Semin Respir Crit Care Med 2008; 29(2): 211-219
DOI: 10.1055/s-2008-1063859
© Thieme Medical Publishers

Update on Echinocandin Antifungals

Carol A. Kauffman1 , Peggy L. Carver2
  • 1Division of Infectious Diseases, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare System, University of Michigan Medical School, Ann Arbor, Michigan
  • 2University of Michigan College of Pharmacy, Ann Arbor, Michigan
Further Information

Publication History

Publication Date:
26 March 2008 (online)

ABSTRACT

Echinocandins are semisynthetic lipopeptides that competitively inhibit an essential cell wall component of Candida and Aspergillus. They are generally inactive against other fungi. Resistance to these agents is infrequent to date. Echinocandins exhibit low oral bioavailability and are available only as parenteral formulations that are dosed once daily. None of the echinocandins serve as major substrates, inducers, or inhibitors of cytochrome P450 enzymes or the P-glycoprotein transport system; thus they have a low potential for serious drug-drug interactions. In candidemia trials, all echinocandins showed similar rates of success and were as efficacious as fluconazole, amphotericin B, or lipid formulations of amphotericin B.

Caspofungin and micafungin have been studied as single-agent therapy in patients with invasive aspergillosis and will likely remain as second-line agents. However, because of their unique mechanism of action, echinocandins are ideally suited for use in combination with polyenes or azoles and are likely to be used increasingly in immunosuppressed hosts despite a current lack of controlled trials demonstrating efficacy. Limited experience suggests that caspofungin and micafungin are safe to use in pediatric patients. Hospital formulary committees are likely to view the three echinocandins as equivalent agents and place the least expensive agent on formulary.

