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Antifungal Therapy in Patients with Fever and Neutropenia — More Rational and Less Empirical?
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     Empirical antibacterial therapy for fever and neutropenia has dramatically improved outcomes in a large number of patients, making it possible for many to undergo successful antineoplastic therapy. Because the diagnosis of fungal infection in patients with neutropenia can be difficult and because delays in instituting effective antifungal therapy are associated with increased mortality, the concept of empirical antifungal therapy with amphotericin B has emerged. Empirical antifungal therapy has become accepted clinical practice, and there are now alternatives to conventional amphotericin B — namely, liposomal amphotericin B and voriconazole.1

    In this issue of the Journal, Walsh et al.2 report the results of a double-blind, randomized study comparing caspofungin, which is a new type of antifungal agent, with liposomal amphotericin B as empirical therapy in patients with persistent fever and neutropenia. Caspofungin belongs to the echinocandin class of antifungal agents, which inhibit the synthesis of fungal cell-wall 1,3--D-glucan — a different mechanism of action from that of other antifungal agents. Caspofungin has been approved for the treatment of severe invasive infections due to candida and aspergillus species.

    Walsh et al. report overall success rates of 33.9 percent for caspofungin and 33.7 percent for liposomal amphotericin B — results that fulfill criteria for the noninferiority of caspofungin. Moreover, in comparing these two agents, they report that caspofungin was associated with a higher proportion of successful outcomes in patients with baseline fungal infections, a higher rate of survival seven days after the completion of therapy, and a lower rate of premature discontinuation of therapy because of adverse reactions. Clearly, caspofungin is another alternative to conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia.

    At this point, it is important to determine whether caspofungin, voriconazole, and liposomal amphotericin B are just alternatives to conventional amphotericin B or whether there is evidence that these newer drugs are superior to conventional amphotericin B. It is crucial to determine whether there are significant differences among these drugs and whether there is a potentially optimal agent for empirical antifungal therapy.

    The data reported by Walsh et al. should be viewed in the context of what is already known about empirical antifungal therapy in patients with fever and neutropenia3 and particularly the results of two studies previously conducted by Walsh and colleagues: one comparing conventional amphotericin B with liposomal amphotericin B4 and another comparing voriconazole with liposomal amphotericin B.5 These three studies provide extensive and solid information about empirical antifungal therapy. All were multicenter, randomized trials that involved large numbers of patients and used the same composite score to evaluate the results. The individual components of the end point were defervescence, survival, successful treatment of baseline fungal infection, prevention of breakthrough infection, and an absence of early discontinuation of therapy because of side effects. Table 1 summarizes the results of these three studies with respect to overall success, based on the composite end point, and the individual components of the end point.

    Table 1. Measures of the Success of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole, or Caspofungin.

    The use of a composite end point has the key advantage of providing a strict method for the evaluation of antifungal therapy. On the other hand, discontinuation of therapy because of toxic effects is not a real measure of the efficacy of a drug, and resolution of fever and survival are not necessarily direct consequences of the efficacy of empirical antifungal therapy. Despite these limitations, the composite end point and its components are extremely helpful in the effort to establish a new standard for the analysis of empirical antifungal therapy.

    The study in which Walsh et al. compared conventional amphotericin B and liposomal amphotericin B4 favored the latter, overall and for each individual component of the score except defervescence (58.0 percent with liposomal amphotericin B and 58.1 percent with conventional amphotericin B). It is noteworthy that the rates of overall success and resolution of fever were higher in that study than in the two subsequent ones, despite the similar methods used. In the next study,5 voriconazole did not meet the criteria for noninferiority to liposomal amphotericin B on the basis of the composite end point (overall success rates, 26.0 percent and 30.6 percent, respectively). The analysis of the individual components of the end point favored liposomal amphotericin B, except for the prevention of breakthrough fungal infections.

