, Volume 68, Issue 14, pp 1941–1962 | Cite as

Patients at High Risk of Invasive Fungal Infections

When and How to Treat
  • Maria J. G. T. Rüping
  • Jörg J. Vehreschild
  • Oliver A. Cornely
Therapy In Practice


When and how to treat invasive fungal infections (IFIs) is discussed in this review, with a focus on the two most prevalent non-endemic IFIs, namely invasive aspergillosis and invasive candidiasis. Early treatment initiation in patients with IFIs has a profound impact on mortality rates, but reliable diagnostic measures are lacking. This situation has led to the parallel use of different treatment strategies, e.g. prophylaxis, empirical and pre-emptive treatment, as well as targeted treatment in response to a definite diagnosis of IFI. Identifying high-risk patients is the first step in reducing IFI-related mortality. Patients at risk of invasive aspergillosis comprise (i) those with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) during remission induction chemotherapy; (ii) patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT); (iii) recipients of solid organ transplants; and (iv) those with other conditions of severe and prolonged immunosuppression. Patients at high risk of invasive candidiasis are less well defined. Risk factors are diverse and include haematological malignancy, neutropenia, age <1 month or >65 years, and recent abdominal surgery. The individual risk further depends on the presence of a variety of other risk factors, including central venous catheters, use of broad spectrum antibacterials, prolonged intensive care unit (ICU) stay, total parenteral nutrition, mucosal Candida spp. colonization and renal failure.

Extensive research has been conducted to facilitate the best possible treatment strategies for these severe infections. Optimal timing and choice of antifungal agents largely remain a matter of controversy. After having reviewed the major clinical trials, we conclude that comparisons between different treatment strategies cannot be made, neither at present nor in the near future. The complexity of the clinical problem leads to an eclectic treatment approach to reduce morbidity and mortality from IFIs without compromising tolerability. We recommend prophylaxis with posaconazole for allogeneic HSCT recipients, patients receiving induction chemotherapy for AML or MDS, and those undergoing immunosuppressive therapy for graft-versus-host disease after allogeneic HSCT. For the empirical treatment of persistently febrile neutropenia, caspofungin is our first-and liposomal amphotericin B deoxycholate (LAmB) our second-line choice. Once a diagnosis of invasive aspergillosis has been established, voriconazole should be the preferred treatment option, with LAmB being an alternative. Fluconazole prophylaxis for invasive candidiasis should remain restricted to high-risk ICU patients. Once a diagnosis has been established, the drug of choice for adequate treatment depends largely on neutrophil count and haemodynamic stability. In non-neutropenic patients, an echinocandin should be considered the first-line treatment option, while patients with susceptible Candida spp. may be switched to fluconazole. In neutropenic patients, caspofungin or micafungin might be preferred to anidulafungin as first-line treatment. LAmB is a second-line treatment option in both settings.

Early diagnosis of IFIs is imperative to facilitate treatment success. In all patients at risk for IFIs, blood cultures, galactomannan antigen and diagnostic imaging should be rigorously enforced.


Fluconazole Voriconazole Intensive Care Unit Patient Invasive Aspergillosis Caspofungin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors did not receive any funding or external help for the completion of this article. Dr Rüping has received travel grants from Schering-Plough/Essex and Gilead. Dr Vehreschild has received travel grants from Merck Sharp & Dohme/Merck, Pfizer, Schering-Plough and Viropharma. Dr Cornely is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN0706) and has received research grants from, is an advisor to, or served at the speakers’ bureau of Astellas, Basilea, Bayer, F2G, Genzyme, Gilead, Pfizer, Merck, Mölnlycke, Nektar, Optimer, Schering-Plough, SpePharm, United Medical, Vicuron and Zeneus.


  1. 1.
    Maschmeyer G, Haas A, Cornely OA. Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drags 2007; 67(11): 1567–601Google Scholar
  2. 2.
    Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 2007 Jan; 20(1): 133–63PubMedGoogle Scholar
  3. 3.
