P0176 Synergistic interaction of voriconazole and terbinafine against intrinsically azole-resistant Aspergillus calidoustus

Emmanouil Glampedakis*1, Alix Coste2, Marion Aruanno2, Daniel Bachmann2, Frederic Lamoth3

1Lausanne University Hospital , Infectious Diseases Service, Lausanne, Switzerland, 2Lausanne University Hospital , Institute of Microbiology , Lausanne, Switzerland, 3Lausanne University Hospital , Infectious Diseases Service and Institute of Microbiology, Lausanne, Switzerland

Background: Invasive aspergillosis (IA) is an important cause of morbidity and mortality for immunocompromised hosts, especially hematopoietic stem cell and solid organ transplant recipients. While Aspergillus fumigatus remains the main cause of IA, the systematic use of triazole prophylaxis in the post-engraftment period or during neutropenia has shifted the epidemiology of IA towards other Aspergillus spp. Aspergillus calidoustus (section Usti) is an emerging pathogen causing breakthrough infections with high mortality rate because of its intrinsic resistance to triazoles. The aim of this study was to assess the in vitro and in vivo effect of antifungal drug combinations against Aspergillus calidoustus.

Methods: Two clinical isolates of Aspergillus calidoustus, for which species identification was confirmed by multilocus sequencing, were used. Antifungal susceptibility testing was performed using broth microdilution method according to CLSI recommendations. Antifungal drug combinations were tested in vitro by chequerboard dilutions and interactions were characterized by calculation of the fractional inhibitory concentration index (FICI). A survival study of Galleria mellonella larvae infected by a larvicidal inoculum of A. calidoustus was performed to assess the in vivo efficacy of antifungal drugs used alone and in combinations.

Results: Both isolates showed high MICs to commonly used azoles. A synergistic effect was observed between terbinafine and triazoles (voriconazole and posaconazole, FICI = 0.5). However, combining amphotericin B with terbinafine or voriconazole resulted in an antagonistic effect. Our preliminary data with the in vivo G.mellonella model showed a trend towards an improved survival in the group treated by the voriconazole-terbinafine combination compared to the individual drugs and untreated groups (figure).

Conclusion: Our in vitro data coupled with an in vivo G.mellonella model suggest that the adjunction of terbinafine could potentiate the effect of triazoles in the treatment of A.calidoustus infection. Figure. Survival of Galleria mellonella infected with 5*106 Aspergillus calidoustus spores