    In the study reported in this issue,2 caspofungin met the criteria for noninferiority to liposomal amphotericin B, and the analysis of the individual components favored caspofungin except with regard to the prevention of breakthrough infections and resolution of fever (41.2 percent with caspofungin and 41.4 percent with liposomal amphotericin B). Caspofungin also cured more documented baseline fungal infections than did liposomal amphotericin B. That result is surprising, since one would expect any antifungal agent to be more active in preventing breakthrough infections than in curing established infection. The distinction made between baseline infections (those present on or before day 2) and breakthrough infections (those with an onset on day 3 or later) may be artificial. Both established and breakthrough infections are most likely objective failures of empirical therapy, which may be the most solid end point for evaluating efficacy. To compare objectively the antifungal efficacy of the four regimens, one can look at the rates of microbiologically documented failure (i.e., breakthrough infections and persistent baseline infections) in each of the studies summarized in Table 1. The failure rates are 13.3 percent for conventional amphotericin B, 8.2 percent for liposomal amphotericin B, 3.5 percent for voriconazole, and 7.7 percent for caspofungin.

    At this point, what can be concluded from these three pivotal studies? Clearly, conventional amphotericin B is less well tolerated than liposomal amphotericin B in terms of infusion-related reactions and nephrotoxicity. Moreover, the efficacy of conventional amphotericin B as empirical antifungal therapy appears to be inferior to that of liposomal amphotericin B (which can be given at a dose of 3 mg or more per kilogram of body weight, with minimal dose-dependent toxic effects), as indicated by the lower rate of microbiologically documented failures with the latter regimen. Both voriconazole and caspofungin are better tolerated than liposomal amphotericin B in terms of nephrotoxicity and infusion-related events. Moreover, both may be more active than liposomal amphotericin B in the control of baseline fungal infections and the prevention of breakthrough infections.

    Thus, on the basis of the currently available and credible evidence, voriconazole and caspofungin both appear to be suitable, and perhaps preferable, alternatives to conventional and liposomal amphotericin B as empirical antifungal therapy in patients with persistent fever and neutropenia. Clearly, a comparative study of voriconazole and caspofungin should be conducted, with special attention to clinical effectiveness (evaluated on the basis of microbiologically documented events) and to comparative overall costs.

    The important issue now facing clinicians is determining which patients are most likely to benefit from empirical antifungal therapy. The definition of the population at risk according to criteria such as prolonged and severe neutropenia is probably too broad, since only a minority of patients present with an infection that can be microbiologically documented. About 50 percent of treated patients have a response to empirical antifungal therapy, but resolution of fever is not absolute proof that an occult fungal infection has been cured. Thus, it is likely that many patients who receive empirical antifungal therapy have coexisting conditions.

    There are several possible ways to help reduce empirical overtreatment of persistent febrile neutropenia with expensive antifungal drugs. One alternative is to use preemptive, rather than empirical, antifungal therapy, limiting the administration of antifungal drugs to the patients with "probable" fungal infection, as defined recently in an international consensus statement.6 Another possibility may be to improve the early laboratory diagnosis of occult fungal infection. Finally, a better definition of the risk factors predisposing patients to fungal infection would help to identify more precisely the population most likely to benefit from the empirical approach. My colleagues and I have developed and validated a score for predicting the risk of complications during febrile neutropenia.7 Such a score may allow clinicians to make better decisions about antimicrobial therapy on the basis of a given patient's risk and thus avoid expensive therapy that is unnecessary and potentially toxic.8 For empirical antifungal therapy in patients with persistent fever and neutropenia, the real issue is no longer the choice of the "best" agent but rather the identification, on a rational basis, of the population of patients who will benefit from a given agent the most.

    Source Information

    From the Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Brussels.

    References

    Marr KA. Empirical antifungal therapy -- new options, new tradeoffs. N Engl J Med 2002;346:278-280.

    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;351:1391-1402.

    Klastersky J. Empirical antifungal therapy. Int J Antimicrob Agents 2004;23:105-112.

    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;340:764-771.

    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.

    Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34:7-14.

    Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association of Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038-3051.

    Innes HE, Smith DB, O'Reilly SM, Clark PI, Kelly V, Marshall E. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: a prospective randomised controlled single centre study. Br J Cancer 2003;89:43-49.

    Related Letters:

    Caspofungin versus Liposomal Amphotericin B for Empirical Therapy

    Kontoyiannis D. P., Lewis R. E., Tattevin P., Bareau B., Camus C., Marty F. M., Lowry C. M., Schneemann M., Imhof A., Danaher P. J., Jones B. L., McLintock L. A., Walsh T. J., Donowitz G. R., dePauw B. E.(Jean Klastersky, M.D., Ph)