    Morris A, Lundgren JD, Masur H, et al. Current epidemiology of Pneumocystis pneumonia: emerging infectious diseases 2004 Oct; 10(10): 1713–20PubMedGoogle Scholar
  4. 4.
    Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002 Apr 1; 34(7): 909–17PubMedGoogle Scholar
  5. 5.
    Husain S, Alexander BD, Munoz P, et al. Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin Infect Dis 2003 Jul 15; 37(2): 221–9PubMedGoogle Scholar
  6. 6.
    Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med 1999 Mar 11; 340(10): 764–71PubMedGoogle Scholar
  7. 7.
    Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002 Jan 24; 346(4): 225–34PubMedGoogle Scholar
  8. 8.
    Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004 Sep 30; 351(14): 1391–402PubMedGoogle Scholar
  9. 9.
    Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002 Aug 8; 347(6): 408–15PubMedGoogle Scholar
  10. 10.
    Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002 Dec 19; 347(25): 2020–9PubMedGoogle Scholar
  11. 11.
    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 Jan 1; 34(1): 7–14PubMedGoogle Scholar
  12. 12.
    Cornely OA, Ullmann AJ, Karthaus M. Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies. Blood 2003 May 1; 101(9): 3365–72PubMedGoogle Scholar
  13. 13.
    Ullmann AJ, Cornely OA. Antifungal prophylaxis for invasive mycoses in high risk patients. Curr Opin Infect Dis 2006 Dec; 19(6): 571–6PubMedGoogle Scholar
  14. 14.
    Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006 Aug; 91(8): 1068–75PubMedGoogle Scholar
  15. 15.
    Denning DW. Invasive aspergillosis. Clin Infect Dis 1998 Apr; 26(4): 781–803; quiz 4-5PubMedGoogle Scholar
  16. 16.
    Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002 Dec 15; 100(13): 4358–66PubMedGoogle Scholar
  17. 17.
    Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis: disease spectrum, treatment practices, and outcomes. 13 Aspergillus Study Group. Medicine (Baltimore) 2000 Jul; 79(4): 250–60Google Scholar
  18. 18.
    Martino R, Parody R, Fukuda T, et al. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 2006 Nov 1; 108(9): 2928–36PubMedGoogle Scholar
  19. 19.
    Cornet M, Fleury L, Maslo C, et al. Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area. J Hosp Infect 2002 Aug; 51(4): 288–96PubMedGoogle Scholar
  20. 20.
    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 May 15; 44(10): 1289–97PubMedGoogle Scholar
  21. 21.
    Cordonnier C, Ribaud P, Herbrecht R, et al. 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 Apr 1; 42(7): 955–63PubMedGoogle Scholar
  22. 22.
    Martino R, Subira M, Rovira M, et al. Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients. Br J Haematol 2002 Feb; 116(2): 475–82PubMedGoogle Scholar
  23. 23.
    Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis 1993 May; 16(5): 677–88PubMedGoogle Scholar
  24. 24.
    Winston DJ, Emmanouilides C, Busuttil RW. Infections in liver transplant recipients. Clin Infect Dis 1995 Nov; 21(5): 1077–89; quiz 90-1PubMedGoogle Scholar
  25. 25.
    Infectious disease community of practice, fungal infections. Am J Transplant 2004; 4 Suppl. 10: 110–34Google Scholar
  26. 26.
    Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007 Dec 20; 357(25): 2601–14PubMedGoogle Scholar
  27. 27.
    Singh N. Antifungal prophylaxis for solid organ transplant recipients: seeking clarity amidst controversy. Clin Infect Dis 2000 Aug; 31(2): 545–53PubMedGoogle Scholar
  28. 28.
    Singh N, Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management. J Heart Lung Transpl 2003 Mar; 22(3): 258–66Google Scholar
  29. 29.
    Fortun J, Martin-Davila P, Moreno S, et al. Risk factors for invasive aspergillosis in liver transplant recipients. Liver Transpl 2002 Nov; 8(11): 1065–70PubMedGoogle Scholar
  30. 30.
    Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev 2005 Jan; 18(1): 44–69PubMedGoogle Scholar
  31. 31.
    Hellinger WC, Bonatti H, Yao JD, et al. Risk stratification and targeted antifungal prophylaxis for prevention of aspergillosis and other invasive mold infections after liver transplantation. Liver Transpl 2005 Jun; 11(6): 656–62PubMedGoogle Scholar
  32. 32.
    Gavalda J, Len O, San Juan R, et al. Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study. Clin Infect Dis 2005 Jul 1; 41(1): 52–9PubMedGoogle Scholar
  33. 33.
    Patterson JE. Epidemiology of fungal infections in solid organ transplant patients. Transpl Infect Dis 1999 Dec; 1(4): 229–36PubMedGoogle Scholar
  34. 34.
    Singh N. Impact of current transplantation practices on the changing epidemiology of infections in transplant recipients. Lancet 2003 Mar; 3(3): 156–61Google Scholar
  35. 35.
    Lortholary O, Meyohas MC, Dupont B, et al. Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. French Cooperative Study Group on Aspergillosis in AIDS. Am J Med 1993 Aug; 95(2): 177–87PubMedGoogle Scholar
  36. 36.
    Bruck HM, Nash G, Foley D, et al. Opportunistic fungal infection of the burn wound with phycomycetes and Aspergillus: a clinical-pathologic review. Arch Surg 1971 May; 102(5): 476–82PubMedGoogle Scholar
  37. 37.
    Stone HH, Cuzzell JZ, Kolb LD, et al. Aspergillus infection of the burn wound. J Trauma 1979 Oct; 19(10): 765–7PubMedGoogle Scholar
  38. 38.
    Becker WK, Cioffi Jr WG, McManus AT, et al. Fungal burn wound infection: a 10-year experience. Arch Surg 1991 Jan; 126(1): 44–8PubMedGoogle Scholar
  39. 39.
    Labbe AC, Su SH, Laverdiere M, et al. High incidence of invasive aspergillosis associated with intestinal graft-versus-host disease following nonmyeloablative transplantation. Biol Blood Marrow Transplant 2007 Oct; 13(10): 1192–200PubMedGoogle Scholar
  40. 40.
    Narreddy S, Mellon-Reppen S, Abidi MH, et al. Non-bacterial infections in allogeneic non-myeloablative stem cell transplant recipients. Transpl Infect Dis 2007 Mar; 9(1): 3–10PubMedGoogle Scholar
  41. 41.
    Thursky KA, Worth LJ, Seymour JF, et al. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. Br J Haematol 2006 Jan; 132(1): 3–12PubMedGoogle Scholar
  42. 42.
    Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002 May 15; 99(10): 3554–61PubMedGoogle Scholar
  43. 43.
    Meersseman W, Van Wijngaerden E. Invasive aspergillosis in the ICU: an emerging disease. Intensive Care Med 2007 Oct; 33(10): 1679–81PubMedGoogle Scholar
  44. 44.
    Meersseman W, Vandecasteele SJ, Wilmer A, et al. Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004 Sep 15; 170(6): 621–5PubMedGoogle Scholar
  45. 45.
    Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004 Aug 1; 39(3): 309–17PubMedGoogle Scholar
  46. 46.
    Almirante B, Rodriguez D, Park BJ, et al. Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, Barcelona, Spain, from 2002 to 2003. J Clin Microbiol 2005 Apr; 43(4): 1829–35PubMedGoogle Scholar
  47. 47.
    Asmundsdottir LR, Erlendsdottir H, Gottfredsson M. Increasing incidence of candidemia: results from a 20-year nationwide study in Iceland. J Clin Microbiol 2002 Sep; 40(9): 3489–92PubMedGoogle Scholar
  48. 48.
