Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial

Viscoli, Claudio; Castagnola, Elio; Lint, Maria Teresa Van; Moroni, C.; Garaventa, Alberto; Rossi, Massimiliano; Fanci, Rosa; Menichetti, Francesco; Caselli, Desireé; Giacchino, M; Congiu, M.

doi:10.1016/0959-8049(95)00619-2

Cited by 114 publications

(69 citation statements)

References 24 publications

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“…In 1996, Viscoli et al [5] reported the first randomized trial of fluconazole as empirical antifungal therapy. They investigated a selected population of 112 patients who were not receiving fluconazole prophylaxis and who were at low risk for invasive aspergillosis.…”

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%

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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%

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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“…With the exclusion of the German study by Abele-Horn et al [17], which used a dose of fluconazole inconsistent with the four other studies, trials comparing fluconazole with AmB had the following patient inclusion criteria: Malik et al [26] and Winston et al [32] required neutropenia [absolute neutrophil count (ANC) <500 cells/ mm 3 ]; Viscoli et al [18], Malik et al [26], and Winston et al [32] included only patients with hematologic malignancies and defined "fever" as >38°C, whereas Anaissie et al [19] used a threshold of >38.3°C (101°F). Days on broad-spectrum antibiotics varied between 2 and 4 in four studies [18,19,26,32]. These studies were statistically homogeneous, however, and showed that fluconazole was associated less often with fever than AmB.…”

Section: Infusion-related and Acute Drug Reactionsmentioning

confidence: 99%

Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis

Girois

Chapuis

Decullier

et al. 2006

Eur J Clin Microbiol Infect Dis

121

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Amphotericin B is the main therapeutic agent for the treatment of invasive fungal infections; however, it is associated with significant toxicities that limit its use. Other systemic antifungal agents have been developed to improve tolerability while maintaining the efficacy profile of conventional amphotericin B. Fifty-four studies involving 9,228 patients were assessed for the frequency of adverse effects of the main systemic antifungal agents. While the results suggest that liposomal amphotericin B is the least nephrotoxic of the lipid formulations (14.6%), that conventional amphotericin B is the most nephrotoxic (33.2%), and that itraconazole is the most hepatotoxic (31.5%), the lack of standard definitions of antifungalrelated adverse effects limits the validity of these results. Furthermore, heterogeneous patient pools and differing protocols make it difficult to draw direct comparisons between studies. With the advent of newer classes of systemic antifungal agents, future trials should conform to definitions that are universally applicable and clinically relevant to allow for such comparisons and to enable evidence-based decision-making.

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“…• Nephrotoxicity occurs in 1-3% of patients receiving fluconazole (significantly less than AmB-D) 82,86,112 • IRAEs are rarely reported with fluconazole: fever and/or chills 0-1% (significantly less than AmB-D) 82,122 Itraconazole Gastrointestinal toxicity…”

Section: Nephrotoxicitymentioning

confidence: 99%

Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in patients with haematological disorders

Worth

Blyth

Booth

et al. 2008

Internal Medicine Journal

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Antifungal prophylaxis, empirical therapy and treatment of established fungal infections in the haematology population may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes. These risks may be minimised by clinical assessment, laboratory monitoring of biochemical or haematological indices, avoidance of particular drug combinations and dose modification in certain circumstances. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. For certain agents, therapeutic drug monitoring (TDM) is warranted where non-compliance, non-linear pharmacokinetics, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Pharmacokinetics and pharmacodynamics of clinical relevance to the haematology population are discussed for the azole, polyene and echinocandin classes of antifungal agents. The evidence supporting an association between TDM and enhanced treatment outcomes is presented for individual antifungal drugs, and recommendations for clinical practice are provided. Further randomised study of newer antifungal agents, such as posaconazole, is required to explore the potential for improved clinical outcomes in association with TDM.Understanding a drug's pharmacokinetics and its pharmacodynamic effects affords the clinician the capacity to optimize drug exposure while minimizing or avoiding drug interactions and toxicities. Therapeutic drug monitoring (TDM) may also be employed during the treatment period to ensure that the selected drug dosage falls within the therapeutic window for an individual patient.These clinical caveats are particularly relevant to the haematology population where the frequent requirement for polypharmacy and the complexity of comorbidities can significantly influence the success of antifungal therapy. This section of the guidelines describes the potential drugdrug interactions and toxicities related to antifungal use and how they may be avoided. It also considers the latest

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Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial

Cited by 114 publications

References 24 publications

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

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

Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis

Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in patients with haematological disorders

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