PDF
ePub
Citation
Print
Si-Hyun Kim, Dong-Gun Lee
, Su-Mi Choi, Jae-Cheol Kwon, Sun Hee Park, Jung-Hyun Choi, Jin-Hong Yoo, Sung-Eun Lee, Byung-Sik Cho, Yoo-Jin Kim, Seok Lee, Hee-Je Kim, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min, Jong-Won Park
, Su-Mi Choi, Jae-Cheol Kwon, Sun Hee Park, Jung-Hyun Choi, Jin-Hong Yoo, Sung-Eun Lee, Byung-Sik Cho, Yoo-Jin Kim, Seok Lee, Hee-Je Kim, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min, Jong-Won Park
Abstract
Background
Micafungin, a potent inhibitor of 1,3-β-D-glucan synthase, is a novel antifungal agent of the echinocandin class. In vitro study showed that micafungin was effective against Aspergillus species as well as Candida species, but clinical data on the prophylactic efficacy against invasive fungal infections (IFIs) other than candidiasis are still lacking.
Materials and Methods
We identified 60 consecutive adult hematopoietic stem cell transplantation (HSCT) recipients who received at least 3 doses of micafungin during neutropenic period. Micafungin was started as an alternative in patients who were intolerant or had adverse events (AEs) to primary prophylactic antifungal agents. We retrospectively reviewed the medical records and analyzed the efficacy and safety of micafungin for prophylaxis against IFIs.
Results
The patients either had autologous (n=9) or allogeneic (n=51: 1 syngeneic, 24 sibling, 26 unrelated donor) HSCT. Itraconazole oral solution (n=58) was the most frequently used first line antifungal agent for prophylaxis and was administered for median 11 days. The most frequent cause of switch to micafungin was vomiting (n=42). The duration of neutropenia and micafungin administration was median 13 and 12 days, respectively. A successful outcome was achieved in 45 (75%) patients. Empirical antifungal therapy was initiated in 13 (22%) patients. There were 2 cases (3.3%) of breakthrough fungal infections which comprised a probable invasive pulmonary aspergillosis and a possible invasive fungal sinusitis. There was no case of invasive candidiasis. A total of 53 (88%) patients experienced at least one AE regardless of causality during micafungin administration. The most frequent AEs were hypokalemia, vomiting, diarrhea, and elevated serum aspartate aminotransferase or alanine aminotransferase. Among the aforementioned AEs, only 1 case of diarrhea could be classified as a probable relation with micafungin when causality was assessed. There was no AEs that caused discontinuation of micafungin.
Figures and Tables
Table 3
Summary of Drug Adverse Events
*Adverse events were graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events version 3.0.
†The probability of adverse drug reactions were defined by Naranjo probability scale.
ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; Cr, creatinine; GGP, γ-glutamyl transpeptidase; LFTs, liver function tests; TB, total bilirubin.
Table 4
Clinical Data from Reports of Patients Undergoing Hematopoietic Stem Cell Transplantation with Micafungin Prophylaxis during Neutropenia
*'Empirical therapy' means the use of systemic antifungal agents for treatment of suspected fungal infections in patients with fever persisted for >96 h during the neutropenic phase despite broad-spectrum antibacterial therapy.
†'Breakthrough IFI' means the development of proven or probable invasive fungal infections defined by the EORTC/MSG in 2002 (33) during the administration of micafungin, except for in the study by Choi et al that counted possible cases in.
‡P=0.024
Allo-HSCT, allogeneic hematopoietic stem cell transplantation; IFI, invasive fungal infection; IV, intravenous; No., numbers of patients.
References
1. Mandell GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. 2005. 6th ed. Philadelphia: Elsevier Inc.;3495.
2. Viscoli C, Girmenia C, Marinus A, Collette L, Martino P, Vandercam B, Doyen C, Lebeau B, Spence D, Krcmery V, De Pauw B, Meunier F. Candidemia in cancer patients: a prospective multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of cancer (EORTC). Clin Infect Dis. 1999. 28:1071–1079.
3. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001. 32:358–366.
4. von Eiff M, Roos N, Schulten R, Hesse M, Zühlsdorf M, van de Loo J. Pulmonary aspergillosis: early diagnosis improves survival. Respiration. 1995. 62:341–347.
5. Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis. 2005. 5:609–622.
6. Maertens JA, Frère P, Lass-Flörl C, Heinz W, Cornely OA. Primary antifungal prophylaxis in leukaemia patients. Eur J Cancer. 2007. Suppl 5. 43–48.
7. Michallet M, Ito JI. Approaches to the management of invasive fungal infections in hematologic malignancy and hematopoietic cell transplantation. J Clin Oncol. 2009. 27:3398–3409.
8. Kuse ER, 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. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet. 2007. 369:1519–1527.
9. Pappas PG, Rotstein CM, 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. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007. 45:883–893.
10. van Burik JA, 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. 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.
11. 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. European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group. National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. 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. 2008. 43:1813–1821.
12. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Cancer Therapy Evaluation Program. Accessed 6 May 2009. Available at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
13. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981. 30:239–245.
14. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation. 1974. 18:295–304.
15. Lass-Flörl C. The changing face of epidemiology of invasive fungal diseases in Europe. Mycoses. 2009. 52:197–205.
16. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007. 20:133–163.
