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

耐药性对结核分枝杆菌传播性和致病性的影响

基本信息

批准号：
7728408
负责人：
Philip C Hopewell
金额：
$ 73.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-28 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728408
关键词：
Amikacin Antitubercular Agents Area Asians Behavior California Capromycin Centers for Disease Control and Prevention (U.S.)Characteristics Clinical Data Country Data Disease Drug Resistant Tuberculosis Drug resistance Drug resistance in tuberculosis Epidemic Epidemiologic Studies Epidemiology Extreme drug resistant tuberculosis Fluoroquinolones Genes Genotype Incidence Infection Injectable Intervention Investigation Isoniazid resistance Kanamycin Locales Low income Molecular Epidemiology Mono-S Multi-Drug Resistance Mutation Mycobacterium tuberculosis Names Nature Organism Pathogenicity Patients Pharmaceutical Preparations Population Population Heterogeneity Prospective Studies Relative (related person)Resistance Rifampin Risk Factors San Francisco Site Tuberculin Test Tuberculosis United States base comparison group design epidemiologic data examination questions fitness indexing isoniazid programs public health relevance resistance mutation resistant strain secondary infection sound transmission process tuberculosis drugs

项目摘要

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.

描述（由申请人提供）：本研究的目的是单独或与对其他药物的耐药性（多种耐药性[MDR]和广泛的耐药性[XDR]）对抗性药物的耐药性和耐药性对结核分枝杆菌的透射率和致病性的影响。先前在旧金山的研究表明：1）结核分枝杆菌的耐药菌株导致较少的继发病例； 2）降低的致病性与KATG中S315T突变以外的异念珠菌抗性突变密切相关； 3）特定的抗性突变与生物体的植物地理谱系有关。但是，这些观察结果的适用性受到限制，因为该研究是在独特的地方进行的。未检查接触的特征；未发现接触之间的新感染；而且只有少数MDR病例。拟议研究的具体目的是基于旧金山的观察结果，如下：1。确定来自指数病例的结核分枝杆菌的等异念珠菌耐药性突变； 2。比较索引病例与结核病的接触率的新结核病感染率和主动结核病的发生率：完全易感的结核分枝杆菌； b。具有KATG S315T突变和INHA PROM -15CT的异烟肼抗性生物； c。除S315T以外的其他KATG突变的异烟肼抗药性抗药性；和d。 MDR/XDR生物； 3。确定从指数病例中分离出的结核分枝杆菌的植物地理谱系； 4。确定有机体的抗性突变与植物地理谱系之间是否存在关联。我们建议使用一项名为“美国MDR分子流行病学的分析”的前瞻性研究数据。该项目将提供大量的MDR病例和完全易感的病例进行比较。此外，从加利福尼亚州的结核分枝杆菌ESC站点中，我们还将包括所有由抗异烟肼耐药的生物引起的结核病患者和完全易感生物体的患者的比较组。我们将获得流行病学和临床数据，以及接触调查的结果。我们将确定异念珠菌抗性突变和植物地理谱系。基因分型信息将与流行病学数据集成，以确定指数案例命名的接触和基因分型定义的次要病例率比率之间的二级感染率比。与易感生物相比，在现代性结核病控制的背景下，产生的数据将表明结核分枝杆菌的可传播性和致病性与易感生物相比。公共卫生相关性：迄今为止，几乎所有有关耐药性结核病的全球信息，包括抗多药（MDR）和广泛的耐药性（XDR）结核病，都是描述性的。已经确定结核分枝杆菌抗性菌株是可传播，但完全未知的是与完全易感生物相比，耐药菌株传播并引起疾病的程度。拥有有关耐药性结核分枝杆菌的相对适应性的信息，可以更准确地预测MDR和XDR对全球结核病流行的影响，并有助于确定结核病控制干预措施最有效。