Effectiveness of tuberculosis chemotherapy correlates with resistance to Mycobacterium tuberculosis infection in animal models
Effectiveness of tuberculosis chemotherapy correlates with resistance to Mycobacterium tuberculosis infection in animal models
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DOI：
10.1093/jac/dkr188
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发表时间：
2011-07-01
影响因子：
5.2
通讯作者：
Karakousis, Petros C.
中科院分区：
文献类型：
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作者：
Ahmad, Zahoor;Fraig, Mostafa M.;Karakousis, Petros C.
目的：人们普遍认为，持久性结核分枝杆菌居住在人类坏死的肺肉芽肿中，其中遇到的微环境条件使杆菌对抗生素具有表型耐受性，这是成功治疗结核病所需的长时间。为了验证这一观点，我们直接比较了利福平/异烟肼/吡嗪酰胺（RHZ）对豚鼠和小鼠慢性结核感染的活性，豚鼠在组织学上表现为干酪样肉芽肿，与人类干酪样灶相似，而小鼠没有坏死肉芽肿。方法：将豚鼠和小鼠雾化感染结核分枝杆菌CDC1551, 4周后开始RHZ治疗，每周2次。在治疗3个月和4个月后评估各组豚鼠的培养阳性复发情况。结果：所有豚鼠肺均表现出具有中心干酪化的肉芽肿组织学证据，而小鼠肺在抗生素治疗开始时表现出细胞病变。每周给豚鼠两次等量RHZ治疗2个月后，豚鼠肺呈培养阴性。治疗3个月和4个月后，豚鼠的复发率均为0%（0/10）。相比之下，所有小鼠的肺在同等RHZ暴露4个月后仍保持培养阳性。结论：干酪样坏死不会降低RHZ标准抗结核方案的灭菌活性。我们的发现对于使用替代动物模型来测试新型结核病药物方案和模拟结核分枝杆菌持久性具有重要意义。
Objectives: It is widely believed that persistent Mycobacterium tuberculosis inhabits necrotic lung granulomas in humans and that the microenvironmental conditions encountered therein render the bacilli phenotypically tolerant to antibiotics, accounting for the long duration required for successful treatment of tuberculosis (TB). To validate this belief, we directly compared the activity of rifampicin/isoniazid/pyrazinamide (RHZ) against chronic TB infection in guinea pigs, which exhibit caseous granulomas histologically resembling human caseous foci, and in mice, which lack necrotic granulomas. Methods: Guinea pigs and mice were aerosol-infected with M. tuberculosis CDC1551 and twice weekly treatment with RHZ was started 4 weeks later. Culture-positive relapse was assessed in subgroups of guinea pigs after 3 months and 4 months of treatment.Results: All guinea pig lungs exhibited histological evidence of granulomas with central caseation, while mouse lungs exhibited cellular lesions at the initiation of antibiotic treatment. Guinea pig lungs became culture-negative after 2 months of RHZ given twice weekly at human-equivalent doses. Relapse rates in guinea pigs were 0% (0/10) both after 3 months and 4 months of treatment. In contrast, all mouse lungs remained culture-positive after 4 months of equivalent RHZ exposures.Conclusions: Caseous necrosis does not reduce the sterilizing activity of the standard antituberculosis regimen of RHZ. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.