Caspofungin versus Liposomal Amphotericin B for Empirical Therapy

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1 correspondence Caspofungin versus Liposomal Amphotericin B for Empirical Therapy THIS WEEK S LETTERS 410 Caspofungin versus Liposomal Amphotericin B 414 Single-Dose Azithromycin for Trachoma 415 Controlling Health Care Costs 416 Bell s Palsy 418 Pulmonary Hypertension 419 Case : A Woman with Paresthesias 420 Increased Serum Lipase in West Nile Virus Infection to the editor: In the important study by Walsh et al. (Sept. 30 issue), 1 the most unexpected finding was the difference in response rates between the liposomal amphotericin B group and the caspofungin group among patients who had aspergillosis at baseline. The rate of response to liposomal amphotericin B (8.3 percent) is the lowest ever reported in the treatment of aspergillosis. This finding raises the question of whether there were imbalances between the treatment groups in terms of host factors (i.e., neutrophil recovery) or prior use of azole therapy, since sequential therapy with itraconazole and amphotericin B has been shown to attenuate the efficacy of amphotericin B, 2 and sequential itraconazole and caspofungin enhances the activity of caspofungin against aspergillus. 3 The poor response may also have been influenced by the arbitrary definition of breakthrough infections as those occurring on the third day of therapy or later; the presence of aspergillus galactomannan antigen is usually confirmed after several days of clinical evidence of aspergillosis in patients with leukemia who have fever and neutropenia, 4 and antifungal agents may require more than 72 hours to reach effective concentrations in tissue. 5 Investigators designing future studies should consider these issues in defining what really constitutes a breakthrough fungal infection. Dimitrios P. Kontoyiannis, M.D. Russell E. Lewis, Pharm.D. University of Texas M.D. Anderson Cancer Center Houston, TX dkontoyi@mdanderson.org Dr. Kontoyiannis reports having served on an advisory board for Schering-Plough and having received honoraria and research support from and served on speakers bureaus for Merck, Pfizer, Fujisawa, and Enzon; Dr. Lewis reports having received research support from Merck, Fujisawa, and Pfizer and having served on advisory boards for Pfizer and Schering-Plough. 1. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004;351: Lewis RE, Prince RA, Chi J, Kontoyiannis DP. Itraconazole preexposure attenuates the efficacy of subsequent amphotericin B therapy in a murine model of acute invasive pulmonary aspergillosis. Antimicrob Agents Chemother 2002;46: Kontoyiannis DP, Lewis RE, Lionakis MS, Albert ND, May GS, Raad II. Sequential exposure of Aspergillus fumigatis to itraconazole and caspofungin: evidence of enhanced in vitro activity. Diagn Microbiol Infect Dis 2003;47: Kawazu M, Kanda Y, Nannya Y, et al. Prospective comparison of the diagnostic potential of real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1 3)- beta-d-glucan test in weekly screening for invasive aspergillosis in patients treated with hematological disorders. J Clin Microbiol 2004;42: Becker MJ, de Marie S, Fens MH, Hop WC, Verbrugh HA, Bakker- Woudenberg IA. Enhanced antifungal efficacy in experimental invasive pulmonary aspergillosis by combination of AmBisome with Fungizone as assessed by several parameters of antifungal response. J Antimicrob Chemother 2002;49: to the editor: In their large study of caspofungin as compared with liposomal amphotericin B for em- 410

2 correspondence pirical antifungal therapy in patients with persistent fever and neutropenia, Walsh et al. observed an unexpectedly low rate of resolution of baseline fungal infections in the liposomal amphotericin B group 25.9 percent; the rate was 66.7 percent when liposomal amphotericin B was compared with voriconazole 1 and 81.8 percent when it was compared with conventional amphotericin B in two very similar previous studies. 2 Although historical comparisons are not valid, such an unexpectedly high failure rate deserves further investigation. In the current study, 56.4 percent of the patients were receiving systemic antifungal prophylaxis at baseline; systemic antifungal prophylaxis is now commonly used at increasing dosages (e.g., fluconazole at 400 mg per day) for high-risk patients. Because amphotericin B exerts its antifungal effect by binding to ergosterol, previous prolonged exposure to azoles that has reduced ergosterol concentrations in the fungal cytoplasmic membrane could modify fungal susceptibility to amphotericin B. 3 Did the authors compare the rate of response of baseline fungal infections to liposomal amphotericin B between patients who had previous azole exposure and those who did not? Pierre Tattevin, M.D. Benoît Bareau, M.D. Christophe Camus, M.D. Pontchaillou University Hospital Rennes, France pierre.tattevin@chu-rennes.fr 1. 