Klemens S P, Cynamon M H
Department of Medicine, SUNY Health Science Center, Syracuse 13210, USA.
Antimicrob Agents Chemother. 1996 Feb;40(2):298-301. doi: 10.1128/AAC.40.2.298.
The activity of KRM-1648, alone and in combination with isoniazid, was compared with those of isoniazid, rifampin, and the combination of rifampin plus isoniazid in a murine model of tuberculosis. Four-week-old female CD-1 mice were infected intravenously with approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms. Treatment was started 1 week postinfection and was given by gavage 5 days per week. The duration of the treatment phase was 12 weeks, with groups of mice sacrificed at 2, 4, 6, 8, and 12 weeks. For the observation phase, additional groups of treated mice were sacrificed at 4, 8, 16, and 24 weeks after the cessation of treatment. Viable cell counts were determined from homogenates of the spleens and the right lungs. KRM-1648 was the most active single agent evaluated and resulted in no detectable CFUs in the spleens and lungs by the end of 6 weeks of treatment. Neither rifampin nor isoniazid reduced cell counts to undetectable levels, even after 12 weeks of treatment. The combination of KRM-1648 plus isoniazid was much more active than rifampin plus isoniazid. KRM-1648 plus isoniazid resulted in the apparent sterilization of organs at 6 months following the cessation of treatment. The promising activity of KRM-1648 may allow for ultrashort-course therapy of tuberculosis, i.e., treatment regimens of 4 months or less.
在结核病小鼠模型中，将KRM-1648单独及与异烟肼联合使用时的活性，与异烟肼、利福平以及利福平加异烟肼联合用药的活性进行了比较。4周龄雌性CD-1小鼠通过静脉注射约10(7)个存活的结核分枝杆菌ATCC 35801菌株进行感染。感染后1周开始治疗，每周5天通过灌胃给药。治疗阶段持续12周，在2、4、6、8和12周处死小鼠组。在观察阶段，在治疗停止后的4、8、16和24周处死额外的治疗小鼠组。从脾脏和右肺匀浆中测定活菌数。KRM-1648是所评估的最具活性的单一药物，在治疗6周结束时，脾脏和肺中未检测到集落形成单位。即使在治疗12周后，利福平和异烟肼都未将细胞数降低到检测不到的水平。KRM-1648加异烟肼的联合用药比利福平加异烟肼的活性高得多。KRM-1648加异烟肼在治疗停止后6个月导致器官明显灭菌。KRM-1648有前景的活性可能允许结核病的超短程治疗，即4个月或更短的治疗方案。
