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.
Highlights
Candida is the most common cause of invasive fungal infection in the pediatric population, and dissemination to distant organs, including the central nervous system (CNS) occurs at a higher frequency than in the adult population
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)
We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice and determined the pharmacokinetics and efficacy of caspofungin in this model
Summary
Candida is the most common cause of invasive fungal infection in the pediatric population, and dissemination to distant organs, including the central nervous system (CNS) occurs at a higher frequency than in the adult population. Current guidelines recommend amphotericin B at 1 mg/kg of body weight/day for the treatment of neonatal candidiasis (14); short-term mortality remains high (Ͼ30%) and long-term prognosis is poor (1). Several published reports suggest that echinocandins may be useful for the treatment of candidiasis in neonates (7, 9, 12, 13). Caspofungin is an echinocandin antifungal agent approved for the treatment of invasive candidiasis in adults and children (11). The efficacy of caspofungin against CNS candidiasis has not been described previously, but it is commonly thought that penetration of the echinocandins into the CNS is poor (8, 10). We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice and determined the pharmacokinetics and efficacy of caspofungin in this model
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