Johansen, H.K., & Gøtzsche, P.C. (2002). Amphotericin B versus fluconazole for controlling fungal infections in neutropenic cancer patients. Cochrane Database of Systematic Reviews, 2, CD000239.

To examine fluconazole (oral or intravenous [IV]) compared with amphotericin B (oral or IV) in patients with cancer who were neutropenic.

Databases searched were The Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed (through November 2007).  The authors also searched the proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) (1990–2007), the General Meeting of the American Society for Microbiology (ASM) (1990–2007), and the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) (1995–2007). In addition, the authors contacted researchers in the field and industry and reviewed reference lists to identify unpublished trials.

• Seventeen randomized, controlled trials were reviewed.
• The total number of participants was 3,798.
• The sample consisted of patients with cancer who were neutropenic.
• Most patients had acute leukemia or were undergoing hematopoietic stem cell transplantation.

No significant difference was found between fluconazole and amphotericin B with regard to

• Mortality
• Invasive fungal infection
• Colonization
• Use of rescue therapy
• Dropouts.

The major adverse effects were hepatic impairment and gastrointestinal adverse effects with fluconazole and infusion-related toxicity, renal impairment, and gastrointestinal adverse effects with amphotericin B.

Considerable heterogeneity existed in the studies, and amphotericin B was not favored in several of the largest trials through the trial design or data analysis.  Of particular concern was that seven trials compared oral fluconazole to oral amphotericin B. Oral amphotericin B is poorly absorbed and is not recommended for prophylaxis or the treatment of systemic fungal infections. No trial report offered a rationale for this design, and attempts by the authors to obtain additional information from the investigators were unsuccessful.

In the 10 trials that compared oral or IV fluconazole to IV amphotericin B, the design disfavored the amphotericin B arm. Clinicians familiar with the optimal administration of amphotericin B routinely prescribe premedication to prevent infusion-related toxicity and fluids (potassium and magnesium) to prevent nephrotoxicity. Supplemental fluids (i.e., potassium and magnesium) were not prescribed in any trial reviewed, and premedication was prescribed in only two trials. 

The majority of these trials were sponsored by the company that manufactured fluconazole, and the authors were unable to obtain additional information or access to certain trial data held by the company.

The authors concluded that there was not sufficient data from the available trials to judge the effectiveness of fluconazole compared with amphotericin B. Amphotericin B should be preferred because it is the only antifungal for which evidence suggests an effect on mortality.