Dosage-Dependent Antifungal Efficacy of V-Echinocandin (LY303366) against Experimental Fluconazole-Resistant Oropharyngeal and Esophageal Candidiasis

Abstract

V-echinocandin (VER-002; LY303366) is a semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1, 3)-␤-D-glucan synthase. We studied the antifungal efficacy, the concentrations in saliva and tissue, and the safety of VER-002 at escalating dosages against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant Candida albicans in immunocompromised rabbits. Study groups consisted of untreated controls, animals treated with VER-002 at 1, 2.5, and 5 mg/kg of body weight/day intravenously (i.v.), animals treated with fluconazole at 2 mg/kg/day i.v., or animals treated with amphotericin B at 0.3 mg/kg/day. VER-002-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, esophagus, stomach, and duodenum in comparison to that for untreated controls. VER-002 also was superior to amphotericin B and fluconazole in clearing the organism from all sites studied. These in vivo findings are consistent with the results of in vitro time-kill assays, which demonstrated that VER-002 has concentration-dependent fungicidal activity. Esophageal tissue VER-002 concentrations were dosage proportional and exceeded the MIC at all dosages. Echinocandin concentrations in saliva were greater than or equal to the MICs at all dosages. There was no elevation of serum hepatic transaminase, alkaline phosphatase, bilirubin, potassium, or creatinine levels in VER-002-treated rabbits. In summary, the echinocandin VER-002 was well tolerated, penetrated the esophagus and salivary glands, and demonstrated dosagedependent antifungal activity against fluconazole-resistant esophageal candidiasis in immunocompromised rabbits.

Tissue Penetration of Antifungal Agents

“…Anidulafungin is present in both the saliva and esophagus in rabbits with oropharyngeal and esophageal candidiasis, but only at concentrations between 1% and 33% of those in plasma (167). However, all three echinocandins show efficacy at the end of therapy equivalent to that of fluconazole after intravenous administration to patients with AIDS and oropharyngeal or esophageal candidiasis (168,169,170).…”

Development and Validation of an In Vivo Candida albicans Biofilm Denture Model

“…Systemic drug treatments included micafungin at 5 mg/kg intraperitoneally once daily or fluconazole at 16 mg/kg subcutaneously twice daily. The dosing regimens were chosen based on maximal efficacy in treatment of oral candidiasis in animal models (27,51). All therapies were continued for 48 h, after which devices were removed and processed for viable burden determination as described above.…”

New Model of Oropharyngeal Candidiasis in Mice

“…To date, a number of animal models have been developed for studying OPC (1,4,6,8,10). Some of these models, such as the one presented here, are best suited for evaluating the therapeutic efficacy of selected antifungal agents (1,4,6,10).…”