Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques
Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques
复制标题
DOI：
10.1073/pnas.1121497109
复制
发表时间：
2012-08-28
影响因子：
11.1
通讯作者：
Flynn, JoAnne L.
中科院分区：
文献类型：
--
作者：
Lin, Philana Ling;Dartois, Veronique;Flynn, JoAnne L.
针对低氧微环境中的结核分枝杆菌，如干酪样肉芽肿，已被假设有可能缩短活动性结核病（TB）的治疗，并防止潜伏感染的再激活。我们之前报道过，在低剂量M.结核病感染后，等比例的食蟹猴发展为活动性疾病或潜伏感染，并且潜伏感染的动物在TNF中和后重新激活。使用这个模型，我们现在表明，化学预防潜伏感染的食蟹猴与6个月的异烟肼（INH）有效地防止抗TNF抗体诱导的再激活。同样，在该模型中，用INH和利福平（RIF）联合给药潜伏期动物2个月对预防再活化疾病非常有效。甲硝唑（MTZ），它只对厌氧，非复制细菌的活动，是有效的，这些治疗在防止潜伏感染的再激活。由于活动性TB也会出现缺氧性病变，我们进一步表明，在INH/RIF中加入MTZ可在2个月内有效治疗活动性TB动物。愈合病变与细胞病理学的明显变化相关，向纤维化和钙化病变的增加转变。我们在活动性和潜伏性TB的非人灵长类动物模型中的数据支持在低氧环境中靶向细菌，以防止潜伏感染的再激活，并可能缩短活动性TB的治疗持续时间。
Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB.