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Breakthrough Invasive Fungal Infections in Patients with Acute Myeloid Leukemia

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Abstract

Objectives

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.

Results

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.

Conclusions

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.

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References

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  11. Cronin S, Chandrasekar P. Safety of triazole antifungal drugs in patients with cancer. J Antimicrob Chemother. 2010;65:410–6.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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)

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  22. Kimura M, Araoka H, Yamamoto H, et al. Micafungin breakthrough fungemia in patients with hematological disorders. Antimicrob Agents Chemother. 2018;62:e02183–e2217.

    Article  CAS  Google Scholar 

  23. Pang KA, Godet C, Fekkar A, et al. Breakthrough invasive mould infections in patients treated with caspofungin. J Infect. 2012;64:424–9.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. Farmakiotis D, Tarrand J, Kontoyiannis DP. Drug-resistant Candida glabrata infection in cancer patients. Emerg Infect Dis. 2014;20:1833–40.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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Funding

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.

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Anastasia Wasylyshyn, Kathleen A. Linder, Caroline G. Castillo, Shiwei Zhou, Carol A. Kauffman & Marisa H. Miceli

  2. VA Ann Arbor Health Care System, Ann Arbor, MI, USA

    Kathleen A. Linder & Carol A. Kauffman

  3. Division of Infectious Diseases, University of Michigan Health System, F4005 University Hospital South, 1500 East Medical Dr., Ann Arbor, MI, 48109-5378, USA

    Marisa H. Miceli

Authors
  1. Anastasia Wasylyshyn
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  2. Kathleen A. Linder
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  3. Caroline G. Castillo
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  4. Shiwei Zhou
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  5. Carol A. Kauffman
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Correspondence to Marisa H. Miceli.

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Wasylyshyn, A., Linder, K.A., Castillo, C.G. et al. Breakthrough Invasive Fungal Infections in Patients with Acute Myeloid Leukemia. Mycopathologia 185, 299–306 (2020). https://doi.org/10.1007/s11046-019-00418-8

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  • DOI: https://doi.org/10.1007/s11046-019-00418-8

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