Efficacy of micafungin alone or in combination against experimental pulmonary aspergillosis

Abstract

Mortality from invasive pulmonary aspergillosis approaches 80% with few useful therapeutic options available. In these studies, we examined the efficacy of micafungin (MICA) alone or in combination with other antifungals in a model of pulmonary aspergillosis in immunosuppressed DBA/2 mice infected intranasally with conidia of Aspergillus fumigatus 10AF. In the initial study, groups of mice were given saline, or 1, 3 or 10 mg kg(-1) of MICA b.i.d., s.c. All saline controls, and 90% of untreated mice succumbed to infection. The efficacy of MICA was difficult to assess because of an apparent toxicity at 10 mg kg(-1). MICA given at 1 mg/kg significantly prolonged survival over the saline controls (P = 0.008). MICA at 3 or 10 mg kg(-1) versus the saline controls approached significance. No treatment regimen differed in efficacy. The efficacy of combination therapy was assessed, with mice given either no treatment, MICA at 1 mg/kg/dose, 0.8 mg kg(-1) of intravenous amphotericin B (AMB), 100 mg kg(-1) of oral itraconazole (ICZ), or 100 mg/kg/dose of twice-daily subcutaneous nikkomycin Z (NIK). AMB alone and MICA + AMB or MICA +NIK significantly prolonged survival (P < 0.05 - 0.02) over that of the controls. ICZ alone, ICZ+MICA and NIK alone did not significantly prolong survival. MICA alone at 1 mg/kg approached significance in prolonging survival. The combination of MICA and ICZ appeared to be potentially antagonistic. Although AMB+MICA was efficacious, no synergistic activity was noted for any of the regimens. Overall, these results indicate that MICA has moderate activity against pulmonary aspergillosis and might be useful in combination with conventional AMB.