Broad-Spectrum Antifungal Prophylaxis in Patients With Cancer at High Risk for Invasive Mold Infections: Counterpoint

Authors:
Johan Maertens From the Department of Hematology, Acute Leukemia and Hematopoietic Stem Cell Transplantation Unit, Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Leuven, Belgium, and Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Search for other papers by Johan Maertens in
Current site
Google Scholar
PubMed
Close
 MD
,
Kristel Buvé From the Department of Hematology, Acute Leukemia and Hematopoietic Stem Cell Transplantation Unit, Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Leuven, Belgium, and Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Search for other papers by Kristel Buvé in
Current site
Google Scholar
PubMed
Close
 MD
, and
Elias Anaissie From the Department of Hematology, Acute Leukemia and Hematopoietic Stem Cell Transplantation Unit, Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Leuven, Belgium, and Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Search for other papers by Elias Anaissie in
Current site
Google Scholar
PubMed
Close
 MD
Full access

Management of invasive mold infections in patients with prolonged neutropenia and hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) has been hampered by the difficulty in diagnosing these infections. Definite diagnosis invariably centers on histologic identification of hyphae in tissue or on culture from a sterile body site. Therefore, most practitioners have relied on prophylaxis and empiric therapy. Currently, emphasis is shifting from routine prophylaxis and empiric therapy to screening of patients with neutropenia at high risk so that clinicians can administer appropriate antifungal therapy early, when it can potentially improve patient outcome. Non–culture-based microbiologic tools are at the forefront of this paradigm shift. Commercially available methods to detect fungal antigens and sophisticated techniques to detect fungal DNA may be used as screening tools during the highest risk period. Together with assessment of clinical signs, cultures, and especially CT scanning, these methods are useful for starting antifungal therapy preemptively. While awaiting further evaluation of these tools during the postengraftment period of allogeneic HSCT, mold-active prophylaxis targeting the subgroup of patients with severe acute or chronic GVHD may be justified. However, some critical issues have not yet been adequately addressed, including the generalizability of study results, impact of mucositis and gastrointestinal GVHD on drug bioavailability, need for therapeutic drug monitoring, impact of prophylaxis on the performance of diagnostic assays, and optimal treatment of breakthrough invasive fungal infections.

Correspondence: Johan Maertens, MD, University Hospital Gasthuisberg, Department of Hematology, Acute Leukemia and Hematopoietic Stem Cell Transplantation Unit, Herestraat 49, B-3000, Leuven, Belgium. E-mail: johan.maertens@uz.kuleuven.ac.be
  • Collapse
  • Expand
  • 1.

    Goodman JL, Winston DJ, Greenfield RA et al.. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992;326:845851.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Slavin MA, Osborne B, Adams R et al.. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation-a prospective, randomized double blind study. J Infect Dis 1995;171:15451552.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Cornely OA, Ullmann AJ, Karthaus M. Evidence-based assessment of primary antifungal prophylaxis in patients with haematological malignancies. Blood 2003;101:33653372.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Bow EJ, Laverdiere M, Lussier N et al.. Antifungal prophylaxis for severely neutropenic chemotherapy patients. A meta-analysis of randomized-controlled clinical trials. Cancer 2002;94:32303246.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Glasmacher A, Prentice A, Gorschluter M et al.. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J Clin Oncol 2003;21:46154626.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Vardakas KZ, Michalopoulos A, Falagas ME. Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta-analysis of randomised-controlled trials. Br J Haematol 2005;131:2228.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Cornely OA, Maertens J, Winston DJ et al.. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348359.

  • 8.

    Ullmann AJ, Lipton JH, Vesole DH et al.. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335347.

  • 9.

    Maertens J, Deeren D, Dierickx D, Theunissen K. Pre-emptive antifungal therapy: still a way to go. Curr Opin Infect Dis 2006;19:551556.

  • 10.

    Mennink-Kersten MA, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis 2004;4:349357.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Maertens J, Verhaegen J, Lagrou K et al.. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 2001;97:16041610.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Pagano L, Caira M, Picardi M et al.. Invasive aspergillosis in patients with acute leukemia: update on morbidity and mortality—SEIFEM-C Report. Clin Infect Dis 2007;44:15241525.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Upton A, Kirby KA, Carpenter P et al.. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis 2007;44:531540.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Maertens J, Van Eldere J, Verhaegen J et al.. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis 2002;186:12971306.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Odabasi Z, Mattiuzzi G, Estey E et al.. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff, development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004;39:199205.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Marr KA, Balajee SA, McLaughlin L et al.. Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis 2004;190:641649.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Maertens J, Theunissen K, Lodewyck T et al.. Advances in the serological diagnosis of invasive Aspergillus infections in patients with haematological disorders. Mycoses 2007;50:217.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Maertens JA, Klont R, Masson C et al.. Optimization of the cutoff value for the Aspergillus double-sandwich enzyme immunoassay. Clin Infect Dis 2007;44:13291336.

  • 19.

    Ascioglu S, Rex JH, De Pauw B et al.. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34:714.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:14171427.

  • 21.

