title: 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)-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.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: V
authors.initials: V
authors.lastname: Petraitis
authors.forename: R
authors.initials: R
authors.lastname: Petraitiene
authors.forename: A H
authors.initials: AH
authors.lastname: Groll
authors.forename: T
authors.initials: T
authors.lastname: Sein
authors.forename: R L
authors.initials: RL
authors.lastname: Schaufele
authors.forename: C A
authors.initials: CA
authors.lastname: Lyman
authors.forename: A
authors.initials: A
authors.lastname: Francesconi
authors.forename: J
authors.initials: J
authors.lastname: Bacher
authors.forename: S C
authors.initials: SC
authors.lastname: Piscitelli
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use; D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D002180:Candidiasis, Oral / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D004352:Drug Resistance, Microbial; D054714:Echinocandins; D004935:Esophageal Diseases / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D004947:Esophagus / Q000378:metabolism; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D007165:Immunosuppression Therapy; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010608:Pharyngeal Diseases / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D011817:Rabbits; D012463:Saliva / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D010456:Peptides, Cyclic; D000666:Amphotericin B; D015725:Fluconazole; D000077612:Anidulafungin