Effect of Drug Resistance on Transmissibility and Pathogenicity of M. tuberculosi

描述（由申请方提供）：本研究的目的是确定异烟肼耐药突变单独或与其他药物耐药（多药耐药[MDR]和广泛耐药[XDR]）联合对结核分枝杆菌传播性和致病性的影响。弗朗西斯科的研究表明：1）耐药菌株的M。结核病引起较少的继发病例; 2）降低的致病性与KatG中除S315T突变以外的异烟肼耐药突变强烈相关;和3）特异性耐药突变与生物体的地理谱系相关。然而，这些观察结果的适用性有限，因为该研究是在一个独特的地点进行的;没有检查接触者的特征;没有发现接触者中的新感染;只有少数MDR病例。本研究的具体目的是基于对旧金山弗朗西斯科的观测，具体如下：1.以鉴定M.索引病例的结核病; 2.比较由以下原因引起的结核病指示病例的接触者中新结核病感染率和活动性结核病率：a.完全敏感M.结核病; B.具有katG S315T突变和inhA prom-15ct的异烟肼抗性生物体; c.具有除S315T以外的katG突变的异烟肼抗性生物体;和d. MDR/XDR微生物; 3.以确定M.从指示病例中分离的结核病; 4.以确定是否存在赋予抗性的突变和生物体的地理谱系之间的关联。我们建议使用由结核病流行病学研究联合会（M。结核病ESC），由CDC赞助，14 M参与。全国各地的结核病ESC站点。本项目将提供足够多的MDR病例和完全易感病例进行比较。从一个M。结核病ESC研究中心，加州，我们将包括，此外，所有结核病患者引起的异烟肼耐药微生物和一个比较组的患者完全敏感的微生物。我们将获得流行病学和临床数据，以及接触调查的结果。我们将确定异烟肼耐药突变和地理谱系。将基因分型信息与流行病学数据相结合，以确定由索引病例命名的接触者中的继发感染率比和由基因分型定义的继发病例率比。所产生的数据将提供抗性M的传播性和致病性的指示。结核病与易感微生物相比，在现代结核病控制的背景下，在低发病率地区。公共卫生相关性：迄今为止，几乎所有关于耐药结核病（包括多重耐药（MDR）和广泛耐药（XDR）结核病）的全球信息都是描述性的。已经确定结核分枝杆菌耐药菌株是 虽然耐药菌株是可传播的，但与完全易感的生物体相比，耐药菌株传播和致病的程度仍然完全未知。了解耐药M.结核病的研究将能够更准确地预测MDR和XDR对全球结核病流行的影响，并将有助于确定最有可能有效的结核病控制干预措施。

DESCRIPTION (provided by applicant): The objective of this study is to determine the effect of isoniazid resistance-conferring mutations alone or in combination with resistance to other drugs (multidrug resistant [MDR] and extensively drug resistant [XDR]) on transmissibility and pathogenicity of Mycobacterium tuberculosis. Previous studies in San Francisco demonstrated that: 1) drug resistant strains of M. tuberculosis cause fewer secondary cases; 2) that the reduced pathogenicity is strongly associated with isoniazid resistance mutations other than the S315T mutation in KatG; and 3) that specific resistance mutations are associated with phylogeographic lineages of the organism. However, the applicability of these observations is limited because the study was conducted in a unique locale; characteristics of the contacts were not examined; new infections among contacts were not identified; and there was only a small number of MDR cases. The specific aims of the proposed study are based on the observations from San Francisco and are as follows: 1. to identify the isoniazid resistance-conferring mutations of M. tuberculosis from index cases; 2. to compare the rates of new tuberculosis infection and active tuberculosis in contacts of index cases with tuberculosis caused by: a. fully susceptible M. tuberculosis; b. isoniazid resistant organisms with the katG S315T mutation and inhA prom -15ct ; c. isoniazid resistant-organisms with katG mutations other than other than S315T; and d. MDR/XDR organisms; 3. to determine the phylogeographic lineage of M. tuberculosis isolated from index cases; 4. to determine if there are associations between resistance-conferring mutations and phylogeographic lineage of the organism. We propose to use data from a prospective study entitled "An analysis of Molecular Epidemiology of MDR in the United States" conducted by the Tuberculosis Epidemiologic Studies Consortium (M. tuberculosis ESC) sponsored by the CDC and with the participation of 14 M. tuberculosis ESC sites across the country. This project will provide sufficiently large numbers of MDR cases and fully susceptible cases for comparison. From one of the M. tuberculosis ESC sites, California, we will include, in addition, all patients with tuberculosis caused by isoniazid resistant organisms and a comparison group of patients with fully susceptible organisms. We will obtain epidemiological and clinical data, as well as the results of the contact investigations. We will determine isoniazid resistance mutations and phylogeographic lineage. The genotyping information will be integrated with the epidemiologic data to determine secondary infection rate ratios among the contacts named by the index cases and secondary case rate ratios defined by genotyping. The data generated will provide an indication of the transmissibility and pathogenicity of resistant M. tuberculosis compared with susceptible organisms in the context of modern tuberculosis control in a low-incidence area. PUBLIC HEALTH RELEVANCE: To date, nearly all the global information on drug resistant tuberculosis, including multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis, is descriptive in nature. It has been established that Mycobacterium tuberculosis resistant strains are transmissible, but what remains completely unknown is the degree to which drug resistant strains are transmitted and cause disease as compared with fully susceptible organisms. Having information on the relative fitness of drug resistant M. tuberculosis would enable more accurate predictions about the impact of MDR and XDR on the tuberculosis epidemic globally, and would serve to identify the tuberculosis control interventions most likely to be effective.