Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA; Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, Florida, USA.
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona, Florida, USA.
Int J Antimicrob Agents. 2019 Mar;53(3):275-283. doi: 10.1016/j.ijantimicag.2018.10.012. Epub 2018 Oct 29.
There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance.
Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis was studied in the hollow-fiber infection model system in log-phase growth under neutral pH and slow growth in an acidic environment. Doses that achieved maximum bacterial kill while suppressing the emergence of drug resistance were determined. Through Monte Carlo simulations the quantitative output of this in vitro study was bridged to the human patient population to inform optimal dosage regimens while accounting for clinical minimum inhibitory concentration (MIC) distributions.
Moxifloxacin activity was significantly decreased in an acidified environment. The loss of activity was compensated by accumulation of the drug in TB lung lesions; therefore, moderate efficacy can be expected. Moxifloxacin 800 mg/day is the dose that most likely leads to resistance suppression while exerting maximum bacterial kill. Linezolid demonstrated very good activity even at a reduced pH. Linezolid 900 mg once-daily (QD) is likely to achieve a maximum killing effect and prevent the emergence of drug resistance; 600 mg QD in a robust drug regimen may have similar potential.
目前迫切需要新的抗结核（TB）药物并优化现有的 TB 治疗方案。莫西沙星和利奈唑胺是治疗耐药性结核病的有价值选择；然而，找到既能发挥高疗效又能抑制进一步耐药性发展的药物剂量至关重要。
在中空纤维感染模型系统中，在中性 pH 值和酸性环境下的缓慢生长的对数生长期研究莫西沙星和利奈唑胺对结核分枝杆菌的活性。确定了在抑制耐药性出现的同时实现最大杀菌效果的剂量。通过蒙特卡罗模拟，将该体外研究的定量结果与人体患者人群联系起来，以告知最佳剂量方案，同时考虑临床最低抑菌浓度（MIC）分布。
莫西沙星在酸化环境中的活性显著降低。通过药物在结核肺部病变中的积累来补偿活性的丧失；因此，可以预期适度的疗效。莫西沙星 800mg/天是最有可能抑制耐药性同时发挥最大杀菌效果的剂量。即使在降低的 pH 值下，利奈唑胺也表现出非常好的活性。利奈唑胺每天 900mg（QD）一次可能会达到最大杀菌效果并防止耐药性的出现；在强大的药物方案中，每天 600mg QD 可能具有类似的潜力。
