Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of micafungin as an empirical therapy for invasive fungal infections in patients with hematologic disorders: a multicenter, prospective study

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of β-d-glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150 mg/day and 13 days, respectively. The overall response rate for suspected IFIs (n = 119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n = 81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163

    Article  PubMed  CAS  Google Scholar 

  2. Marr KA, Carter RA, Crippa F, Wald A, Corey L (2002) Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 34:909–917

    Article  PubMed  Google Scholar 

  3. Kume H, Yamazaki T, Abe M, Tanuma H, Okudaira M, Okayasu I (2006) Epidemiology of visceral mycoses in patients with leukemia and MDS—analysis of the data in annual of pathological autopsy cases in Japan in 1989, 1993, 1997 and 2001. Jpn J Med Mycol 47:15–24

    Article  Google Scholar 

  4. Aisner J, Schimpff SC, Wiernik PH (1977) Treatment of invasive aspergillosis: relation of early diagnosis and treatment to response. Ann Intern Med 86:539–543

    PubMed  CAS  Google Scholar 

  5. Morrell M, Fraser VJ, Lollef MH (2005) Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factors for hospital mortality. Antimicrob Agents Chemother 49:3640–3645

    Article  PubMed  CAS  Google Scholar 

  6. EORTC International Antimicrobial Therapy Cooperative Project Group (1989) Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 86:668–672

    Article  Google Scholar 

  7. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, Feld R, Pizzo PA, Rolston KV, Shenep JL, Young LS (2002) 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730–751

    Article  PubMed  Google Scholar 

  8. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS, National Institute of Allergy and Infectious Diseases Mycoses Study Group (1999) Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 340:764–771

    Article  PubMed  CAS  Google Scholar 

  9. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, Yanovich S, Stiff P, Greenberg R, Donowitz G, Lee J, National Institute of Allergy and Infectious Diseases Mycoses Study Group (2002) Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 346:225–234

    Article  PubMed  CAS  Google Scholar 

  10. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, Cornely OA, Bourque MR, Lupinacci RJ, Sable CA, dePauw BE (2004) Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 351:1391–1402

    Article  PubMed  CAS  Google Scholar 

  11. Boogaerts M, Winston DJ, Bow EJ, Garber G, Reboli AC, Schwarer AP, Novitzky N, Boehme A, Chwetzoff E, De Beule K, Itraconazole Neutropenia Study Group (2001) Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. Ann Intern Med 135:412–422

    PubMed  CAS  Google Scholar 

  12. Hatano K, Morishita Y, Nakai T, Ikeda F (2002) Antifungal mechanism of FK463 against Candida albicans and Aspergillus fumigatus. J Antibiot (Tokyo) 55:219–222

    CAS  Google Scholar 

  13. Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Diekema DJ (2008) In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol 46:150–156

    Article  PubMed  CAS  Google Scholar 

  14. Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Diekema DJ (2009) In vitro susceptibility of clinical isolates of Aspergillus spp. to anidulafungin, caspofungin, and micafungin: a head-to-head comparison using the CLSI M38-A2 broth microdilution method. J Clin Microbiol 47:3323–3325

    Article  PubMed  CAS  Google Scholar 

  15. Kohno S, Masaoka T, Yamaguchi H, Mori T, Urabe A, Ito A, Niki Y, Ikemoto H (2004) A multicenter, open-label clinical study of micafungin (FK463) in the treatment of deep-seated mycosis in Japan. Scand J Infect Dis 36:372–379

    Article  PubMed  CAS  Google Scholar 

  16. Ostrosky-Zeichner L, Kontoyiannis D, Raffalli J, Mullane KM, Vazquez J, Anaissie EJ, Lipton J, Jacobs P, van Rensburg JH, Rex JH, Lau W, Facklam D, Buell DN (2005) International, open-label, noncomparative, clinical trial of micafungin alone and in combination for treatment of newly diagnosed and refractory candidemia. Eur J Clin Microbiol Infect Dis 24:654–661

    Article  PubMed  CAS  Google Scholar 

  17. Denning DW, Marr KA, Lau WM, Facklam DP, Ratanatharathorn V, Becker C, Ullmann AJ, Seibel NL, Flynn PM, van Burik JA, Buell DN, Patterson TF (2006) Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 53:337–349

    Article  PubMed  Google Scholar 

  18. de Wet NTE, Bester AJ, Viljoen JJ, Filho F, Suleiman JM, Ticona E, Llanos EA, Fisco C, Lau W, Buell D (2005) A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther 21:899–907

    Article  PubMed  Google Scholar 

  19. Kuse E-R, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, Sekhon JS, Freire A, Ramasubramanian V, Demeyer I, Nucci M, Leelarasamee A, Jacobs F, Decruyenaere J, Pittet D, Ullmann AJ, Ostrosky-Zeichner L, Lortholary O, Koblinger S, Diekmann-Berndt H, Cornely OA, Micafungin Invasive Candidiasis Working Group (2007) Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 369:1519–1527