17. Tortorano AM, Kibbler C, Peman J, Bernhardt H, Klingspor L, Grillot R. Candidaemia in Europe: epidemiology and resistance. Int J Antimicrob Agents. 2006. 27:359–366.
18. Sanz MA, Jarque I, Salavert M, Pemán J. Epidemiology of invasive fungal infections due to Aspergillus spp. and zygomycetes. Clin Microbiol Infect. 2006. 12:2–6.
19. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, Wingard JR, Young JA, Boeckh MA. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009. 15:1143–1238.
20. Lee JS, Shin JH, Jung SI, Park KH, Choi HW, Cho D, Kee SJ, Kim SH, Shin MG, Suh SP, Ryang DW. In vitro susceptibilities of clinical isolates of Aspergillus species against echinocandins. Infect Chemother. 2007. 39:151–158.
21. Denning DW. Echinocandin antifungal drugs. Lancet. 2003. 362:1142–1151.
22. Arikan S, Yurdakul P, Hascelik G. Comparison of two methods and three end points in determination of in vitro activity of micafungin against Aspergillus spp. Antimicrob Agents Chemother. 2003. 47:2640–2643.
23. Chandrasekar PH, Sobel JD. Micafungin: a new echinocandin. Clin Infect Dis. 2006. 42:1171–1178.
24. Cross SA, Scott LJ. Micafungin: a review of its use in adults for the treatment of invasive and oesophageal candidiasis, and as prophylaxis against Candida infections. Drugs. 2008. 68:2225–2255.
25. Yoon MJ, Yoo DG, Hong YS, Park SY, Shin WS, Kang MW, Kim CC, Kim DJ. The spectrum of infection in patients with acute leukemia. Korean J Infect Dis. 1985. 17:45–52.
26. Choi H, Yoo JH, Shin WS, Kim YR, Kang MW, Kim DW, Lee JW, Park JW, Kim CC, Kim DJ. The spectrum of infection in patients with acute leukemia. Korean J Med. 1994. 46:496–504.
27. Choi JH, Kim YJ, Lee DG, Shin WS, Kim SW, Bae SS, Kimg SH, Yoo JH, Kim KM, Han KJ, Lee JW, Min WS, Kim CC. Infectious features in patients with acute leukemia. Korean J Infect Dis. 1999. 31:217–224.
28. Choi SM, Lee DG, Park YH, Kim YJ, Kim HJ, Lee S, Choi JH, Yoo JH, Kim DW, Lee JW, Min WS, Shin WS, Kim CC. Infections in patients with acute leukemia: comparison of induction chemotherapy group and reinduction chemotherapy group. Infect Chemother. 2003. 35:78–85.
29. Woo HY, Park SH, Lee DG, Jo HS, Min CK, Kim M, Han K, Shin WS. Two cases of Candida inconspicua infection in neutropenic patients with acute leukemia. Infect Chemother. 2006. 38:164–168.
30. Yoo JH, Choi JH, Lee DG, Choi S, Shin WS, Kim CC. Analysis of invasive fungal infection after hematopoietic stem cell transplantation or chemotherapy in patients with hematologic diseases. Infect Chemother. 2004. 36:40–45.
31. Choi SM, Lee DG, Choi JH, Park SH, Eom KS, Kim YJ, Kim HJ, Min CK, Yoo JH, Kim DW, Lee JW, Min WS, Shin WS, Kim CC. Itraconazole oral solution versus fluconazole syrup for prevention of invasive fungal infections in patients receiving hematopoietic stem cell transplantation: prospective, randomized, comparative clinical trial. Infect Chemother. 2005. 37:71–78.
32. Hiramatsu Y, Maeda Y, Fujii N, Saito T, Nawa Y, Hara M, Yano T, Asakura S, Sunami K, Tabayashi T, Miyata A, Matsuoka K, Shinagawa K, Ikeda K, Matsuo K, Tanimoto M. West-Japan Hematology and Oncology Group. Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation. Int J Hematol. 2008. 88:588–595.
33. 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 Infections Cooperative Group of the European Organization for Research and Treatment of Cancer. Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants an international consensus. Clin Infect Dis. 2002. 34:7–14.
34. Glasmacher A, Cornely O, Ullmann AJ, Wedding U, Bodenstein H, Wandt H, Boewer C, Pasold R, Wolf HH, Hänel M, Dölken G, Junghanss C, Andreesen R, Bertz H. Itraconazole Research Group of Germany. An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia. J Antimicrob Chemother. 2006. 57:317–325.
35. Harousseau JL, Dekker AW, Stamatoullas-Bastard A, Fassas A, Linkesch W, Gouveia J, De Bock R, Rovira M, Seifert WF, Joosen H, Peeters M, De Beule K. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrob Agents Chemother. 2000. 44:1887–1893.
36. Sohn HS, Lee TJ, Kim J, Kim D. Cost-effectiveness analysis of micafungin versus fluconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplantation in Korea. Clin Ther. 2009. 31:1105–1115.
37. Schonfeld W, Wang Cheng J, Tong KB, Seifeldin R. Cost-effectiveness analysis of antifungal prophylaxis in patients undergoing hematopoietic stem cell transplantation. Clin Ther. 2008. 30:964–973.
XML Download