Correspondence

Voriconazole versus Amphotericin B for Invasive Aspergillosis

N Engl J Med 2002; 347:2080-2081December 19, 2002

Article

To the Editor:

Herbrecht et al. (Aug. 8 issue)1 show the superiority of voriconazole over amphotericin B for primary therapy of invasive aspergillosis. However, we are concerned about the striking difference in the duration of treatment: a median of 10 days with amphotericin B, as compared with 77 days with voriconazole. How can one be so sure that “the superiority of voriconazole . . . was not the result of excessive interruptions” of amphotericin B? First, the use of one of the lipid formulations of amphotericin B, which are tolerated better by the kidneys than amphotericin B deoxycholate,2 would probably have reduced the number of discontinuations in the control group. Second, an alternative antifungal agent was given to 107 patients in the amphotericin B group and to 52 patients in the voriconazole group. Because severe adverse events accounted for 45 discontinuations in the amphotericin B group and for 26 discontinuations in the voriconazole group, we wonder whether the other interruptions were explained by a poor response to initial therapy (which may be problematic in an open-label study). Therapy was switched from amphotericin B to itraconazole, the efficacy of which remains debatable in this setting, in 38 patients and from voriconazole to itraconazole in only 17 patients. This difference may partly account for the worse results in the amphotericin B group. The excess mortality in the amphotericin B group was evident after about 10 days, which coincides with the median duration of amphotericin B treatment.

François Blot, M.D.
Cyrille Edé, M.D.
Gérard M. Nitenberg, M.D.
Institut Gustave Roussy, 94805 Villejuif, France
blot@igr.fr

2 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest 2002;121:1988-1999
   CrossRef | Web of Science | Medline

To the Editor:

In the study by Herbrecht et al., treatment of invasive aspergillosis was planned to take place over a 12-week period, so amphotericin B in a liposomal formulation would have been the more appropriate drug to answer the question of whether amphotericin B or voriconazole would be the optimal method of treatment for this infection. Herbrecht et al. show that use of amphotericin B is not the optimal approach, because it is not safe to administer this drug as required for an extended period. The crucial question of whether initial treatment with liposomal amphotericin B is as efficacious as treatment with voriconazole remains unanswered but is still of utmost clinical importance.

Meinolf Karthaus, M.D.
Evangelisches Johannes-Krankenhaus, D-33611 Bielefeld, Germany
meinolf-karthaus@johanneswerk.de

Author/Editor Response

The authors reply:

To the Editor: We agree with Blot and colleagues that the reasons for early discontinuation are important to the analysis. Thus, we have carefully reviewed the reasons for discontinuation in all the patients who received at least one dose of study drug (185 patients in the amphotericin B group and 194 patients in the voriconazole group) to avoid any misinterpretation of the difference in the duration of the initial, randomly assigned therapy. Progression of the infection (as assessed by the data-review committee, which was blinded to the study-drug assignment) and toxic effects accounted for discontinuation in 72 patients (38.9 percent) and 80 patients (43.2 percent), respectively, in the amphotericin B group and in 54 patients (27.8 percent) and 14 patients (7.2 percent), respectively, in the voriconazole group. Other reasons (in 21 patients in the amphotericin B group [11.4 percent] and in 20 patients in the voriconazole group [10.3 percent]) included progression of underlying cancer, withdrawal of consent, and the investigator's decision. Hence, there were no excess unjustified discontinuations in the amphotericin B group. Restriction of the analysis to the modified intention-to-treat population does not change the conclusion.

As the study results suggest, conventional amphotericin B is no longer considered a sustainable treatment for invasive aspergillosis. However, when the study was designed, intravenous amphotericin B and oral itraconazole were the only drugs approved for primary therapy of invasive aspergillosis. None of the lipid formulations were licensed in any country for primary therapy. Thus, no lipid formulation was chosen for use in a reference group in our study.

Whether a lipid formulation would have improved the results in the amphotericin B group, as suggested by Karthaus, is a speculation not supported by any data from the literature. We accept the superiority of lipid amphotericin B over conventional amphotericin B in terms of tolerance. Unfortunately, there is no evidence from any large randomized study that the lipid formulation has improved efficacy in invasive aspergillosis. A recent study showed that amphotericin B colloidal dispersion and conventional amphotericin B have similar efficacy, with 18.0 percent and 22.7 percent rates of complete or partial response, respectively.1 In that study, the rate of response to amphotericin B was identical to the rate of response in our study at the end of amphotericin B therapy (21.8 percent), although the median duration of treatment was slightly longer (14.5 days, as compared with 10 days in our study). This identical response rate confirms the poor efficacy of amphotericin B for the treatment of invasive aspergillosis.

The benefit in terms of survival for patients treated with voriconazole became evident after only two weeks of therapy. These data suggest that the first days of therapy are critical for the outcome of invasive aspergillosis and also indicate the insufficient efficacy of amphotericin B given as initial treatment.

Raoul Herbrecht, M.D.
Hôpital de Hautepierre, 67098 Strasbourg, France
raoul.herbrecht@chru-strasbourg.fr

Thomas F. Patterson, M.D.
University of Texas Health Science Center, San Antonio, TX 78229-3900

John E. Bennett, M.D.
National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892

1 References

1. 1

   Bowden R, Chandrasekar P, White MH, et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2002;35:359-366
   CrossRef | Web of Science | Medline

Citing Articles (8)

Citing Articles

1. 1

   Meinolf Karthaus, Marcus Hentrich. (2011) Wait and see or rush and switch? New questions for the management of patients with febrile neutropenia receiving antifungal prophylaxis. Mycoses 54, 1-6
   CrossRef

2. 2

   M. Karthaus. (2010) Leitliniengerechte Therapie der invasiven Aspergillose. Mycoses 53, 36-43
   CrossRef

3. 3

   Marit D. Moen, Katherine A. Lyseng-Williamson, Lesley J. Scott. (2009) Liposomal Amphotericin B. Drugs 69:3, 361-392
   CrossRef

4. 4

   Kazuo Tamura, Akio Urabe, Minoru Yoshida, Akihisa Kanamaru, Yoshihisa Kodera, Shinichiro Okamoto, Shigefumi Maesaki, Tohru Masaoka. (2009) Efficacy and safety of micafungin, an echinocandin antifungal agent, on invasive fungal infections in patients with hematological disorders. Leukemia & Lymphoma 50:1, 92-100
   CrossRef

5. 5

   Karsten Juhl Jørgensen, Peter C Gøtzsche, Helle Krogh Johansen, Karsten Juhl Jørgensen. 2006. Voriconazole versus amphotericin B in cancer patients with neutropenia. .
   CrossRef

6. 6

   W. W. Hope, D. W. Denning. (2004) Optimising antifungal therapy for individual patients. Internal Medicine Journal 34:4, 147-149
   CrossRef

7. 7

   W. W. Hope, D. W. Denning. (2004) Invasive aspergillosis: current and future challenges in diagnosis and therapy. Clinical Microbiology and Infection 10:1, 2-4
   CrossRef

8. 8

   Dimitrios P. Kontoyiannis, Ray Hachem, Russell E. Lewis, Gustavo A. Rivero, Harrys A. Torres, John Thornby, Richard Champlin, Hagop Kantarjian, Gerald P. Bodey, Issam I. Raad. (2003) Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 98:2, 292-299
   CrossRef