Advertisement

Drugs & Aging

, Volume 17, Issue 5, pp 339–351 | Cite as

Fungal Infections in Patients With Neutropenia

Challenges in Prophylaxis and Treatment
  • Raoul HerbrechtEmail author
  • Ségolène Neuville
  • Valérie Letscher-Bru
  • Shanti Natarajan-Amé
  • Olivier Lortholary
Disease Management

Abstract

Fungal infections are a leading cause of mortality in patients with neutropenia. Candidiasis and aspergillosis account for most invasive fungal infections.

General prophylactic measures include strict hygiene and environmental measures. Haemopoietic growth factors shorten the duration of neutropenia and thus may reduce the incidence of fungal infections. Fluconazole is appropriate for antifungal prophylaxis and should be offered to patients with prolonged neutropenia, such as high-risk patients with leukaemia undergoing remission induction or consolidation therapy and high-risk stem cell transplant recipients.

Empirical antifungal therapy is mandatory in patients with persistent febrile neutropenia who fail to respond to broad-spectrum antibacterials. Intravenous amphotericin B at a daily dose of 0.6 to 1 mg/kg is preferred whenever aspergillosis cannot be ruled out. Lipid formulations of amphotericin B have demonstrated similar efficacy and are much better tolerated.

Fluconazole is the best choice for acute candidiasis in stable patients; amphotericin B should be used in patients with unstable disease. Use of fluconazole is restricted by the existence of resistant strains (Candida krusei and, to a lesser extent, C. glabrata).

Amphotericin B still remains the gold standard for invasive aspergillosis. Lipid formulations of amphotericin B are effective in aspergillosis and because they are less nephrotoxic are indicated in patients with poor renal function. Itraconazole is an alternative in patients who have good intestinal function and are able to eat.

Mucormycosis, trichosporonosis, fusariosis and cryptococcosis are less common but require specific management.

New antifungal agents, especially new azoles, are under development. Their broad in vitro spectrum and preliminary clinical results are promising.

Keywords

Fluconazole Itraconazole Aspergillosis Invasive Aspergillosis Invasive Fungal Infection 
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.

