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Amphotericin B Is Still the Drug of Choice for Invasive Aspergillosis

We appreciate the comments made by Drs. Agarwal and Singh concerning our recent article (1). Our conclusion that voriconazole is superior to conventional amphotericin B as primary therapy for invasive aspergillosis is based on the landmark study by Herbrecht and coworkers (2). In this prospective, randomized study, patients in the voriconazole group and the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. The study was open-label, but decisions about outcome were made by a blinded data review committee. Voriconazole recipients had a significantly higher rate of successful outcomes (53 vs. 32%, respectively) in the modified intent-to-treat analysis and improved overall survival (71 vs. 58%, respectively) at 12 wk. Agarwal and Singh believe that this trial was flawed in its design because it did not prespecify requirements for premedication and fluid and electrolyte replacement in amphotericin B recipients. We disagree that leaving such decisions to the judgment of site investigators renders the trial flawed. Premedication with acetaminophen and diphenhydramine, although widely used, has questionable benefit in the prevention of acute infusion-related reactions. Prespecification of saline loading is neither feasible nor safe. Assessing whether patients may be able to tolerate a given saline load requires individual bedside assessment that is best left to skilled clinicians.

We also disagree with the statement that because fewer voriconazole recipients were switched to other licensed antifungal therapy (OLAT), no meaningful comparison between the drugs can be made. The protocol did not equate switching to OLAT either because of drug toxicity or refractory infection as study failure; rather, the primary endpoint for success was assessed at 12 wk after study entry without regard to use of OLAT. The effect of OLAT would therefore be to diminish the likelihood of demonstrating that one regimen was superior to the other. Patterson and coworkers (3) shed further light on the impact of OLAT on outcome in this trial. Lipid formulations of amphotericin B were the most common OLAT. Switches were made because of intolerance or insufficient response in 70% for amphotericin B recipients, compared with 24% of voriconazole recipients. Favorable responses to OLAT in the amphotericin B group occurred in 19% of patients with initial insufficient response and in 38% of those with intolerance.

We mentioned empirical antifungal therapy for neutropenic fever in our article as part of the diagnostic algorithm for invasive aspergillosis. Agarwal and Singh used the term "misleading definitions" related to the empirical antifungal trial comparing voriconazaole with liposomal amphotericin B (4). They then stated that "voriconazole was significantly inferior to amphotericin B." This is incorrect. The overall success rate among patients in the modified intention-to-treat population was 26.0% for those receiving voriconazole and 30.6% for those receiving liposomal amphotericin B (95% confidence interval for the difference, –10.6 to 1.6%). This 95% confidence interval falls just outside the predefined lower limit of –10%. Thus, the study failed to demonstrate the noninferiority of voriconazole (the primary endpoint of the study); however, it did not show that liposomal amphotericin B was superior. There was no significant difference in overall mortality between the voriconazole and liposomal amphotericin B groups. Agarwal and Singh make a legitimate point about the difficulty of distinguishing between baseline and breakthrough fungal infections. The distinction between baseline and breakthrough infections was prospectively defined and applied by a blinded data review committee to apply to all invasive fungal infections, not just aspergillosis. Using these prespecified criteria, fewer documented breakthrough fungal infections occurred in patients treated with voriconazole than in those treated with liposomal amphotericin B (1.9 vs. 5.0%, p = 0.02).

Brahm H. Segal

Roswell Park Cancer Institute Buffalo, New York

Thomas J. Walsh

National Cancer Institute National Institutes of Health Bethesda, Maryland

FOOTNOTES

Conflict of Interest Statement: B.H.S. has been reimbursed by Schering-Plough for serving on data review committees. He has received speaking honoraria from Merck and Pfizer, and laboratory support from Fujisawa (now Astellas) and Enzon. T.J.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2006;173:707–717.[Abstract/Free Full Text]
2. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, et al.; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Pfizer Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–415.[Abstract/Free Full Text]
3. Patterson TF, Boucher HW, Herbrecht R, Denning DW, Lortholary O, Ribaud P, Rubin RH, Wingard JR, DePauw B, Schlamm HT, et al. European Organisation for Research and Treatment of Cancer (EORTC) Invasive Fungal Infections Group (IFIG); Pfizer Global Aspergillus Study Group. Strategy of following voriconazole versus amphotericin B therapy with other licensed antifungal therapy for primary treatment of invasive aspergillosis: impact of other therapies on outcome. Clin Infect Dis 2005;41:1448–1452.[Medline]
4. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, Yanovich S, Stiff P, Greenberg R, Donowitz G, et al.; National Institute of Allergy and Infectious Diseases Mycoses Study Group. 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.[Abstract/Free Full Text]

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