    Laupland KB, Gregson DB, Church DL, et al. Invasive Candida species infections: a 5 year population-based assessment. J Antimicrob Chemother 2005 Sep; 56(3): 532–7PubMedGoogle Scholar
  49. 49.
    Poikonen E, Lyytikainen O, Anttila VJ, et al. Candidemia in Finland, 1995–1999. Emerg Infect Dis 2003 Aug; 9(8): 985–90PubMedGoogle Scholar
  50. 50.
    Sandven P, Bevanger L, Digranes A, et al. Candidemia in Norway (1991 to 2003): results from a nationwide study. J Clin Microbiol 2006 Jun; 44(6): 1977–81PubMedGoogle Scholar
  51. 51.
    Arendrup MC, Fuursted K, Gahrn-Hansen B, et al. Seminational surveillance of fungemia in Denmark: notably high rates of fungemia and numbers of isolates with reduced azole susceptibility. J Clin Microbiol 2005 Sep; 43(9): 4434–40PubMedGoogle Scholar
  52. 52.
    Diekema DJ, Messer SA, Brueggemann AB, et al. Epidemiology of candidemia: 3-year results from the emerging infections and the epidemiology of Iowa organisms study. J Clin Microbiol 2002 Apr; 40(4): 1298–302PubMedGoogle Scholar
  53. 53.
    Kao AS, Brandt ME, Pruitt WR, et al. The epidemiology of candidemia in two United States cities: results of a population-based active surveillance. Clin Infect Dis 1999 Nov; 29(5): 1164–70PubMedGoogle Scholar
  54. 54.
    Hajjeh RA, Sofair AN, Harrison LH, et al. Incidence of bloodstream infections due to Candida species and in vitro susceptibilities of isolates collected from 1998 to 2000 in a populationbased active surveillance program. J Clin Microbiol 2004 Apr; 42(4): 1519–27PubMedGoogle Scholar
  55. 55.
    Lin MY, Carmeli Y, Zumsteg J, et al. Prior antimicrobial therapy and risk for hospital-acquired Candida glabrata and Candida knisei fungemia: a case-case-control study. Antimicrob Agents Chemother 2005 Nov; 49(11): 4555–60PubMedGoogle Scholar
  56. 56.
    Abi-Said D, Anaissie E, Uzun O, et al. The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis 1997 Jun; 24(6): 1122–8PubMedGoogle Scholar
  57. 57.
    Antoniadou A, Torres HA, Lewis RE, et al. Candidemia in a tertiary care cancer center: in vitro susceptibility and its association with outcome of initial antifungal therapy. Medicine (Baltimore) 2003 Sep; 82(5): 309–21Google Scholar
  58. 58.
    Blumberg HM, Jarvis WR, Soucie JM, et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis 2001 Jul 15; 33(2): 177–86PubMedGoogle Scholar
  59. 59.
    Eggimann P, Garbino J, Pittet D. Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. Lancet Infect Dis 2003 Nov; 3(11): 685–702PubMedGoogle Scholar
  60. 60.
    Marr KA, Scidel 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 Jan; 181(1): 309–16PubMedGoogle Scholar
  61. 61.
    Pappas PG, Rex JH, Lee J, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis 2003; 37: 634–43PubMedGoogle Scholar
  62. 62.
    Wey SB, Mori M, Pfaller MA, et al. Risk factors for hospital-acquired candidemia: a matched case-control study. Arch Int Med 1989; 149(10): 2349–53Google Scholar
  63. 63.
    Martino P, Girmenia C, Micozzi A, et al. Prospective study of Candida colonization, use of empiric amphotericin B and development of invasive mycosis in neutropenic patients. Eur J Clin Microbiol Infect Dis 1994; 13(10): 797–804PubMedGoogle Scholar
  64. 64.
    Diekema DJ, Pfaller MA. Nosocomial candidemia: an ounce of prevention is better than a pound of cure. Infect Control Hosp Epidemiol 2004 Aug; 25(8): 624–6PubMedGoogle Scholar
  65. 65.
