9,267
Views
21
CrossRef citations to date
0
Altmetric
Review

Echinocandins – structure, mechanism of action and use in antifungal therapy

ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 876-894 | Received 31 Jul 2021, Accepted 02 Mar 2022, Published online: 16 Mar 2022

References

  • Bongomin F, Gago S, Oladele RO, et al. Global and multi-national prevalence of fungal diseases-estimate precision. J Fungi 2017;3:57.
  • MacNeil A, Glaziou P, Sismanidis C, et al. Global epidemiology of tuberculosis and progress toward achieving global targets – 2017. Morb Mortal Wkly Rep 2019;68:263–6.
  • Brown GD, Denning DW, Gow NA, et al. Hidden killers: human fungal infections. Sci Transl Med 2012;4:165rv13.
  • Neoh CF, Slavin M, Chen SC, et al. Echinocandins in the treatment of candidaemia and invasive candidiasis: clinical and economic perspectives. Int J Antimicrob Agents 2014;43:207–14.
  • Vazquez JA, Sobel JD. Anidulafungin: a novel echinocandin. Clin Infect Dis 2006;43:215–22.
  • Wall G, Lopez-Ribot JL. Current antimycotics, new prospects, and future approaches to antifungal therapy. Antibiotics 2020;9:445.
  • Hull CM, Parker JE, Bader O, et al. Facultative sterol uptake in an ergosterol-deficient clinical isolate of Candida glabrata harboring a missense mutation in ERG11 and exhibiting cross-resistance to azoles and amphotericin B. Antimicrob Agents Chemother 2012;56:4223–32.
  • Lindsay J, Teh BW, Micklethwaite K, et al. Azole antifungals and new targeted therapies for hematological malignancy. Curr Opin Infect Dis 2019;32:538–45.
  • Mroczyńska M, Brillowska-Dąbrowska A. Review on current status of echinocandins use. Antibiotics 2020;9:227.
  • Garcia-Effron G. Rezafungin-mechanisms of action, susceptibility and resistance: similarities and differences with the other echinocandins. J Fungi 2020;6:262.
  • Hüttel W. Echinocandins: structural diversity, biosynthesis, and development of antimycotics. Appl Microbiol Biotechnol 2021;105:55–66.
  • Patil A, Majumdar S. Echinocandins in antifungal pharmacotherapy. J Pharm Pharmacol 2017;69:1635–60.
  • Balkovec JM, Hughes DL, Masurekar PS, et al. Discovery and development of first in class antifungal caspofungin (CANCIDAS®)-a case study. Nat Prod Rep 2014;31:15–34.
  • Cappelletty D, Eiselstein-McKitrick K. The echinocandins. Pharmacotherapy 2007;27:369–88.
  • Krishnan BR, James KD, Polowy K, et al. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J Antibiot 2017;70:130–5.
  • ClinicalTrials. Study of rezafungin compared to caspofungin in subjects with candidemia and/or invasive candidiasis (ReSTORE). Available from: https://clinicaltrials.gov/ct2/show/NCT03667690?cond=NCT03667690&draw=2&rank=1. [last accessed 1 Jul 2021]
  • Stan CD, Tuchiluş C, Stan CI. Echinocandins-new antifungal agents. Rev Med Chir Soc Med Nat Iasi 2014;118:528–36.
  • Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs 2011;71:11–41.
  • Hashimoto S. Micafungin: a sulfated echinocandin. J Antibiot 2009;62:27–35.
  • Taormina G, Gopinath R, Moore J, et al. A regulatory review approach for evaluation of micafungin for treatment of neonatal candidiasis. Clin Infect Dis 2021;73:2335–40.
  • St. Germain RM, Ellis JM. Anidulafungin. Formulary 2006;41:387–403.
  • Zhao Y, Perlin DS. Review of the novel echinocandin antifungal rezafungin: animal studies and clinical data. J Fungi 2020;6:192.
  • Sofjan AK, Mitchell A, Shah DN, et al. Rezafungin (CD101), a next-generation echinocandin: a systematic literature review and assessment of possible place in therapy. J Glob Antimicrob Resist 2018;14:58–64.
  • Hu ZC, Li WJ, Zou SP, et al. Mutagenesis of echinocandin B overproducing Aspergillus nidulans capable of using starch as main carbon source. Prep Biochem Biotechnol 2020;50:745–52.
  • Yao J, Liu H, Zhou T, et al. Total synthesis and structure–activity relationships of caspofungin-like macrocyclic antifungal lipopeptides. Tetrahedron 2012;68:3074–85.
