Binational Transmission of Multidrug-Resistant Tuberculosis, California & Mexico

描述（由申请人提供）：耐多药结核病（MDR-TB）是由结核分枝杆菌菌株引起的，该菌株对两种最有效的抗结核药物：异烟肼（INH）和利福平（RIF）具有耐药性。尽管加州努力预防耐多药结核病的发生，但每年仍有40-50例病例。80%以上的耐多药结核病病例是在国外出生的，其中25%来自墨西哥。但是尚不清楚这些进入美国的病例是否已经感染了耐多药结核病，或者他们的耐多药结核病是否是由于在美国治疗药物敏感结核病失败而获得的。利用2004年以来由疾病预防控制中心资助的对加州所有结核病病例进行基因分型的项目，以及墨西哥第一次全国耐多药结核病调查（计划于2008年底完成），我建议将加州耐多药结核病病例的基因分型和耐药突变与墨西哥耐多药结核病病例的基因分型和耐药突变进行比较。这一分析将使我们能够确定耐多药结核病原体种群是否正在边境两侧独立发展，或者耐药结核菌株是否正在通过移民在两国传播。推动这一提议的假设是，西班牙裔的加利福尼亚耐多药结核病菌株主要是墨西哥耐多药结核病菌株的一个子集，这表明初级耐药是两国传播的，而不是在边境两侧独立获得耐药性。为了验证这一假设，提出了以下目标：目标1：通过比较加利福尼亚西班牙裔耐多药结核分离株的基因型与墨西哥国家耐多药结核调查的耐多药结核基因型，确定加州耐多药结核病原体菌株与墨西哥耐多药结核菌株的相关性程度。目的2：确定目的1中鉴定的匹配耐多药结核分离株的INH和RIF耐药突变是由直接传播（相同基因型，相同药物突变）还是独立获得（相同基因型，不同药物突变）引起的。目的3：通过对墨西哥和加利福尼亚参考实验室数据的回顾性分析，以及对加利福尼亚圣地亚哥县和墨西哥蒂华纳耐多药结核病病例的前瞻性调查，比较加利福尼亚和墨西哥耐多药结核病病例之间的耐多药结核病危险因素和流动性特征。相关性（见说明书）：耐多药结核病病例比药物敏感结核病复杂得多，治疗费用高达20倍，病死率从12%到90%不等。在结核病控制预算有限的情况下，了解如何重点开展耐多药结核病预防工作至关重要。这项研究将确定跨界耐多药结核病的风险因素和传播动态，以便制定未来的公共卫生干预措施。

DESCRIPTION (provided by applicant): Multidrug-resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains that are resistant to the two most effective anti-TB drugs: isoniazid (INH) and rifampin (RIF). Despite efforts to prevent MDR- TB from occurring in California, there are still 40-50 cases per year. Over 80% of the MDR-TB cases are foreign-born and 25% of these cases are from Mexico. But it is not clear whether these cases entered the US already infected with MDR-TB or whether their MDR-TB was acquired from treatment failures of drug- sensitive TB within the US. Taking advantage of a CDC-funded program to genotype all California TB cases since 2004, and the first Mexican national MDR-TB survey-scheduled to be completed by the end of 2008-I propose to compare the genotypes and drug resistance mutations of MDR-TB cases from California, with genotypes and drug-resistance mutations of MDR-TB cases from Mexico. This analysis will allow us to determine if the MDR-TB pathogen population is developing independently on both sides of the border, or if drug resistant strains of TB are being transmitted binationally via migration.The hypothesis driving this proposal is that California MDR-TB strains in Hispanics are predominantly a subset of the Mexico MDR-TB strains, indicating binational transmission of primary drug resistance rather than independent acquisition of resistance on both sides of the border. In order to test this hypothesis, the following aims are proposed: Aim 1: To determine the extent to which MDR-TB pathogen strains in California are related to those in Mexico by comparing the genotypes of MDR-TB isolates from Hispanics in California, with MDR-TB genotypes from the Mexican National MDR-TB Survey. Aim 2: To determine whether INH and RIF drug resistance mutations in the matched MDR-TB isolates identified in Aim 1 resulted from direct transmission (same genotype, same drug mutations) or independent acquisition (same genotype, different drug mutation). Aim 3: To compare MDR-TB risk factors and mobility characteristics between MDR-TB cases from California and Mexico using a combination of retrospective analysis of reference laboratory data from Mexico and California, and from a prospective survey of MDR-TB cases in San Diego County, California and Tijuana, Mexico. RELEVANCE (See instructions): MDR-TB cases are exponentially more complicated and up to 20 times more expensive to treat than drug- sensitive TB, and case fatality ranges from 12% up to 90%. With only a limited TB control budget, it is critical to know how to focus MDR-TB prevention efforts. This study will identify the risk factors and transmission dynamics of cross-border MDR-TB in order to shape future public health interventions.