title: Efficacy and pharmacodynamics of voriconazole combined with anidulafungin in azole-resistant invasive aspergillosis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medical Microbiology,  Radboud University Nijmegen Medical Centre, Nijmegen,  The Netherlands.
authors.forename: Seyedmojtaba
authors.initials: S
authors.lastname: Seyedmousavi
authors.forename: Roger J M
authors.initials: RJ
authors.lastname: Brüggemann
authors.forename: Willem J G
authors.initials: WJ
authors.lastname: Melchers
authors.forename: Antonius J M M
authors.initials: AJ
authors.lastname: Rijs
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
mesh_terms: D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D054714:Echinocandins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D051379:Mice; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016019:Survival Analysis; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D011743:Pyrimidines; D014230:Triazoles; D000077612:Anidulafungin; D065819:Voriconazole