    Ostrosky-Zeichner L. Prophylaxis and treatment of invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis 2004 Oct; 23(10): 739–44PubMedGoogle Scholar
  66. 66.
    Paphitou NI, Ostrosky-Zeichner L, Rex JH. Rules for identifying patients at increased risk for candidal infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials. Med Mycol 2005 May; 43(3): 235–43PubMedGoogle Scholar
  67. 67.
    Wenzel RP, Gennings C. Bloodstream infections due to Candida species in the intensive care unit: identifying especially high-risk patients to determine prevention strategies. Clin Infect Dis 2005 Sep 15; 41 Suppl. 6: S389–93PubMedGoogle Scholar
  68. 68.
    Pelz RK, Hendrix CW, Swoboda SM, et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg 2001 Apr; 233(4): 542–8PubMedGoogle Scholar
  69. 69.
    Leon C, Ruiz-Santana S, Saavedra P, et al. A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med 2006 Mar; 34(3): 730–7PubMedGoogle Scholar
  70. 70.
    Ostrosky-Zeichner L, Sable C, Sobel J, et al. Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis 2007 Apr; 26(4): 271–6PubMedGoogle Scholar
  71. 71.
    Pittet D, Monod M, Suter PM, et al. Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 1994 Dec; 220(6): 751–8PubMedGoogle Scholar
  72. 72.
    Dupont H, Bourichon A, Paugam-Burtz C, et al. Can yeast isolation in peritoneal fluid be predicted in intensive care unit patients with peritonitis? Crit Care Med 2003 Mar; 31(3): 752–7PubMedGoogle Scholar
  73. 73.
    Richet H, Roux P, Des Champs C, et al. Candidemia in French hospitals: incidence rates and characteristics. Clin Microbiol Infect 2002; 8: 405–12PubMedGoogle Scholar
  74. 74.
    Tortorano AM, Biraghi E, Astofi A, et al. European Confederation of Medical Mycology (ECMM) prospective survey of candidaemia: report from one Italian region. J Hosp Infect 2002; 51: 297–304PubMedGoogle Scholar
  75. 75.
    Marchetti O, Bille J, Fluckinger U, et al. Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991–2000. Clin Infect Dis 2004; 38: 311–20PubMedGoogle Scholar
  76. 76.
    Chen YC, Chang SC, Luh KT, et al. Stable susceptibility of Candida blood isolates to fluconazole despite increasing use during the past 10 years. J Antimicrob Chemother 2003; 52: 71–7PubMedGoogle Scholar
  77. 77.
    Hsueh PR, Lau YJ, Chuang YC, et al. Antifungal susceptibilities of clinical isolates of Candida species, Cryptococcus neoformans, and Aspergillus species from Taiwan: surveillance of multicenter antimicrobial resistance in Taiwan program data from 2003. Antimicrob Agents Chemother 2005 Feb; 49(2): 512–7PubMedGoogle Scholar
  78. 78.
    Pfaller MA, Boyken L, Hollis RJ, et al. In vitro susceptibilities of Candida spp. to caspofungin: four years of global surveillance. J Clin Microbiol 2006 Mar; 44(3): 760–3PubMedGoogle Scholar
  79. 79.
    Colombo AL, Nucci M, Salomao R, et al. High rate of non-albicans candidemia in Brazilian tertiary care hospitals. Diagn Microbiol Infect Dis 1999 Aug; 34(4): 281–6PubMedGoogle Scholar
  80. 80.
    Pfaller MA, Messer SA, Boyken L, et al. Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to seven systemically active antifungal agents: a global assessment from the ARTEMIS Antifungal Surveillance Program conducted in 2001 and 2002. J Clin Microbiol 2004; 42: 3142–6PubMedGoogle Scholar
  81. 81.
    Klevay MJ, Ernst EJ, Hollanbaugh JL, et al. Therapy and outcome of Candida glabrata versus Candida albicans bloodstream infection. Diagn Microbiol Infect Dis 2008 Mar; 60(3): 273–7PubMedGoogle Scholar
  82. 82.
    Gudlaugsson O, Gillespie S, Lee K, et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003 Nov 1;37(9): 1172–7PubMedGoogle Scholar
  83. 83.
    Pfaller MA, Diekema DJ, Gibbs DL, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance study, 1997 to 2005: an 8.5-year analysis of susceptibilities of Candida species and other yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol 2007 Jun; 45(6): 1735–45PubMedGoogle Scholar
  84. 84.
    Scifert H, Aurbach U, Stefanik D, et al. In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates. Antimicrob Agents Chemother 2007 May; 51(5): 1818–21Google Scholar
  85. 85.
    National Center for Biotechnology Information. The NCBI taxonomy homepage [online]. Available from URL: [Accessed 2008 Jul 16]
  86. 86.
    De Pauw B, Walsh TJ, Donnelly JP, 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. Clin Infect Dis 2008 Jun 15; 46(12): 1813–21PubMedGoogle Scholar
  87. 87.
    Kuhlman JE, Fishman EK, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology 1985 Dec; 157(3): 611–4PubMedGoogle Scholar
  88. 88.
    Vandewoude KH, Blot SI, Depuydt P, et al. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Crit Care 2006 Feb; 10(1): R31PubMedGoogle Scholar
  89. 89.
    Garnacho-Montero J, Amaya-Villar R. A validated clinical approach for the management of aspergillosis in critically ill patients: ready, steady, go! [letter]. Crit Care 2006; 10(2): 132PubMedGoogle Scholar
  90. 90.
    Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 2005 Oct; 5(10): 609–22PubMedGoogle Scholar
  91. 91.
    Uffredi ML, Mangiapan G, Cadranel J, et al. Significance of Aspergillus fumigatus isolation from respiratory specimens of nongranulocytopenic patients. Eur J Clin Microbiol Infect Dis 2003 Aug; 22(8): 457–62PubMedGoogle Scholar
  92. 92.
    Husain S, Kwak EJ, Obman A, et al. Prospective assessment of Platelia Aspergillus galactomannan antigen for the diagnosis of invasive aspergillosis in lung transplant recipients. Am J Transplant 2004 May; 4(5): 796–802PubMedGoogle Scholar
  93. 93.
    Kwak EJ, Husain S, Obman A, et al. Efficacy of galactomannan antigen in the Platelia Aspergillus enzyme immunoassay for diagnosis of invasive aspergillosis in liver transplant recipients. J Clin Microbiol 2004 Jan; 42(1): 435–8PubMedGoogle Scholar
  94. 94.
    Digby J, Kalbfleisch J, Glenn A, et al. Serum glucan levels are not specific for presence of fungal infections in intensive care unit patients. Clin Diagn Lab Immunol 2003 Sep; 10(5): 882–5PubMedGoogle Scholar
  95. 95.
    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 Oct; 131(1): 22–8PubMedGoogle Scholar
  96. 96.
    Glasmacher A, Cornely O, Ullmann AJ, et al. 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 Feb; 57(2): 317–25PubMedGoogle Scholar
  97. 97.
    Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007 Jan 25; 356(4): 348–59PubMedGoogle Scholar
  98. 98.
    Vehreschild JJ, Böhme A, Buchheidt D, et al. A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML). J Infect 2007 Nov; 55(5): 445–9PubMedGoogle Scholar
  99. 99.
    Cornely OA, Stollorz A, Beisel C, et al. Impact of posaconazole prophylaxis on the epidemiology of invasive aspergillosis. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL)Google Scholar
  100. 100.
    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 Mar 26; 326(13): 845–51PubMedGoogle Scholar
  101. 101.
    Slavin MA, Osbome 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(6): 1545–52PubMedGoogle Scholar
  102. 102.
