Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs
Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs
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DOI：
10.1128/aac.00500-12
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发表时间：
2012-07-01
影响因子：
4.9
通讯作者：
Karakousis, Petros C.
中科院分区：
文献类型：
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作者：
Dutta, Noton K.;Illei, Peter B.;Karakousis, Petros C.
利福霉素是目前治疗活动性结核病（TB）的关键杀菌药物。在小鼠活动性TB模型中，每日给予利福喷丁（P）（一种具有高细胞内蓄积的强效利福霉素）代替标准抗结核方案中的利福平（R）显著缩短了预防复发所需的治疗持续时间。我们进行了目前的研究，直接比较活动的人等效剂量的P和R在豚鼠模型的慢性结核病，其中杆菌主要是细胞外的人样坏死性肉芽肿。Hartley品系豚鼠用类似于200个结核分枝杆菌H37 Rv的杆菌气溶胶感染，并且在6周后开始给予5天/周的治疗。单独口服给予100 mg/kg体重的R和100 mg/kg Pat，或与60 mg/kg异烟肼（H）和300 mg/kg吡嗪酰胺（Z）联合给药。完成1个月和2个月治疗后，在豚鼠亚组中评估培养阳性复发。当单独使用和联合治疗时，人体等效剂量的R和P显示出等效的杀菌活性。在接受利福平、异烟肼和吡嗪酰胺（RHZ）或PHZ给药的豚鼠中，8/10只接受1个月给药的动物和0/10只接受2个月给药的动物的肺部发生微生物复发。在标准抗结核治疗方案中用P替代R并没有缩短豚鼠慢性结核病模型的治愈时间。正在进行的比较这两种药物活性的临床试验的数据有待确定豚鼠TB模型在临床前药物筛选中的相关性。
Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with similar to 200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and Pat 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening.