Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
Int J Antimicrob Agents. 2017 Mar;49(3):302-307. doi: 10.1016/j.ijantimicag.2016.11.027. Epub 2017 Feb 2.
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.
当前，耐多药结核病（MDR-TB）的出现使得结核病的治疗变得复杂。因此，急需新的强效抗结核方案和新的策略。在这项研究中，我们旨在通过使用外排泵抑制剂维拉帕米和替莫唑胺以及作用于分枝杆菌细胞壁稳定性的药物如多粘菌素和 SQ109 来增强莫西沙星+利奈唑胺作为 MDR-TB 治疗的基础。我们使用时间杀伤动力学测定法评估了莫西沙星、利奈唑胺、维拉帕米、替莫唑胺、多粘菌素和 SQ109 作为单一药物对结核分枝杆菌的活性。此外，评估了莫西沙星+利奈唑胺基础与一种增效剂药物联合使用的活性。暴露 6 天后，只需 0.125mg/L 的莫西沙星即可达到 99%的结核分枝杆菌杀灭率。利奈唑胺显示出中等的杀菌作用，但未达到 99%的杀灭率。只有在测试的最高浓度下，维拉帕米、替莫唑胺和多粘菌素才会导致杀菌，但未达到 99%的杀菌率。暴露于 256mg/L 的 SQ109 后，1 天即可完全消除，暴露于 1mg/L 的 SQ109 后 6 天即可达到 99%的消除。此外，多粘菌素添加到莫西沙星+利奈唑胺基础中可增加消除率，而维拉帕米、替莫唑胺和 SQ109 对基础无附加价值。这一发现表明，多粘菌素可增强莫西沙星+利奈唑胺基础对结核分枝杆菌的活性，这表明其在进一步研究莫西沙星+利奈唑胺治疗耐多药结核病的适用性方面具有潜在作用。
