Intravenous and Oral Itraconazole versus Intravenous Amphotericin B Deoxycholate as Empirical Antifungal Therapy for Persistent Fever in Neutropenic Patients with Cancer Who Are Receiving Broad-Spectrum Antibacterial Therapy

Boogaerts, Marc; Dj, Winston; Ej, Bow; Garber, Gary; Ac, Reboli; Ap, Schwarer; Novitzky, Nicolás; Boehme, Angelika; Chwetzoff, E.; K, De Beule

doi:10.7326/0003-4819-135-6-200109180-00010

Cited by 311 publications

(216 citation statements)

References 24 publications

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“…Recent trials with these triazoles have compared itraconazole with amphotericin B deoxycholate [7] and voriconazole with liposomal amphotericin B [8]. Two randomized double-blind trials have compared efficacy of amphotericin B formulations as empirical therapy for persistent fever in neutropenic patients.…”

Section: Drugs For Empirical Antifungal Therapymentioning

confidence: 99%

“…Patients with clinically documented bacterial, fungal, viral, or protozoan infections were excluded from the EORTC study, the fluconazole trial [5], and the itraconazole trial [7]. The trials of liposomal amphotericin B and voriconazole included an unspecified number of patients with "controlled" bacteremia; however, no definition of "controlled" bacteremia was provided in the reports.…”

Section: Selection Of High-risk Patientsmentioning

confidence: 99%

“…However, blinding would have reduced potential investigator bias in early discontinuations of patients from the study. The studies of itraconazole and voriconazole for empirical therapy clearly demonstrated this problem [7,8]. There were more early discontinuations due to persistence of fever, perceived as inefficacy, among patients receiving the experimental drug than among those receiving the comparator drug.…”

Section: Need For Blinding the Studiesmentioning

confidence: 99%

“…In the early EORTC trial, the incidence of fungal infections among patients randomized to the group that did not receive empirical antifungal therapy was 9.4% [3]. More recent empirical antifungal therapy trials in which all patients have received empirical antifungal therapy have shown incidences of baseline and breakthrough infections ranging from 2% to 9% [7][8][9]. A study with adequate statistical power to show a reduction in breakthrough fungal infections from 9% to 4% with a new drug compared with some standard therapy (a superiority trial design) would require a sample size of 11000 patients.…”

Section: Absence Of Breakthrough Fungal Infectionsmentioning

confidence: 99%

“…For example, in the study evaluating liposomal amphotericin B [9], resolution of fever was assessed at the time the absolute neutrophil count reached 500/mL and was 58% for liposomal amphotericin B and 58% for amphotericin B deoxycholate. In the study evaluating itraconazole compared with amphotericin B deoxycholate [7], the time point for assessment of resolution of fever was up to 28 days after start of therapy. The success rates for the resolution-of-fever component of the composite end point were 73% for itraconazole and 70% for amphotericin B deoxycholate.…”

Section: Absence Of Breakthrough Fungal Infectionsmentioning

confidence: 99%

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Forum Report: Issues in Clinical Trials of Empirical Antifungal Therapy in Treating Febrile Neutropenic Patients

Bennett

Powers

Walsh

et al. 2003

Clinical Infectious Diseases

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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. BASIS FOR THE CONCEPT OF EMPIRICAL ANTIFUNGAL THERAPYThe practice of administering empirical antifungal therapy to persistently febrile neutropenic patients who are apparently not responding to antibacterial therapy has become a standard of care in many centers. Although this practice is based on sound theoretical principles, the actual data from clinical trials supporting the use a Additional participants are listed after the text.

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Section: Drugs For Empirical Antifungal Therapymentioning

confidence: 99%

Section: Selection Of High-risk Patientsmentioning

confidence: 99%

Section: Need For Blinding the Studiesmentioning

confidence: 99%

Section: Absence Of Breakthrough Fungal Infectionsmentioning

confidence: 99%

Section: Absence Of Breakthrough Fungal Infectionsmentioning

confidence: 99%

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