    Wingard JR, Carter SL, Walsh TJ, et al. Results of a randomized, double-blind trial of fluconazole (FLU) vs voriconazole (VORI) for the prevention of invasive fungal infections (IFI) in 600 allogeneic blood and marrow transplant (BMT) Patients. ASH Annual Meeting; 2007 Dec 8–11; Atlanta (GA)Google Scholar
  103. 103.
    Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007 Jan 25; 356(4): 335–47PubMedGoogle Scholar
  104. 104.
    Ullmann AJ, Heussel CP, Cornely OA. Voriconazole versus liposomal amphotericin B for empirical antifungal therapy. N Engl J Med 2002 May 30; 346(22): 1745–7; discussion 1747PubMedGoogle Scholar
  105. 105.
    Marr KA. Empirical antifungal therapy: new options, new tradeoffs. N Engl J Med 2002 Jan 24; 346(4): 278–80PubMedGoogle Scholar
  106. 106.
    Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy: a randomized, controlled trial. Ann Intern Med 2001 Sep 18; 135(6): 412–22PubMedGoogle Scholar
  107. 107.
    Link H, Böhme A, Cornely OA, et al. Antimicrobial therapy of unexplained fever in neutropenic patient: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003 Oct; 82 Suppl. 2: S105–17PubMedGoogle Scholar
  108. 108.
    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 Nov 1; 41(9): 1242–50PubMedGoogle Scholar
  109. 109.
    Viscoli C, Herbrecht R, Akan H, et al. Caspofungin as first-line therapy of invasive aspergillosis in haematological patients: a study of the EORTC Infectious Diseases Group. Trends in Medical Mycology Congress 2007; 2007 Oct 28–31; TurinGoogle Scholar
  110. 110.
    van’t Wout JW, Novakova I, Verhagen CA, et al. The efficacy of itraconazole against systemic fungal infections in neutropenic patients: a randomised comparative study with amphotericin B. J Infect 1991 Jan; 22(1): 45–52Google Scholar
  111. 111.
    Caillot D, Bassaris H, McGeer A, et al. Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS. Clin Infect Dis 2001 Oct 15; 33(8): e83–90PubMedGoogle Scholar
  112. 112.
    Denning DW, Lee JY, Hostetler JS, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med 1994 Aug; 97(2): 135–44PubMedGoogle Scholar
  113. 113.
    Ostrosky-Zeichner L. Combination antifungal therapy: a critical review of the evidence. Clin Microbiol Infect 2008 May; 14 Suppl. 4: 65–70PubMedGoogle Scholar
  114. 114.
    Eggimann P, Francioli P, Bille J, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med 1999 Jun; 27(6): 1066–72PubMedGoogle Scholar
  115. 115.
    Garbino J, Lew DP, Romand JA, et al. Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: a randomized, double-blind, placebo-controlled trial in patients treated by selective digestive decontamination. Intensive Care Med 2002 Dec; 28(12): 1708–17PubMedGoogle Scholar
  116. 116.
    Swoboda SM, Merz WG, Lipsetta PA. Candidemia: the impact of antifungal prophylaxis in a surgical intensive care unit. Surg Infect 2003 Winter; 4(4): 345–54Google Scholar
  117. 117.
    Cruciani M, de Lalla F, Mengoli C. Prophylaxis of Candida infections in adult trauma and surgical intensive care patients: a systematic review and meta-analysis. Intensive Care Med 2005 Nov; 31(11): 1479–87PubMedGoogle Scholar
  118. 118.
    Playford EG, Webster AC, Sorrell TC, et al. Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: systematic review and meta-analysis of randomized clinical trials. J Antimicrob Chemother 2006 Apr; 57(4): 628–38PubMedGoogle Scholar
  119. 119.
    Rex JH, Sobel JD. Prophylactic antifungal therapy in the intensive care unit. Clin Infect Dis 2001 Apr 15; 32(8): 1191–200PubMedGoogle Scholar
  120. 120.
    Ostrosky-Zeichner L, Sobel J, Pappas P, et al. Lessons from a multicenter, randomized, double-blind trial and insights into diagnostic performance of surrogate markers; M-1158. Interscience Conference on Antimicrobial Agents and Chemotherapy 2007; 2007 Sep 17–20; Chicago (IL)Google Scholar
  121. 121.