  • Chen L, Yue Q, Li Y, et al. Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate. Appl Environ Microbiol 2015;81:1550–8.
  • Bouffard FA, Zambias RA, Dropinski JF, et al. Synthesis and antifungal activity of novel cationic pneumocandin B(o) derivatives. J Med Chem 1994;37:222–5.
  • Cândido ES, Affonseca F, Cardoso MH, et al. Echinocandins as biotechnological tools for treating Candida auris infections. J Fungi 2020;6:185.
  • Leonard WR, Jr, Belyk KM, Conlon DA, et al. Synthesis of the antifungal beta-1,3-glucan synthase inhibitor CANCIDAS (caspofungin acetate) from pneumocandin B0. J Org Chem 2007;72:2335–43.
  • Pratt A, Garcia-Effron G, Zhao Y, et al. Evaluation of fungal-specific fluorescent labeled echinocandin probes as diagnostic adjuncts. Med Mycol 2013;51:103–7.
  • Jaber QZ, Bibi M, Ksiezopolska E, et al. Elevated vacuolar uptake of fluorescently labeled antifungal drug caspofungin predicts echinocandin resistance in pathogenic yeast. ACS Cent Sci 2020;6:1698–712.
  • Mulder MP, Kruijtzer JA, Breukink EJ, et al. Synthesis and evaluation of novel macrocyclic antifungal peptides. Bioorg Med Chem 2011;19:6505–17.
  • Mulder MP, Fodran P, Kemmink J, et al. Mutual influence of backbone proline substitution and lipophilic tail character on the biological activity of simplified analogues of caspofungin. Org BioMol Chem 2012;10:7491–502.
  • Yao J, Liu H, Zhou T, et al. Total synthesis and structure-activity relationships of new echinocandin-like antifungal cyclolipohexapeptides. Eur J Med Chem 2012;50:196–208.
  • Tomishima M, Ohki H, Yamada A, et al. Novel echinocandin antifungals. Part 2: optimization of the side chain of the natural product FR901379. Discovery of micafungin. Bioorg Med Chem Lett 2008;18:2886–90.
  • Denning DW. Echinocandin antifungal drugs. Lancet 2003;362:1142–51.
  • Marena GD, Dos Santos Ramos MA, Bauab TM, et al. Biological properties and analytical methods for micafungin: a critical review. Crit Rev Anal Chem 2021;51:312–28.
  • Norris T, VanAlsten J, Hubbs S, et al. Commercialization and late-stage development of a semisynthetic antifungal API: anidulafungin/D-fructose (Eraxis). Org Proc Res and Develop 2008;12:447–55.
  • Singh SB, Herath K, Nielsen Kahn J, et al. Synthesis and antifungal evaluation of pentyloxyl-diphenylisoxazoloyl pneumocandins and echinocandins. Bioorg Med Chem Lett 2013;23:3253–6.
  • Torre PD, Reboli AC. Anidulafungin: a new echinocandin for candidal infections. Expert Rev anti Infect Ther 2007;5:45–52.
  • Zhu B, Dong Y, Ma J, et al. The synthesis and activity evaluation of N-acylated analogs of echinocandin B with improved solubility and lower toxicity. J Pept Sci 2020;26:e3278.
  • Gow NAR, Latge JP, Munro CA. The fungal cell wall: structure, biosynthesis, and function. MiCrobiol Spectr 2017;5:1.
  • Ong V, Hough G, Schlosser M, et al. Preclinical evaluation of the stability, safety, and efficacy of CD101, a novel echinocandin. Antimicrob Agents Chemother 2016;60:6872–9.
  • Garcia-Rubio R, de Oliveira HC, Rivera J, et al. The fungal cell wall: Candida, Cryptococcus, and Aspergillus species. Front Microbiol 2019;10:2993.
  • Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of antifungals. Ann Pharmacother 2009;43:1647–57.
  • Steinbach WJ, Reedy JL, Cramer RA, et al. Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections. Nat Rev Microbiol 2007;5:418–30.
  • Liu W, Yuan L, Wang S. Recent progress in the discovery of antifungal agents targeting the cell wall. J Med Chem 2020;63:12429–59.
  • Aguilar-Zapata D, Petraitiene R, Petraitis V. Echinocandins: the expanding antifungal armamentarium. Clin Infect Dis 2015;61: S604–S611.
