Array ( [0] => {{short description|Group of chemical compounds}} [1] => [[Image:Echinocandin B.png|thumb|right|[[Echinocandin B]]]] [2] => '''Echinocandins''' are a class of [[antifungal drug]]s{{cite journal|last1=Denning|first1=DW|title=Echinocandins: a new class of antifungal.|journal=The Journal of Antimicrobial Chemotherapy|date=June 2002|volume=49|issue=6|pages=889–91|doi=10.1093/jac/dkf045|pmid=12039879|doi-access=free}} that inhibit the synthesis of [[Beta-glucan|β-glucan]] in the fungal [[cell wall]] via [[noncompetitive inhibition]] of the [[enzyme]] [[1,3-β glucan synthase]].{{cite journal |vauthors=Morris MI, Villmann M |title=Echinocandins in the management of invasive fungal infections, part 1 |journal=American Journal of Health-System Pharmacy |volume=63 |issue=18 |pages=1693–703 |date=September 2006 |pmid=16960253 |doi=10.2146/ajhp050464.p1 }}{{cite journal |vauthors=Morris MI, Villmann M |title=Echinocandins in the management of invasive fungal infections, Part 2 |journal=American Journal of Health-System Pharmacy |volume=63 |issue=19 |pages=1813–20 |date=October 2006 |pmid=16990627 |doi=10.2146/ajhp050464.p2 }} The class has been termed the "[[penicillin]] of antifungals," along with the related [[Papulacandin B|papulacandins]], as their mechanism of action resembles that of penicillin in bacteria. β-glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components, the fungal equivalent to bacterial [[peptidoglycan]]. [[Caspofungin]], [[micafungin]], and [[anidulafungin]] are semisynthetic echinocandin derivatives with limited clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.{{cite journal | vauthors = Debono M, Gordee RS | title = Antibiotics that inhibit fungal cell wall development | journal = Annual Review of Microbiology | volume = 48 | pages = 471–97 | date = 1994 | pmid = 7826015 | doi = 10.1146/annurev.mi.48.100194.002351 }} [3] => [4] => == Medical uses == [5] => Drugs and drug candidates in this class are fungicidal against some yeasts (most species of ''Candida'', but not ''[[Cryptococcus]]'', ''[[Trichosporon]]'', and ''[[Rhodotorula]]''). Echinocandins also have displayed activity against ''Candida'' biofilms, especially in synergistic activity with amphotericin B and additive activity with fluconazole. Echinocandins are fungistatic against some molds (''[[Aspergillus]]'', but not ''[[Fusarium]]'' and ''[[Rhizopus]]''), and modestly or minimally active against dimorphic fungi (''[[Blastomyces]]'' and ''[[Histoplasma]]''). They have some activity against the spores of the fungus ''[[Pneumocystis jirovecii]]'', formerly known as ''Pneumocystis carinii''. Caspofungin is used in the treatment of febrile neutropenia and as "salvage" therapy for the treatment of invasive aspergillosis.{{cite journal | vauthors = Sucher AJ, Chahine EB, Balcer HE | title = Echinocandins: the newest class of antifungals | journal = Annals of Pharmacotherapy | volume = 43 | issue = 10 | pages = 1647–57 | date = October 2009 | pmid = 19724014 | doi = 10.1345/aph.1M237 | s2cid = 207263606 }}{{clarify|date=October 2023}} Micafungin is used as prophylaxis against ''Candida'' infections in hematopoietic stem cell transplantation patients. [6] => [7] => ==Side effects== [8] => All three agents are well-tolerated, with the most common adverse effects being fever, rash, nausea, and [[phlebitis]] at the infusion site. They can also cause a histamine-like reaction (flushing) when infused too rapidly.{{Cite book|title=Lippincott pharmacology}} Toxicity is uncommon. Its use has been associated with elevated aminotransferases and alkaline phosphatase levels.Cancidas. Prescribing information-(caspofungin acetate) for injection. Merck & Co Inc, Whitehouse Station, NJ 2008. [9] => [10] => == Chemistry == [11] => [[Image:Caspofungin.svg|thumb|[[Caspofungin]]]] [12] => The present-day clinically used echinocandins are semisynthetic pneumocandins, which are chemically lipopeptide in nature, consisting of large cyclic hexapeptoids. Caspofungin, micafungin, and anidulafungin are similar cyclic hexapeptide antibiotics linked to long modified N-linked acyl fatty acid chains. The chains serve as anchors on the fungal cell membrane to facilitate antifungal activity.