4.7 Article

Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis

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出版社

AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.00308-22

关键词

amphotericin B; chronic mucocutaneous candidiasis; cochleated; mouse model; mucosal candidiasis; phase 2 trial

资金

  1. Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases (NIAID)

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A new oral formulation of Amphotericin B (CAMB) was evaluated for its efficacy in mouse models and patients with azole-resistant chronic mucocutaneous candidiasis (CMC). CAMB significantly reduced tongue and vaginal fungal burdens in mice and showed good efficacy and tolerability in CMC patients.
Candida albicans causes debilitating, often azole-resistant, infections in patients with chronic mucocutaneous candidiasis (CMC). Amphotericin B (AMB) resistance is rare, but AMB use is limited by parenteral administration and nephrotoxicity. In this study, we evaluated cochleated AMB (CAMB), a new oral AMB formulation, in mouse models of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) and in patients with azole-resistant CMC. OPC and VVC were modeled in Act1(-/-) mice, and mucosal tissue fungal burden was assessed after once-daily treatment with CAMB, vehicle, or AMB-deoxycholate (AMB-d). Four patients with azole-resistant CMC enrolled in a phase 2 CAMB dose-escalation study. The primary endpoint was clinical improvement at 2 weeks followed by optional extension for long-term CMC suppression to assess safety and efficacy. CAMB-treated mice had significantly reduced tongue and vaginal fungal burdens compared to vehicle-treated mice and exhibited comparable fungal burden reduction relative to AMB-d-treated mice. All CAMB-treated patients reached clinical efficacy by 2 weeks, three at 400 mg twice daily and one at 200 mg twice-daily dosing. All patients continued to the extension phase, with three having sustained clinical improvement of OPC and esophageal candidiasis (EC) for up to 60 months. One patient had a relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical responses were not seen for onychomycosis or VVC. CAMB was safe and well-tolerated, without any evidence of nephrotoxicity. In summary, oral CAMB reduced tongue and vaginal fungal burdens during murine candidiasis. A proof-of-concept clinical trial in human CMC showed efficacy with good tolerability and safety.

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