UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pharmacology of echinocandins

Author
Russell E Lewis, PharmD, FCCP
Section Editor
Carol A Kauffman, MD
Deputy Editor
Anna R Thorner, MD

INTRODUCTION

The development of echinocandins, the first class of antifungals to target the fungal cell wall, was a milestone achievement in antifungal chemotherapy. Echinocandins were discovered as fermentation metabolites with antifungal activity during screening programs for new antibiotics [1]. The candidate molecules were subsequently modified to improve solubility, antifungal spectrum of activity, and pharmacokinetic characteristics [2]. Three semi-synthetic echinocandin derivatives have been developed for clinical use: caspofungin, micafungin, and anidulafungin.

All three echinocandins are structurally similar cyclic hexapeptide antibiotics with modified N-linked acyl lipid side chains (figure 1), which play a role in anchoring the hexapeptide nucleus to the fungal cell membrane where the drug interacts with the target enzyme complex involved in cell wall synthesis [3]. Like other large lipopeptide antibiotics, these drugs have limited oral bioavailability and must be administered by intravenous infusion. Experience with this antifungal class suggests that it is among the best tolerated and safest class of antifungals available.

The pharmacology of echinocandin antifungals will be reviewed here. Indications for the clinical use of echinocandins, antifungal susceptibility testing, and the pharmacology of other systemic antifungal agents, such as amphotericin B, the azoles, and flucytosine, are discussed separately. (See "Treatment of candidemia and invasive candidiasis in adults" and "Treatment and prevention of invasive aspergillosis" and "Antifungal susceptibility testing" and "Pharmacology of amphotericin B" and "Pharmacology of azoles" and "Pharmacology of flucytosine (5-FC)".)

OVERVIEW OF CLINICAL USES

Echinocandins are widely used for the treatment of invasive candidiasis, especially in critically ill and neutropenic patients [4]. They are also used for empiric antifungal therapy in patients with neutropenic fever. They are sometimes used in combination with voriconazole for the initial treatment of invasive aspergillosis or as part of a combination antifungal regimen with voriconazole or a lipid formulation of amphotericin B for salvage therapy of invasive aspergillosis. (See "Treatment and prevention of invasive aspergillosis".)

The major advantages of echinocandins relative to other antifungal agents are their fungicidal activity against Candida spp, including fluconazole-resistant C. glabrata and C. krusei, combined with their relatively low potential for renal or hepatic toxicity or serious drug-drug interactions. Specific recommendations regarding the use of these agents are presented separately. (See "Treatment of candidemia and invasive candidiasis in adults" and "Treatment and prevention of invasive aspergillosis" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent'.)

                                       

