Breakthrough Zygomycosis after Voriconazole Treatment in Recipients of Hematopoietic Stem-Cell Transplants
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《新英格兰医药杂志》
To the Editor: The Food and Drug Administration (FDA) approved voriconazole for the treatment of invasive aspergillosis partly on the basis of data published in a report in the Journal,1 which showed an improved clinical response and improved survival with voriconazole treatment as compared with a strategy of initial treatment with amphotericin B deoxycholate. In patients with neutropenia and persistent fever, the use of voriconazole as empirical therapy failed to fulfill criteria for noninferiority as compared with liposomal amphotericin B,2 and the results of that trial generated substantial discussion after the FDA declined approval of the drug for that indication.3 Nevertheless, the use of voriconazole has become common in the management of neutropenia and persistent fever, in the treatment of high-risk patients with pneumonia, and as prophylaxis in patients who are at risk for the development of invasive fungal infections. These uses of voriconazole are probably attributable to its lower overall toxicity, its ease of oral administration, and its broad antifungal spectrum, especially against aspergillus species.
Since September 2002, when voriconazole became available at our institution, we have noted an increased frequency of cases of zygomycosis among recipients of allogeneic hematopoietic stem-cell transplants. From September 2002 to June 2003, 124 patients underwent hematopoietic stem-cell transplantation. During this period, zygomycosis was diagnosed in four patients on the basis of pathological or mycologic identification (Table 1). The diagnosis was made a median of 125 days after transplantation. All patients had received a diagnosis of graft-versus-host disease and were receiving treatment for it. Voriconazole was being given to three patients as antifungal prophylaxis and to one as empirical treatment for pulmonary nodules for a median of 36 days (range, 21 to 99) before diagnosis and a median of 20 days (range, 0 to 94) before the onset of symptoms that led to the diagnosis of zygomycosis. Initially, clinicians did not consider breakthrough or resistant invasive fungal infections. During the preceding 32 months, 370 patients underwent hematopoietic stem-cell transplantation, and only 2 had documented zygomycosis (4 cases in 119.6 patient-years, vs. 2 cases in 282.6 patient-years after hematopoietic stem-cell transplantation; unadjusted rate ratio, 4.73; 95 percent confidence interval, 0.87 to 25.8). There was no clustering of cases, and no zygomycetes were isolated from samples obtained during hospital environmental surveillance.
Table 1. Characteristics of Patients with Breakthrough Zygomycosis.
Zygomycetes are resistant to voriconazole in vitro.4 Thus, selective pressure from prolonged use of voriconazole or increased survival among profoundly immunosuppressed patients may explain the increased frequency of zygomycosis among patients who remain at high risk for invasive fungal infections. This observation underscores the need to make an etiologic diagnosis of such infections, to consider resistant pathogens promptly, and to consider the risks, benefits, and tradeoffs5 of prophylactic therapy carefully.
Francisco M. Marty, M.D.
Lisa A. Cosimi, M.D.
Brigham and Women's Hospital
Boston, MA 02115
fmarty@partners.org
Lindsey R. Baden, M.D.
Editor's note: Dr. Baden reports having received research support from Merck and Pfizer.
References
Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-415.
Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225-234.
Powers JH, Dixon CA, Goldberger MJ. Voriconazole versus liposomal amphotericin B in patients with neutropenia and persistent fever. N Engl J Med 2002;346:289-290.
Sun QN, Fothergill AW, McCarthy DI, Rinaldi MG, Graybill JR. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother 2002;46:1581-1582.
Marr KA. Empirical antifungal therapy -- new options, new tradeoffs. N Engl J Med 2002;346:278-280.
Since September 2002, when voriconazole became available at our institution, we have noted an increased frequency of cases of zygomycosis among recipients of allogeneic hematopoietic stem-cell transplants. From September 2002 to June 2003, 124 patients underwent hematopoietic stem-cell transplantation. During this period, zygomycosis was diagnosed in four patients on the basis of pathological or mycologic identification (Table 1). The diagnosis was made a median of 125 days after transplantation. All patients had received a diagnosis of graft-versus-host disease and were receiving treatment for it. Voriconazole was being given to three patients as antifungal prophylaxis and to one as empirical treatment for pulmonary nodules for a median of 36 days (range, 21 to 99) before diagnosis and a median of 20 days (range, 0 to 94) before the onset of symptoms that led to the diagnosis of zygomycosis. Initially, clinicians did not consider breakthrough or resistant invasive fungal infections. During the preceding 32 months, 370 patients underwent hematopoietic stem-cell transplantation, and only 2 had documented zygomycosis (4 cases in 119.6 patient-years, vs. 2 cases in 282.6 patient-years after hematopoietic stem-cell transplantation; unadjusted rate ratio, 4.73; 95 percent confidence interval, 0.87 to 25.8). There was no clustering of cases, and no zygomycetes were isolated from samples obtained during hospital environmental surveillance.
Table 1. Characteristics of Patients with Breakthrough Zygomycosis.
Zygomycetes are resistant to voriconazole in vitro.4 Thus, selective pressure from prolonged use of voriconazole or increased survival among profoundly immunosuppressed patients may explain the increased frequency of zygomycosis among patients who remain at high risk for invasive fungal infections. This observation underscores the need to make an etiologic diagnosis of such infections, to consider resistant pathogens promptly, and to consider the risks, benefits, and tradeoffs5 of prophylactic therapy carefully.
Francisco M. Marty, M.D.
Lisa A. Cosimi, M.D.
Brigham and Women's Hospital
Boston, MA 02115
fmarty@partners.org
Lindsey R. Baden, M.D.
Editor's note: Dr. Baden reports having received research support from Merck and Pfizer.
References
Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-415.
Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225-234.
Powers JH, Dixon CA, Goldberger MJ. Voriconazole versus liposomal amphotericin B in patients with neutropenia and persistent fever. N Engl J Med 2002;346:289-290.
Sun QN, Fothergill AW, McCarthy DI, Rinaldi MG, Graybill JR. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother 2002;46:1581-1582.
Marr KA. Empirical antifungal therapy -- new options, new tradeoffs. N Engl J Med 2002;346:278-280.