Efficacy and pharmacodynamics of voriconazole combined with anidulafungin in azole-resistant invasive aspergillosis.
J Antimicrob Chemother. 2012 Nov 5;
Authors: Seyedmousavi S, Brüggemann RJ, Melchers WJ, Rijs AJ, Verweij PE, Mouton JW
Abstract
OBJECTIVES: Azole resistance is an emerging problem in the treatment of Aspergillus fumigatus infections. Combination therapy may be an alternative approach to improve therapeutic outcome in azole-resistant invasive aspergillosis (IA). The in vivo efficacy of voriconazole and anidulafungin was investigated in a non-neutropenic murine model of IA using voriconazole-susceptible and voriconazole-resistant A. fumigatus clinical isolates. METHODS: Treatment groups consisted of voriconazole monotherapy, anidulafungin monotherapy and voriconazole?+?anidulafungin at 2.5, 5, 10 and 20 mg/kg body weight/day for 7 consecutive days. In vitro and in vivo drug interactions were analysed by non-parametric Bliss independence and non-linear regression analysis. RESULTS: Synergistic interaction between voriconazole and anidulafungin against the voriconazole-susceptible isolate (AZN 8196) was observed in vitro and in vivo. However, among animals infected with the voriconazole-resistant isolate (V 52-35), 100% survival was observed only in groups receiving the highest doses (20 mg/kg voriconazole?+?20 mg/kg anidulafungin). For this isolate, additivity, but not synergy, was observed in vivo. CONCLUSIONS: Combination of voriconazole and anidulafungin was synergistic in voriconazole-susceptible IA, but additive in voriconazole-resistant IA. There is a clear benefit of combining voriconazole and anidulafungin, but the reduced effect of combination therapy in azole-resistant IA raises some concern.
PMID: 23129729 [PubMed - as supplied by publisher]