Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis in combination with potentiator drugs verapamil, timcodar, colistin and SQ109.
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.
Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. Electronic address: g.deknegt@erasmusmc.nl.
Gerjo J
GJ
de Knegt
Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Aart
A
van der Meijden
Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Corné P
CP
de Vogel
Department of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands.
Rob E
RE
Aarnoutse
Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Jurriaan E M
JE
de Steenwinkel
D000995:Antitubercular Agents / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004347:Drug Interactions; D024841:Fluoroquinolones / Q000494:pharmacology*; D000069349:Linezolid / Q000494:pharmacology*; D050296:Microbial Viability / Q000187:drug effects*; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology
D000995:Antitubercular Agents; D024841:Fluoroquinolones; D000069349:Linezolid; D000077266:Moxifloxacin
Colistin; Linezolid; Moxifloxacin; Mycobacterium tuberculosis; SQ109; Verapamil