Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model.
Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model.
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DOI：
10.1371/journal.pmed.0040344
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发表时间：
2007-12
期刊：
影响因子：
15.8
通讯作者：
Nuermberger EL
中科院分区：
文献类型：
--
作者：
Rosenthal IM;Zhang M;Williams KN;Peloquin CA;Tyagi S;Vernon AA;Bishai WR;Chaisson RE;Grosset JH;Nuermberger EL
能够在2至3个月内治愈结核病患者的超短期药物方案的可用性将显著改善全球控制工作。由于新型缩短治疗时间的药物的近期前景仍然不确定，我们研究了更好地使用现有药物是否可以缩短治疗时间。利福喷丁是一种长效利福霉素衍生物，目前仅推荐用于每周一次的延续期治疗方案。莫西沙星是一种8-甲氧基氟喹诺酮类药物，目前用于二线治疗。我们使用一个成熟的具有高细菌负荷和人类等效药物剂量的小鼠模型，比较了含有利福喷丁和莫西沙星的方案与基于利福平、异烟肼和吡嗪酰胺的标准每日短期方案的疗效。通过肺部菌落形成单位计数来评估杀菌活性，并通过治疗2、3、4和6个月后培养阳性复发的小鼠比例来评估杀菌活性。在这里，我们证明用利福平代替利福喷丁，用莫西沙星代替异烟肼显著增加了标准日常治疗方案的活性。仅在治疗2个月后，接受含利福喷丁和莫西沙星方案的小鼠发现肺培养呈阴性，而给予标准方案的小鼠肺中仍有3.17 log10集落形成单位（p < 0.01）。每天和每周三次给予含利福喷丁和莫西沙星的方案治疗3个月后未观察到复发，而标准的每日方案需要6个月才能防止所有小鼠复发。利福喷丁不应再仅仅被视为每周给药一次的利福霉素。我们的研究结果表明，每天和每周三次给予利福喷丁和莫西沙星的治疗方案可以将目前6个月的治疗时间缩短到3个月或更短。这种治疗方案需要紧急的临床研究。Eric Nuermberger和他的同事们发现，经过两个月的治疗，肺培养呈肺结核阳性的小鼠每天接受含有利福喷丁和莫西沙星的治疗后，肺培养变为阴性。这一发现可能使人类开发更短的治疗方案成为可能。每年有近900万人患上肺结核——一种最常见的肺部细菌感染——大约200万人死于这种疾病。结核病是由结核分枝杆菌引起的，这种细菌在活动性肺结核患者打喷嚏或咳嗽时通过空气飞沫传播。大多数感染者永远不会生病——他们的免疫系统成功地控制了感染。然而，这种细菌在体内处于休眠状态，若干年后，如果宿主免疫力下降，就会引发疾病。活动性结核病可以通过每天服用几种抗生素（对于结核病治疗，每天可能意味着每周5或7次）至少6个月来治愈。需要联合使用药物来防止细菌对治疗产生耐药性，但也因为结核分枝杆菌的复杂生物学。在活动性肺结核期间，肺部有快速繁殖的细菌，但身体其他部位也有繁殖速度较慢和接近休眠的细菌。有效的治疗方法包括一种“杀菌”药物，如杀死活跃繁殖的细菌的异烟肼，一种杀死繁殖不活跃的细菌的药物（如吡嗪酰胺），以及一种杀死接近休眠的细菌的消毒药物（其中最有效的是利福平），从而防止疾病复发。不幸的是，许多患者未能完成这种治疗，因为它是漫长而复杂的，因为药物可能有令人不快的副作用。治疗依从性差会导致耐药性的出现，并意味着人们保持传染性的时间更长，更有可能复发。因此，它阻碍了全球控制结核病的努力。较短的治疗过程可能会改善病情，但许多研究人员认为，这将需要开发新的药物，尽管有几种很有希望的候选药物，但要在患者身上使用还需要几年的时间。因此，在这项研究中，研究人员询问更好地使用现有药物是否可以缩短治疗时间。他们特别研究了动物结核病，以调查一种长效的类似利福平的药物利福喷丁与莫西沙星（异烟肼的替代品）联合使用是否会缩短治疗时间。研究人员使用了几种不同的疗程（“方案”），包括利福喷丁、莫西沙星和吡嗪酰胺，以及标准的每日短期疗程，包括利福平、异烟肼和吡嗪酰胺，来治疗感染结核分枝杆菌的小鼠。对于每个方案，他们通过计算在治疗期间特定时间小鼠肺部可以生长的细菌菌落数量来测量其杀菌活性，并通过评估治疗完成后肺部含有任何活细菌的小鼠比例（培养阳性复发）来测量其杀菌活性。治疗2个月后，接受含利福喷丁和莫西沙星方案的小鼠肺培养呈阴性，这是标准方案在治疗4个月后才达到的。每天或每周三次含利福喷丁和莫西沙星的治疗方案三个月足以防止任何培养阳性复发，而标准的每日治疗方案必须持续6个月才能治愈。对其他药物组合的测试表明，利福喷丁是新方案中最重要的药物，在该实验模型中，仅仅用利福喷丁代替利福平并保留异烟肼也足以将治疗时间缩短至3个月。这些发现提供了第一个证据，证明用利福喷丁代替利福平可能使治愈结核病所需的治疗时间缩短一半。他们还指出，有可能每周给药三次，而不是像目前的治疗那样每天给药。世界卫生组织建议对所有结核病治疗进行监督（所谓的直接观察治疗），以确保治疗依从性。因此，每周只需三剂，持续3个月的治疗方案将大大减少治疗结核病所需的资源，并有可能提高治疗依从性。然而，应该强调的是，目前的研究是实验性的，在治愈率和副作用方面，小鼠和人类对拟议药物方案的反应可能存在重要差异。然而，这些结果强烈提示，应尽快在人群中评估利福喷丁和吡嗪酰胺联合莫西沙星或异烟肼治疗方案的安全性、耐受性和有效性。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0040344访问这些网站。MedlinePlus百科全书包含一个关于结核病的页面（英语和西班牙语），美国国家过敏和传染病研究所提供了关于结核病的所有方面的信息，美国疾病控制和预防中心提供了一些关于结核病的情况说明书和其他信息资源，世界卫生组织提供2007年全球结核病控制报告（英文本，以法文和西班牙文提供主要发现）、控制结核病行动的信息和最近的一份结核病治疗公报（英文本，以法文、西班牙文和阿拉伯文提供摘要）。
Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens. Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice. Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation. Eric Nuermberger and colleagues found that after two months of treatment, mice with lung cultures positive for tuberculosis that received daily doses of rifapentine- and moxifloxacin-containing regimens converted to negative lung cultures. This finding could make possible the development of shorter treatment regimens for humans. Every year, nearly 9 million people develop tuberculosis—a bacterial infection most commonly of the lungs—and about 2 million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with active tuberculosis sneeze or cough. Most infected people never become ill—their immune system successfully contains the infection. However, the bacteria remain dormant within the body and can cause disease years later if host immunity declines. Active tuberculosis can be cured by taking several antibiotics daily (for tuberculosis treatments, daily may mean five or seven times a week) for at least 6 mo. Combinations of drugs are needed to prevent the bacteria from developing resistance to the treatment, but also because of the complex biology of M. tuberculosis. During active tuberculosis, there are rapidly multiplying bacteria in the lungs but also less rapidly multiplying and near-dormant bacteria elsewhere in the body. Effective treatments contain a “bactericidal” drug such as isoniazid to kill the actively multiplying bacteria, a drug to kill the less actively multiplying bugs (for example, pyrazinamide), and a sterilizing drug (the most potent of which is rifampin) to kill the near-dormant bacteria and thus prevent the disease from recurring. Unfortunately, many patients fail to complete this treatment because it is long and complicated and because the drugs may have unpleasant side effects. Poor adherence to treatment contributes to the emergence of drug resistance and means that people stay infectious for longer and are more likely to have relapses. Consequently, it is hampering global efforts to control tuberculosis. A shorter course of treatment might improve matters, but many researchers believe that this will require the development of new drugs and, although there are several promising candidates, it will be several years before they can be used in patients. In this study, therefore, the researchers asked whether better use of existing drugs could shorten treatment times. In particular, they studied tuberculosis in animals to investigate whether a long-lived rifampin-like drug called rifapentine combined with moxifloxacin (an alternative to isoniazid) might shorten treatment times. The researchers used several different courses (“regimens”) of treatment containing rifapentine, moxifloxacin, and pyrazinamide, and the standard daily short-course regimen containing rifampin, isoniazid, and pyrazinamide to treat mice infected with M. tuberculosis. For each regimen, they measured its bactericidal activity by counting how many bacterial colonies could be grown from the lungs of the mice at specific times during the treatment, and its sterilizing activity by assessing the proportion of mice with any live bacteria in their lungs (a culture-positive relapse) after treatment completion. After 2 mo of