title: Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial.
abstract: 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.
authors.affiliation: Hematology Department, Henri Mondor Teaching Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP) and Paris 12 University, Créteil, France. carlcord@club-internet.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Cordonnier
authors.forename: Cécile
authors.initials: C
authors.lastname: Pautas
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maury
authors.forename: Anne
authors.initials: A
authors.lastname: Vekhoff
authors.forename: Hassan
authors.initials: H
authors.lastname: Farhat
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhédin
authors.forename: Francoise
authors.initials: F
authors.lastname: Isnard
authors.forename: Lionel
authors.initials: L
authors.lastname: Ades
authors.forename: Frédérique
authors.initials: F
authors.lastname: Kuhnowski
authors.forename: Françoise
authors.initials: F
authors.lastname: Foulet
authors.forename: Mathieu
authors.initials: M
authors.lastname: Kuentz
authors.forename: Patrick
authors.initials: P
authors.lastname: Maison
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bretagne
authors.forename: Michaël
authors.initials: M
authors.lastname: Schwarzinger
mesh_terms: D000328:Adult; D000368:Aged; D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use; D019072:Antibiotic Prophylaxis; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016009:Chi-Square Distribution; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D004338:Drug Combinations; D005260:Female; D005334:Fever / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009181:Mycoses / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control; D009503:Neutropenia / Q000150:complications*; D009894:Opportunistic Infections / Q000188:drug therapy* / Q000517:prevention & control; D012307:Risk Factors; D018709:Statistics, Nonparametric
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination