Randomized, Double-Blind, Multicenter Study of Caspofungin versus Amphotericin B for Treatment of Oropharyngeal and Esophageal Candidiases

Abstract

Caspofungin is an antifungal agent of the novel echinocandin class. We investigated its efficacy, safety, and tolerability as therapy for oropharyngeal and/or esophageal candidiasis in a phase II dose-ranging study. Patients were randomized in a double-blind manner to receive either caspofungin acetate (35, 50, or 70 mg) or amphotericin B (0.5 mg/kg of body weight) intravenously once daily for 7 to 14 days. A favorable response required both complete resolution of symptoms and quantifiable improvement of mucosal lesions 3 to 4 days after discontinuation of study drug. Efficacy was assessed using a modified intent-to-treat analysis. No hypothesis testing of efficacy was planned or performed. Of 140 enrolled patients, 63% had esophageal involvement and 98% were infected with the human immunodeficiency virus (HIV) (median CD4 count, 30/mm 3 ). A modestly higher proportion of patients in each of the caspofungin groups (74 to 91%) achieved favorable responses compared to amphotericin B recipients (63%), but there was considerable overlap in the 95% confidence intervals surrounding these point estimates. Similar trends were found in the subgroups with esophageal involvement, a history of fluconazole failure, and CD4 counts of <50/mm 3 . A smaller proportion of patients receiving any dose of caspofungin experienced drug-related adverse events compared to patients given standard doses of conventional amphotericin B (P < 0.01). Caspofungin provided a generally well-tolerated parenteral therapeutic option for HIV-infected patients with oropharyngeal and/or esophageal candidiasis in this study.Mucosal candidiasis, although not life-threatening, causes significant morbidity in patients infected with the human immunodeficiency virus (HIV) (16). The development of drug resistance in the causative strain or the selection of intrinsically more resistant species may complicate therapy of recurrent candidal infections (19,20,28,34,36,40,43). This study describes the use of a new echinocandin, caspofungin (Cancidas; formerly MK-0991), as treatment for oropharyngeal and esophageal candidiasis in an immunocompromised patient population.Oral fluconazole is widely regarded as the treatment of choice for mucosal candidiasis under most circumstances (36). Amphotericin B deoxycholate has been the standard recourse for patients infected with Candida sp. unresponsive to azole therapy (5,10,24,36). The use of conventional amphotericin B preparations is complicated by its significant toxicity. Newer lipid formulations of amphotericin have reduced, but not eliminated, some of these adverse effects (15).Caspofungin possesses activity in vitro (6,17,23,30,31,42) and in vivo (1, 2, 11, 13) against a variety of fungal pathogens, including Candida and Aspergillus species. Echinocandins noncompetitively inhibit 1,3-␤-D-glucan synthesis, interfering with the normal formation of the fungal cell wall (3). Since glucans are not present in mammalian cells, it is hoped that echinocandins will have a relatively high therapeutic index. Crossresistance with...

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