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: Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340: Sugar AM. Use of amphotericin B with azole antifungal drugs: what are we doing? Antimicrob Agents Chemother 1995;39: to the editor: Walsh and colleagues report the noninferiority of caspofungin to liposomal amphotericin B when given empirically in patients with fever and neutropenia but report a lower overall survival rate and worse outcomes among patients with baseline fungal infections (in most cases, invasive aspergillosis) who were assigned to treatment with liposomal amphotericin B. The trial used liposomal amphotericin B at a dose of 3 mg per kilogram of body weight per day, with an increase to 5 mg per kilogram per day after five days if the clinical response was not adequate. Current practice is to treat invasive aspergillosis with voriconazole, 1 liposomal amphotericin B at a dose of 5 mg per kilogram per day or higher, 2,3 or caspofungin at the doses used in the trial. Thus, patients in the liposomal amphotericin B group who had baseline invasive aspergillosis may have received suboptimal doses of that drug at a time when frontloading 4 of therapy is critical to gain control of the infection. This situation may account for the differences observed in the prespecified end points. We would like to know whether the overall difference in survival shown by the Kaplan Meier curves persisted after patients with baseline fungal infections were excluded from the analysis. Therapeutic prescriptions beyond empirical therapy need to be studied in this population. Francisco M. Marty, M.D. Colleen M. Lowry, Pharm.D. Brigham and Women s Hospital Boston, MA fmarty@partners.org Dr. Marty reports having received research support from Fujisawa. 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: Stevens DA, Kan VL, Judson MA, et al. Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis 2000;30: Walsh TJ, Goodman JL, Pappas P, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother 2001;45: Baden LR, Teplick R, Rubin RH. Antimicrobial therapy. In: Parrillo JE, Dellinger RP, eds. Critical care medicine: principles of diagnosis and management in the adult. St. Louis: Mosby, 2001: to the editor: Walsh et al. report the noninferiority of caspofungin to liposomal amphotericin B when given as empirical therapy in patients with fever and neutropenia. Both caspofungin and liposomal amphotericin B are expensive drugs, costing more than $500 per day. We use conventional amphotericin B deoxycholate, given as a continuous infusion over a 24-hour period, as standard empirical therapy in patients with fever and neutropenia. The infusion is administered with the use of multilumen central venous catheters, one of which is reserved for continuous infusion of amphotericin B deoxycholate. This approach has been shown to be less toxic than, and as effective as, standard short-term infusion of amphotericin B 1-4 ; the efficacy and tox- 411

3 icity are in the range of those reported for liposomal amphotericin B. 1,2 Continuous infusion of amphotericin B deoxycholate costs about $50 per day. The use of this approach instead of liposomal amphotericin B or caspofungin saves our medical center more than $400,000 per year in medication expenses. Hospitals with tight budgets should weigh the differences in cost for these equally effective drugs. Markus Schneemann, M.D. Alexander Imhof, M.D. University of Zurich Medical School CH-8091 Zurich, Switzerland markus.schneemann@usz.ch Dr. Schneemann reports having received lecture fees and travel grants from Merck Sharp & Dohme (Europe), Pfizer, and Bristol- Myers Squibb; Dr. Imhof reports having received lecture fees and travel grants from Merck, Pfizer, Gilead, and Bristol-Myers Squibb. 1. Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ 2001;322: Imhof A, Walter RB, Schaffner A. Continuous infusion of escalated doses of amphotericin B deoxycholate: an open-label observational study. Clin Infect Dis 2003;36: Furrer K, Schaffner A, Vavricka SR, Halter J, Imhof A, Schanz U. Nephrotoxicity of cyclosporine A and amphotericin B deoxycholate as a continuous infusion in allogenic stem cell transplantation. Swiss Med Wkly 2002;132: Speich R, Dutly A, Naef R, Russi EW, Weder W, Boehler A. Tolerability, safety and efficacy of conventional amphotericin B administered by 24-hour infusion to lung transplant recipients. Swiss Med Wkly 2002;132: to the editor: In his editorial accompanying the report by Walsh et al., Klastersky 1 states that there is current evidence that voriconazole and caspofungin are suitable, and possibly preferable, alternatives to amphotericin B deoxycholate and liposomal amphotericin B as empirical antifungal therapy in patients with persistent fever and neutropenia. He suggests that a head-to-head comparison may reveal one to be a more rational choice. He neglects to mention a study by Eriksson et al., 2 who showed that administration of 1 mg of amphotericin B per kilogram per day over a 24-hour period, instead of the conventional 4-hour period, was associated with a dramatic decrease in nephrotoxic and infusionrelated side effects. More strikingly, there was a decrease in mortality, the most concrete of end points, in the continuous-infusion group. Given the wide discrepancy in the costs of the available agents, this finding warrants further research. Specifically, for a 70-kg person, the cost per day of maintenance intravenous therapy is as follows: amphotericin B (1 mg per kilogram), $17; voriconazole (4 mg per kilogram), $298; and caspofungin (50 mg), $ A larger study confirming the efficacy and tolerability of continuous-infusion amphotericin B may show that it is the most rational choice. (The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the official policy of the Department of Defense or other departments of the U.S. government.) Patrick J. Danaher, M.D. David Grant U.S. Air Force Medical Center Travis AFB, CA patrick.danaher@travis.af.mil 1. Klastersky J. Antifungal therapy in patients with fever and neutropenia more rational and less empirical? N Engl J Med 2004; 351: Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ 2001;322: Antifungal therapy cost analysis. (Accessed January 6, 2005, at to the editor: We urge caution regarding Klastersky s suggestion that antifungal agents should be reserved for patients with probable infection. Early initiation of antifungal therapy, when the fungal burden is low, plays a crucial role in improving survival. 1 As Klastersky asserts, the identification of patients at highest risk for invasive fungal infection is critical. Risk stratification may be further refined with the use of sensitive diagnostic tools such as an enzyme-linked immunosorbent assay for galactomannan and a polymerase-chain-reaction (PCR) assay for fungal genomic DNA to screen high-risk patients prospectively for early evidence of fungal infection. These assays have excellent negative predictive values, and they may be used to determine whether antifungal therapy can be withheld in patients who have antibiotic-resistant neutropenic fever with no other evidence of invasive fungal infection. 2 However, we believe that the real issue is how to treat patients earlier. Positive results of PCR and aspergillus galactomannan assays are often recorded before the development of fever, which is the trigger for empirical therapy. 2 These techniques may 412

4 correspondence allow earlier initiation of therapy, shifting the emphasis from empirical to preemptive therapy, with the potential for an improved outcome. This concept merits further investigation. Brian L. Jones, M.B., Ch.B. Glasgow Royal Infirmary Glasgow G4 0SF, United Kingdom Lorna A. McLintock, M.B., Ch.B. University of Glasgow Glasgow G31 2ER, United Kingdom 1. Aisner J, Wiernik PH, Schimpff SC. Treatment of invasive aspergillosis: relation of early diagnosis and treatment to response. Ann Intern Med 1977;86: McLintock LA, Jones BL. Advances in the molecular and serological diagnosis of invasive fungal infection in haemato-oncology patients. Br J Haematol 2004;126: dr. walsh and colleagues reply: In collaboration with Dr. Hedy Teppler and Merck Research Laboratories, we conducted additional analyses to address the correspondents questions. In addressing the questions of Drs. Kontoyiannis and Lewis, we note that several factors may have affected the rate of response of baseline invasive fungal infections. The data on the response of invasive aspergillosis to liposomal amphotericin B in patients with profound neutropenia are sparse and noncomparative, thus making comparisons difficult. The blinded review and assessments of the therapeutic response in this trial applied to all cases a uniform definition of breakthrough invasive fungal infection: infection on day 3 of therapy or later. Patients with baseline invasive fungal infections in the two treatment groups were balanced with respect to the underlying disease, the risk category, the proportion with previous exposure to antifungal prophylaxis, and the proportion with profound neutropenia. The duration of neutropenia during the study among patients with baseline invasive fungal infections was also similar between the two groups. After enrollment, the mean (±SEM) time to neutrophil recovery among patients whose neutropenia resolved before the end of therapy was 8.3±1.3 days in the caspofungin group as compared with 9.5±1.7 days in the liposomal amphotericin B group (P=0.56). Among patients whose study therapy was discontinued while they still had neutropenia, the mean duration of neutropenia was at least 7.9±1.7 days in the caspofungin group and 8.7±1.1 days in the liposomal amphotericin B group (P=0.66). Because patients data were censored at the end of therapy, the time to neutrophil recovery in these patients is not known. In response to Drs. Marty and Lowry: we used the approved dosage of liposomal amphotericin B for empirical antifungal therapy 3 mg per kilogram per day. When our clinical trial was designed and initiated, in 1999, voriconazole had not been approved for the primary treatment of invasive aspergillosis. At the time of enrollment, no patient had a documented invasive fungal infection. Liposomal amphotericin B is approved for salvage treatment of invasive aspergillosis at a dosage of 3 to 5 mg per kilogram per day in the United States and at 3 mg per kilogram per day in most countries in Europe. Other groups have advocated liposomal amphotericin B dosages for the treatment of invasive aspergillosis of 1 mg per kilogram per day, 1 4 mg per kilogram per day, 2 or at least 5 mg per kilogram per day. 3 Thus, given the regulatory and clinical considerations with respect to liposomal amphotericin B dosage, use of 3 mg per kilogram per day was the most tenable initial dosing strategy. Finally, when the Kaplan Meier survival curves were plotted for patients in the modified intentionto-treat