Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: In Vitro and In Vivo Correlation of the Concentration and Dose Dependent Interaction between Anidulafungin and Voriconazole by Bliss Independence Drug Interaction Analysis
Author:
Petraitis V, Petraitiene R, Hope WW, Meletiadis J, Mickiene D, Hughes JE, Cotton MP, Stergiopoulou T, Kasai M, Francesconi A, Schaufele RL, Sein T, Avila NA, Bacher J, Walsh TJ
Date: 8 May 2009
Abstract:
We studied the antifungal activity of anidulafungin in combination with voriconazole against experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits and further explored the in vitro and in vivo correlation – using Bliss independence drug interaction analysis. Treatment groups consisted of anidulafungin at 5(AFG5) and 10(AFG10) mg/kg/day, voriconazole at 10(VRC) mg/kg q8h, AFG5+VRC, AFG10+VRC, and untreated controls. Survival throughout the study was 60% for AFG5+VRC, 50% for VRC, 27% for AFG10+VRC, 22% for AFG5, 18% for AFG10 and 0% for control rabbits, (p<0.001). There was a significant reduction of organism-mediated pulmonary injury measured by infarct scores, lung weights, residual fungal burden, and galactomannan index in AFG5+VRC-treated rabbits versus AFG5 and VRC alone, (p<0.05). By comparison, AFG10+VRC significantly lowered only infarct scores and lung weights in comparison to those of AFG10 (p<0.05). AFG10+VRC showed no significant difference in other outcome variables. Significant Bliss synergy was found in vivo between AFG5 and VRC, with observed effects being 24-30% higher than expected levels if the drugs were acting independently. These synergistic interactions were also found between anidulafungin and voriconazole in vitro. However, for anidulafungin at 10 mg/kg/day and voriconazole (AFG10+VRC), only independence and antagonism were observed among the outcome variables. We conclude that the combination of anidulafungin with voriconazole in treatment of experimental IPA in persistently neutropenic rabbits was independent to synergistic at a dosage of 5mg/kg/day, but independent to antagonistic at 10mg/kg/day, as assessed by Bliss independence analysis, suggesting that higher dosages of an echinocandin may be deleterious to the combination.
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