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Fri Feb 05 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Hector RF. Compounds active against cell walls of medically important fungi. Clin Microbiol Rev 1993; 6:1.
  2. Debono M, Gordee RS. Antibiotics that inhibit fungal cell wall development. Annu Rev Microbiol 1994; 48:471.
  3. Denning DW. Echinocandin antifungal drugs. Lancet 2003; 362:1142.
  4. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62:e1.
  5. Douglas CM. Fungal beta(1,3)-D-glucan synthesis. Med Mycol 2001; 39 Suppl 1:55.
  6. Cabib E, Roh DH, Schmidt M, et al. The yeast cell wall and septum as paradigms of cell growth and morphogenesis. J Biol Chem 2001; 276:19679.
  7. Fleet GH. Composition and structure of yeast cell walls. Curr Top Med Mycol 1985; 1:24.
  8. Bernard M, Latgé JP. Aspergillus fumigatus cell wall: composition and biosynthesis. Med Mycol 2001; 39 Suppl 1:9.
  9. Beauvais A, Bruneau JM, Mol PC, et al. Glucan synthase complex of Aspergillus fumigatus. J Bacteriol 2001; 183:2273.
  10. Beauvais A, Latgé JP. Membrane and cell wall targets in Aspergillus fumigatus. Drug Resist Updat 2001; 4:38.
  11. Kurtz MB, Heath IB, Marrinan J, et al. Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-D-glucan synthase. Antimicrob Agents Chemother 1994; 38:1480.
  12. Wheeler RT, Fink GR. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog 2006; 2:e35.
  13. Wheeler RT, Kombe D, Agarwala SD, Fink GR. Dynamic, morphotype-specific Candida albicans beta-glucan exposure during infection and drug treatment. PLoS Pathog 2008; 4:e1000227.
  14. Hohl TM, Feldmesser M, Perlin DS, Pamer EG. Caspofungin modulates inflammatory responses to Aspergillus fumigatus through stage-specific effects on fungal beta-glucan exposure. J Infect Dis 2008; 198:176.
  15. Ibrahim AS, Bowman JC, Avanessian V, et al. Caspofungin inhibits Rhizopus oryzae 1,3-beta-D-glucan synthase, lowers burden in brain measured by quantitative PCR, and improves survival at a low but not a high dose during murine disseminated zygomycosis. Antimicrob Agents Chemother 2005; 49:721.
  16. Lamaris GA, Lewis RE, Chamilos G, et al. Caspofungin-mediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae. J Infect Dis 2008; 198:186.
  17. Pfaller MA, Boyken L, Hollis RJ, et al. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol 2008; 46:150.
  18. Pfaller MA, Castanheira M, Lockhart SR, et al. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol 2012; 50:1199.
  19. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med 2012; 125:S3.
  20. Zimbeck AJ, Iqbal N, Ahlquist AM, et al. FKS mutations and elevated echinocandin MIC values among Candida glabrata isolates from U.S. population-based surveillance. Antimicrob Agents Chemother 2010; 54:5042.
  21. Chapeland-Leclerc F, Hennequin C, Papon N, et al. Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient. Antimicrob Agents Chemother 2010; 54:1360.
  22. Dannaoui E, Desnos-Ollivier M, Garcia-Hermoso D, et al. Candida spp. with acquired echinocandin resistance, France, 2004-2010. Emerg Infect Dis 2012; 18:86.
  23. Dodgson KJ, Dodgson AR, Pujol C, et al. Caspofungin resistant C. glabrata. Clin Microbiol Infect 2005; 11 (Suppl 2):364.
  24. Kofteridis DP, Lewis RE, Kontoyiannis DP. Caspofungin-non-susceptible Candida isolates in cancer patients. J Antimicrob Chemother 2010; 65:293.
  25. Krogh-Madsen M, Arendrup MC, Heslet L, Knudsen JD. Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. Clin Infect Dis 2006; 42:938.
  26. Pfaller MA, Castanheira M, Lockhart SR, et al. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol 2012; 50:1199.
  27. Pham CD, Iqbal N, Bolden CB, et al. Role of FKS Mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance. Antimicrob Agents Chemother 2014; 58:4690.
  28. Alexander BD, Johnson MD, Pfeiffer CD, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 2013; 56:1724.
  29. Beyda ND, John J, Kilic A, et al. FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis 2014; 59:819.
  30. Wang E, Farmakiotis D, Yang D, et al. The ever-evolving landscape of candidaemia in patients with acute leukaemia: non-susceptibility to caspofungin and multidrug resistance are associated with increased mortality. J Antimicrob Chemother 2015; 70:2362.