    Article  PubMed  CAS  Google Scholar 

  20. Pappas PG, Rotstein CMF, Betts RF, Nucci M, Talwar D, De Waele JJ, Vazquez JA, Dupont BF, Horn DL, Ostrosky-Zeichner L, Reboli AC, Suh B, Digumarti R, Wu C, Kovanda LL, Arnold LJ, Buell DN (2007) Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 45:883–893

    Article  PubMed  CAS  Google Scholar 

  21. Yanada M, Kiyoi H, Murata M, Suzuki M, Iwai M, Yokozawa T, Baba H, Emi N, Naoe T (2006) Micafungin, a novel antifungal agent, as empirical therapy in acute leukemia patients with febrile neutropenia. Intern Med 45:259–264

    Article  PubMed  Google Scholar 

  22. Toubai T, Tanaka J, Ota S, Shigematsu A, Shono Y, Ibata M, Hashino S, Kondo T, Kakinoki Y, Masauzi N, Kasai M, Iwasaki H, Kurosawa M, Asaka M, Imamura M (2007) Efficacy and safety of micafungin in febrile neutropenic patients treated for hematological malignancies. Intern Med 46:3–9

    Article  PubMed  Google Scholar 

  23. Tamura K, Urabe A, Yoshida M, Kanamaru A, Kodera Y, Okamoto Y, Maesaki S, Masaoka T (2009) Efficacy and safety of micafungin, an echinocandin antifungal agent, on invasive fungal infections in patients with hematological disorders. Leuk Lymphoma 50:92–100

    Article  PubMed  CAS  Google Scholar 

  24. Kubiak DW, Bryar JM, McDonnell AM, Delgado-Flores JO, Mui E, Baden LR, Marty FM (2010) Evaluation of caspofungin or micafungin as empiric antifungal therapy in adult patients with persistent febrile neutropenia: a retrospective, observational, sequential cohort analysis. Clin Therapeut 32:637–648

    Article  CAS  Google Scholar 

  25. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ, Invasive Fungal Infectious Cooperative Group of the European Organization for Research and Treatment of Cancer, Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34:7–14

    Article  PubMed  CAS  Google Scholar 

  26. Marr KA, Balajee SA, McLsughlin L, Tabouret M, Bentsen C, Walsh TI (2004) Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis 190:641–649

    Article  PubMed  CAS  Google Scholar 

  27. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Muñoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813–1821

    Article  PubMed  Google Scholar 

  28. Maertens J, Glasmacher A, Selleslag D, Ngai A, Ryan D, Layton M, Taylor A, Sable C, Kartsonis N (2005) Evaluation of serum sandwich enzyme-linked immunosorbent assay for circulating galactomannan during caspofungin therapy: results from the caspofungin invasive aspergillosis study. Clin Infect Dis 41:e9–e14

    Article  PubMed  Google Scholar 

  29. Pazos C, Ponton J, Del Palacio A (2005) Contribution of (1→3)-β-d-glucan chromogenic assay to diagnosis and therapeutic monitoring of invasive aspergillosis in neutropenic adult patients: a comparison with serial screening for circulating galactomannan. J Clin Microbiol 43:299–305

    Article  PubMed  CAS  Google Scholar 

  30. Ostrosky-Zeichner L, Alexander BD, Kett DH, Vasquez J, Pappas PG, Saeki F, Ketchum PA, Wingard J, Schiff R, Tamura H, Finkelman MA, Rex JH (2005) Multicenter clinical evaluation of the (1→3) beta-d-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 41:654–659

    Article  PubMed  CAS  Google Scholar 

  31. Kawazu M, Kanda Y, Nannya Y, Aoki K, Kurokawa M, Chiba S, Motokura T, Hirai H, Ogawa S (2004) Prospective comparison of the diagnostic potential of real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1→3)-β-d-glucan test in weekly screening for invasive aspergillosis in patients with hematological disorders. J Clin Microbiol 42:2733–2741

    Article  PubMed  CAS  Google Scholar 

  32. Masaoka T (2004) Evidence-based recommendations for antimicrobial use in febrile neutropenia in Japan: executive summary. Clin Infect Dis 39:S49–S52

    Article  PubMed  Google Scholar 

  33. de Pauw BE, Sable CA, Walsh TJ, Lupinacci RJ, Bourque MR, Wise BA, Nguyen BY, DiNubile MJ, Teppler H (2006) Impact of alternate definitions of fever resolution on the composite endpoint in clinical trials of empirical antifungal therapy for neutropenic patients with persistent fever: analysis of results from the Caspofungin Empirical Therapy Study. Transpl Infect Dis 8:31–37

    Article  PubMed  Google Scholar 

  34. National Committee for Clinical Laboratory Standards (2008) Reference method for broth dilution antifungal susceptibility testing of yeast. Approved standard M27-A2. NCCLS, Wayne

