title: Efficacy of caspofungin in a juvenile mouse model of central nervous system candidiasis.
abstract: Neonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB). Juvenile mice were inoculated intravenously with 5.64 × 10(4) CFU of Candida albicans MY1055. Treatment with caspofungin at 1, 2, 4, and 8 mg/kg of body weight/day, AmB at 1 mg/kg/day, or a vehicle control (VC) was initiated 30 h after infection and continued for 7 days. Pharmacokinetic parameters for caspofungin were also determined. Culture and histology showed evidence of disseminated candidiasis with multifocal encephalitis at the start of antifungal therapy. Survival was 100% in all treated groups, while mortality was 100% in the VC by day 11 after infection. By day 5, all mice in the caspofungin treatment (four doses) groups showed reductions in kidney and brain burden relative to the VC, while AmB treatment reduced kidney burden but gave no reduction of brain fungal burden. Systemic levels of caspofungin were similar in infected and uninfected mice, while brain levels were higher in infected animals. In this juvenile mouse model, caspofungin demonstrated dose-dependent activity, equivalent to or better than that of AmB at 1 mg/kg, against disseminated candidiasis with CNS involvement.
authors.affiliation: Department of Infectious Diseases, Merck & Co, Inc, Rahway, New Jersey, USA. amy.flattery@merck.com
authors.forename: Amy M
authors.initials: AM
authors.lastname: Flattery
authors.forename: Emily
authors.initials: E
authors.lastname: Hickey
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gill
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Powles
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Misura
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Galgoci
authors.forename: Joan D
authors.initials: JD
authors.lastname: Ellis
authors.forename: Rena
authors.initials: R
authors.lastname: Zhang
authors.forename: Punam
authors.initials: P
authors.lastname: Sandhu
authors.forename: John
authors.initials: J
authors.lastname: Ronan
authors.forename: George K
authors.initials: GK
authors.lastname: Abruzzo
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000382:microbiology; D002177:Candidiasis / Q000188:drug therapy*; D000077336:Caspofungin; D020314:Central Nervous System Fungal Infections / Q000188:drug therapy*; D054714:Echinocandins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000382:microbiology; D055666:Lipopeptides; D051379:Mice
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077336:Caspofungin