• Helle Krogh Johansen and Peter C Gøtzsche.
• The Nordic Cochrane Centre, Rigshospitalet, Blegdamsvej 9, 3343, Copenhagen, Denmark, DK 2100.
• Cochrane Db Syst Rev. 2014 Sep 4; 2014 (9): CD000239CD000239.

BackgroundSystemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or empirically to patients with persistent fever.ObjectivesTo compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia.Search MethodsWe searched PubMed from 1966 to 7 July 2014 and the reference lists of identified articles.Selection CriteriaRandomised clinical trials comparing fluconazole with amphotericin B.Data Collection And AnalysisThe two review authors independently assessed trial eligibility and risk of bias, and abstracted data.Main ResultsSeventeen trials (3798 patients, 381 deaths) were included. In two large three-armed trials, results for amphotericin B were combined with results for nystatin in a 'polyene' group. Because nystatin is an ineffective drug in these circumstances, this approach creates a bias in favour of fluconazole. Furthermore, most patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. There was overlap among the 'polyene' trials but we were unable to obtain any information from the trial authors or from Pfizer, the manufacturer of fluconazole, to clarify these issues. There were no significant differences in effect between fluconazole and amphotericin B, but the confidence intervals were wide. More patients dropped out of the study when they received amphotericin B, but as none of the trials were blinded decisions on premature interruption of therapy could have been biased. Furthermore, amphotericin B was not given under optimal circumstances, with premedication to reduce infusion-related toxicity, slow infusion, and with fluid, potassium and magnesium supplements to prevent nephrotoxicity. The major harms were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion-related toxicity, renal impairment and gastrointestinal adverse effects with amphotericin B. For the 2011 and 2014 updates no additional trials were identified for inclusion.Authors' ConclusionsAmphotericin B has been disfavoured in several of the trials through their design or analysis, or both. Since intravenous amphotericin B is the only antifungal agent for which an effect on mortality has been shown, and since it is considerably cheaper than fluconazole, it should be the preferred agent.

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