    Google Scholar 

  35. Pfaller MA, Diekema DJ, Ostrosky-Zeichner L, Rex JH, Alexander BD, Andes D, Brown SD, Chaturvedi V, Ghannoum MA, Knapp CC, Sheehan DJ, Walsh TJ (2008) Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints. J Clin Microbiol 46:2620–2629

    Article  PubMed  CAS  Google Scholar 

  36. Goodman D, Pamer E, Jakubowski A, Morris C, Sepkowitz K (2002) Breakthrough trichosporonosis in a bone marrow transplant recipient receiving caspofungin acetate. Clin Infect Dis 35:E35–E36

    Article  PubMed  Google Scholar 

  37. Bayramoglu G, Sonmez M, Tosun I, Aydin K, Aydin F (2008) Breakthrough Trichosporon asahii fungemia in neutropenic patient with acute leukemia while receiving caspofungin. Infection 36:68–70

    Article  PubMed  CAS  Google Scholar 

  38. Matsue K, Uryu H, Koseki M, Asada N, Takeuchi M (2006) Breakthrough trichosporonosis in patients with hematologic malignancies receiving micafungin. Clin Infect Dis 42:753–757

    Article  PubMed  CAS  Google Scholar 

  39. Akagi T, Yamaguti K, Kawamura T, Nakumura T, Kubo K, Takemori H (2006) Breakthrough trichosporonosis in patients with acute myeloid leukemia receiving micafungin. Leuk Lymphoma 47:1182–1183

    Article  PubMed  CAS  Google Scholar 

  40. van Burik JAH, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, Bunin N, Wall DA, Hiemenz JW, Satoi Y, Lee JM, Walsh TJ, National Institute of Allergy and Infectious Diseases Mycoses Study Group (2004) Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 39:1407–1416

    Article  PubMed  Google Scholar 

  41. Usami M, Ohata HT, Nagasawa K, Wakabayashi T, Tanaka S (2002) Positive (1→3)-β-D-glucan in blood components and release of (1→3)-β-D-glucan level. Transfusion 42:1189–1195

    Article  PubMed  CAS  Google Scholar 

  42. Ogawa M, Hori H, Niiguchi S, Azuma E, Komada Y (2004) False-positive plasma (1→3)-β-d-glucan test following immunoglobulin product replacement in an adult bone marrow recipient. Int J Hematol 80:97–98

    Article  PubMed  Google Scholar 

  43. Sulahian A, Touratier S, Ribaud P (2003) False positive test for aspergillosis antigenemia related to concomitant administration of piperacillin and tazobactam. N Engl J Med 349:2366–2367

    Article  PubMed  CAS  Google Scholar 

  44. Walsh TJ, Shoham S, Petraitiene R, Sein T, Schaufele R, Kelaher A, Murray H, Mya-San C, Bacher J, Petraitis V (2004) Detection of galactomannan antigenemia in patients receiving piperacillin–tazobactam and correlations between in vitro, in vivo, and clinical properties of the drug-antigen interaction. J Clin Microbiol 42:4744–4748

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was funded by Astellas Pharma Inc.

Author information

Authors and Affiliations

  1. Department of Hematology, Ishikawa Prefectural Central Hospital, 2-1 Kuratsukihigashi, Kanazawa City, Ishikawa, 920-8530, Japan

    Masaki Yamaguchi, Go Aoki & Mikio Ueda

  2. Department of Internal Medicine, Toyama Prefectural Central Hospital, 2-2-78 Nishinagae, Toyama City, 930-8550, Toyama, Japan

    Toshiro Kurokawa & Takashi Yoshida

  3. Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa City, 920-8641, Ishikawa, Japan

    Ken Ishiyama, Akiyoshi Takami, Hirohito Yamazaki & Shinji Nakao

  4. Department of Hematology, Tonami General Hospital, 1-61 Shintomi-cho, Tonami City, Toyama, 939-1395, Japan

    Sadaya Matano

  5. Department of Internal Medicine, NTT West Kanazawa Hospital, 6-26 Shimoshinmachi, Kanazawa City, Ishikawa, 920-0910, Japan

    Aiko Sawazaki

  6. Department of Internal Medicine, Kurobe City Hospital, 1108-1 Mikkaichi, Kurobe City, Toyama, 938-8502, Japan

    Hiromasa Yamauchi

Authors
  1. Masaki Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiro Kurokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ken Ishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Go Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mikio Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sadaya Matano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akiyoshi Takami
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hirohito Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Aiko Sawazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiromasa Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takashi Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shinji Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaki Yamaguchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamaguchi, M., Kurokawa, T., Ishiyama, K. et al. Efficacy and safety of micafungin as an empirical therapy for invasive fungal infections in patients with hematologic disorders: a multicenter, prospective study. Ann Hematol 90, 1209–1217 (2011). https://doi.org/10.1007/s00277-011-1277-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-011-1277-1

Keywords

Search

Navigation