Empirical antifungal therapy in neutropaenic cancer patients with persistent fever

https://doi.org/10.1016/j.ejcsup.2007.06.005Get rights and content

Abstract

Invasive fungal infections are frequent and severe complications in leukaemic patients with prolonged neutropaenia. Empirical antifungal therapy has become the standard of care in patients with persistent fever despite treatment with broad-spectrum antibiotics. For decades amphotericin B deoxycholate has been the sole option for empirical antifungal therapy. Recently, several new antifungal agents became available. The choice of the most appropriate drug should be guided by efficacy and safety criteria. The recommendations from the First European Conference on Infections in Leukaemia (ECIL-1) on empirical antifungal therapy in neutropaenic cancer patients with persistent fever have been developed by an expert panel after assessment of clinical practices in Europe and evidence-based review of the literature. Many antifungal regimens can now be recommended for empirical therapy in neutropaenic cancer patients. However, persistent fever lacks specificity for initiation of therapy. Development of empirical and pre-emptive strategies using new clinical parameters, laboratory markers and imaging techniques for early diagnosis of invasive mycoses are needed.

Introduction

Patients with acute leukaemia and allogeneic haematopoietic stemcell transplant (HSCT) recipients are at high risk of invasive fungal infections (IFI) due to prolonged and profound neutropaenia or immunosuppression for graft-versus-host disease.[1], [2] Based on studies conducted in the 1980s, empirical antifungal therapy has become the standard of care in neutropaenic patients in whom fever persists despite treatment with broad-spectrum antibiotics.3 The rationale for early administration of antifungal agents in these patients include the fact that clinically occult IFI (primarily due to Candida or Aspergillus species) are a frequent autopsy finding and that persistent fever is often the only early sign of IFI.4

For decades amphotericin B (AmB) deoxycholate has been the only option for empirical antifungal therapy. Recently, several new antifungal agents became available. The choice of the most appropriate drug should be guided by efficacy, safety and economic criteria.

The objectives of the present work were to analyse clinical practices in Europe and to propose evidence-based guidelines for empirical antifungal therapy in neutropaenic cancer patients with persistent fever, based on a systematic review of the literature.

Section snippets

ECIL1 methodology

The common methodology of the ECIL1 working groups has been described in the covering paper.

Questionnaire on clinical practices in Europe

The questionnaire on clinical practices for the management of infections in neutropaenic cancer patients comprised a section on empirical antifungal therapy for persistent fever. The following items were addressed: use of empirical antifungal therapy for persistent fever, time of initiation of therapy according to clinical presentation, choice of antifungal therapy according to various clinical settings,

Questionnaire on clinical practices in Europe

Thirty eight questionnaires were evaluated. Empirical antifungal therapy was considered to be standard practice by a majority of experts (97%). Median time to initiation of antifungal therapy was 5 days (range: 3–8.5 days) for the first febrile episode compared to 3 days (range: 1–8.5 days) for relapsing fever (p < 0.001). Half of the experts thought the time of initiation should be delayed in patients with microbiologically documented bacterial infections compared with patients with clinically

Recommendations

Is there evidence supporting the use of empirical antifungal therapy in neutropaenic patients with persistent fever to reduce the incidence, the morbidity and/or the mortality of invasive fungal infections?

Yes, Grading: BII.

Comments. The concept of empirical antifungal therapy as standard of care in neutropaenic patients with prolonged fever of undetermined origin is supported by the results of two pioneer, open, not placebo-controlled, randomised studies conducted in the 1980s. However, both

Conclusions

Many antifungal regimens can now be recommended for empirical therapy in neutropaenic cancer patients. Initiation of empirical antifungal therapy is triggered by the persistence of fever after 3–7 days of broad spectrum antibiotic therapy. This frequent but non-specific sign of fungal infection does not take into account recent developments regarding non-invasive diagnosis of IFI using new laboratory markers and imaging techniques. Although the vast majority of European experts use empirical

Conflict of interest statement

Oscar Marchetti has received grants and research supports from Bristol-Myers Squibb, Essex/Schering-Plough, Gilead, Merck Sharp & Dohme-Chibret and Pfizer.

Catherine Cordonnier has received grants and research supports from Gilead, Merck Sharp & Dohme-Chibret, Pfizer, Schering-Plough and has been a consultant for Gilead, Schering-Plough and Zeneus Pharma.

Thierry Calandra has received grants and research supports from Bristol-Myers Squibb, Essex/Schering-Plough, Gilead Merck Sharp & Dohme-Chibret

Sources of support

The ECIL 1 meeting has been supported by unrestricted educational grants from Astellas Pharma, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Schering Plough, Wyeth and Zeneus Pharma.

