Binational Transmission of Multidrug-Resistant Tuberculosis, California & Mexico

描述（由申请方提供）：耐多药结核病（MDR-TB）是由对两种最有效的抗结核药物（异烟肼（INH）和利福平（RIF））耐药的结核分枝杆菌菌株引起的。尽管努力防止耐多药结核病在加州发生，但每年仍有40-50例病例。80%以上的耐多药结核病例是在外国出生的，其中25%来自墨西哥。但目前尚不清楚这些病例是已经感染了耐多药结核病进入美国，还是他们的耐多药结核病是在美国境内因药物敏感性结核病治疗失败而获得的。利用疾控中心资助的一项计划，对2004年以来所有加州结核病例进行基因分型，以及计划于2008年底完成的第一次墨西哥国家耐多药结核病调查，我建议将来自加州的耐多药结核病例的基因型和耐药突变与来自墨西哥的耐多药结核病例的基因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病原体群体是否在边境两侧独立发展，或者耐药结核菌株是否通过迁移进行双向传播。推动这一提议的假设是，西班牙裔美国人中的加州耐多药结核菌株主要是墨西哥耐多药结核菌株的一个子集，这表明原发性耐药性在两国传播，而不是在边境两侧独立获得耐药性。为了检验这一假设，提出了以下目标：目标1：通过比较来自加州西班牙裔的耐多药结核病分离株的基因型与来自墨西哥国家耐多药结核病调查的耐多药结核病基因型，确定加州耐多药结核病病原体菌株与墨西哥耐多药结核病病原体菌株的相关程度。目标二：确定目标1中鉴定的匹配MDR-TB分离株中的INH和RIF耐药突变是直接传播（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）所致。目标3：比较来自加州和墨西哥的耐多药结核病例的耐多药结核风险因素和流动性特征，方法是结合对来自墨西哥和加州的参考实验室数据的回顾性分析，以及来自加州圣地亚哥县和墨西哥蒂华纳的耐多药结核病例的前瞻性调查。相关性（参见说明）：耐多药结核病例比药物敏感结核病例复杂得多，治疗费用高达20倍，病死率为12%至90%。在结核病控制预算有限的情况下，了解如何集中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.