References

  1. 1.
    Denning DW, Evans EG, Kibbler CC, et al. Guidelines for the investigation of invasive fungal infections in haematological malignancy and solid organ transplantation. British Society for Medical Mycology. Eur J Clin Microbiol Infect Dis 1997; 16(6): 424–36PubMedCrossRefGoogle Scholar
  2. 2.
    Nucci M, Pulcheri W, Spector N, et al. Fungal infections in neutropenic patients: an 8-year prospective study. Rev Inst Med Trop Sao Paulo 1995; 37(5): 397–406PubMedCrossRefGoogle Scholar
  3. 3.
    Karabinis A, Hill C, Leclercq B, et al. Risk factors for candidemia in cancer patients: a case-control study. J Clin Microbiol 1988; 26(3): 429–32PubMedGoogle Scholar
  4. 4.
    Wald A, Leisenring W, van Burik JA, et al. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175(6): 1459–66PubMedCrossRefGoogle Scholar
  5. 5.
    Herbrecht R. The changing epidemiology of fungal infections: are the lipid-forms of amphotericin B an advance? Eur J Haematol 1996; 57 Suppl.: 12–7Google Scholar
  6. 6.
    Walsh TJ, Groll AH. Emerging fungal pathogens: evolving challenges to immunocompromised patients for the twenty-first century. Transpl Infect Dis 1999; 1: 247–61PubMedCrossRefGoogle Scholar
  7. 7.
    Patterson TF. Approaches to fungal diagnosis in transplantation. Transpl Infect Dis 1999; 1(4): 262–72PubMedCrossRefGoogle Scholar
  8. 8.
    Marr KA, Bowden RA. Fungal infections in patients undergoing blood and marrow transplantation. Transpl Infect Dis 1999; 1(4): 237–46PubMedCrossRefGoogle Scholar
  9. 9.
    Herbrecht R, Letscher V, Kurtz JE, et al. Amphotericin B lipid complex in the management of new emerging fungal infections. Int J Infect Dis 1997; 1Suppl. 1: S42–6Google Scholar
  10. 10.
    Uzun O, Anaissie EJ. Antifungal prophylaxis in patients with hematologic malignancies: a reappraisal. Blood 1995; 86(6): 2063–72PubMedGoogle Scholar
  11. 11.
    Lortholary O, Dupont B. Antifungal prophylaxis during neutropenia and immunodeficiency. Clin Microbiol Rev 1997; 10(3): 477–504PubMedGoogle Scholar
  12. 12.
    Lortholary O, Ascioglu S, Moreau P, et al. Invasive aspergillosis as an opportunistic infection in nonallografted patients with multiple myeloma. Clin Infect Dis 2000; 30(1): 41–6PubMedCrossRefGoogle Scholar
  13. 13.
    Guiot HF, Fibbe WE, van’t Wout JW. Risk factors for fungal infection in patients with malignant hematologic disorders: implications for empirical therapy and prophylaxis. Clin Infect Dis 1994; 18(4): 525–32PubMedCrossRefGoogle Scholar
  14. 14.
    Working Party of the British Society for Antimicrobial Chemotherapy. Chemoprophylaxis for candidosis and aspergillosis in neutropenia and transplantation: a review and recommendations. J Antimicrob Chemother 1993; 32(1): 5–21CrossRefGoogle Scholar
  15. 15.
    Pfaller MA. Nosocomial candidiasis: emerging species, reservoirs, and modes of transmission. Clin Infect Dis 1996; 22Suppl. 2: S89–94PubMedCrossRefGoogle Scholar
  16. 16.
    Nemunaitis J. A comparative review of colony-stimulating factors. Drugs 1997; 54(5): 709–29PubMedCrossRefGoogle Scholar
  17. 17.
    Yeo E, Alvarado T, Fainstein V, et al. Prophylaxis of oropharyngeal candidiasis with clotrimazole. J Clin Oncol 1985; 3(12): 1668–71PubMedGoogle Scholar
  18. 18.
    Wingard JR, Vaughan WP, Braine HG, et al. Prevention of fungal sepsis in patients with prolonged neutropenia: a randomized, double-blind, placebo-controlled trial of intravenous miconazole. Am JMed 1987; 83(6): 1103–10Google Scholar
  19. 19.
    Palmblad J, Lonnqvist B, Carlsson B, et al. Oral ketoconazole prophylaxis for Candida infections during induction therapy for acute leukaemia in adults: more bacteraemias. J Intern Med 1992; 231(4): 363–70PubMedCrossRefGoogle Scholar
  20. 20.
    Benhamou E, Hartmann O, Nogues C, et al. Does ketoconazole prevent fungal infection in children treated with high dose chemotherapy and bone marrow transplantation? Results of a randomized placebo-controlled trial. Bone Marrow Transplant 1991; 7(2): 127–31PubMedGoogle Scholar
  21. 21.