REFERENCES

  • 1 Denning D W. Echinocandin antifungal drugs.  Lancet. 2003;  362 1142-1151
  • 2 Pfaller M A, Boyken L, Hollis R J et al.. In vitro activities of anidulafungin against more than 2500 clinical isolates of Candida spp. including 315 isolates resistant to fluconazole.  J Clin Microbiol. 2005;  43 5425-5427
  • 3 Pfaller M A, Boyken L, Hollis R J et al.. In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance.  J Clin Microbiol. 2006;  44 760-763
  • 4 Ghannoum M, D'Angelo M. Anidulafungin: a potent antifungal that targets Candida and Aspergillus .  Infect Dis Clin Pract. 2005;  13 165-178
  • 5 Pfaller M A, Boyken L, Hollis R J et al.. Global surveillance of in vitro activity of micafungin against Candida: a comparison with caspofungin by CLSI-recommended methods.  J Clin Microbiol. 2006;  44 3533-3538
  • 6 Ostrosky-Zeichner L, Rex J H, Pappas P G et al.. Antifungal susceptibility survey of 2000 Candida bloodstream isolates in the United States.  Antimicrob Agents Chemother. 2003;  47 3149-3154
  • 7 Pfaller M A, Diekema D J. Epidemiology of invasive candidiasis: a persistent public health problem.  Clin Microbiol Rev. 2007;  20 133-163
  • 8 Barchiesi F, Sprehhini E, Tomassetti S et al.. Effects of caspofungin against Candida guilliermondii and Candida parapsilosis .  Antimicrob Agents Chemother. 2006;  50 2719-2727
  • 9 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 2950-2956
  • 10 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 57-62
  • 11 Messer S A, Kirby J T, Sader H S et al.. Initial results from a longitudinal international surveillance programme for anidulafungin.  J Antimicrob Chemother. 2004;  54 1051-1056
  • 12 Deresinski S C, Stevens D A. Caspofungin.  Clin Infect Dis. 2003;  36 1445-1457
  • 13 Chandrasekar P H, Sobel J A. Micafungin: a new echinocandin.  Clin Infect Dis. 2006;  42 1171-1178
  • 14 Vazquez J A, Sobel J D. Anidulafungin: a novel echinocandin.  Clin Infect Dis. 2006;  43 215-222
  • 15 Odds F C, Motyl M, Andrade R et al.. Interlaboratory comparison of results of susceptibility testing with caspofungin against Candida and Aspergillus species.  J Clin Microbiol. 2004;  42 3475-3482
  • 16 Park S, Kelly R, Kahn J N et al.. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates.  Antimicrob Agents Chemother. 2005;  49 3264-3273
  • 17 Miller C D, Lomaestro B W, Park S et al.. Progressive esophagitis caused by Candida albicans with reduced susceptibility to caspofungin.  Pharmacotherapy. 2006;  26 877-880
  • 18 Laverdiere M, Lalonde R G, Baril J G et al.. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis.  J Antimicrob Chemother. 2006;  57 705-708
  • 19 Hernandez S, Lopez-Ribot J L, Najvar L K, McCarthy D I, Bocanegra R, Graybill J R. Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis.  Antimicrob Agents Chemother. 2004;  48 1382-1383
  • 20 Krogh-Madsen M, Arendrup M C, Heslet L, Knudsen J D. Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient.  Clin Infect Dis. 2006;  42 938-944
  • 21 Dodgson K J, Dodgson A R, Pujol C et al.. Caspofungin resistant C. glabrata .  Clin Microbiol Infect. 2005;  11(Suppl 2) 364
  • 22 Moudgal V, Little T, Boikov D et al.. Multiechinocandin- and multiazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis.  Antimicrob Agents Chemother. 2005;  49 767-769
  • 23 Hakki M, Staab J F, Marr K A. Emergence of a Candida krusei isolate with reduced susceptibility to caspofungin during therapy.  Antimicrob Agents Chemother. 2006;  50 2522-2524
  • 24 Perlin D S. Resistance to echinocandin-class antifungal drugs.  Drug Resist Updat. 2007;  10 121-130
  • 25 Eschenauer G, DePestel D D, Carver P L. Comparison of echinocandin antifungals.  Therap Clin Risk Management. 2007;  3 71-97
  • 26 Dowell J A, Stogniew M, Krause D, Damle B. Anidulafungin does not require dosage adjustment in subjects with varying degrees of hepatic or renal impairment.  J Clin Pharmacol. 2007;  47 461-470
  • 27 Hebert M F, Smith H E, Marbury T C et al.. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction.  J Clin Pharmacol. 2005;  45 1145-1152
  • 28 Goicoechea M, Fierer J, Johns S. Treatment of candidal cholangitis with caspofungin therapy in a patient with a liver transplant: documentation of biliary excretion of caspofungin.  Clin Infect Dis. 2004;  38 1040-1041
  • 29 Carver P L. Micafungin.  Ann Pharmacother. 2004;  38 1707-1721
  • 30 Cancidas [package insert]. Rahway, NJ; Merck 2005
  • 31 Eraxis [package insert]. New York, NY; Pfizer 2006
  • 32 Mycamine [package insert]. Osaka, Japan; Fujisawa 2005
  • 33 Okugawa S, Ota Y, Tatsuno K, Tsukada K, Kishino S, Koike K. A case of invasive central nervous system aspergillosis treated with micafungin with monitoring of micafungin concentrations in the cerebrospinal fluid.  Scand J Infect Dis. 2007;  39 344-346
  • 34 Sandhu P, Lee W, Xu X et al.. Hepatic uptake of the novel antifungal agent caspofungin.  Drug Metab Dispos. 2005;  33 676-682
  • 35 Keirns J, Sawamoto T, Holum M, Buell D, Wisemandle W, Alak A. Steady-state pharmacokinetics of micafungin and voriconazole after separate and concomitant dosing in healthy adults.  Antimicrob Agents Chemother. 2007;  51 787-790
  • 36 Dowell J A, Schranz J, Baruch A, Foster G. Safety and pharmacokinetics of coadministered voriconazole and anidulafungin.  J Clin Pharmacol. 2005;  45 1373-1382
  • 37 Dowell J A, Stogniew M, Krause D et al.. Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine.  J Clin Pharmacol. 2005;  45 227-233
  • 38 Hebert M F, Townsend R W, Austin S et al.. Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers.  J Clin Pharmacol. 2005;  45 954-960
