Low-dose aerosol infection model for testing drugs for efficacy against Lycobacterium tuberculosis
Low-dose aerosol infection model for testing drugs for efficacy against Lycobacterium tuberculosis
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DOI：
10.1128/aac.40.12.2809
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发表时间：
1996-12-01
影响因子：
4.9
通讯作者：
Orme, IM
中科院分区：
文献类型：
--
作者：
Kelly, BP;Furney, SK;Orme, IM
结核病作为一种慢性传染病，其临床表现多种多样，从原发性肺结核到再活化性肺结核和空洞性疾病。迄今为止，用于评估结核病化疗的动物模型一直是模拟疾病传播形式的高剂量静脉内模型。在本研究中，我们使用了一个低剂量气溶胶暴露模型，我们觉得更好地反映了新诊断的结核病患者转化为结核菌素阳性。作为化疗的适当实例，首先在体外鼠巨噬细胞模型中，然后在低剂量气溶胶感染模型中测试四种利福霉素（利福平、利福替尼、利福喷丁和KRM-1648）对结核分枝杆菌的活性。在两种模型中，KRM-1648具有四种化合物中最高水平的活性。在感染肺模型中，当以5 mg/kg体重/天经口给予利福朋肽、利福喷丁和KRM-1648时，均具有杀菌活性。当以2.5 mg/kg/天剂量给药时，KRM-1648在四种药物中具有最高水平的活性，在35天的治疗中将细菌负荷降低了2.7 log。
As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.