population who did not have a baseline invasive fungal infection, the pattern of the curves was similar but the log-rank chi-square was not significant (P=0.29), indicating that there was no difference between the treatment groups with respect to survival among patients without a baseline invasive fungal infection. In response to Dr. Tattevin and colleagues: we did not see increased resistance to therapy among patients who had previously received azole prophylaxis. For patients with documented baseline invasive fungal infections, the proportion with a successful outcome was 46.2 percent (6 of 13) in the caspofungin group versus 23.1 percent (3 of 13) in the liposomal amphotericin B group, among those who received azole prophylaxis, and 57.1 percent (8 of 14) in the caspofungin group versus 28.6 percent (4 of 14) in the liposomal amphotericin B group, among those who received no prophylaxis. Because the pharmacodynamics of the efficacy of amphotericin B deoxycholate are thought to be concentration-dependent rather than time- 413

5 dependent, 4,5 so the continuous-infusion method proposed by Drs. Schneemann and Imhof seems counterintuitive. No clinical trial of continuous infusion has had sufficient power to demonstrate equal efficacy between continuous infusion and intermittent infusion of amphotericin B deoxycholate. Thomas J. Walsh, M.D. National Cancer Institute Bethesda, MD Gerald R. Donowitz, M.D. University of Virginia Health System Charlottesville, VA Ben E. depauw, M.D., Ph.D. University Hospital St. Radboud 6525 GA Nijmegen, the Netherlands 1. Ellis M, Spence D, de Pauw B, et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis 1998;27: Karp JE, Merz WG. Randomized trial of lipid-based amphotericin B for invasive aspergillosis in neutropenic hosts is an important step forward. Clin Infect Dis 1998;27: Walsh TJ, Goodman JL, Pappas P, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother 2001;45: Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother 2001;45: Van der Auwera P, Ceuppens AM, Heymans C, Meunier F. In vitro evaluation of various antifungal agents alone and in combination by using an automatic turbidimetric system combined with viable count determinations. Antimicrob Agents Chemother 1986;29: Single-Dose Azithromycin for Trachoma to the editor: Solomon et al. (Nov. 4 issue) 1 suggest that the ocular chlamydia that causes trachoma can be eliminated by a single mass antibiotic treatment. Two years after distributing oral azithromycin in a village, they identified only a single infection. The authors state that this finding contrasts starkly with the prediction of our mathematical model. 2,3 Yes and no. We do predict that infection will eventually return after a single mass treatment. However, with 97.5 percent coverage of a moderately infected area, this return may take a long time. Our model predicts that less than 3 percent of persons will be infected at one year and an even smaller proportion in this case, since Solomon et al. also distributed tetracycline ointment. Furthermore, this estimate is only an expectation (or average), and chance can have a large effect. We recently monitored 24 villages in Ethiopia after a single mass treatment; in some villages, infection was eliminated at two months, and in others it returned relatively rapidly. 3 Unfortunately, the evidence so far suggests that, on average, infection returns after a single mass treatment, but to test this properly, one must look at more than one village. Thomas M. Lietman, M.D. Bruce Gaynor, M.D. University of California, San Francisco San Francisco, CA tml@itsa.ucsf.edu Travis Porco, Ph.D. California Department of Health Services Berkeley, CA Solomon AW, Holland MJ, Alexander NDE, et al. Mass treatment with single-dose azithromycin for trachoma. N Engl J Med 2004;351: Lietman T, Porco T, Dawson C, Blower S. Global elimination of trachoma: how frequently should we administer mass chemotherapy? Nat Med 1999;5: Melese M, Chidambaram JD, Alemayehu W, et al. Feasibility of eliminating ocular Chlamydia trachomatis with repeat mass antibiotic treatments. JAMA 2004;292: the authors reply: Two main factors differentiate our study from the model of Lietman et al. 1 First, our primary outcome measure was an adjusted geometric mean of the ocular Chlamydia trachomatis load, determined with the use of a quantitative polymerase-chain-reaction assay. The model, in contrast, used the prevalence of active trachoma, which correlates poorly with chlamydial infection. 2 Second, we reported that after high-coverage mass treatment, the load of infection dropped and then continued to fall for at least two years, whereas the model predicted that (in communities like ours, where the disease is mesoendemic) the prevalence of disease would double every four to eight months after a treatment-induced fall. Our results suggest that there may be a threshold level of infection, below which the transmission of trachoma ceases; its return might then depend on reintroduction from the outside by persons with heavy shedding of C. trachomatis. We agree that our data are from only a single community case study but note that six months after mass treatment, six Ethiopian villages studied by Lietman s group had a prevalence of infection of 414