  31. Ramage G, VandeWalle K, Bachmann SP, et al. In vitro pharmacodynamic properties of three antifungal agents against preformed Candida albicans biofilms determined by time-kill studies. Antimicrob Agents Chemother 2002; 46:3634.
  32. Kuhn DM, George T, Chandra J, et al. Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob Agents Chemother 2002; 46:1773.
  33. Nett J, Lincoln L, Marchillo K, Andes D. Beta -1,3 glucan as a test for central venous catheter biofilm infection. J Infect Dis 2007; 195:1705.
  34. Cassone A, Kerridge D, Gale EF. Ultrastructural changes in the cell wall of Candida albicans following cessation of growth and their possible relationship to the development of polyene resistance. J Gen Microbiol 1979; 110:339.
  35. Gale EF, Ingram J, Kerridge D, et al. Reduction of amphotericin resistance in stationary phase cultures of Candida albicans by treatment with enzymes. J Gen Microbiol 1980; 117:383.
  36. Nett J, Lincoln L, Marchillo K, et al. Putative role of beta-1,3 glucans in Candida albicans biofilm resistance. Antimicrob Agents Chemother 2007; 51:510.
  37. Bowman JC, Hicks PS, Kurtz MB, et al. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother 2002; 46:3001.
  38. Ben-Ami R, Lewis RE, Kontoyiannis DP. Immunocompromised hosts: immunopharmacology of modern antifungals. Clin Infect Dis 2008; 47:226.
  39. Espinel-Ingroff A. Comparison of In vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998; 36:2950.
  40. Tawara S, Ikeda F, Maki K, et al. In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi. Antimicrob Agents Chemother 2000; 44:57.
  41. Kahn JN, Hsu MJ, Racine F, et al. Caspofungin susceptibility in Aspergillus and non-Aspergillus molds: inhibition of glucan synthase and reduction of beta-D-1,3 glucan levels in culture. Antimicrob Agents Chemother 2006; 50:2214.
  42. Del Poeta M, Schell WA, Perfect JR. In vitro antifungal activity of pneumocandin L-743,872 against a variety of clinically important molds. Antimicrob Agents Chemother 1997; 41:1835.
  43. Ito M, Nozu R, Kuramochi T, et al. Prophylactic effect of FK463, a novel antifungal lipopeptide, against Pneumocystis carinii infection in mice. Antimicrob Agents Chemother 2000; 44:2259.
  44. Schmatz DM, Powles M, McFadden DC, et al. Treatment and prevention of Pneumocystis carinii pneumonia and further elucidation of the P. carinii life cycle with 1,3-beta-glucan synthesis inhibitor L-671,329. J Protozool 1991; 38:151S.
  45. Kottom TJ, Limper AH. Cell wall assembly by Pneumocystis carinii. Evidence for a unique gsc-1 subunit mediating beta -1,3-glucan deposition. J Biol Chem 2000; 275:40628.
  46. Kohler S, Wheat LJ, Connolly P, et al. Comparison of the echinocandin caspofungin with amphotericin B for treatment of histoplasmosis following pulmonary challenge in a murine model. Antimicrob Agents Chemother 2000; 44:1850.
  47. Dodds Ashley ES, Lewis R, Lewis JS, et al. Pharmacology of Systemic Antifungal Agents. Clin Infect Dis 2006; 43 Suppl 1:S28.
  48. Cancidas. Prescribing information-(caspofungin acetate) for injection. Merck & Co Inc, Whitehouse Station, NJ 2008.
  49. Stone JA, Holland SD, Wickersham PJ, et al. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother 2002; 46:739.
  50. Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of antifungals. Ann Pharmacother 2009; 43:1647.
  51. Stone JA, Xu X, Winchell GA, et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother 2004; 48:815.
  52. Boucher HW, Groll AH, Chiou CC, Walsh TJ. Newer systemic antifungal agents : pharmacokinetics, safety and efficacy. Drugs 2004; 64:1997.
  53. Mycamine (micafungin sodium) - Highlights of prescribing information. http://www.us.astellas.com/docs/mycamine.pdf (Accessed on April 21, 2015).
  54. Theuretzbacher U. Pharmacokinetics/pharmacodynamics of echinocandins. Eur J Clin Microbiol Infect Dis 2004; 23:805.
  55. Cappelletty D, Eiselstein-McKitrick K. The echinocandins. Pharmacotherapy 2007; 27:369.
  56. de Wet NT, Bester AJ, Viljoen JJ, et al. A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther 2005; 21:899.