    Maertens J, Theunissen K, Deeren D et al.. Defining a case of invasive aspergillosis by serum galactomannan. Med Mycol 2006;44:S173178.

  • 22.

    Viscoli C, Machetti M, Cappellano P et al.. False-positive galactomannan Platelia Aspergillus test results for patients receiving piperacillin-tazobactam. Clin Infect Dis 2004;38:913916.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Surmont I, Stockman W. Gluconate-containing intravenous solutions: another cause of false-positive galactomannan assay reactivity. J Clin Microbiol 2007;45:1373.

  • 24.

    Upton A, Leisenring W, Marr K. (1→3) beta-D-Glucan assay in the diagnosis of invasive fungal infections. Clin Infect Dis 2006;42:10541056.

  • 25.

    Mennink-Kersten M, Warris A, Verweij P. 1,3-beta-D-glucan in patients receiving intravenous amoxicillin-clavulanic acid. N Engl J Med 2006;354:28342835.

  • 26.

    White PL, Linton CJ, Perry MD et al.. The evolution and evaluation of a whole blood polymerase chain reaction assay for the detection of invasive aspergillosis in hematology patients in a routine clinical setting. Clin Infect Dis 2006;42:479486.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Denning DW, Kibbler CC, Barnes. British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections. Lancet Infect Dis 2003;3:230240.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Caillot D, Casasnovas O, Bernard A et al.. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997;15:139147.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Caillot D, Couaillier JF, Bernard A et al.. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001;19:253259.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Greene RE, Schlamm HT, Oestmann JW et al.. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 2007;44:373379.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Greene R. The radiological spectrum of pulmonary aspergillosis. Med Mycol 2005;43(Suppl 1):S147154.

  • 32.

    Segal BH, Almyroudis NG, Battiwalla M et al.. Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts. Clin Infect Dis 2007;44:402409.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Cordonnier C, Ribaud P, Herbrecht R et al.. Société Française de Greffe de Moelle et de Thérapie Cellulaire. Prognostic factors for death due to invasive aspergillosis after hematopoietic stem cell transplantation: a 1-year retrospective study of consecutive patients at French transplantation centers. Clin Infect Dis 2006;42:955963.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Rex JH, Anaissie EJ, Boutati E et al.. Systemic antifungal prophylaxis reduces invasive fungal in acute myelogenous leukemia: a retrospective review of 833 episodes of neutropenia in 322 adults. Leukemia 2002;16:11971199.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Jantunen E, Nihtinen A, Volin L et al.. Candidaemia in allogeneic stem cell transplant recipients: low risk without fluconazole prophylaxis. Bone Marrow Transplant 2004;34:891895.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Chamilos G, Marom EM, Lewis RE et al.. Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer. Clin Infect Dis 2005;41:6066.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Lass-Flörl C, Resch G, Nachbaur D et al.. The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients. Clin Infect Dis 2007;45:e101104.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Maertens J, Theunissen K, Lagrou K et al.. Pre-emptive antifungal therapy in neutropenic onco-hematology patients. J Invasive Fungal Infect 2007;1:49.

  • 39.

    Severens JL, Donnelly JP, Meis JF et al.. Two strategies for managing invasive aspergillosis: a decision analysis. Clin Infect Dis 1997;25:11481154.

  • 40.

    Maertens J, Theunissen K, Verhoef G et al.. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 2005;41:12421250.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Oshima K, Kanda Y, Asano-Mori Y et al.. Presumptive treatment strategy for aspergillosis in allogeneic hematopoietic stem cell transplant recipients. J Antimicrob Chemother 2007;60:350355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Cordonnier C, Pautas C, Maury S et al.. Empirical versus pre-emptive antifungal therapy in high-risk febrile neutropenic patients: a prospective, randomized study. Presented at the 48th Annual Meeting of the American Society of Hematology; Orlando, Florida; December 9–12, 2006. Abstract 197-II.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Cornely OA, Maertens J, Bresnik M et al.. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007;44:12891297.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Marr KA, Crippa F, Leisenring W et al.. Cyclophosphamide metabolism is affected by azole antifungals. Blood 2004;103:15571559.

  • 45.

    Potoski BA, Brown J. The safety of voriconazole. Clin Infect Dis 2002;35:12731275.

  • 46.

    Imhof A, Schaer DJ, Schanz U, Schwarz U. Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring. Swiss Med Wkly 2006;136:739742.

  • 47.

    Trifilio S, Pennick G, Pi J et al.. Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients. Cancer 2007;109:15321535.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Marr KA, Seidel K, White TC et al.. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000;181:309316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Lionakis MS, Lewis RE, Torres HA et al.. Increased frequency of non-fumigatus Aspergillus species in amphotericin B- or triazole-pre-exposed cancer patients with positive cultures for aspergilli. Diagn Microbiol Infect Dis 2005;52:1520.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Kontoyiannis DP, Lionakis MS, Lewis RE 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. J Infect Dis 2005;191:13501360.

    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1203 483 100
PDF Downloads 302 103 14
EPUB Downloads 0 0 0