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Invasive fungal disease is a common, often fatal complication in patients with neutropenia following chemotherapy for hematologic malignancies and in patients who have undergone allogeneic hematopoietic stem-cell transplantation. Posaconazole is a newly approved oral triazole with activity against several medically important molds, including aspergillus. Fluconazole, an older triazole that has been used for fungal prophylaxis, lacks such activity. Another older triazole, itraconazole, possesses activity against aspergillus but is erratically absorbed and is often poorly tolerated. Now, in two industry-funded, randomized, multicenter studies, researchers have examined posaconazole’s efficacy in preventing fungal infections among highly immunosuppressed patients.
In a prospective investigation, Cornely and colleagues compared posaconazole with fluconazole or itraconazole among 602 patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome. During the study period (the first 100 days after randomization), only 5% of patients in the posaconazole group, compared with 11% of those in the fluconazole or itraconazole group, developed invasive fungal infections (P<0.01). Sixty-nine percent of all fungal infections were caused by aspergillus species. Compared with patients in the fluconazole or itraconazole group, those in the posaconazole group showed a greater mean time to developing an invasive fungal infection (P<0.01) and decreased mortality, both overall (P=0.04) and due to fungal infection (P=0.01). Incidence of treatment-related adverse reactions was similar between groups.
In a double-blind trial, Ullmann and coworkers compared posaconazole with fluconazole among 600 patients who had undergone allogeneic hematopoietic stem-cell transplantation. All had developed graft-versus-host disease or were receiving intensive immunosuppressive therapy. The incidence of invasive fungal disease during the treatment period (the first 112 days after randomization) was 5.3% for the posaconazole group and 9.0% for the fluconazole group (P=0.07); death from invasive fungal disease was also less common in the posaconazole group than in the fluconazole group (P<0.05). In other analyses, posaconazole was superior to fluconazole in preventing invasive aspergillosis (P<0.01). Incidence of treatment-related adverse reactions was similar between groups.
Cornely OA et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007 Jan 25; 356:348-59.
Ullmann AJ et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007 Jan 25; 356:335-47.
De Pauw BE and Donnelly JP. Prophylaxis and aspergillosis — Has the principle been proven? N Engl J Med 2007 Jan 25; 356:409-11.
Comment
In both studies, posaconazole was superior to fluconazole in preventing death from invasive fungal disease, and this effect was principally due to reducing infections from aspergillus species. Hence, the findings support the use of prophylactic posaconazole when the risk of infection from aspergillus species and other molds is high. Such infections, however, occur only after prolonged neutropenia and immunosuppression. Most patients with chemotherapy-induced neutropenia would not benefit from such prophylaxis. Moreover, as editorialists note, the incidence of these infections varies widely among centers that treat such highly immunosuppressed patients. Only in centers where a threshold of cases is reached would posaconazole prophylaxis be a sensible therapeutic approach.