Breakthrough Invasive Fungal Infections in Patients with Acute Myeloid Leukemia

  • Anastasia Wasylyshyn
  • Kathleen A. Linder
  • Caroline G. Castillo
  • Shiwei Zhou
  • Carol A. Kauffman
  • Marisa H. MiceliEmail author
Original Article



We sought to determine the occurrence, risk factors, effect of antifungal prophylaxis, and outcomes of invasive fungal infections (IFIs) in patients with acute myeloid leukemia (AML).

Patients and Methods

We performed a retrospective analysis of all adult patients admitted to the University of Michigan Health System for AML over a 3-year period from 2010 to 2013. We determined comorbidities, hematopoietic cell transplant (HCT) status, antifungal prophylaxis, proven and probable IFI, and outcomes at 12 weeks after initiation of appropriate antifungal therapy.


Of 333 patients in our cohort, 116 of whom had received a HCT, 98 (29%) developed an IFI. Of the 30 (9%) patients who had a proven or probable IFI, 18 had breakthrough infection while on micafungin (n = 5), voriconazole (n = 4), posaconazole (n = 5), or fluconazole (n = 4). Breakthrough IFIs were due to Aspergillus species (n = 11), other molds (n = 4), and Candida species (n = 3). Factors associated with breakthrough IFI were prolonged severe neutropenia (p = .05) and having received tacrolimus (p = .04). Antifungal therapy was successful in 7 of the 18 (39%) patients with breakthrough IFI and 8 of the 12 (67%) patients with non-breakthrough IFI, p = .13. Mortality at 12 weeks was 27%, 5 with breakthrough IFI and 3 with non-breakthrough IFI and was associated with prolonged severe neutropenia, p = .04.


Patients with AML remain at risk for IFI despite the use of several different antifungal agents for prophylaxis. Mortality remains high in patients with AML who develop IFI.


Breakthrough invasive fungal infections Mold infections Acute leukemia Antifungal prophylaxis Aspergillosis 



Carol A. Kauffman is a member of the Data Safety Monitoring Board for CIDARA. Marisa H. Miceli is a consultant for Astellas and a member of the Data Review Committee for Scynexis.


