Efficacy and Dose-Response Relationships of Liposomal Amphotericin B (L-AmB) against Different Azole-Resistant Aspergillus fumigatus Isolates in a Non-Neutropenic Murine Model of Disseminated Aspergillosis

Ref ID: 18679

Author:

S. Seyedmousavi, DVM, PhD – Scientific Researcher1,2, W. J. G. Melchers, PhD – Associate Professor 1,2, J. W. Mouton, MD, PhD – Professor 1,2, P. E. Verweij, MD, PhD – Professor 1,2;

Author address:

1Radboud Univ. Nijmegen Med. Ctr., Nijmegen, Netherlands, 2Nijmegen Inst. for Infection, Inflammation and Immunity, Nijmegen, Netherlands.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: The management of invasive aspergillosis (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 up to 88%. Treatment with a L-AmB may be a useful alternative to improve therapeutic outcome in azole-resistant IA. Methods: Three clinical A. fumigatus isolates obtained from patients with proven IA were studied in a non-neutropenic murine model of IA: a voriconazole-susceptible (VCZ-S) isolate without mutations in the cyp51A-gene and two VCZ-resistant (VCZ-R) isolates harbouring the M220I and TR34/L98H resistance mechanism, respectively. Female CD-1 mice were infected intravenously 24 h prior to start therapy. Groups of 11 mice were treated i.v. 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. Data analyses were performed using GraphPad Prism, version 5.0. Results: Survival for all 3 isolates at day 14 was significantly better than that of controls and a dose-response relationship was observed dependent on the L-AmB dose level, and independent of the azole-resistant mechanisms. The maximum effect (100% survival) for all isolates was reached at a dose 16 mg/kg. The Hill equation with a variable slope fitted the relationship between the dose and 14-day survival well, with a 50% effective dose (ED50) of 0.28, 0.20 and 0.51 mg/kg (95%CI 0.11 to 0.71, 0.08 to 0.48 and 0.17 to 1.5 mg/kg) for the VCZ-S and VCZ-R isolates harboring M220I and TR34/L98H mutations (R2= 0.94, 0.96 and 0.85), respectively. Conclusions: L-AmB was able to prolong survival in vivo in disseminated IA due to VCZ-S and VCZ-R A.fumigatus isolates independent of the presence of an azole resistance mechanism in a dose dependent manner. Our results support a role of L-AmB in azole-resistant IA.

Abstract Number: M-988

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Conference Year: 2012

Link to conference website: NULL

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