    Alangaden G, Chandrasekar PH, Bailey E, et al. Antifungal prophylaxis with low-dose fluconazole during bone marrow transplantation: the Bone Marrow Transplantation Team. Bone Marrow Transplant 1994; 14(6): 919–24PubMedGoogle Scholar
  22. 22.
    Samonis G, Rolston K, Karl C, et al. Prophylaxis of oropharyngeal candidiasis with fluconazole. Rev Infect Dis 1990; 12Suppl. 3: S369–73PubMedCrossRefGoogle Scholar
  23. 23.
    Winston DJ, Chandrasekar PH, Lazarus HM, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, double-blind, multicenter trial. Ann Intern Med 1993; 118(7): 495–503PubMedGoogle Scholar
  24. 24.
    Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group. Clin Infect Dis 1999; 28(2): 331–40PubMedCrossRefGoogle Scholar
  25. 25.
    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(6): 1545–52PubMedCrossRefGoogle Scholar
  26. 26.
    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(13): 845–51PubMedCrossRefGoogle Scholar
  27. 27.
    Ninane J. A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies: Multicentre Study Group. Eur J Clin Microbiol Infect Dis 1994; 13(4): 330–7PubMedCrossRefGoogle Scholar
  28. 28.
    Philpott-Howard JN, Wade JJ, Mufti GJ, et al. Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia: Multicentre Study Group. J Antimicrob Chemother 1993; 31(6): 973–84PubMedCrossRefGoogle Scholar
  29. 29.
    Brammer KW. Management of fungal infection in neutropenic patients with fluconazole. Hamatol Bluttransfus 1990; 33: 546–50Google Scholar
  30. 30.
    Menichetti F, Del Favero A, Martino P, et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B: the GIMEM A Infection Program. Ann Intern Med 1994; 120(11): 913–8PubMedGoogle Scholar
  31. 31.
    Takatsuka H, Takemoto Y, Okamoto T, et al. Fluconazole versus amphotericin B for the prevention of fungal infection in neutropenic patients with hematologic malignancy. Drugs Exp Clin Res 1999; 25(4): 193–200PubMedGoogle Scholar
  32. 32.
    Young GA, Bosly A, Gibbs DL, et al. A double-blind comparison of fluconazole and nystatin in the prevention of candidiasis in patients with leukaemia: Antifungal Prophylaxis Study Group. Eur J Cancer 1999; 35(8): 1208–13PubMedCrossRefGoogle Scholar
  33. 33.
    Glasmacher A, Hahn C, Leutner C, et al. Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses 1999; 42(7–8): 443–51PubMedCrossRefGoogle Scholar
  34. 34.
    Glasmacher A, Molitor E, Hahn C, et al. Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia. Leukemia 1998; 12(9): 1338–43PubMedCrossRefGoogle Scholar
  35. 35.
    Menichetti F, Del Favero A, Martino P, et al. Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: a randomized, placebo-controlled, double-blind, multicenter trial. GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche dell’ Adulto. Clin Infect Dis 1999; 28(2): 250–5PubMedCrossRefGoogle Scholar
  36. 36.
    Montesinos J, Sola C, Maroto P, et al. Incidence of fungal infections and efficacy of itraconazole prophylaxis in solid tumor patients treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation: a prospective non-randomized sequential study. Support Care Cancer 2000; 8: 150Google Scholar
  37. 37.
    Huijgens PC, Simoons-Smit AM, van Loenen AC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J Clin Pathol 1999; 52(5): 376–80PubMedCrossRefGoogle Scholar
  38. 38.
    Morgenstern GR, Prentice AG, Prentice HG, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. U.K. Multicentre Antifungal Prophylaxis Study Group. Br J Haematol 1999; 105(4): 901–11PubMedCrossRefGoogle Scholar
  39. 39.
    Yamada T, Dan K, Nomura T. Prevention of bacterial and fungal infections in acute leukemia patients: a new and potent combination of oral norfloxacin and amphotericin B. Intern Med 1993; 32(9): 710–5PubMedCrossRefGoogle Scholar
  40. 40.
    O’Donnell MR, Schmidt GM, Tegtmeier BR, et al. Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients. J Clin Oncol 1994; 12(4): 827–34PubMedGoogle Scholar
  41. 41.
    Rousey SR, Russler S, Gottlieb M, et al. Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation. Am J Med 1991; 91(5): 484–92PubMedCrossRefGoogle Scholar
  42. 42.
