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

描述（由申请人提供）：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（多重耐药[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。先前在旧金山的研究表明：1)耐药结核分枝杆菌菌株引起的继发病例较少；2)致病性降低与KatG中S315T突变以外的异烟肼耐药突变密切相关；3)特定的抗性突变与生物体的系统地理谱系有关。然而，这些观察结果的适用性是有限的，因为研究是在一个独特的地点进行的；没有检查接触者的特征；没有发现接触者之间的新感染；只有少数耐多药病例。所提议的研究的具体目的是基于旧金山的观察，如下：1。鉴定指示病例结核分枝杆菌异烟肼耐药突变；2. 比较由：a.完全易感结核分枝杆菌引起的结核的指示病例接触者的新发结核感染率和活动性结核率；b.具有katG S315T突变和ha prom -15ct的异烟肼耐药菌；c.除S315T外具有katG突变的异烟肼耐药生物；d. MDR/XDR微生物；3. 确定从指示病例分离的结核分枝杆菌的系统地理谱系；4. 以确定是否存在抗性突变之间的联系和系统地理谱系的生物体。我们建议使用一项名为“美国耐多药分子流行病学分析”的前瞻性研究的数据，该研究由美国疾病控制与预防中心（CDC）赞助的结核病流行病学研究联盟（M. Tuberculosis ESC）开展，全国有14个结核分枝杆菌ESC站点参与。该项目将提供足够数量的耐多药耐药性病例和完全易感病例进行比较。此外，我们将从加利福尼亚的一个结核分枝杆菌ESC站点纳入所有由异烟肼耐药菌引起的结核病患者和一组完全易感菌患者。我们将获得流行病学和临床数据以及接触者调查结果。我们将确定异烟肼抗性突变和系统地理谱系。基因分型信息将与流行病学数据相结合，确定由指示病例命名的接触者的继发感染率比率和由基因分型确定的继发感染率比率。所产生的数据将提供在低发病率地区的现代结核病控制背景下，耐药结核分枝杆菌与易感生物相比的传播性和致病性的指示。公共卫生相关性：迄今为止，几乎所有关于耐药结核病的全球信息，包括耐多药结核病和广泛耐药结核病的信息，都是描述性的。已经确定结核分枝杆菌耐药菌株是

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.