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

• 批准号: 8131094
• 负责人: Philip C Hopewell
• 金额: $ 73.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/8131094
• 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; Health; 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; resistance mutation; resistant strain; secondary infection; sound; transmission process; tuberculosis drugs

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(申请人提供)：这项研究的目的是确定导致异烟肼耐药性的突变单独或与对其他药物(多药耐药[MDR]和广泛耐药[XDR])的耐药性一起对结核分枝杆菌的传播性和致病性的影响。之前在旧金山进行的研究表明：1)结核分枝杆菌耐药株导致的继发性病例较少；2)致病性降低与异烟肼耐药突变密切相关，而不是KatG中的S315T突变；以及3)特定的耐药突变与该生物的系统地理谱系有关。然而，这些观察的适用性是有限的，因为这项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；并且只有少量耐多药病例。这项研究的具体目的如下：1.从指示病例中鉴定与异烟肼耐药有关的结核分支杆菌的突变；2.比较由以下原因引起的结核病例接触者中新的结核病感染率和活动性肺结核：a.完全敏感的结核杆菌；b.具有katG S315T突变和inha prom-15ct的异烟肼耐药生物；C.异烟肼耐药生物--除S315T以外具有katG突变的生物；以及d.mdr/xdr生物；3.确定从指示病例分离的结核分支杆菌的系统地理谱系；4.确定导致抗药性的突变与生物体的系统地理谱系之间是否存在关联。我们建议使用一项名为“美国耐多药的分子流行病学分析”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.TB ESC)进行，全国有14个结核流行病学研究站点参与。该项目将提供足够多的耐多药病例和完全易感病例，以供比较。从加州结核分枝杆菌ESC站点之一，我们还将包括所有由异烟肼耐药微生物引起的结核病患者，以及一组完全易感微生物的对照患者。我们将获得流行病学和临床数据，以及接触调查结果。我们将确定异烟肼耐药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，以确定由指数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病例比率。产生的数据将提供在低发病率地区现代结核病控制的背景下，耐药结核分枝杆菌与敏感生物相比的传播性和致病性。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，包括多药耐药(MDR)和广泛耐药(XDR)结核病，都是描述性的。已经确定结核分枝杆菌耐药株是 但与完全敏感的生物体相比，抗药性菌株传播和致病的程度仍然完全未知。掌握有关耐药结核分枝杆菌相对适合性的信息，将能够更准确地预测耐多药和广泛耐药对全球结核病流行的影响，并有助于确定最有可能有效的结核病控制干预措施。