Anidulafungin versus Caspofungin in a Mouse Model of Candidiasis Caused by Anidulafungin-Susceptible Candida parapsilosis Isolates with Different Degrees of Caspofungin Susceptibility

摘要

Candida parapsilosis isolates occasionally display resistance in vitro to echinocandins and cause breakthrough infections to echinocandins. The degree of the in vivo cross-resistance among echinocandins and the fitness loss associated with caspofungin (CAS) resistance of C. parapsilosis are not well studied. We compared the activities of CAS and anidulafungin (ANF), each given at 2 dosing schedules (high dose or low dose) in a nonneutropenic mouse model of invasive candidiasis (IC) caused by ANF-susceptible isolates of C. parapsilosis with different degrees of susceptibility to CAS (CAS resistant [CAS-R], MIC, >16 mg/liter; CAS intermediate [CAS-I], MIC, 4 mg/liter; and CAS susceptible [CAS-S], MIC, 2 mg/liter). We analyzed tissue fungal burden, histopathology, and weight loss patterns. Increasing CAS resistance was associated with reduced virulence of C. parapsilosis isolates (mortality rates for CAS-S versus CAS-I versus CAS-R, 100% versus 11.1% versus 0%, respectively; P < 0.001). High doses of either echinocandin were active against infection with the CAS-I isolate when assessed by fungal burden reduction and weight gain. In contrast to CAS-S and CAS-I isolates, there was no reduction in fungal burden in mice infected with the CAS-R isolate following treatment with either echinocandin, each given at a high or low dose. Nevertheless, mice infected with the CAS-R isolate had reduced disease severity following echinocandin treatment, suggesting that echinocandins have activity in vivo, even against echinocandin-resistant strains. A complex interplay of residual echinocandin activity, decreased virulence, and/or fitness of isolates with altered cell wall and possible immunomodulatory effects can be encountered in vivo during infection with CAS-resistant C. parapsilosis isolates.