Echinocandin-Based Initial Therapy in Fungemic Patients with Cancer: A Focus on Recent Guidelines of the Infectious Diseases Society of America

To the Editor—I read with interest the recently published Infectious Diseases Society of America guidelines regarding treatment of candidiasis, the most common fungal infection in humans [1]. This long-awaited document is an important contribution in summarizing the best available evidence as derived from a series of recent prospective, multicentered candidemia industry-sponsored trials. On the basis of these studies, echinocandins are recommended as one of the preferred primary options for treatment of documented candidiasis and/or candidemia. The authors are cautious not to endorse the indiscriminate empirical use of echinocandins for high-risk patients with immunosuppression. For these patients, a lipid formulation of amphotericin B (3–5 mg/kg/day; A-I), an echinocandin (caspofungin; A-I), or voriconazole (B-I) are suggested [1]. I would like expand on 2 points that put these recommendations in perspective as they relate to empirical and early (“preemptive”) therapy for fungemic patients with cancer.

First, highly immunocompromised patients, especially ones with hematologic malignancies and/or who underwent stem cell transplantation were not included in the trials of all classes of modern antifungal agents (polyenes, triazoles, and echinocandins). These patients could be highly immunosuppressed (eg, because of a high dose of systemic corticosteroids) but not myelosuppressed, making the distinction of recommendation between neutropenic and nonneutropenic patients somewhat artificial. The lack of representation of highly compromised patients in modern candidemia trials is hardly surprising, because multiple comorbidities and frequent empirical or preemptive prior use of antifungals are common among this complex patient population and preclude enrollment. For example, in my institution for the last 6 months (July 2008–January 2009), we screened candidemic adult patients with cancer for enrollment in a candidemia trial. Of these 28 patients, only 3 were evaluable for enrollment according to the study's restrictive eligibility criteria (1 was finally enrolled, because 2 patients declined to participate because they were not ill enough and wanted oral outpatient therapy). Thus, of the 28 patients screened initially, only 1 (4%) entered in the trial! The reasons for nonevaluability of the remaining 25 patients were prior systemic antifungal therapy given for >4 days at diagnosis of candidemia (13 patients), outpatient status (8 patients), advanced terminal cancer (2 patients), and other reasons (2 patients). Caution needs to be exercised for all these agents; polyenes have poor activity in neutropenic patients with candidiasis [2], and voriconazole might not be immune to problems of cross-resistance or tolerance (at least for some relatively common Candida species, such as Candida glabrata ) in a patient population that is typically heavily pre-exposed to another azole, fluconazole, as prophylaxis [3]. Special vigilance is needed to assess large-scale experience in outcomes of highly compromised patients with fungemia who receive echinocandins, given the narrower spectrum of these agents. Although emerging data regarding the efficacy and tolerability of echinocandins in cancer patients are reassuring, these are derived from ad hoc analysis of randomized studies [2, 4] or single-institution experiences [5], in which patient selection bias is unquestionably high. More data are needed regarding the efficacy of echinocandin monotherapy, especially for neutropenic patients with active leukemia. Because coinfections in these patients are quite common [6], special emphasis needs to be given to whether the treatment of concomitant infections was appropriate, to decrease confounders for evaluation of response.