title: Forum report: issues in clinical trials of empirical antifungal therapy in treating febrile neutropenic patients.
abstract: There is inferential evidence that some patients with prolonged neutropenia and fever not responding to antibacterial agents are at sufficient risk of deep mycoses to warrant empirical therapy, although superiority of an antifungal agent over placebo has not been conclusively demonstrated. Amphotericin B deoxycholate, liposomal amphotericin B, and intravenous itraconazole followed by oral itraconazole solution are licensed in the United States for this indication. Fluconazole and voriconazole have given favorable results in clinical trials of patients with low and high risk of deep mold infections, respectively. Design features that can profoundly influence outcome of empirical trials are (1) inclusion of low-risk patients, (2) failure to blind the study, (3) obscuration of antifungal effects by changing antibacterial antibiotics, (4) failure to balance both arms of the study in terms of patients with prior antifungal prophylaxis or with severe comorbidities, (5) the merging of end points evaluating safety with those of efficacy, and (6) choice of different criteria for resolution of fever.
authors.affiliation: Clinical Mycology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. jbennett@niaid.nih.gov
authors.forename: John E
authors.initials: JE
authors.lastname: Bennett
authors.forename: John
authors.initials: J
authors.lastname: Powers
authors.forename: Thomas
authors.initials: T
authors.lastname: Walsh
authors.forename: Claudio
authors.initials: C
authors.lastname: Viscoli
authors.forename: Ben
authors.initials: B
authors.lastname: de Pauw
authors.forename: William
authors.initials: W
authors.lastname: Dismukes
authors.forename: John
authors.initials: J
authors.lastname: Galgiani
authors.forename: Michel
authors.initials: M
authors.lastname: Glauser
authors.forename: Raoul
authors.initials: R
authors.lastname: Herbrecht
authors.forename: Carol
authors.initials: C
authors.lastname: Kauffman
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Pappas
authors.forename: John
authors.initials: J
authors.lastname: Rex
authors.forename: Paul
authors.initials: P
authors.lastname: Verweij
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D018890:Chemoprevention; D002986:Clinical Trials as Topic; D005334:Fever / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D009181:Mycoses / Q000150:complications / Q000188:drug therapy*; D009503:Neutropenia / Q000188:drug therapy* / Q000209:etiology; D018579:Patient Selection; D012107:Research Design
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents