在潜伏性结核感染小鼠模型中采用利福喷汀每日给药的短程疗法。
Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection.
作者信息
Zhang Tianyu, Zhang Ming, Rosenthal Ian M, Grosset Jacques H, Nuermberger Eric L
机构信息
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
出版信息
Am J Respir Crit Care Med. 2009 Dec 1;180(11):1151-7. doi: 10.1164/rccm.200905-0795OC. Epub 2009 Sep 3.
RATIONALE
Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin+pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less.
OBJECTIVES
To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens.
METHODS
Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very low-dose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10(4) CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin+isoniazid, rifampin+pyrazinamide) or test (rifapentine alone, rifapentine+isoniazid, rifapentine+pyrazinamide, rifapentine+isoniazid+pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment.
MEASUREMENTS AND MAIN RESULTS
M. tuberculosis CFU counts remained stable around 3.65 log(10) in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin+isoniazid cured 0 and 53% of mice and rifampin+pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin+isoniazid and indistinguishable from rifampin+pyrazinamide.
CONCLUSIONS
In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin+pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks.
理论依据
推荐用于治疗潜伏性结核感染（LTBI）的方案疗程为3至9个月。不再推荐使用2个月的利福平+吡嗪酰胺方案。更短疗程的方案非常值得期待。由于在活动性结核病的标准方案中用利福喷汀替代利福平可将小鼠预防复发所需的治疗时间减半，我们推测基于利福喷汀的每日方案可将LTBI治疗时间缩短至2个月或更短。
目的
改进现有的LTBI化疗模型并评估基于利福喷汀的每日方案的疗效。
方法
用免疫原性更强的重组卡介苗菌株（rBCG30）对小鼠进行免疫，并接受极低剂量的结核分枝杆菌气溶胶感染，以在不进行药物治疗的情况下建立稳定的肺部细菌负荷，低于10⁴CFU。小鼠接受对照（单独使用异烟肼、单独使用利福平、利福平+异烟肼、利福平+吡嗪酰胺）或试验（单独使用利福喷汀、利福喷汀+异烟肼、利福喷汀+吡嗪酰胺、利福喷汀+异烟肼+吡嗪酰胺）方案治疗8周。利福霉素剂量为10mg/kg/d，与人类剂量相同。观察指标为每两周的肺部CFU计数以及治疗4至8周后的复发情况。
测量结果与主要结果
在免疫但未治疗的小鼠中，结核分枝杆菌CFU计数在3.65 log₁₀左右保持稳定。异烟肼或利福平在第8周时使所有或大多数小鼠培养结果呈阳性。利福平+异烟肼在4周和8周时分别治愈了0%和53%的小鼠，利福平+吡嗪酰胺在4周和8周时分别治愈了47%和100%的小鼠。基于利福喷汀的方案比利福平+异烟肼更有效，且与利福平+吡嗪酰胺无差异。
结论
在这个肺部负荷极低的改进型LTBI化疗小鼠模型中，现有方案得到了很好的体现。基于利福喷汀的每日方案至少与利福平+吡嗪酰胺一样有效，表明它们可在6至8周内有效治疗LTBI。
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