  • 39 Dowell J A, Stogniew M, Krause D, Henkel T, Damle B. Lack of pharmacokinetic interaction between anidulafungin and tacrolimus.  J Clin Pharmacol. 2007;  47 305-314
  • 40 Hebert M F, Blough D K, Townsend R W et al.. Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers.  J Clin Pharmacol. 2005;  45 1018-1024
  • 41 Bennett J E. Echinocandins for candidemia in adults without neutropenia.  N Engl J Med. 2006;  355 1154-1159
  • 42 Villanueva A, Gotuzzo E, Arathoon E et al.. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis.  Am J Med. 2002;  113 294-299
  • 43 de Wet N, Llanos-Cuentas A, Suleiman J et al.. A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients.  Clin Infect Dis. 2004;  39 842-849
  • 44 Krause D S, Sinjee A E, van Rensburg C et al.. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis.  Clin Infect Dis. 2004;  39 770-775
  • 45 Mora-Duarte J, Betts R, Rotstein C et al.. Caspofungin vs amphotericin B deoxycholate in the treatment of invasive candidiasis in neutropenic and non-neutropenic patients: a multi-centre, randomized, double-blind study.  N Engl J Med. 2002;  347 2020-2029
  • 46 Kuse E R, Chetchotisakd P, da Cunha C A et al.. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial.  Lancet. 2007;  369 1519-1524
  • 47 Pappas P G, Rotstein C MF, Betts R F et al.. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis.  Clin Infect Dis. 2007;  45 883-893
  • 48 Reboli A C, Rotstein C, Pappas P G et al.. Anidulafungin versus fluconazole for invasive candidiasis.  N Engl J Med. 2007;  356 2472-2482
  • 49 Nevado J, De Alarcon A, Hernandez A. Caspofungin: a new therapeutic option for fungal endocarditis.  Clin Microbiol Infect. 2005;  11 248
  • 50 Rajendram R, Alp N J, Mitchell A R et al.. Candida prosthetic valve endocarditis cured by caspofungin therapy without valvular replacement.  Clin Infect Dis. 2005;  40 e72-e74
  • 51 Prabhu R M, Orenstein R. Failure of caspofungin to treat brain abscesses secondary to Candida albicans prosthetic valve endocarditis.  Clin Infect Dis. 2004;  39 1253-1254
  • 52 Gauthier G M, Nork T M, Prince R et al.. Subtherapeutic ocular penetration of caspofunguin and associated treatment failure in Candida albicans endophthalmitis.  Clin Infect Dis. 2005;  41 e27-e28
  • 53 Sarria J C, Bradley J C, Habash R et al.. Candida glabrata endophthalmitis treated successfully with caspofungin.  Clin Infect Dis. 2005;  40 e46-e48
  • 54 Liu K H, Wu C J, Chou C H et al.. Refractory candidal meningitis in an immunocompromised patient cured by caspofungin.  J Clin Microbiol. 2004;  42 5950-5953
  • 55 Maertens J, Raad I, Petrikkos G et al.. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy.  Clin Infect Dis. 2004;  39 1563-1571
  • 56 Candoni A, Mestroni R, Damiani D et al.. Caspofungin as first line therapy of pulmonary invasive fungal infections in 32 immunocompromised patients with hematological malignancies.  Eur J Haematol. 2005;  75 227-233
  • 57 Denning D W, Marr K A, Lau W M et al.. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis.  J Infect. 2006;  53 337-349
  • 58 Aliff T B, Maslak P G, Jurcic J G et al.. Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin B.  Cancer. 2003;  97 1025-1032
  • 59 Kontoyiannis D P, Hachem R, Lewis R E et al.. Efficacy and toxicity of caspofungin in combination with amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies.  Cancer. 2003;  98 292-299
  • 60 Marr K A, Boeckh M, Carter R A, Kim H W, Corey L. Combination antifungal therapy for invasive aspergillosis.  Clin Infect Dis. 2004;  39 797-802
  • 61 Singh N, Limaye A, Forrest G et al.. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study.  Transplantation. 2006;  81 320-326
  • 62 Walsh T J, Teppler H, Donowitz G R et al.. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia.  N Engl J Med. 2004;  351 1391-1402
  • 63 Van Burik J-AH, Ratanatharathorn V, Stepan D E et al.. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation.  Clin Infect Dis. 2004;  39 1407-1416
  • 64 Krause D S, Reinhardt J, Vazquez J A et al.. Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia.  Antimicrob Agents Chemother. 2004;  48 2021-2024
  • 65 Sable C A, Nguyen B Y, Chodakewitz J A, DiNubile M J. Safety and tolerability of caspofungin acetate in the treatment of fungal infections.  Transpl Infect Dis. 2002;  4 25-30
  • 66 Heresi G P, Gerstmann D R, Reed M D et al.. The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants.  Pediatr Infect Dis J. 2006;  25 1110-1115
  • 67 Benjamin Jr D K, Driscoll T, Seibel N L et al.. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections.  Antimicrob Agents Chemother. 2006;  50 632-638
  • 68 Seibel N L, Schwartz C, Arrieta A et al.. Safety, tolerability, and pharmacokinetics of micafungin (FK463) in febrile neutropenic pediatric patients.  Antimicrob Agents Chemother. 2005;  49 3317-3324
  • 69 Walsh T J, Adamson P C, Seibel N L et al.. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents.  Antimicrob Agents Chemother. 2005;  49 4536-4545
  • 70 Marr K A, Hachem R, Papanicolaou G et al.. Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporine A.  Transpl Infect Dis. 2004;  3 110-116
  • 71 Sanz-Rodriguez C, Lopez-Duarte M, Jurado M et al.. Safety of the concomitant use of caspofungin and cyclosporine A in patients with invasive fungal infections.  Bone Marrow Transplant. 2004;  34 13-20

Carol A KauffmanM.D. 

Veterans Affairs Ann Arbor Healthcare System

2215 Fuller Rd., Ann Arbor, MI 48105

Email: ckauff@umich.edu