  • Gamaletsou MN, Walsh TJ, Sipsas NV. Invasive fungal infections in patients with hematological malignancies: emergence of resistant pathogens and new antifungal therapies. Turk J Haematol 2018;35:1–11.
  • Perlin DS, Cell wall-modifying antifungal drugs. In: Latgé JP, ed. The fungal cell wall. Current topics in microbiology and immunology. vol 425. Cham: Springer; 2019.
  • Eschenauer G, Depestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag 2007;3:71–97.
  • Martos AI, Romero A, González MT, et al. Evaluation of the Etest method for susceptibility testing of Aspergillus spp. and Fusarium spp. to three echinocandins. Med Mycol 2010;48:858–61.
  • Kauffman CA, Pappas PG, Sobel JD, et al. Essentials of clinical mycology. New York: Springer; 2011.
  • Lockhart SR, Zimbeck AJ, Baddley JW, et al. In vitro echinocandin susceptibility of Aspergillus isolates from patients enrolled in the T\transplant-associated infection surveillance network. Antimicrob Agents Chemother 2011;55:3944–6.
  • Pfaller MA, Espinel-Ingroff A, Bustamante B, et al. Multicenter study of anidulafungin and micafungin MIC distributions and epidemiological cutoff values for eight Candida species and the CLSI M27-A3 broth microdilution method. Antimicrob Agents Chemother 2014;58:916–22.
  • Guarro J, Gams W, Pujol I, et al. Acremonium species: new emerging fungal opportunists-in vitro antifungal susceptibilities and review. Clin Infect Dis 1997;25:1222–9.
  • Pujol I, Aguilar C, Gené J, et al. In vitro antifungal susceptibility of Alternaria spp. and Ulocladium spp. J Antimicrob Chemother 2000;46:337.
  • Rodriguez-Tudela JL, Diaz-Guerra TM, Mellado E, et al. Susceptibility patterns and molecular identification of Trichosporon species. Antimicrob Agents Chemother 2005;49:4026–34.
  • Ashley ESD, Lewis R, Lewis JS, et al. Pharmacology of systemic antifungal agents. Clin Inf Dis 2006;43:S28–S39.
  • Perdomo H, Sutton DA, García D, et al. Spectrum of clinically relevant Acremonium species in the United States. J Clin Microbiol 2011;49:243–56.
  • Vitale RG, de Hoog GS, Schwarz P, et al. Antifungal susceptibility and phylogeny of opportunistic members of the order mucorales. J Clin Microbiol 2012;50:66–75.
  • da Cunha KC, Sutton DA, Fothergill AW, et al. In vitro antifungal susceptibility and molecular identity of 99 clinical isolates of the opportunistic fungal genus Curvularia. Diagn Microbiol Infect Dis 2013;76:168–74.
  • Sandoval-Denis M, Sutton DA, Cano-Lira JF, et al. Phylogeny of the clinically relevant species of the emerging fungus Trichoderma and their antifungal susceptibilities. J Clin Microbiol 2014;52:2112–25.
  • Sherry L, Ramage G, Kean R, et al. Biofilm-forming capability of highly virulent, multidrug-resistant candida auris. Emerg Infect Dis 2017;23:328–31.
  • Nishiyama Y, Uchida K, Yamaguchi H. Morphological changes of Candida albicans induced by micafungin (FK463), a water-soluble echinocandin-like lipopeptide. J Electron Microsc 2002;51:247–55.
  • Meletiadis J, Siopi M, Kanioura L, et al. Development and multicentre validation of an agar-based screening method for echinocandin susceptibility testing of Aspergillus species. J Antimicrob Chemother 2019;74:2247–54.
  • Aruanno M, Glampedakis E, Lamoth F. Echinocandins for the treatment of invasive Aspergillosis: from laboratory to bedside. Antimicrob Agents Chemother 2019;63:e00399–19.
  • Odabasi Z, Paetznick VL, Rodriguez JR, et al. In vitro activity of anidulafungin against selected clinically important mold isolates. Antimicrob Agents Chemother 2004;48:1912–5.
  • Hoffman JA, Walsh TJ. Echinocandins in children. Pediatr Infect Dis J 2011;30:508–9.
  • Diekema DJ, Messer SA, Hollis RJ, et al. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 2003;41:3623–6.
  • Bal AM. The echinocandins: three useful choices or three too many? Int J Antimicrob Agents 2010;35:13–8.
  • Hashemian SM, Farhadi T, Velayati AA. Caspofungin: a review of its characteristics, activity, and use in intensive care units. Expert Rev Anti Infect Ther 2020;18:1213–20.
