Incidence Density of Invasive Fungal Infections during Primary Antifungal Prophylaxis in Newly Diagnosed Acute Myeloid Leukemia Patients in a Tertiary Cancer Center, 2009 to 2011

ABSTRACT Although primary antifungal prophylaxis (PAP) is routinely administered in patients with acute myeloid leukemia (AML) during remission-induction and consolidation chemotherapy, the impact of PAP on the incidence of invasive fungal infections (IFIs) is not well described. We retrospectively analyzed the incidence of IFIs in 152 patients with AML who had been admitted to a tertiary cancer center between August 2009 and March 2011 and received PAP within 120 days after first remission-induction chemotherapy. We excluded patients who had undergone stem cell transplantation. Patients received a PAP drug with anti-Aspergillus activity during 72% (7,660/10,572) of prophylaxis-days. The incidence of documented IFIs (definite or probable according to revised European Organization for Research and Treatment of Cancer [EORTC] criteria) was 2.0/1,000 prophylaxis-days (95% confidence interval [CI], 1.23 to 3.04). IFIs due to molds were more common than IFIs due to yeasts (1.5/1,000 prophylaxis-days versus 0.4/1,000 prophylaxis-days; P = 0.01). Echinocandin-based PAP (8.6 and 7.1/1,000 prophylaxis-days, respectively) was associated with higher rates of documented IFIs than anti-Aspergillus azoles (voriconazole or posaconazole) (2.4 and 1.1/1,000 prophylaxis-days, respectively) at both 42 days (P = 0.03) and 120 days (P < 0.0001) after first remission-induction chemotherapy. The incidence of overall (documented and presumed) IFIs (P < 0.001), documented IFIs (P < 0.01), and empirical antifungal therapies (P < 0.0001) was higher during the first 42 days than after day 42. Despite the broad use of PAP with anti-Aspergillus activity, IFIs, especially molds, remain a significant cause of morbidity and mortality in AML patients, predominantly during the remission-induction phase. Patients receiving echinocandin-based PAP experienced higher rates of IFIs than did those receiving anti-Aspergillus azoles.

[1]  John Moore,et al.  Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial. , 2013, The Lancet. Infectious diseases.

[2]  H. Einsele,et al.  Combined real‐time PCR and galactomannan surveillance improves diagnosis of invasive aspergillosis in high risk patients with haematological malignancies , 2013, British journal of haematology.

[3]  G. Gastl,et al.  Invasive fungal 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. , 2012, The Journal of antimicrobial chemotherapy.

[4]  R. Foà,et al.  Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience , 2012, Haematologica.

[5]  Tim Spelman,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 , 2012, Haematologica.

[6]  Russell E. Lewis,et al.  Importance of Pharmacokinetic Considerations for Selecting Therapy in the Treatment of Invasive Fungal Infections , 2012, American journal of therapeutics.

[7]  D. Kontoyiannis,et al.  Resistance to echinocandins comes at a cost , 2012, Virulence.

[8]  R. Haupt,et al.  Empirical versus pre-emptive antifungal therapy for persistent febrile neutropenia , 2012, Haematologica.

[9]  E. Estey,et al.  Continuing medical education activity in American Journal of Hematology , 2011 .

[10]  F. Grenouillet,et al.  Candida spp. with Acquired Echinocandin Resistance, France, 2004–2010 , 2012, Emerging infectious diseases.

[11]  D. Kontoyiannis Invasive mycoses: strategies for effective management. , 2012, The American journal of medicine.

[12]  M. Roberts,et al.  Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review. , 2012, International journal of antimicrobial agents.

[13]  A. Tortorano,et al.  Cross-Reactivity of Fusarium spp. in the Aspergillus Galactomannan Enzyme-Linked Immunosorbent Assay , 2011, Journal of Clinical Microbiology.

[14]  F. Dromer,et al.  Prior Caspofungin Exposure in Patients with Hematological Malignancies Is a Risk Factor for Subsequent Fungemia Due to Decreased Susceptibility in Candida spp.: a Case-Control Study in Paris, France , 2011, Antimicrobial Agents and Chemotherapy.

