Randomized trials and metaanalyses of empiric antifungal therapy

Multiple randomized trials have been performed using different antifungal agents, in patients who either have persistent fever or who require prophylaxis. A randomized trial by Winston et al. compared fluconazole (400 mg) to placebo at initiation of chemotherapy.22 Fluconazole decreased fungal colonization and superficial fungal infections, but did not clearly decrease invasive fungal infections; aspergillosis was infrequent in both groups.22 A later randomized trial of 317 patients by Winston et al. compared i.v. fluconazole versus amphotericin B for patients with persistent fever, and found no significant differences, inefficacy, and fewer infusion-related reactions with fluconazole.23 Similarly, in another randomized trial, Boogaerts et al. found that the efficacy of itraconazole was similar to that of amphotericin B, but itraconazole was associated with fewer side effects.24

Antifungal agents may also be used as prophylaxis prior to the onset of fever. The Canadian Fluconazole Prophylaxis Study Group found that fluconazole, compared with placebo, reduced invasive fungal infection and fungal-related mortality.25 A study by Menichetti et al. of 820 patients receiving prophylaxis with oral fluconazole versus oral amphotericin showed no difference in efficacy, but better tolerability of oral fluconazole.26 The same group performed a placebo-controlled trial of itraconazole oral solution and found that itra-conazole reduced proven and suspected deep fungal infection and candidemia.27 Concerns have been raised, however, about the increasing incidence of colonization with C. glabrata and C. krusei in patients receiving fluconazole prophylaxis.28

Several trials have assessed lipid formulations of amphotericin B. Prentice et al. conducted two multicenter trials (one in adults and one in children) comparing conventional versus liposomal amphotericin in patients with fever and neutropenia.29 Liposomal amphotericin was associated with fever side effects, and defervescence occurred in 64% of those on 3 mg/kg/day liposomal amphotericin as opposed to 49% of those on conventional amphotericin (p = 0.03).29 Mattiuzzi et al. compared liposomal amphotericin B versus the combination of fluconazole and itraconazole prophylaxis.30 Efficacy was similar, but liposomal amphotericin was associated with more increases in serum creatinine and bilirubin.30 Wingard et al. compared liposomal amphotericin with ABLC and found similar efficacy, but fewer infusion-related reactions with liposomal amphotericin.31 Walsh et al. (NIAID Mycoses Study Group) compared liposomal amphotericin B with conventional amphotericin B in a study of 687 patients.32 Resolution of fever, survival, and rates of discontinuation of the study drug were similar in both groups, but there were fewer proven breakthrough fungal infections in the liposomal amphotericin group as well as less infusion-related toxicity and nephrotoxicity.32

Walsh et al. also compared voriconazole with liposomal amphotericin B in a randomized trial of 837 patients with persistent fever and neutropenia.33 The overall success rate was similar; however, there were fewer breakthrough fungal infections, less nephrotoxi-city, and fewer infusion-related reactions with voriconazole.33

Given the number of randomized trials comparing antifungal medications, several meta-analyses have been performed. Gotzsche and Johansen in 2002 analyzed 30 trials in which antifungal therapy had been compared with placebo or no treatment.34 Antifungal treatment with amphotericin B, itraconazole, or flu-conazole decreased the incidence of invasive fungal infection. A meta-analysis of 38 trials from 2002 by Bow et al. showed that antifungal prophylaxis reduced the use of parenteral antifungal therapy, and superficial and deep fungal infections. For the overall population, mortality was not reduced, but it was reduced in the subgroups with prolonged neutropenia and who had received hematopoietic stem cell transplanta-tion.35 Glasmacher et al. analyzed 13 randomized trials of itraconazole prophylaxis and concluded that itra-conazole solution (not capsules) reduced the incidence of invasive fungal infections, invasive yeast infections, and mortality from fungal infections but not overall mortality.36

There is still no consensus on the optimal antifun-gal agent to use, or whether to start this agent before fever occurs. The 2002 IDSA guidelines state that amphotericin B has usually been the drug of choice.1 Lipid formulations of amphotericin B can be used as alternatives, with similar efficacy, less toxicity, and higher cost. Fluconazole is an acceptable alternative at institutions at which invasive mold infections and C. krusei infections are uncommon. Voriconazole and caspofungin are increasingly used, and newer antifun-gal agents are still being developed.

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