In vitro Combination Therapy of Isavuconazole against Medically Important Aspergillus spp

Ref ID: 19508

Author:

A Katragkou1, M McCarthy1, J Meletiadis2, V Petraitis1, PW Moradi1, GE Strauss1, K Hussain1,
K Myint1, LL Kovanda3, R Petraitiene1, E Roilides4, TJ Walsh1*

Author address:

1Medicine, Weill Cornell Medical Center of Cornell University, New York, USA
2Attikon University General Hospital, Medical School, University of Athens, Athens, Greece
3Astellas Pharma Global Development, Inc., Northbrook, USA
4School of Medicine,

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Isavuconazole is an extended-spectrum antifungal triazole with in vitro, in vivo, and clinical activity
against Aspergillus spp. and invasive pulmonary aspergillosis. The purpose of our study was to
assess whether isavuconazole has synergistic activity in combination with an echinocandin or
amphotericin B.
Methods:
Clinical isolates of three Aspergillus species (A. fumigatus, A. flavus and A. terreus) were studied.
Minimum inhibitory concentrations (MICs) were determined by broth microdilution methods
according to the reference procedure of antifungal susceptibility testing of filamentous fungi (CLSIM38-
A2). In vitro interactions between isavuconazole and micafungin or amphotericin B were
studied using a two-dimensional checkerboard microdilution method in 96-well flat-bottom plates.
Each isolate was tested three times on different days. The choice of the appropriate range of drug
concentrations was based on the MICs of the individual drug and isolate. The combined effects of
antifungal agents were quantified after 48 h of incubation at 37ºC by the metabolic reduction XTT
(2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]2H-tetrazolim-5-carboxanilide) assay. The interactions
between antifungal agents were analyzed using the fractional inhibitory concentration index (FICI)
and the Bliss independence model.
Results:
For the isavuconazole-amphotericin B interactions, the median FIC indices of all isolates ranged
from 1 to 1.5 indicating an additive or indifferent effect. No value of FICI>4, which is indicative of
antagonism, was observed. However, according to the Bliss model, the combination of isavuconazole
and amphotericin B resulted in antagonistic interactions in A. fumigatus and A. flavus. Treatment
of A. terreus with isavuconazole (0.030 to 16 mg/liter) and amphotericin B (0.125 to 8 mg/liter)
showed antagonistic interactions at high amphotericin B (1 to 8 mg/liter) and isavuconazole (1 to
16 mg/liter) concentrations, while at low amphotericin B (0.125 to 0.5 mg/liter) and isavuconazole
(0.250 to 2 mg/liter) the interaction was synergistic. However, the magnitude of these interactions
(related to the 916;917; value which were 0.04% and 1.35% for the antagonistic and synergistic effect,
respectively) was not considered to be pharmcologically significant.
For isavuconazole-micafungin interactions, median FICIs of all strains ranged from 0.28 to 1.06,
which were compatible with synergy. The combination of isavuconazole and micafungin resulted in
synergistic interaction in all strains when analyzed by Bliss modeling. The degree of synergy was
ranged significantly from 19.3% to 65.59% (mean 916;917; value) with the highest was noted in A. flavus.
Conclusion:
The combination of isavuconazole with micafungin demonstrates strong in vitro synergy against
A. fumigatus, A. flavus, and A. terreus. In vivo studies are required to validate this synergy as a
potentially effective strategy in treatment of invasive aspergillosis.

Abstract Number: 36

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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