  • Lakota EA, Ong V, Flanagan S, et al. Population pharmacokinetic analyses for rezafungin (CD101) efficacy using phase 1 data. Antimicrob Agents Chemother 2018;62:e02603–17.
  • Ong V, Flanagan S, Sandison T, et al. 1286. Pharmacokinetics, excretion, and mass balance of [14C]-rezafungin following intravenous (IV) administration in healthy adults. Open Forum Infect Dis 2020;7:S658–S659.
  • Muilwijk EW, Lempers VJ, Burger DM, et al. Impact of special patient populations on the pharmacokinetics of echinocandins. Expert Rev Anti Infect Ther 2015;13:799–815.
  • Sandison T, Ong V, Lee J,et al. Safety and pharmacokinetics of CD101 IV, a novel echinocandin, in healthy adults. Antimicrob Agents Chemother 2017;61:e01627–16.
  • Lempers VJ, Schouten JA, Hunfeld NG, et al. Altered micafungin pharmacokinetics in intensive care unit patients. Antimicrob Agents Chemother 2015;59:4403–9.
  • Liu P, Ruhnke M, Meersseman W, et al. Pharmacokinetics of anidulafungin in critically ill patients with candidemia/invasive candidiasis. Antimicrob Agents Chemother 2013;57:1672–6.
  • Hajdu R, Thompson R, Sundelof JG, et al. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob Agents Chemother 1997;41:2339–44.
  • Flevari A, Theodorakopoulou M, Velegraki A, et al. Treatment of invasive candidiasis in the elderly: a review. Clin Interv Aging 2013;8:1199–208.
  • Dekkers BGJ, Veringa A, Marriott DJE, et al. Invasive candidiasis in the elderly: considerations for drug therapy. Drugs Aging 2018;35:781–9.
  • Isnard C, Hernandez SB, Guérin F, et al. Unexpected cell wall alteration-mediated bactericidal activity of the antifungal caspofungin against vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother 2020;64:e01261–20.
  • Keating G, Figgitt D. Caspofungin: a review of its use in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis. Drugs 2003;63:2235–63.
  • Houšť J, Spížek J, Havlíček V. Antifungal Drugs. Metabolites 2020;10:106.
  • McCormack PL, Perry CM. Caspofungin: a review of its use in the treatment of fungal infections. Drugs 2005;65:2049–68.
  • Yang Q, Zhang T, Zhao D, et al. Factors influencing caspofungin plasma concentrations in kidney transplant patients with high incidence of invasive fungal infections. J Clin Pharm Ther 2020;45:72–80.
  • Nguyen TH, Hoppe-Tichy T, Geiss HK, et al. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J Antimicrob Chemother 2007;60:100–6.
  • Prabhakar H. Pharmacology in clinical neurosciences. Singapore: Springer; 2020.
  • Arendrup MC, Meletiadis J, Zaragoza O, et al. Multicentre determination of rezafungin (CD101) susceptibility of Candida species by the EUCAST method. Clin Microbiol Infect 2018;24:1200–4.
  • Miesel L, Cushion MT, Ashbaugh A, et al. Efficacy of rezafungin in prophylactic mouse models of invasive candidiasis, aspergillosis, and Pneumocystis pneumonia. Antimicrob Agents Chemother 2021;65:e01992–20.
  • Kurland S, Furebring M, Löwdin E, et al. Pharmacokinetics of caspofungin in critically ill patients in relation to liver dysfunction: differential impact of plasma albumin and bilirubin levels. Antimicrob Agents Chemother 2019;63:e02466–18.
  • Yu IG, O'Brien SE, Ryckman DM. Pharmacokinetic and pharmacodynamic comparison of intravenous and inhaled caspofungin. J Aerosol Med Pulm Drug Deliv 2021;34:197–203.
  • Leshinsky J, McLachlan A, Foster DJR, et al. Pharmacokinetics of caspofungin acetate to guide optimal dosing in cats. PLoS One 2017;12:e0178783.
  • Carter NJ, Keating GM. Micafungin: a review of its use in the prophylaxis and treatment of invasive Candida infections in pediatric patients. Paediatr Drugs 2009;11:271–91.
  • Wasmann RE, Muilwijk EW, Burger DM, et al. Clinical pharmacokinetics and pharmacodynamics of micafungin. Clin Pharmacokinet 2018;57:267–86.
