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Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis in combination with potentiator drugs verapamil, timcodar, colistin and SQ109

Author:
de Knegt, Gerjo J., van der Meijden, Aart, de Vogel, Corné P., Aarnoutse, Rob E., de Steenwinkel, Jurriaan E.M.
Source:
International journal of antimicrobial agents 2017 v.49 no.3 pp. 302-307
ISSN:
0924-8579
Subject:
Mycobacterium tuberculosis, cell walls, colistin, linezolid, moxifloxacin, multiple drug resistance, transporters, tuberculosis, verapamil
Abstract:
Current treatment for tuberculosis (TB) is complicated by the emergence of multidrug resistant TB (MDR-TB). As a result, there is an urgent need for new powerful anti-TB regimens and novel strategies. In this study, we aimed to potentiate a moxifloxacin + linezolid backbone as treatment for MDR-TB with the efflux pump inhibitors verapamil and timcodar as well as with drugs that act on mycobacterial cell wall stability such as colistin and SQ109. Using a time–kill kinetics assay, the activities of moxifloxacin, linezolid, verapamil, timcodar, colistin and SQ109 as single drugs against Mycobacterium tuberculosis were evaluated. In addition, the activity of the moxifloxacin + linezolid backbone in combination with one of the potentiator drugs was assessed. As little as 0.125 mg/L moxifloxacin achieved 99% killing of M. tuberculosis after 6 days of exposure. Linezolid showed moderate killing but 99% killing was not achieved. Verapamil, timcodar and colistin only resulted in killing with the highest concentrations tested but 99% killing was not achieved. SQ109 resulted in complete elimination after 1 day of exposure to 256 mg/L and in 99% elimination after 6 days of exposure to 1 mg/L. Furthermore, colistin added to the moxifloxacin + linezolid backbone resulted in increased elimination, whereas verapamil, timcodar and SQ109 showed no added value to the backbone. This finding that colistin potentiates the activity of the moxifloxacin + linezolid backbone against M. tuberculosis suggests its potential role in further studies on the applicability of a moxifloxacin + linezolid treatment of MDR-TB.
Agid:
5627862