    Perfect JR, Klotman ME, Gilbert CC, et al. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis 1992; 165(5): 891–7PubMedCrossRefGoogle Scholar
  43. 43.
    Kelsey SM, Goldman JM, McCann S, et al. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study. Bone Marrow Transplant 1999; 23(2): 163–8PubMedCrossRefGoogle Scholar
  44. 44.
    Buchanan AG, Riben PD, Rayner EN, et al. Nystatin prophylaxis of fungal colonization and infection in granulocytopenic patients: correlation of colonization and clinical outcome. Clin Invest Med 1985; 8(2): 139–47PubMedGoogle Scholar
  45. 45.
    Hofstra W, Vries-Hospers HG, van der Waaij D. Concentrations of amphotericin B in faeces and blood of healthy volunteers after the oral administration of various doses. Infection 1982; 10(4): 223–7PubMedCrossRefGoogle Scholar
  46. 46.
    Ezdinli EZ, O’Sullivan DD, Wasser LP, et al. Oral amphotericin for candidiasis in patients with hematologic neoplasms: an autopsy study. JAMA 1979; 242(3): 258–60PubMedCrossRefGoogle Scholar
  47. 47.
    Wingard JR, Merz WG, Rinaldi MG, et al. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 1991; 325(18): 1274–7PubMedCrossRefGoogle Scholar
  48. 48.
    Wingard JR, Merz WG, Rinaldi MG, et al. Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients. Antimicrob Agents Chemother 1993; 37(9): 1847–9PubMedCrossRefGoogle Scholar
  49. 49.
    Kunova A, Trupl J, Spanik S, et al. Candida glabrata, Candida krusei, non-albicans Candida spp., and other fungal organisms in a sixty-bed national cancer center in 1989–1993: no association with the use of fluconazole. Chemotherapy 1995; 41(1): 39–44PubMedCrossRefGoogle Scholar
  50. 50.
    Bodey GP, Anaissie EJ, Elting LS, et al. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. Cancer 1994; 73(8): 2099–106PubMedCrossRefGoogle Scholar
  51. 51.
    Schwartz S, Behre G, Heinemann V, et al. Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood 1999; 93(11): 3654–61PubMedGoogle Scholar
  52. 52.
    Pizzo PA, Robichaud KJ, Gill FA, et al. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982; 72(1): 101–11PubMedCrossRefGoogle Scholar
  53. 53.
    EORTC International Antimicrobial Therapy Cooperative Group. Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 1989; 86 (6 Pt 1): 668–72CrossRefGoogle Scholar
  54. 54.
    Malik IA, Moid I, Aziz Z, et al. A randomized comparison of fluconazole with amphotericin B as empiric antifungal agents in cancer patients with prolonged fever and neutropenia. Am J Med 1998; 105(6): 478–83PubMedCrossRefGoogle Scholar
  55. 55.
    Viscoli C, Castagnola E, Van Lint MT, et al. Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial. Eur J Cancer 1996; 32A(5): 814–20PubMedCrossRefGoogle Scholar
  56. 56.
    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; 340(10): 764–71PubMedCrossRefGoogle Scholar
  57. 57.
    Prentice HG, Hann IM, Herbrecht R, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol 1997; 98(3): 711–8PubMedCrossRefGoogle Scholar
  58. 58.
    White MH, Bowden RA, Sandler ES, et al. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 1998; 27(2): 296–302PubMedCrossRefGoogle Scholar
  59. 59.
    Wingard JR, White MH, Anaissie EJ, et al. A randomized double-blind safety study of Ambisome and Abelcet in febrile neutropenic patients. Proceedings of the Focus on Fungal Infections 9; 1999 Mar 17–19; San Diego (CA), O15Google Scholar
  60. 60.
    Polsky B. Treatment of thrush in oncology patients. J Mycol Med 1996; 6 Suppl. 2: 20–5Google Scholar
  61. 61.
    Akova M, Akalin HE, Uzun O, et al. Efficacy of fluconazole in the treatment of upper gastrointestinal candidiasis in neutropenic patients with cancer: factors influencing the outcome. Clin Infect Dis 1994; 18(3): 298–304PubMedCrossRefGoogle Scholar
  62. 62.
    Peters C, Minkov M, Matthes-Martin S, et al. Leucocyte transfusions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients. Br J Haematol 1999; 106(3): 689–96PubMedCrossRefGoogle Scholar
  63. 63.
    Viscoli C, Girmenia C, Marinus A, et al. Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 1999; 28 1071–9PubMedCrossRefGoogle Scholar
  64. 64.
