Empirical antifungal therapy in neutropaenic cancer patients with persistent fever☆
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
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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).