Pharmacodynamics of Anidulafungin (AFG) against Clinical Aspergillus fumigatus Isolates in a Non-Neutropenic Murine Model of Disseminated Aspergillosis

Ref ID: 18680

Author:

S. Seyedmousavi, DVM, PhD – Scientific Researcher1,2, R. J. M. Brüggemann, PhD – Clinical Pharmacist 1,2, W. J. G. Melchers, PhD – Associate Professor 1,2, P. E. Verweij, MD, PhD – Professor 1,2, J. W. Mouton, 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: Aspergillus fumigatus may cause life-threatening infections in both immunocompetent and immunocompromised patients. Voriconazole (VCZ) is considered the first choice therapy for invasive aspergillosis (IA). However azole resistance is increasing in A.fumigatus and associated with therapeutic failure. Alternative treatments may improve therapeutic outcome in azole-resistant IA. Little is known about in vivo efficacy of the echinocandin AFG in IA. Methods: Two clinical A.fumigatus isolates with identical AFG minimum effective concentration (0.03 mg/l) in a non-neutropenic mouse model of IA were studied: a wild-type VCZ-susceptible (VCZ-S) and a VCZ-resistant (VCZ-R) A.fumigatus isolate harboring the TR34/L98H resistance mechanism. Groups of 11 female CD-1 mice were infected intravenously. Intraperitoneal AFG therapy was begun 24h post infection for 7 consecutive days, once daily with 2.5, 5, 10 and 20 mg/kg and a loading dose on day 1. Survival was recorded as outcome parameter. Pharmacodynamic indices were calculated from pharmacokinetics studies described previously. Results: Increasing doses increased survival for both isolates 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 VCZ-S and VCZ-R isolate, respectively. The dose-response and exposure-response relationship had a sigmoidal shape. A better relationship existed for the area under the concentration-time curve (AUC) over 24 h. The Hill equation with a variable slope fitted the relationship between 24-h AUC ratio and 14-days survival well (R2= 0.87) (P <0.05). The 50% effective AUC for AFG total drug was 126.5 [95%CI, 79.09 to 202.03]. Conclusion: AFG treatment improved the survival of mice in a dose-dependent manner; however a maximal response was not achieved with either isolates even in those treated with the highest AFG dose. AFG monotherapy was moderately effective in vivo against both VCZ-S and VCZ-R A. fumigatus infection.

Abstract Number: M-989

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

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