treatment, the mice receiving the rifapentine- and moxifloxacin-containing regimens had negative lung cultures, a point not reached with the standard regimen until after 4 mo of treatment. Three months of treatment with daily or thrice-weekly rifapentine- and moxifloxacin-containing regimens was sufficient to prevent any culture-positive relapses, whereas the standard daily regimen had to be continued for 6 mo to achieve cure. Testing of additional drug combinations revealed that rifapentine is the most important drug in the new regimen and that simply replacing rifampin with rifapentine and retaining isoniazid also is sufficient to shorten the duration of therapy to 3 mo in this experimental model. These findings provide the first evidence that replacing rifampin with rifapentine might halve the length of therapy needed to cure tuberculosis. They also indicate that it might be possible to give the drugs thrice-weekly rather than daily as in the current therapy. The World Health Organization recommends that all tuberculosis treatment is supervised (so-called directly observed therapy) to ensure treatment adherence, so a regimen that requires only three doses a week for 3 mo would greatly reduce the resources needed to treat tuberculosis as well as potentially improving treatment adherence. However, it should be emphasized that the current study is experimental, and there may be important differences between how mice and people respond to the proposed drug regimens, both in terms of cure rates and side effects. Nevertheless, these results strongly suggest that the safety, tolerability, and efficacy of tuberculosis treatment regimens containing rifapentine and pyrazinamide, combined with either moxifloxacin or isoniazid, should be evaluated in people as soon as possible. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040344. The MedlinePlus encyclopedia contains a page on tuberculosis (in English and Spanish) The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis The US Centers for Disease Control and Prevention provide several fact sheets and other information resources about tuberculosis, including information for patients and caregivers about treatment adherence The World Health Organization provides a 2007 report on global tuberculosis control (in English with key findings in French and Spanish), information on the Stop TB initiative, and a recent bulletin on tuberculosis treatment (in English with an abstract in French, Spanish, and Arabic)
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DOI：
10.1164/rccm.200605-637oc
发表时间：
2006-11-15
影响因子：
24.7
作者：
Chang, Kwok C.;Leung, Chi C.;Tam, Cheuk M.
通讯作者：
Tam, Cheuk M.
DOI：
10.1164/ajrccm.163.5.2007122
发表时间：
2001-04-01
影响因子：
24.7
作者：
O'Brien, RJ;Nunn, PP
通讯作者：
Nunn, PP
影响因子：
56.9
作者：
Andries, K;Verhasselt, P;Jarlier, V
通讯作者：
Jarlier, V
影响因子：
4.9
作者：
Jayaram, R;Gaonkar, S;Balasubramanian, V
通讯作者：
Balasubramanian, V
影响因子：
105.7
作者：
POOLE, G;STRADLING, P;WORLLEDGE, S
通讯作者：
WORLLEDGE, S