  1. 1.
    Laverdierre M, Rotstein C, Bow EJ, et al. Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. J Antimicrob Chemother. 2000;46:1001–8.CrossRefGoogle Scholar
  2. 2.
    van Burik JH, Leisenring W, Myerson D, et al. The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. An autopsy study of 355 patients. Medicine (Baltimore). 1998;77:246–54.CrossRefGoogle Scholar
  3. 3.
    Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348–59.CrossRefGoogle Scholar
  4. 4.
    Anadah-Rajah MR, Grigg A, Downey MT, et al. Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologia. 2012;97:459–63.CrossRefGoogle Scholar
  5. 5.
    Rausch CR, DiPippo AJ, Bose P, et al. Breakthrough fungal infections in patients with leukemia receiving isavuconazole. Clin Infect Dis. 2018;67:1610–2.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Kim S-H, Choi J-K, Cho S-Y, et al. Risk factors and clinical outcomes of breakthrough yeast bloodstream infections in patients with hematological malignancies in the era of newer antifungal agents. Med Mycol. 2018;56:197–206.CrossRefGoogle Scholar
  7. 7.
    Breda GL, Tuon FF, Meis JF, et al. Breakthrough candidemia after the introduction of broad spectrum antifungal agents: a 5-year retrospective study. Med Mycol. 2018;56:406–15.CrossRefGoogle Scholar
  8. 8.
    Lionakis MS, Lewis RE, Kontoyiannis DP. Breakthrough invasive mold infections in the hematology patient: current concepts and future directions. Clin Infect Dis. 2018;67:1621–30.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Auberger J, Lass-Florl C, Aigner M, et al. Invasive breakthrough infections, fungal colonization and emergence of resistant strains in high-risk patients receiving antifungal prophylaxis with posaconazole: real-life data from a single-centre institutional retrospective observational study. J Antimicrob Chemother. 2012;67:2268–73.CrossRefGoogle Scholar
  10. 10.
    Biehl LM, Vehreschild JJ, Liss B, et al. A cohort study on breakthrough invasive fungal infections in high-risk patients receiving antifungal prophylaxis. J Antimicrob Chemother. 2016;71:2634–41.CrossRefGoogle Scholar
  11. 11.
    Cronin S, Chandrasekar P. Safety of triazole antifungal drugs in patients with cancer. J Antimicrob Chemother. 2010;65:410–6.CrossRefGoogle Scholar
  12. 12.
    Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.CrossRefGoogle Scholar
  13. 13.
    De Pauw B, Walsh TJ, Donnelly JP, et al. Fungal infections cooperative group and the national institute of allergy and infectious disease 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. Clin Infect Dis. 2008;46:813–21.CrossRefGoogle Scholar
  14. 14.
    Donnelly PJ, Chen S, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European organization for research and treatment of cancer and the mycoses study group education and research consortium. Clin Infect Dis. 2019 (in press)Google Scholar
  15. 15.
    Segal BH, Herbrecht R, Stevens DA, et al. Defining responses to therapy and study outcomes in clinical trials of invasive fungal infections: MSG and EORTC consensus criteria. Clin Infect Dis. 2008;47:674–83.CrossRefGoogle Scholar
  16. 16.
    Gomes MZR, Jiang Y, Mulanovich VE, et al. Effectiveness of primary anti-Aspergillus prophylaxis during remission induction chemotherapy of acute myeloid leukemia. Antimicrob Agents Chemother. 2014;58:2775–800.CrossRefGoogle Scholar
  17. 17.
    Kimura M, Araoka H, Yamamoto H, et al. Clinical and microbiological characteristics of breakthrough candidemia in allogeneic hematopoietic stem cell transplant recipients in a Japanese hospital. Antimicrob Agents Chemother. 2017;61:e01791–e1816.PubMedPubMedCentralGoogle Scholar
  18. 18.
    van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infection during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39:407–16.Google Scholar
  19. 19.
    Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335–47.CrossRefGoogle Scholar
  20. 20.
    Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348–59.CrossRefGoogle Scholar
  21. 21.
    Mattiuzi GN, Alvarado G, Giles FJ, et al. Open-label randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother. 2006;50:43–7.CrossRefGoogle Scholar
  22. 22.
    Kimura M, Araoka H, Yamamoto H, et al. Micafungin breakthrough fungemia in patients with hematological disorders. Antimicrob Agents Chemother. 2018;62:e02183–e2217.CrossRefGoogle Scholar
  23. 23.
    Pang KA, Godet C, Fekkar A, et al. Breakthrough invasive mould infections in patients treated with caspofungin. J Infect. 2012;64:424–9.CrossRefGoogle Scholar
  24. 24.
    Lerolle N, Raffoux EA, Socie G, et al. Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a 4-year study. Clin Microbiol infect. 2014;20:O952–O959959.CrossRefGoogle Scholar
  25. 25.
    Cattaneo C, Panzali A, Passi A, et al. Serum posaconazole levels during acute myeloid leukemia induction therapy: correlations with breakthrough infections. Mycoses. 2015;58:362–7.CrossRefGoogle Scholar
  26. 26.
    Cornely O, Ullmann AJ. Lack of evidence for exposure-response relationship in the use of posaconazole as prophylaxis against invasive fungal infections. Clin Pharmacol Ther. 2011;89:351–2.CrossRefGoogle Scholar
  27. 27.
    Tverdek FP, Heo ST, Aitken SL, et al. Real-life assessment of the safety and effectiveness of the new tablet and intravenous formulations of posaconazole in the prophylaxis of invasive fungal infections via analysis of 343 courses. Antimicrob Agents Chemother. 2017;61:e00188–e217.CrossRefGoogle Scholar
  28. 28.
    Pondas GN, Lewis RE, Samonis G, et al. Voriconazole-associated zygomycosis: a significant consequence of evolving antifungal prophylaxis and immunosuppression practices? Clin Microbiol Infect. 2009;15(Suppl. 5):93–7.Google Scholar
  29. 29.
    Farmakiotis D, Tarrand J, Kontoyiannis DP. Drug-resistant Candida glabrata infection in cancer patients. Emerg Infect Dis. 2014;20:1833–40.CrossRefGoogle Scholar
  30. 30.
    Lamoth F, Chung SJ, Damonti L, et al. Changing epidemiology of invasive mold infections in patients receiving azole prophylaxis. Clin Infect Dis. 2017;64:1619–21.CrossRefGoogle Scholar
  31. 31.
    Desnos-Ollivier M, Ragon M, Robert V, et al. Debaryomyces hansenii (Candida famata), a rare human fungal pathogen often misidentified as Pichia guilliermondii (Candida guilliermondii). J Clin Microbiol. 2008;46:3237–42.CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2020

Authors and Affiliations

  • Anastasia Wasylyshyn
    • 1
  • Kathleen A. Linder
    • 1
    • 2
  • Caroline G. Castillo
    • 1
  • Shiwei Zhou
    • 1
  • Carol A. Kauffman
    • 1
    • 2
  • Marisa H. Miceli
    • 1
    • 3
    Email author
  1. 1.Division of Infectious Diseases, Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  2. 2.VA Ann Arbor Health Care SystemAnn ArborUSA
  3. 3.Division of Infectious DiseasesUniversity of Michigan Health SystemAnn ArborUSA

Personalised recommendations