Bax Hannelore I, Bakker-Woudenberg Irma A J M, de Vogel Corné P, van der Meijden Aart, Verbon Annelies, de Steenwinkel Jurriaan E M
Department of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Tuberculosis (Edinb). 2017 Jul;105:80-85. doi: 10.1016/j.tube.2017.04.010. Epub 2017 Apr 27.
Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework.
迫切需要新型结核病治疗策略。有许多不同的评估抗结核药物活性的临床前模型，但尚不清楚哪种模型组合对临床治疗效果的预测性最强。本研究的目的是确定我们的体外时间杀菌动力学试验在评估抗结核药物活性的预测性临床前建模框架中的作用。在暴露期间，测定了六种抗结核药物作为单一药物或二联、三联和四联组合对结核分枝杆菌北京基因型菌株的浓度和时间依赖性分枝杆菌杀伤能力，并评估了耐药性。链霉素、利福平和异烟肼对快速生长的结核分枝杆菌活性最强。异烟肼与利福平或高剂量乙胺丁醇是仅有的协同药物组合。在异烟肼中添加利福平或链霉素可防止异烟肼耐药。体外排名显示，部分但并非所有抗结核药物在结核病患者中的早期杀菌活性与之相符。时间杀菌动力学试验提供了关于药物暴露早期抗结核药物分枝杆菌杀伤动力学的重要信息。因此，该试验是临床前建模框架的一个有价值的组成部分。
