Management of azole-resistant invasive aspergillosis (IA): in vivo pharmacodynamics of antifungals

Ref ID: 19189

Author:

S. Seyedmousavi*, R.J.M. Brüggemann, W.J.G. Melchers, P.E. Verweij, J.W. Mouton

Author address:

Nijmegen, NL

Full conference title:

23rd European Congress of Clinical Microbiology and
Infectious Diseases

Date: 27 April 2014

Abstract:

Objectives: The management of IA has become more complicated due to the emergence of acquired azole resistance in Aspergillus fumigatus, which is associated with treatment failure and a mortality rate of 88%. Alternative treatment approaches may improve therapeutic outcome in azole-resistant IA.
Methods: The in vivo efficacy of voriconazole (VRC), anidulafungin (AFG) and liposomal amphotericin B (L-AmB) monotherapy and the combination of VRC and AFG was assessed against a VRC-susceptible (VRC-S) A. fumigatus isolate without mutations in the cyp51A-gene (AZN 8196) and a VCZ-resistant (VRC-R) isolate (V 52-35) harboring the TR34/L98H resistance mechanism, in an in vivo model of IA.
Results: The maximum dose of VRC (20 mg/kg) resulted in 100% survival in mice infected with the VRC-S isolate compared to 72.2% in VRC-R, indicating that higher doses of voriconazole were required to achieve similar efficacy. For AFG, increasing doses from 2.5 to 20 mg/kg, increased survival for both isolates that was dependent on the AFG dose level (R2 value of 0.99 and 0.95) up to a maximum of 72.7% and 45.45% for the VRC-S and VRC-R isolate, respectively. For the combination of VRC and AFG, the survival of 100% was observed in the groups of mice infected by VRC-S isolate and treated with 10 mg/kg VRC combined with 10 and 20 mg/kg AFG. In contrast, in the groups infected by the VRC-R isolate, 100% survival was achieved in groups receiving 20 mg/kg VRC+20 mg/kg AFG. While, tha L-AmB was able to prolong survival in vivo independent of the presence of an azole resistance mechanism and the maximum effect (100% survival) for the wild-type and TR34/L98H isolate was reached at a dose of 16 mg/kg.
Conclusion: Our results indicated that for both VRC and AFG monotherapy in mice, the response was lower in those infected with the VRC-R isolate than in those infected with the VRC-S. The reduced effect of combination therapy in azole-resistant IA raises some concern. However, our observations support a role of L-AmB in the treatment of azole-resistant IA.

Abstract Number: P1083

Conference Year: 2013

Link to conference website: http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=164615&XNSPRACHE_ID=2&XNKONGRESS_ID=180&XNMASK

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