    Cruciani M, Mengoli C, Malena M, et al. Antifungal prophylaxis in liver transplant patients: a systematic review and meta-analysis. Liver Transpl 2006 May; 12(5): 850–8PubMedGoogle Scholar
  122. 122.
    Cruciani M, Serpelloni G. Management of Candida infections in the adult intensive care unit. Expert Opin Pharmacother 2008 Feb; 9(2): 175–91PubMedGoogle Scholar
  123. 123.
    Piarroux R, Grenouillet F, Balvay P, et al. Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med 2004 Dec; 32(12): 2443–9PubMedGoogle Scholar
  124. 124.
    Rex JH, Bennett JE, Sugar AM, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 1994 Nov 17; 331(20): 1325–30PubMedGoogle Scholar
  125. 125.
    Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised noninferiority trial. Lancet 2005 Oct 22–28; 366(9495): 1435–42PubMedGoogle Scholar
  126. 126.
    Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007 May 5; 369(9572): 1519–27PubMedGoogle Scholar
  127. 127.
    Pappas PG, Rotstein CM, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007 Oct 1; 45(7): 883–93PubMedGoogle Scholar
  128. 128.
    Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007 Jun 14; 356(24): 2472–82PubMedGoogle Scholar
  129. 129.
    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 Feb 1; 44(3): 373–9PubMedGoogle Scholar
  130. 130.
    Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008 Feb 1; 46(3): 327–60PubMedGoogle Scholar
  131. 131.
    Karthaus M. Treatment of aspergillosis. Clin Infect Dis 2008; 47(3): 427PubMedGoogle Scholar
  132. 132.
    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 Mar 15; 97(6): 1604–10PubMedGoogle Scholar
  133. 133.
    Rovira M, Jimenez M, De La Bellacasa JP, et al. Detection of Aspergillus galactomannan by enzyme immunoabsorbent assay in recipients of allogeneic hematopoietic stem cell transplantation: a prospective study. Transplantation 2004 Apr 27; 77(8): 1260–4PubMedGoogle Scholar
  134. 134.
    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 Nov 1; 186(9): 1297–306PubMedGoogle Scholar
  135. 135.
    Maschmeyer G, Beinert T, Buchheidt D, et al. Diagnosis and antimicrobial therapy of pulmonary infiltrates in febrile neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003 Oct; 82 Suppl. 2: S118–26PubMedGoogle Scholar
  136. 136.
    Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005 Sep; 49(9): 3640–5PubMedGoogle Scholar
  137. 137.
    Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006 Jul 1; 43(1): 25–31PubMedGoogle Scholar
  138. 138.
    Magill SS, Shields C, Sears CL, et al. Triazole cross-resistance among Candida spp.: occurrence among bloodstream isolates, and implications for antifungal therapy [case report]. J Clin Microbiol 2006 Feb; 44(2): 529–35PubMedGoogle Scholar
  139. 139.
    Perlin DS. Resistance to echinocandin-class antifungal drugs. Drug Resist Updat 2007 Jun; 10(3): 121–30PubMedGoogle Scholar
  140. 140.
    Pfaller MA, Diekema DJ, Gibbs DL, et al. Geographic and temporal trends in isolation and antifungal susceptibility of Candida parapsilosis: a global assessment from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J Clin Microbiol 2008 Mar; 46(3): 842–9PubMedGoogle Scholar
  141. 141.
    van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004 Nov 15; 39(10): 1407–16PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Maria J. G. T. Rüping
    • 1
  • Jörg J. Vehreschild
    • 1
  • Oliver A. Cornely
    • 1
    • 2
  1. 1.Department I of Internal Medicine, Clinical Trials Unit Infectious Diseases IIHospital of the University of CologneCologneGermany
  2. 2.Clinical Trials Center CologneHospital of the University of CologneCologneGermany

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