  • Scott LJ. Micafungin: a review of its use in the prophylaxis and treatment of invasive Candida infections. Drugs 2012;72:2141–65.
  • Epstein DJ, Seo SK, Huang YT, et al. Micafungin versus posaconazole prophylaxis in acute leukemia or myelodysplastic syndrome: a randomized study. J Infect 2018;77:227–34.
  • Guirao-Abad JP, Sánchez-Fresneda R, Machado F, et al. Micafungin enhances the human macrophage response to Candida albicans through β-glucan exposure. Antimicrob Agents Chemother 2018;62:e02161–17.
  • Murdoch D, Plosker GL. Anidulafungin. Anidulafungin Drugs 2004;64:2249–58.
  • Staab JF, Kahn JN, Marr KA. Differential Aspergillus lentulus echinocandin susceptibilities are Fksp independent. Antimicrob Agents Chemother 2010;54:4992–8.
  • Kofla G, Ruhnke M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur J Med Res 2011;16:159–66.
  • Xie R, McFadyen L, Raber S, et al. Population analysis of anidulafungin in infants to older adults with confirmed or suspected invasive candidiasis. Clin Pharmacol Ther 2020;108:316–25.
  • Kullberg BJ, Vasquez J, Mootsikapun P, et al. Efficacy of anidulafungin in 539 patients with invasive candidiasis: a patient-level pooled analysis of six clinical trials. J Antimicrob Chemother 2017;72:2368–77.
  • Sganga G, Wang M, Capparella MR, et al. Evaluation of anidulafungin in the treatment of intra-abdominal candidiasis: a pooled analysis of patient-level data from 5 prospective studies. Eur J Clin Microbiol Infect Dis 2019;38:1849–56.
  • Cornely FB, Cornely OA, Salmanton-García J, et al. Attributable mortality of candidemia after introduction of echinocandins. Mycoses 2020;63:1373–81.
  • Chen PY, Yu CJ, Chien JY, et al. Anidulafungin as an alternative treatment for Pneumocystis jirovecii pneumonia in patients who cannot tolerate trimethoprim/sulfamethoxazole. Int J Antimicrob Agents 2020;55:105820.
  • Vera-González N, Bailey-Hytholt CM, Langlois L, et al. Anidulafungin liposome nanoparticles exhibit antifungal activity against planktonic and biofilm Candida albicans. J Biomed Mater Res A 2020;108:2263–76.
  • Wiederhold NP, Locke JB, Daruwala P, et al. Rezafungin (CD101) demonstrates potent in vitro activity against Aspergillus, including azole-resistant Aspergillus fumigatus isolates and cryptic species. J Antimicrob Chemother 2018;73:3063–7.
  • Gintjee TJ, Donnelley MA, Thompson GR. 3rd., Aspiring antifungals: review of current antifungal pipeline developments. J Fungi 2020;6:28.
  • Zhao Y, Perez WB, Jiménez-Ortigosa C, et al. CD101: a novel long-acting echinocandin. Cell Microbiol 2016;18:1308–16.
  • Stover KR, Cleary JD. Antifungal penetration and distribution into organs and tissue. Curr Fun Infe Rep 2020;14:279–88.
  • Chandra J, Ghannoum MA. CD101, a novel echinocandin, possesses potent antibiofilm activity against early and mature Candida albicans biofilms. Antimicrob Agents Chemother 2018;62:e01750–17.
  • Nyirjesy P, Alessio C, Jandourek A, et al. CD101 topical compared with oral fluconazole for acute vulvovaginal candidiasis: a randomized controlled trial. J Low Genit Tract Dis 2019;23:226–9.
  • Khalifa HO, Majima H, Watanabe A, et al. In vitro characterization of twenty-one antifungal combinations against echinocandin-resistant and -susceptible Candida glabrata. J Fungi 2021;7:108.
  • Buil JB, Brüggemann RJM, Bedin Denardi L, et al. In vitro interaction of isavuconazole and anidulafungin against azole-susceptible and azole-resistant Aspergillus fumigatus isolates. J Antimicrob Chemother 2020;75:2582–6.
  • Kovács R, Nagy F, Tóth Z, et al. Synergistic effect of nikkomycin Z with caspofungin and micafungin against Candida albicans and Candida parapsilosis biofilms. Lett Appl Microbiol 2019;69:271–8.
  • Bidaud AL, Djenontin E, Botterel F, et al. Colistin interacts synergistically with echinocandins against Candida auris. Int J Antimicrob Agents 2020;55:105901.