{{cite journal | vauthors = Denning DW | title = Echinocandin antifungal drugs | journal = Lancet | volume = 362 | issue = 9390 | pages = 1142–51 | date = October 2003 | pmid = 14550704 | doi = 10.1016/S0140-6736(03)14472-8 | s2cid = 35067894 }} Due to their limited oral bioavailability, echinocandins are administered through intravenous infusion.{{cite journal | vauthors = Chang CC, Slavin MA, Chen SC | title = New developments and directions in the clinical application of the echinocandins | journal = Archives of Toxicology | volume = 91 | issue = 4 | pages = 1613–1621 | date = April 2017 | pmid = 28180946 | doi = 10.1007/s00204-016-1916-3 | s2cid = 31029386 }} [13] => [14] => == Mechanism of action == [15] => Echinocandins noncompetitively inhibit beta-1,3-D-glucan synthase enzyme complex in susceptible fungi to disturb fungal cell glucan synthesis.{{cite journal | vauthors = Douglas CM | title = Fungal beta(1,3)-D-glucan synthesis | journal = Medical Mycology | volume = 39 | pages = 55–66 | date = 2001 | issue = Suppl 1 | pmid = 11800269 | doi = 10.1080/mmy.39.1.55.66 | doi-access = free }} Beta-glucan destruction prevents resistance against osmotic forces, which leads to cell lysis.{{cite journal | vauthors = Beauvais A, Latgé JP | title = Membrane and cell wall targets in Aspergillus fumigatus | journal = Drug Resistance Updates | volume = 4 | issue = 1 | pages = 38–49 | date = February 2001 | pmid = 11512152 | doi = 10.1054/drup.2001.0185 }} They have fungistatic activity against ''Aspergillus'' species and fungicidal activity against most ''Candida'' spp., including strains that are resistant to fluconazole. ''In vitro'' and mouse models show echinocandins may also enhance host immune responses by exposing highly antigenic beta-glucan [[epitope]]s that can accelerate host cellular recognition and inflammatory responses.{{cite journal | vauthors = Wheeler RT, Fink GR | title = A drug-sensitive genetic network masks fungi from the immune system | journal = PLOS Pathogens | volume = 2 | issue = 4 | pages = e35 | date = April 2006 | pmid = 16652171 | pmc = 1447670 | doi = 10.1371/journal.ppat.0020035 | doi-access = free }} [16] => [17] => == Resistance == [18] => Echinocandin [[Antimicrobial resistance|resistance]] is rare among ''Candida'' spp. However, case studies have shown some resistance in ''C. albicans'', ''C. glabrata'', ''C. lusitaniae'', ''C. tropicalis'', and ''C. parapsilosis''. Resistance patterns include alterations in the glucan synthase (Fks1-Fks2 complex), overexpression of efflux pumps, strengthening of cell wall by increased chitin production, upregulation of stress-response pathways,{{cite journal |last1=Perlin |first1=DS |title=Echinocandin Resistance in Candida. |journal=Clinical Infectious Diseases |date=1 December 2015 |volume=61 |issue=Suppl 6 |pages=S612-7 |doi=10.1093/cid/civ791 |pmid=26567278|pmc=4643482 }} and dysregulation of mismatch repair pathways. In addition a few species and strains of ''Candida'' spp. and ''Aspergillus'' spp. show a "paradoxic effect", i.e., they are susceptible to low concentrations but resistant to high concentrations in broth microdilution studies.{{cite journal |last1=Wagener |first1=Johannes |last2=Loiko |first2=Veronika |title=Recent Insights into the Paradoxical Effect of Echinocandins |journal=Journal of Fungi |date=28 December 2017 |volume=4 |issue=1 |pages=5 |doi=10.3390/jof4010005 |pmid=29371498 |pmc=5872308 |doi-access=free }} [19] => [20] => Several non-candidal yeasts, e.g., ''Cryptococcus'', ''Trichosporon'', ''Rhodotorula'' and ''Blastoschizomyces'' and filamentous fungi like ''Fusarium'', zygomycetes and ''Scedosporium'' are often resistant to echinocandins.{{cite journal |last1=Chandrasekar |first1=P H |title=Increased dose of echinocandins for invasive fungal infections: bonanza for the patient or the pharmaceutical industry? |journal=Bone Marrow Transplantation |date=24 January 2007 |volume=39 |issue=3 |pages=129–131 |doi=10.1038/sj.bmt.1705563|pmid=17245422 |doi-access=free }} Echinocandins have weak in vitro activity (a high minimum inhibitory concentration) and very little clinical efficacy against ''Histoplasma'', ''Blastomyces'', and ''Coccidioides'', especially their yeast forms.