ASP9726, A Unique 2nd Generation Echinocandin (1), Discovery of A Novel In Vitro Marker Correlated with in vivo Anti-Aspergillus Efficacy

Ref ID: 18689

Author: T. Nakai, PhD (Doctor of Philosophy) – Research Fellow, S. Matsumoto, MS – Research Fellow, S. Uchida, BS – Researcher, S. Takeda, PhD – Senior Researcher, S. Akamatsu, MS – Researcher, K. Maki, MS – Senior Research Fellow;

Author address:

Astellas Pharma Inc., Tsukuba, Japan.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: We have observed that 1st generation echinocandins (ECs), caspofungin (CAS) and micafungin (MCFG) inhibit Aspergillus fumigatus (Af) hyphal elongation and germination at greater than MIC concentrations in vitro, however, the maximum inhibitory effect on Af hypha (Emax) varies largely depending on Af strains. We hypothesized that better Emax would result in improved treatment outcome in vivo and could be a novel screening efficacy endpoint in addition to a potency endpoint, MIC for discovering next generation EC. Methods: MIC was determined microscopically by a microdilution method using human serum as a test medium. Emax was also determined as % inhibition at 4 x MIC in comparison to growth control (0%) and medium control (100%) in an MTT assay. An experimental invasive pulmonary aspergillosis (IPA) model in cyclophosphamide-treated mice was used for in vivo studies. The mice were treated with ECs once daily for 4 days starting 3 hr after infection. Results: Emaxs of CAS and MCFG for 10 isolates of Af were ranging from 40% to 83% and from 53% to 85%, respectively, although these compounds showed consistent MIC against the strains. In a mouse IPA model, whereas CAS achieved 100% survival when we used the strain with the highest Emax (82%), survival rate was worsened to 25 – 75% (varied among experiments) when we used strain 20030 with lower Emax (48%). This phenomena was also observed for MCFG. When compared using strain 20030, we found a positive correlation between Emax and survival rate for new EC derivatives from MCFG as well as 1st generation ECs. Only ECs with higher Emax attenuated pathogenicity of Af by localizing pulmonary lesions and decreasing hemorrhage in bronchoalveolar lavage fluid in mice. Conclusions: Emax for hyphal growth inhibition correlated well with in vivo efficacy, suggesting hyphal elongation in lungs as an important virulence determinant in IPA. This novel efficacy marker is considered significantly useful to discover 2nd generation EC candidates with improved efficacy for the treatment of Af infections.

Abstract Number: F-817

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

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