  • Grau S, Azanza JR, Ruiz I, et al. Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain. Clinicoecon Outcomes Res 2017;9:39–47.
  • Nagy F, Tóth Z, Nyikos F, et al. In vitro and in vivo interaction of caspofungin with isavuconazole against Candida auris planktonic cells and biofilms. Med Mycol 2021;59:1015–23.
  • Nagy F, Tóth Z, Daróczi L, et al. Farnesol increases the activity of echinocandins against Candida auris biofilms. Med Mycol 2020;58:404–7.
  • Polvi EJ, Averette AF, Lee SC, et al. Metal chelation as a powerful strategy to probe cellular circuitry governing fungal drug resistance and morphogenesis. PLoS Genet 2016;12:e1006350.
  • Laniado-Laborín R, Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Rev Iberoam Micol 2009;26:223–7.
  • Swaminathan S, Kamat S, Pinto NA. Echinocandins: their role in the management of Candida biofilms. Indian J Med Microbiol 2018;36:87–92.
  • Pilmis B, Jullien V, Sobel J, et al. Antifungal drugs during pregnancy: an updated review. J Antimicrob Chemother 2015;70:14–22.
  • Chen YC, Lu JW, Yeh CT, et al. Micafungin inhibits dengue virus infection through the disruption of virus binding, entry, and stability. Pharmaceuticals 2021;14:338.
  • Kim C, Kang H, Kim DE, et al. Antiviral activity of micafungin against enterovirus 71. Virol J 2016;13:99.
  • Ho YJ, Liu FC, Yeh CT, et al. Micafungin is a novel anti-viral agent of chikungunya virus through multiple mechanisms. Antiviral Res 2018;159:134–42.
  • Healey KR, Perlin DS. Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata. J Fungi 2018;4:105.
  • Pristov KE, Ghannoum MA. Resistance of Candida to azoles and echinocandins worldwide. Clin Microbiol Infect 2019;25:792–8.
  • Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem?. Curr Opin Infect Dis 2014;27:484–92.
  • Levin DE. Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 2005;69:262–91.
  • Lesage G, Sdicu AM, Ménard P, et al. Analysis of beta-1,3-glucan assembly in Saccharomyces cerevisiae using a synthetic interaction network and altered sensitivity to caspofungin. Genetics 2004;167:35–49.
  • Suwunnakorn S, Wakabayashi H, Kordalewska M, et al. FKS2 and FKS3 genes of opportunistic human pathogen Candida albicans influence echinocandin susceptibility. Antimicrob Agents Chemother 2018;62:e02299–17.
  • Hou X, Healey KR, Shor E, et al. Novel FKS1 and FKS2 modifications in a high-level echinocandin resistant clinical isolate of Candida glabrata. Emerg Microbes Infect 2019;8:1619–25.
  • Perlin DS. Echinocandin resistance in Candida. Clin Infect Dis 2015;61:S612–S617.
  • Perlin DS. Current perspectives on echinocandin class drugs. Future Microbiol 2011;6:441–57.
  • Garcia-Effron G, Lee S, Park S, et al. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother 2009;53:3690–9.
  • Sharma C, Chowdhary A. Molecular bases of antifungal resistance in filamentous fungi. Int J Antimicrob Agents 2017;50:607–16.
  • Cowen LE, Sanglard D, Howard SJ, et al. Mechanisms of antifungal drug resistance. Cold Spring Harb Perspect Med 2014;5:a019752.
  • Ben-Ami R, Garcia-Effron G, Lewis RE, et al. Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance. J Infect Dis 2011;204:626–35.
  • Yu SJ, Chang YL, Chen YL. Calcineurin signaling: lessons from Candida species. FEMS Yeast Res 2015;15:fov016.
  • Stevens DA, White TC, Perlin DS, et al. Studies of the paradoxical effect of caspofungin at high drug concentrations. Diagn Microbiol Infect Dis 2005;51:173–8.
  • Chamilos G, Lewis RE, Albert N, et al. Paradoxical effect of echinocandins across Candida species in vitro: evidence for echinocandin-specific and Candida species-related differences. Antimicrob Agents Chemother 2007;51:2257–9.
  • Vanstraelen K, Lagrou K, Maertens J, et al. The eagle-like effect of echinocandins: what's in a name?. Expert Rev Anti Infect Ther 2013;11:1179–91.
  • Emri T, Majoros L, Tóth V, et al. Echinocandins: production and applications. Appl Microbiol Biotechnol 2013;97:3267–84.