Combination Antifungal Therapy for Invasive Aspergillosis

SIR—We read with interest the data reported by Marr et al. [1] in the 15 September 2004 issue of the journal. They found that the use of a combination of voriconazole and caspofungin for treatment of invasive aspergillosis in patients for whom initial therapy with amphotericin B formulations was unsuccessful was associated with an improved 3-month survival rate, compared with a historical control group of patients who received voriconazole alone. The benefit was confirmed by multivariate analysis, with combination therapy being associated with reduced mortality, irrespective of any other prognostic factors [1].

In his editorial commentary, Viscoli [2] pointed out correctly that these results require further confirmation by future prospective, controlled, randomized trials, because several factors may undermine the strength of evidence coming from an observational study that involves comparison with a historical control group. In particular, the recent availability of noninvasive diagnostic tools, standardization of the definition of proven or probable aspergillosis, and guidelines for changes to salvage therapy may significantly influence the results obtained by Marr et al. [1] when they are compared with historical data.

In addition to these considerations, the combination of caspofungin and liposomal amphotericin B has been successfully used as salvage therapy, as others have recently reported [3]; the results were further improved or maintained using sequential therapy with voriconazole. The different targeting of echinocandins and azoles or polyenes to cell membrane and cell wall, respectively, make the combination of these drugs very attractive for the patients who are at higher risk of treatment failure, but reliable clinical data are scanty. Although Marr et al. [1] measured the benefit of therapy on the basis of a firm end point (i.e., 3-month survival), they did not provide any data on the type and the speed at which the best response to therapy was obtained in the combination therapy group. These factors may be crucial for justifying the adoption of combination therapy in cases refractory to treatment. Actually, minor or stable responses to antifungal combination therapy may not translate into better 6-month or 1-year survival rates among hematopoietic stem cell transplant recipients if they are affected by—and treated for—steroid-refractory acute or chronic graft-versus-host disease [4]. Moreover, marked prolongation of the time to completion of the treatment regimen or to obtain a major response to therapy may delay in dose-intensity-scheduled chemotherapy and a higher risk of relapse of the underlying malignancy [5]. In both situations, an initial but slow response to combination therapy may not influence the eventual outcome for the patient.

In conclusion, the study by Marr et al. [1] clearly suggests that the intensification of antifungal therapy has potential benefit for immunocompromised patients with refractory infection, but the question of whether its superiority will translate into a sustained survival advantage needs to addressed by further studies.

• © 2005 by the Infectious Diseases Society of America