Journal Article

Empirical versus Preemptive Antifungal Therapy for High-Risk, Febrile, Neutropenic Patients: A Randomized, Controlled Trial

Catherine Cordonnier, Cécile Pautas, Sébastien Maury, Anne Vekhoff, Hassan Farhat, Felipe Suarez, Nathalie Dhédin, Francoise Isnard, Lionel Ades, Frédérique Kuhnowski, Françoise Foulet, Mathieu Kuentz, Patrick Maison, Stéphane Bretagne and Michaël Schwarzinger

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 48, issue 8, pages 1042-1051
Published in print April 2009 | ISSN: 1058-4838
Published online April 2009 | e-ISSN: 1537-6591 | DOI:
Empirical versus Preemptive Antifungal Therapy for High-Risk, Febrile, Neutropenic Patients: A Randomized, Controlled Trial

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Background. Empirical antifungal therapy is the standard of care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Recent diagnostic improvements may ensure the early diagnosis of potentially invasive fungal disease. Reserving antifungals for this stage may achieve similar survival rates and reduce treatment toxicity and costs.

Methods. In this multicenter, open-label, randomized noninferiority trial, we compared an empirical antifungal strategy with a preemptive one. Empirical treatment was defined as antibacterial treatment of patients who have persistent or recurrent fever. Preemptive treatment was defined as treatment of patients who have clinical, imaging, or galactomannan-antigen-assay evidence suggesting fungal disease. First-line antifungal treatment was amphotericin B deoxycholate (1 mg/kg/day) or liposomal amphotericin (3 mg/kg/day), depending on daily renal function. The primary efficacy outcome was the proportion of patients alive at 14 days after recovery from neutropenia.

Results. The median duration of neutropenia (neutrophil count, <500 cells/mm3) for the 293 patients enrolled was 18 days (range, 5–69 days). By intention-to-treat analysis, survival was 97.3% with empirical treatment and 95.1% with preemptive treatment. The lower 95% confidence limit for the difference in mortality was −5.9%, which was within the noninferiority margin of −8%. Probable or proven invasive fungal infections were more common among patients who received preemptive treatment than among patients who received empirical treatment (13 of 143 vs. 4 of 150; P<.05 ), and most infections occurred during induction therapy (12 of 73 patients in the preemptive treatment group vs. 3 of 78 patients in the empirical treatment group were infected during induction therapy; P<.01 ). Preemptive treatment did not decrease nephrotoxicity but decreased costs of antifungal therapy by 35%.

Conclusions. Preemptive treatment increased the incidence of invasive fungal disease, without increasing mortality, and decreased the costs of antifungal drugs. Empirical treatment may provide better survival rates for patients receiving induction chemotherapy.

Journal Article.  4579 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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