibitor<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></li> <li><a href="/facts/Piroctone_olamine/Rgjor63K">Piroctone olamine</a></li> <li><a href="/facts/Pentanenitrile/qB2wckdk">Pentanenitrile</a></li> <li><a href="/facts/Potassium_iodide/6023uFnx">Potassium iodide</a> – preferred treatment for lymphocutaneous <a href="/facts/Sporotrichosis/phB5jerz">sporotrichosis</a> and subcutaneous <a href="/facts/Zygomycosis/D5jWFThL">zygomycosis</a> (<a href="/facts/Basidiobolomycosis/AuEWuhhU">basidiobolomycosis</a>). The mode of action is obscure.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a></li> <li><a href="/facts/Potassium_permanganate_(medical_use)/X6sFJJaq">Potassium permanganate</a> - for use only on thicker, more insensitive skin such as the soles of the feet.</li> <li><a href="/facts/Selenium_disulfide/SHzUNLyd">Selenium disulfide</a></li> <li><a href="/facts/Sodium_thiosulfate/qAMvfeuv">Sodium thiosulfate</a></li> <li><a href="/facts/Sulfur/IK0amTfM">Sulfur</a></li> <li><a href="/facts/Tolnaftate/mc9HNcgb">Tolnaftate</a> – a thiocarbamate antifungal, which inhibits fungal squalene epoxidase (similar mechanism to allylamines like terbinafine)[<i>medical citation needed</i>]</li> <li><a href="/facts/Triacetin/UP5hvK5z">Triacetin</a> – hydrolysed to acetic acid by fungal <a href="/facts/Esterase/Ff2bb7LD">esterases</a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></li> <li><a href="/facts/Undecylenic_acid/JK4vPWhH">Undecylenic acid</a> – an <a href="/facts/Unsaturated_fatty_acid/87HcP11s">unsaturated fatty acid</a> derived from natural <a href="/facts/Castor_oil/tag0x1BT">castor oil</a>; fungistatic, antibacterial, antiviral, and inhibits <i>Candida morphogenesis</i></li> <li><a href="/facts/Zinc_pyrithione/KbheQdyH">Zinc pyrithione</a></li></ul> <h2 id="side-effects">Side effects</h2> <p>Incidents of liver injury or failure among modern antifungal medicines are very low to non-existent. However, some can cause allergic reactions in people.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p><p>There are also many <a href="/facts/Drug_interactions/T5VcSVGd">drug interactions</a>. Patients must read in detail the enclosed data sheet(s) of any medicine. For example, the azole antifungals such as ketoconazole or <a href="/facts/Itraconazole/x7IeB92o">itraconazole</a> can be both substrates and inhibitors of the <a href="/facts/P-glycoprotein/RY6qLKjq">P-glycoprotein</a>, which (among other functions) excretes toxins and drugs into the intestines.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> Azole antifungals are also both substrates and inhibitors of the <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> family <a href="/facts/CYP3A4/MqD09gEj">CYP3A4</a>,<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> causing increased concentration when administering, for example, <a href="/facts/Calcium_channel_blockers/st91pD2K">calcium channel blockers</a>, <a href="/facts/Immunosuppressants/ctlB3Hda">immunosuppressants</a>, <a href="/facts/Chemotherapeutic_drugs/fWTLbaUT">chemotherapeutic drugs</a>, <a href="/facts/Benzodiazepines/IgbJr4jy">benzodiazepines</a>, <a href="/facts/Tricyclic_antidepressants/vpBLER2Q">tricyclic antidepressants</a>, <a href="/facts/Macrolide/21qIKr7a">macrolides</a> and <a href="/facts/Selective_serotonin_reuptake_inhibitor/L6jjcmEH">SSRIs</a>.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> </p><p>Before oral antifungal therapies are used to treat <a href="/facts/Nail_disease/Ej3lNvf0">nail disease</a>, a confirmation of the fungal infection should be made.<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> The side effects of oral treatment are significant and people without an infection should not take these drugs.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> </p> <h2 id="resistance">Resistance</h2> <p>Antifungal resistance is a subset of <a href="/facts/Antimicrobial_resistance/jsbAywgx">antimicrobial resistance</a>, that specifically applies to fungi that have become resistant to antifungals. Resistance to antifungals can arise naturally, for example by genetic mutation or through <a href="/facts/Aneuploidy/CmaGcLIY">aneuploidy</a>. Extended use of antifungals leads to the development of antifungal resistance through various mechanisms.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> </p><p>Some fungi (e.g. <a href="/facts/Candida_krusei/gL62xqTx">Candida krusei</a> and <a href="/facts/Fluconazole/UYpk9mKl">fluconazole</a>) exhibit intrinsic resistance to certain antifungal drugs or classes, whereas some species develop antifungal resistance to external pressures. Antifungal resistance is a <a href="/facts/One_Health/udNmyvaU">One Health</a> concern, driven by multiple extrinsic factors, including extensive fungicidal use, overuse of clinical antifungals, <a href="/facts/Environmental_change/ybh0TTR5">environmental change</a> and host factors.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a><a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a><a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> </p><p>The emergence of <i>Candida auris</i> 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.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="http://www.fungalguide.ca/treatments/antifungal_drugs.html">Antifungal Drugs</a> – Detailed information on antifungals from the Fungal Guide written by R. Thomas and K. Barber</li> <li><a href="https://www.canesten.com.ph/canesten-cream">"Clotrimazole"</a>. <i>Clotrimazole (Canesten)</i>. Bayer Philippines.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Fisher MC, Alastruey-Izquierdo A, Berman J, Bicanic T, Bignell EM, Bowyer P, et al. (29 March 2022). "Tackling the emerging threat of antifungal resistance to human health". Nature Reviews Microbiology. 20 (9): 557–571. doi:10.1038/s41579-022-00720-1. ISSN 1740-1526. PMC 8962932. PMID 35352028. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962932" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962932</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Mcgee K (2019). "Chapter 68 - Ocular pharmacology". Naplex review guide (3rd ed.). United states: McGraw Hill Medical. 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