Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis [PublishAheadOfPrint]

Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1->3)-β-D-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole and the echinocandin micafungin, may result in improved outcome in experimental IPA in persistently neutropenic rabbits. Treatment groups included isavuconazole (ISA) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day, micafungin at 2 mg/kg/day (MFG2), or combinations of (ISA20+MFG2), (ISA40+MFG2), (ISA60+MFG2), and untreated rabbits (UC). Galactomannan index (GMI) and (1->3)-β-D-glucan levels were measured in serum. Residual fungal burden (CFU/g) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20+MFG2-, ISA40+MFG2-, and ISA60+MFG2-treated rabbits vs that of MFG2-treated or UC (p<0.01). Measures of organism-mediated pulmonary injury, lung weights and pulmonary infarct score, were lower in ISA40+MFG2-treated rabbits in comparison to those of ISA40 or MFG2 alone (p<0.01). Survival in ISA40+MFG2-treated rabbits was prolonged in comparison to those treated with ISA40 or MFG2 alone (p<0.01). These outcome variables correlated directly with a significant decline of GMI and serum (1->3)-β-D-glucan levels during therapy. GMI correlated with measures of organism-mediated pulmonary injury, lung weights (r=0.764; p<0.001) and pulmonary infarct score (r=0.911; p<0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMI and serum (1->3)-β-D-glucan levels in comparison to that of single agent isavuconazole or micafungin.

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