Acknowledgement

This manuscript has been internally reviewed by Winfried V. Kern (Department of Medicine and Center for Infectious Diseases and Travel Medicine, University Hospital, Freiburg, Germany) and Chris Kibbler (Department of Medical Microbiology, Royal Free Hospital, London, United Kingdom). We thank them for their thorough review and insightful comments.

All the members of the Organising Committee and the Conference participants express their sincere thanks to the sponsors who supported the meeting

References (30)

  • EORTC International Antimicrobial Therapy Cooperative Group. Empiric antifungal therapy in febrile granulocytopenic...
  • A.C. Leenders et al.

    Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections

    Br J Haematol

    (1998)
  • R.V. Fleming et al.

    Comparison of amphotericin B lipid complex (ABLC) vs. ambisome in the treatment of suspected or documented fungal infections in patients with leukemia

    Leuk Lymphoma

    (2001)
  • V. Fainstein et al.

    Amphotericin B or ketoconazole therapy of fungal infections in neutropenic cancer patients

    Antimicrob Agents Chemother

    (1987)
  • G. Silling et al.

    Early empiric antifungal therapy of infections in neutropenic patients comparing fluconazole with amphotericin B/flucytosine

    Mycoses

    (1999)
  • Cited by (61)

    • Assessment of high-priced systemic antifungal prescriptions

      2017, Medecine et Maladies Infectieuses
      Citation Excerpt :

      In addition, potential de-escalation from caspofungin to fluconazole in stable patients with a fluconazole-susceptible Candida infection was also analyzed. The recommendations used to assess compliance with antifungal prescribing were the labeling of each antifungal agent approved by the European Medicines Agency (EMA) in addition to international guidelines issued by the ECIL, ESCMID, and IDSA for Aspergillus spp. and Candida spp. [1–8]. IDSA and ESCMID guidelines were used for non-hematological or non-transplant patients, and ECIL and ESCMID guidelines for hematological and other severely immunosuppressed patients.

    • Most Common Pathogens in Neutropenic Cancer Patients

      2017, Infectious Diseases, 2-Volume Set
    • Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation

      2014, The Lancet Oncology
      Citation Excerpt :

      In the absence of data, no general recommendations can be made about the minimum amount of therapy and the extent of response before continuation of anticancer treatment or initiation of the conditioning regimen for allogeneic HSCT (no grading). Although early clinical trials7 are difficult to interpret with current standards, a recent meta-analysis comparing empirical antifungal treatment to no treatment in adults with persistent febrile granulocytopenia concluded that empirical treatment significantly decreased IFDs, but did not lower mortality.56 Although similar data do not exist for the paediatric population, empirical antifungal therapy has been a common practice in granulocytopenic children with persistent fever despite appropriate empirical antibacterial therapy.

    • Antifungal pre-emptive strategy for high-risk neutropenic patients: Why the story is still ongoing

      2014, Clinical Microbiology and Infection
      Citation Excerpt :

      A large study failed to show that voriconazole was non-inferior to liposomal amphotericin-B [19]. Other antifungals were also evaluated [15]. All these trials raised methodological concerns, using sophisticated, composite endpoints, mainly based on drop in fever, or focusing on toxicity as a primary endpoint [21–23].

    • Infection in Neutropenic Patients with Cancer

      2013, Critical Care Clinics
      Citation Excerpt :

      These bacteria are often multidrug resistant128 and associated with indwelling central venous access devices.97 The addition of antifungal therapy for the empirical treatment of suspected occult invasive fungal infection as a cause of PNF despite 4 to 7 days of broad-spectrum antibacterial therapy has been an international standard of practice.19,96,129–131 By these criteria, the prescription rate for empirical antifungal therapy (22%–69% in patients undergoing treatment of acute leukemia) far exceeds the event rate of 3.6% for proven or probable invasive fungal infection (95% CI 2.9%–4.4%) in persistently febrile neutropenic patients.32

    • Three major achievements of the Infections Disease Group

      2012, European Journal of Cancer, Supplement
    View all citing articles on Scopus

    The ECIL-1 is a common initiative of the following groups or organisations: Infectious Diseases Working Party of the European Blood and Marrow Transplantation Group (EBMT-IDWP), Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (EORTC-IDG), European Leukemia Net (ELN) (EU Grant No.: LSHC-CT-2004), and International Immunocompromised Host Society (ICHS).

    View full text