{{cite journal |last1=Eschenauer |first1=Gregory |last2=DePestel |first2=Daryl D |last3=Carver |first3=Peggy L |title=Comparison of echinocandin antifungals |journal=Therapeutics and Clinical Risk Management |date=February 2007 |volume=3 |issue=1 |pages=71–97 |doi=10.2147/tcrm.2007.3.1.71 |pmid=18360617 |pmc=1936290 |doi-access=free }} [21] => [22] => == Pharmacokinetics == [23] => Due to the large molecular weight of echinocandins, they have poor oral bioavailability and are administered by intravenous infusion. In addition, their large structures limit penetration into cerebrospinal fluid, urine, and eyes. In plasma, echinocandins have a high affinity to serum proteins. Echinocandins do not have primary interactions with CYP450 or P-glycoprotein pumps. Caspofungin has triphasic nonlinear pharmacokinetics, while micafungin (hepatically metabolized by arylsulfatase, catechol O-methyltransferase, and hydroxylation) and anidulafungin (degraded spontaneously in the system and excreted mostly as a metabolite in the urine) have linear elimination.{{cite journal | last1 = Dodds Ashley | first1 = ES | last2 = Lewis | first2 = R | last3 = Lewis | first3 = JS | display-authors = etal | year = 2006 | title = Pharmacology of Systemic Antifungal Agents | journal = Clinical Infectious Diseases | volume = 43 | issue = Suppl 1| page = S28 | doi=10.1086/504492| doi-access = free }}{{cite journal | vauthors = Boucher HW, Groll AH, Chiou CC, Walsh TJ | title = Newer systemic antifungal agents : pharmacokinetics, safety and efficacy | journal = Drugs | volume = 64 | issue = 18 | pages = 1997–2020 | date = 2004 | pmid = 15341494 | doi = 10.2165/00003495-200464180-00001 | s2cid = 46957874 | url = https://zenodo.org/record/1236417 }} Younger patients exhibit a faster rate of elimination of micafungin and caspofungin.{{cite journal | vauthors = Lehrnbecher T, Groll AH | title = Micafungin: a brief review of pharmacology, safety, and antifungal efficacy in pediatric patients | journal = Pediatric Blood & Cancer | volume = 55 | issue = 2 | pages = 229–32 | date = August 2010 | pmid = 20583216 | doi = 10.1002/pbc.22449 | s2cid = 31575233 }} [24] => [25] => ==Interference== [26] => Caspofungin has some interference with [[ciclosporin]] metabolism, and micafungin has some interference with [[sirolimus]] (rapamycin), but anidulafungin needs no dose adjustments when given with ciclosporin, [[tacrolimus]], or [[voriconazole]].{{cite book|vauthors = Hospenthal DR, Rinaldi MG|title=Diagnosis and Treatment of Fungal Infections|date=2015-05-12|publisher=Springer|isbn=978-3-319-13090-3|page=95}} [27] => [28] => ==Advantages== [29] => Advantages of echinocandins:{{cn|date=December 2022}} [30] => * Broad range (especially against all [[Candida (genus)|''Candida'']]), thus can be given empirically in febrile neutropenia and stem cell transplant [31] => * Can be used in case of azole-resistant ''Candida'' or use as a second-line agent for refractory aspergillosis [32] => * Long half-life (polyphasic elimination: alpha phase 1–2 hours + beta phase 9–11 hours + gamma phase 40–50 hours) [33] => * Low toxicity: only histamine release (3%), fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the injection site (2.9%), very rarely allergy and anaphylaxis [34] => * Not an inhibitor, inducer, or substrate of the cytochrome P450 system, or P-glycoprotein, thus minimal drug interactions [35] => * Lack of interference from [[kidney failure]] and hemodialysis [36] => * No dose adjustment is necessary based on age, gender, race [37] => * Better (or no less effective) than amphotericin B and fluconazole against yeast (mainly '''Candida, NOT yeast form of dimorphic''') infections [38] => [39] => ==Disadvantages== [40] => Disadvantages of echinocandins: [41] => * ''Cryptococcus'', ''Trichosporon'', and zygomycetes are often resistant