[15]  R. Lewis Current concepts in antifungal pharmacology. , 2011, Mayo Clinic proceedings.

[16]  S. Lockhart,et al.  Azole Resistance in Aspergillus fumigatus Isolates from the ARTEMIS Global Surveillance Study Is Primarily Due to the TR/L98H Mutation in the cyp51A Gene , 2011, Antimicrobial Agents and Chemotherapy.

[17]  J. Donnelly,et al.  Antifungal prophylaxis during treatment for haematological malignancies: are we there yet? , 2011, British journal of haematology.

[18]  Steven D. Brown,et al.  Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. , 2011, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[19]  G. Wassmer,et al.  Voriconazole serum concentrations in prophylactically treated acute myelogenous leukaemia patients , 2011, Mycoses.

[20]  A. Thiébaut,et al.  European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3—2009 Update , 2011, Bone Marrow Transplantation.

[21]  Russell E. Lewis,et al.  Mucormycosis Caused by Unusual Mucormycetes, Non-Rhizopus, -Mucor, and -Lichtheimia Species , 2011, Clinical Microbiology Reviews.

[22]  L. Pagano,et al.  Invasive aspergillosis in acute leukemias: old and new risk factors and epidemiological trends. , 2011, Medical mycology.

[23]  D. Kontoyiannis Antifungal prophylaxis in hematopoietic stem cell transplant recipients: the unfinished tale of imperfect success , 2011, Bone Marrow Transplantation.

[24]  E. Holler,et al.  Clinical experience with posaconazole prophylaxis – a retrospective analysis in a haematological unit , 2011, Mycoses.

[25]  F. Dromer,et al.  Recent Exposure to Caspofungin or Fluconazole Influences the Epidemiology of Candidemia: a Prospective Multicenter Study Involving 2,441 Patients , 2010, Antimicrobial Agents and Chemotherapy.

[26]  M. Hallek,et al.  Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort. , 2010, The Journal of antimicrobial chemotherapy.

[27]  D. Kontoyiannis,et al.  Fungal infections in leukemia patients: how do we prevent and treat them? , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[28]  V. Preedy,et al.  European Organization for Research and Treatment of Cancer , 2010 .

[29]  Russell E. Lewis,et al.  Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001‐2007) , 2009, Cancer.

[30]  C. Bloomfield,et al.  The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. , 2009, Blood.

[31]  H. Einsele,et al.  Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology , 2009, Haematologica.

[32]  H. Kantarjian,et al.  Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome , 2009, Supportive Care in Cancer.

[33]  L. Pagano,et al.  Invasive fungal infections in patients with acute myeloid leukemia and in those submitted to allogeneic hemopoietic stem cell transplant: who is at highest risk? , 2008, European journal of haematology.

[34]  Patricia Muñoz,et al.  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. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[35]  J. Szer,et al.  Antifungal prophylaxis in adult stem cell transplantation and haematological malignancy , 2008, Internal medicine journal.

[36]  J. Wingard,et al.  Changes in causes of death over time after treatment for invasive aspergillosis , 2008, Cancer.

[37]  T. Walsh,et al.  Cross-reactivity of non-Aspergillus fungal species in the Aspergillus galactomannan enzyme immunoassay. , 2007, Diagnostic microbiology and infectious disease.

[38]  J. Perfect,et al.  Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. , 2007, The New England journal of medicine.

[39]  J. Fine,et al.  Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[40]  E. Estey,et al.  Open-Label, Randomized Comparison of Itraconazole versus Caspofungin for Prophylaxis in Patients with Hematologic Malignancies , 2006, Antimicrobial Agents and Chemotherapy.

[41]  D. Kontoyiannis,et al.  Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003). , 2006, Haematologica.

[42]  L. Pagano,et al.  Design and Methods , 2022 .

[43]  W. Leisenring,et al.  Antifungal therapy decreases sensitivity of the Aspergillus galactomannan enzyme immunoassay. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[44]  Russell E. Lewis,et al.  Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. , 2005, The Journal of infectious diseases.

[45]  D. Denning Echinocandin antifungal drugs , 2003, The Lancet.