title: Therapeutic and prophylactic efficacy of aminocandin (IP960) against disseminated candidiasis in mice.
abstract: Extended interval dosing of the echinocandins has been suggested as a potential strategy to overcome the need for daily intravenous administration. This study evaluated the therapeutic and prophylactic efficacy of single doses of aminocandin, a new echinocandin in preclinical development, in a murine model of invasive candidiasis. For therapy, groups of mice were infected with Candida albicans, followed by a single dose of aminocandin (1-15 mg/kg) or placebo (mannitol 5% w/v) administered 1 day after inoculation. As prophylaxis, mice were given a single dose (5 or 30 mg/kg) of aminocandin, caspofungin, or placebo at increasing intervals between dose and inoculation. In both treatment and prophylaxis studies, survival was assessed at 21 days post-inoculation. The reduction in fungal burden was assessed in kidney tissue on day 8 post-inoculation. For treatment, single doses of aminocandin of >/=2.5 mg/kg prolonged survival significantly. In addition, the two doses evaluated for reductions in fungal burden (5 and 15 mg/kg) revealed fungicidal activity. As prophylaxis, both aminocandin and caspofungin 5 and 30 mg/kg prolonged survival when given 7 days before inoculation. Aminocandin and caspofungin 30 mg/kg were both able to prolong survival when the interval between dose and inoculation was increased to 10 days. When this interval was extended to 14 days, only aminocandin 30 mg/kg prolonged survival and reduced fungal burden. These results demonstrate that single doses of aminocandin are effective as treatment and prophylaxis, and suggest that extended interval dosing may be a useful strategy for treating invasive candidiasis.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. najvar@uthscsa.edu
authors.forename: L K
authors.initials: LK
authors.lastname: Najvar
authors.forename: R
authors.initials: R
authors.lastname: Bocanegra
authors.forename: N P
authors.initials: NP
authors.lastname: Wiederhold
authors.forename: C
authors.initials: C
authors.lastname: Lambros
authors.forename: N
authors.initials: N
authors.lastname: Najarian
authors.forename: T F
authors.initials: TF
authors.lastname: Patterson
authors.forename: J R
authors.initials: JR
authors.lastname: Graybill
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000517:prevention & control*; D000077336:Caspofungin; D015169:Colony Count, Microbial; D018572:Disease-Free Survival; D054714:Echinocandins / Q000008:administration & dosage / Q000627:therapeutic use; D007668:Kidney / Q000382:microbiology; D055666:Lipopeptides; D008074:Lipoproteins / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D008074:Lipoproteins; C476911:aminocandin; D000077336:Caspofungin