  57. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347:2020.
  58. Pappas PG, Rotstein CM, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007; 45:883.
  59. Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007; 369:1519.
  60. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472.
  61. Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer 2006; 107:2888.
  62. Kontoyiannis DP, Ratanatharathorn V, Young JA, et al. Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis. Transpl Infect Dis 2009; 11:89.
  63. Kohno S, Masaoka T, Yamaguchi H, et al. A multicenter, open-label clinical study of micafungin (FK463) in the treatment of deep-seated mycosis in Japan. Scand J Infect Dis 2004; 36:372.
  64. Anidulafungin plus voriconazole versus voriconazole for the treatment of invasive aspergillosis. In: Health NIo, ed, 2008. http://www.clinicaltrials.gov/ct2/show/NCT00531479 (Accessed on July 29, 2009).
  65. Lehrnbecher T, Groll AH. Micafungin: a brief review of pharmacology, safety, and antifungal efficacy in pediatric patients. Pediatr Blood Cancer 2010; 55:229.
  66. Walsh TJ, Adamson PC, Seibel NL, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005; 49:4536.
  67. Neely M, Jafri HS, Seibel N, et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother 2009; 53:1450.
  68. Sáez-Llorens X, Macias M, Maiya P, et al. Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age. Antimicrob Agents Chemother 2009; 53:869.
  69. Seibel NL, Schwartz C, Arrieta A, et al. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother 2005; 49:3317.
  70. Heresi GP, Gerstmann DR, Blumer JL, et al. Pharmacokinetic, safety, and tolerance study of micafungin (FK463) in premature infants. Pediat Res 2003; 53:317A.
  71. Hope WW, Mickiene D, Petraitis V, et al. The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: implications for echinocandin therapy in neonates. J Infect Dis 2008; 197:163.
  72. Hope WW, Smith PB, Arrieta A, et al. Population pharmacokinetics of micafungin in neonates and young infants. Antimicrob Agents Chemother 2010; 54:2633.
  73. Eraxis. Prescribing information-(Anidulafungin) for injection. In: Pfizer I, ed. New York, NY 2008.
  74. Weiler S, Seger C, Pfisterer H, et al. Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy. Antimicrob Agents Chemother 2013; 57:4053.
  75. Movshev BE, Dubrovina NA, Petrova VI, et al. [Plasma macroproteins in the evaluation of the effectiveness of therapeutic plasmapheresis in patients with rheumatoid arthritis]. Revmatologiia (Mosk) 1989; :32.
  76. Martial LC, Brüggemann RJ, Schouten JA, et al. Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure. Clin Pharmacokinet 2016; 55:723.
  77. Dowell JA, Knebel W, Ludden T, et al. Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. J Clin Pharmacol 2004; 44:590.
  78. 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.
  79. Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother 2011; 55:5107.
  80. Amsden J, Slain D. Antifungal dosing in obesity: A review of the literature. Curr Infect Fungal Report 2011; 5:83.
  81. Ryan DM, Lupinacci RJ, Kartsonis NA. Efficacy and safety of caspofungin in obese patients. Med Mycol 2011; 49:748.
  82. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis 2003; 36:1445.
  83. Eschenauer G, Depestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag 2007; 3:71.
  84. Cleary JD, Stover KR. Antifungal-Associated Drug-Induced Cardiac Disease. Clin Infect Dis 2015; 61 Suppl 6:S662.
  85. Sandhu P, Lee W, Xu X, et al. Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos 2005; 33:676.
  86. Meletiadis J, Chanock S, Walsh TJ. Human pharmacogenomic variations and their implications for antifungal efficacy. Clin Microbiol Rev 2006; 19:763.
  87. Stone JA, Migoya EM, Hickey L, et al. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother 2004; 48:4306.
  88. Hebert MF, Blough DK, Townsend RW, et al. Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers. J Clin Pharmacol 2005; 45:1018.
  89. Dowell JA, Stogniew M, Krause D, et al. Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine. J Clin Pharmacol 2005; 45:227.