to echinocandins and they show weak activity against yeast forms of ''Histoplasma'', ''Blastomyces, and ''Coccidioides''. [42] => * Embryotoxic in animal studies{{cite web |url=http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2003/antifungal.htm |title=Pharmacotherapy Update - New Antifungal Agents: Additions to the Existing Armamentarium (Part 1) }} (category C) thus should be avoided if possible in pregnancy [43] => * Some need adjustment of dosing for patients with liver disease. [44] => * Poor ocular penetration in fungal endophthalmitis {{cite journal | vauthors = Gauthier GM, Nork TM, Prince R, Andes D | title = Subtherapeutic ocular penetration of caspofungin and associated treatment failure in Candida albicans endophthalmitis | journal = Clinical Infectious Diseases | volume = 41 | issue = 3 | pages = e27–8 | date = August 2005 | pmid = 16007519 | doi = 10.1086/431761 | doi-access = }} [45] => [46] => ==Examples== [47] => List of echinocandins:{{cite journal | vauthors = Eschenauer G, Depestel DD, Carver PL | title = Comparison of echinocandin antifungals | journal = Therapeutics and Clinical Risk Management | volume = 3 | issue = 1 | pages = 71–97 | date = March 2007 | pmid = 18360617 | pmc = 1936290 | doi = 10.2147/tcrm.2007.3.1.71 | doi-access = free }} [48] => * [[Pneumocandin]]s (cyclic hexapeptides linked to a long-chain fatty acid) [49] => * [[Echinocandin B]] not clinically used, risk of hemolysis [50] => * [[Cilofungin]] withdrawn from trials due to solvent toxicity [51] => * [[Caspofungin]] (trade name Cancidas, by Merck) [52] => * [[Micafungin]] (FK463) (trade name Mycamine, by Astellas Pharma.) [53] => * [[Anidulafungin]] (VER-002, V-echinocandin, LY303366) (trade name Eraxis, by Pfizer) [54] => * [[Rezafungin]] formerly CD101 IV, Rezafungin is considered to be safest echinocandins which also acts longest (weekly single dose). It is developed by Cidara Therapeutics. The STRIVE Trial (phase 2) showed weekly treatment with Rezafungin was safe and efficacious in the treatment of candidemia and/or invasive candidiasis.Rezafungin versus Caspofungin in a Phase 2, Randomized, Double-Blind Study for the Treatment of Candidemia and Invasive Candidiasis- The STRIVE Trial |https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1380/5909460#.X2j03oyvxDQ.twitter [55] => [56] => == History == [57] => [[Image:Anidulafungin.svg|thumb|[[Anidulafungin]]]] [58] => Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of ''Papularia sphaerosperma'' (Pers.), which were liposaccharide - i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase - and had action only on ''Candida'' spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins, a new group of antifungals with broad-range activity against ''Candida'' spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first of these newer echinocandins to be approved by the U.S. Food and Drug Administration was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations have very low oral bioavailability, so they must be given intravenously to be useful. Echinocandins have become one of the first-line treatments for ''Candida'' before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.{{citation needed|date=September 2020}} [59] => [60] => ==See also== [61] => * [[Papulacandin B]] [62] => [63] => ==References== [64] => {{Reflist}} [65] => [66] => ==External links== [67] => * {{Commons category-inline}} [68] => [69] => {{Antifungals}} [70] => [71] => [[Category:Antifungals]] [72] => [[Category:Echinocandins| ]] [73] => [[Category:Embryotoxins]] [74] => [[Category:Hexapeptides]] [75] => [[Category:Cyclic peptides]] [] => )
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Echinocandin

Echinocandins are a class of antifungal drugs that inhibit the synthesis of β-glucan in the fungal cell wall via noncompetitive inhibition of the enzyme 1,3-β glucan synthase. The class has been termed the "penicillin of antifungals," along with the related papulacandins, as their mechanism of action resembles that of penicillin in bacteria.

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