Amphotericin B is Still the Drug of Choice for Invasive Aspergillosis

We read with interest the recent article by Drs. Segal andWalsh, wherein the authors review the epidemiology, diagnosis, and management of invasive aspergillosis (1). The authors recommend voriconazole as the drug of choice in the treatment of invasive aspergillosis. However, we do not agree with the recommendations of the authors that voriconazole be considered the new standard of care for invasive aspergillosis. We believe that it is too early to accept voriconazole as the drug of choice for invasive aspergillosis. Amphotericin B is a highly effective antifungal agent, and is used as the gold standard against which newer agents are compared in trials of antifungal drugs. The conclusion that amphotericin B is inferior to voriconazole is based on two published trials (2, 3); however, both the trials are limited by their study design (4). The first trial was flawed by its design in using the deoxycholate preparation without requirements for premedication (used for minimizing infusion-related toxicity), or substitutionwith fluid and electrolytes (to reduce nephrotoxicity) (2). Moreover, voriconazole was given on an average of 77 d, but amphotericin B was given only for 10 d, precluding any meaningful comparison of the two study drugs. The second trial was a noninferiority trial that compared voriconazole with liposomal amphotericin B as an empirical treatment of fever of unknown origin in neutropenic cancer patients (3). Despite misleading definitions, voriconazole was significantly inferior to amphotericin B (4, 5). In fact, there was less survival in the voriconazole group, and a claimed significant reduction in the so-called breakthrough fungal infections (defined as those confirmed more than 24 h postenrollment) in favor of voriconazole disappeared when baseline infections that persisted despite treatment (infections arbitrarily excluded from analysis) were included (4). Thus, the available evidence does not support a recommendation to use voriconazole instead of amphotericin B for the treatment of invasive aspergillosis. To the contrary, amphotericin B is significantly more effective than voriconazole and is currently the drug of choice (6).