PNAS：预防潜伏结核病的重新激活

一项刊登在PNAS上的研究报告说，有针对性地把结合分枝杆菌放在低氧环境中可以防止潜伏结核病的重新激活并缩短对活动性感染的治疗。JoAnne L. Flynn及其同事研究了甲硝唑（MTZ）的有效性，这是一种在常见于人类结核感染的小的节结或者说肉芽肿的低氧微环境中作用于非复制期细菌的药物。

常用于治疗潜伏结核病的药物包括异烟肼（INH）和利福平（RIF），它们在从这类环境中清除有机体的效率低。这项研究表明甲硝唑（MTZ）能像6个月的异烟肼治疗或2个月的异烟肼/利福平治疗一样有效地防止潜伏结核病的诱导再激活。这组作者进一步证明了把甲硝唑（MTZ）加入到异烟肼/利福平（INH/RIF）联合用药疗法中，通过瞄准异烟肼和利福平治疗效果较差的低氧微环境中的细菌，能够成功地在2个月里治疗有活动性结核的动物。

尽管结核分枝杆菌感染可能导致活动性结核病，大约20亿人有无临床症状的潜伏感染，终生有10%的再激活的风险。这组作者提出，在低氧环境中针对结合分枝杆菌的药物可以提供应对结核病的重要工具。

doi:10.1073/pnas.1121497109
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Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques

Philana Ling Lina, Veronique Dartoisb, Paul J. Johnstonc, Christopher Janssend, Laura Viae, Michael B. Goodwine, Edwin Kleind, Clifton E. Barry IIIe, and JoAnne L. Flynnc,1

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.