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Antimicrobial Agents and Chemotherapy, February 2001, p. 471-479, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.471-479.2001

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

Vidmantas Petraitis,1 Ruta Petraitiene,1 Andreas H. Groll,1 Tin Sein,1 Robert L. Schaufele,1 Caron A. Lyman,1 Andrea Francesconi,1 John Bacher,2 Stephen C. Piscitelli,3 and Thomas J. Walsh1,*

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1 Surgery Service, Veterinary Resources Program, Office of Research Services,2 and Pharmacokinetics Research Laboratory, Pharmacy Department, Warren Grant Magnuson Clinical Center,3 National Institutes of Health, Bethesda, Maryland

Received 23 March 2000/Returned for modification 30 August 2000/Accepted 9 November 2000

V-echinocandin (VER-002; LY303366) is a semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1, 3)-beta -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 dosage-dependent antifungal activity against fluconazole-resistant esophageal candidiasis in immunocompromised rabbits.

* Corresponding author. Mailing address: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, Rm. 13N240, Center Dr., Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

Antimicrobial Agents and Chemotherapy, February 2001, p. 471-479, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.471-479.2001


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