In vivo efficacy of liposomal amphotericin B (L-AmB) against azole-resistant Aspergillus fumigatus harbouring TR46/Y121F/T289A mutation compared with other Cyp51A-mediated resistance mechanisms

Ref ID: 19187

Author:

S. Seyedmousavi, W.J.G. Melchers, J. W. Mouton, P.E. Verweij

Author address:

Nijmegen, NL

Full conference title:

23rd European Congress of Clinical Microbiology and
Infectious Diseases

Date: 27 April 2014

Abstract:

Objectives: Failure to treatment with azoles has repeatedly been reported in azole-resistant Aspergillus diseases. In azole-resistant invasive aspergillosis (IA) a mortality rate of 88% was reported. The emergence of a new resistance mechanism (TR46/Y121F/T289A), which is highly resistant to voriconazole (MIC>16 mg/l), was recently described in clinical A.fumigatus isolates. We investigated if L-AmB is effective in azole-resistant aspergillosis.
Methods: The efficacy of L-AmB against TR46/Y121F/T289A was compared with that of 2 other azole-resistant isolates (M220I, TR34/L98H) and a wild type control using a non-neutropenic murine model of infection. Female CD-1 mice were infected intravenously 24 h prior to start therapy. Groups of 11 mice were treated at days 1, 2 and 5 post-challenge with increasing 4-fold doses of L-AmB ranging from 0.004 to 16 mg/kg/day and observed for 14 days.
Results: Survival for all 4 isolates at day 14 was significantly better than that of controls. A dose-response relationship was observed independent of the azole resistance mechanism. The Hill-type model with a variable slope fitted the relationship between the dose and 14-days survival well for all isolates with R2=0.94 (TR46/Y121F/T289A), R2=0.97 (M220I), R2=0.85 (TR34/L98H) and R2= 0.95 (wild-type), respectively. The efficacy of L-AmB was not different between the isolates with an azole resistance mechanism and wild type controls (P > 0.05), and no difference in efficacy was found when different azole resistance mechanisms were compared (P > 0.05). Multiple logistic regression analysis also confirmed that there was no significant difference between groups.
Conclusion: The results of these experiments indicate that L-AmB was able to prolong survival in vivo in disseminated IA independent of the presence of an azole resistance mechanism in a dose- dependent manner, and support a role of L-AmB in the treatment of azole-resistant IA.

Abstract Number: P995

Conference Year: 2013

Link to conference website: http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=164598&XNSPRACHE_ID=2&XNKONGRESS_ID=180&XNMASK

New link: NULL

Conference abstracts, posters & presentations

Showing 10 posts of 17325 posts found.

  • Title

    Author

    Year

    Number

    Poster