    Anaissie EJ, Darouiche RO, Abi-Said D, et al. Management of invasive candidal infections: results of a prospective, randomized, multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis 1996; 23(5): 964–72PubMedCrossRefGoogle Scholar
  65. 65.
    Edwards JE, Bodey GP, Bowden RA, et al. International conference for the development of a consensus on the management and prevention of severe candidal infections. Clin Infect Dis 1997; 25(1): 43–59PubMedCrossRefGoogle Scholar
  66. 66.
    Walsh TJ, Hiemenz J, Pizzo PA. Evolving risk factors for invasive fungal infections: all neutropenics are not the same. Clin Infect Dis 1994; 18(5): 793–8PubMedCrossRefGoogle Scholar
  67. 67.
    Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26(4): 781–803PubMedCrossRefGoogle Scholar
  68. 68.
    Tiphine M, Letscher-Bru V, Herbrecht R. Amphotericin B and its new lipids formulations: pharmacologic characteristics, clinical efficacy, and tolerability. Transpl Infect Dis 1999; 1(4): 273–83PubMedCrossRefGoogle Scholar
  69. 69.
    Ellis M, Spence D, de Pauw B, et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis 1998; 27(6): 1406–12PubMedCrossRefGoogle Scholar
  70. 70.
    White MH, Anaissie EJ, Kusne S, et al. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis 1997; 24(4): 635–42PubMedGoogle Scholar
  71. 71.
    Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last 30 years. Arch Intern Med 1999; 159(12): 1301–9PubMedCrossRefGoogle Scholar
  72. 72.
    Lehrer RI, Howard DH, Sypherd PS, et al. Mucormycosis. Ann Intern Med 1980; 93(1): 93–108Google Scholar
  73. 73.
    Morrison VA, McGlave PB. Mucormycosis in the BMT population. Bone Marrow Transplant 1993; 11(5): 383–8PubMedGoogle Scholar
  74. 74.
    Morduchowicz G, Shmueli D, Shapira Z, et al. Rhinocerebral mucormycosis in renal transplant recipients: report of three cases and review of the literature. Rev Infect Dis 1986; 8(3): 441–6PubMedCrossRefGoogle Scholar
  75. 75.
    St Germain G, Robert A, Ishak M, et al. Infection due to Rhizomucor pusillus: report of four cases in patients with leukemia and review. Clin Infect Dis 1993; 16(5): 640–5PubMedCrossRefGoogle Scholar
  76. 76.
    Van Cutsem J, Van Gerven F, Fransen J, et al. Treatment of experimental zygomycosis in guinea pigs with azoles and with amphotericin B. Chemotherapy 1989; 35(4): 267–72PubMedCrossRefGoogle Scholar
  77. 77.
    Koçak R, Tetiker T, Koçak M, et al. Fluconazole in the treatment of three cases of mucormycosis. Eur J Clin Microbiol Infect Dis 1995; 14(6): 559–61PubMedCrossRefGoogle Scholar
  78. 78.
    Otcenasek M, Buchta V. In vitro susceptibility to 9 antifungal agents of 14 strains of Zygomycetes isolated from clinical specimens. Mycopathologia 1994; 128(3): 135–7PubMedCrossRefGoogle Scholar
  79. 79.
    Kumar B, Kaur I, Chakrabarti A, et al. Treatment of deep mycoses with itraconazole. Mycopathologia 1991; 115(3): 169–74PubMedCrossRefGoogle Scholar
  80. 80.
    Herbrecht R, Letscher V, Andres E, et al. Zygomycosis treated with amphotericin B colloidal dispersion: review of 22 cases [abstract]. Blood 1996; 88Suppl. 1, Pt 1: 502aGoogle Scholar
  81. 81.
    Yohai RA, Bullock JD, Aziz AA, et al. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994; 39(1): 3–22PubMedCrossRefGoogle Scholar
  82. 82.
    Tedder M, Spratt JA, Anstadt MP, et al. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 1994; 57(4): 1044–50PubMedCrossRefGoogle Scholar
  83. 83.
    Herbrecht R, Koenig H, Waller J, et al. Trichosporon infections: clinical manifestations and treatment. J Mycol Med 1993; 3 129–36Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Raoul Herbrecht
    • 1
    Email author
  • Ségolène Neuville
    • 2
  • Valérie Letscher-Bru
    • 3
  • Shanti Natarajan-Amé
    • 1
  • Olivier Lortholary
    • 2
    • 4
  1. 1.Département d’Hématologie et d’OncologieHôpitaux Universitaires de StrasbourgStrasbourgFrance
  2. 2.Unité de MycologieInstitut PasteurParisFrance
  3. 3.Institut de Parasitologie et de Pathologie TropicaleStrasbourgFrance
  4. 4.Service de Médecine Interne - Maladies Infectieuses et TropicalesHôpital AvicenneBobignyFrance

Personalised recommendations