Epidemiology of multidrug-resistant tuberculosis in Peru

描述（由申请方提供）：本项目的总体目标是提供关于多药耐药（MDR）M传播动力学的新知识。在秘鲁的一个高结核病负担地区，更好地了解耐多药结核病在高暴露人群中的流行病学和自然史非常重要，因为它将改变我们在美国和其他地方遏制耐多药结核病传播的能力。导致抗生素耐药性的突变通常被认为是在没有抗生素的情况下降低细菌的适应性;这被称为耐药性的适应性“成本”。最近的研究表明，特定的耐药性赋予突变，最大限度地减少抗生素耐药性的适应性成本可能有利于高传播性MDR突变体的出现。这种M.结核菌株威胁着全球结核病控制，因为这些菌株比药物敏感菌株更难治疗，治疗费用也更高。在20世纪90年代，美国的MDR结核病爆发与高死亡率相关。高传播性MDR菌株的存在可能为通过生物恐怖主义故意传播这种疾病创造机会。拟议的研究将建立在结核病高度流行的秘鲁北方利马城市棚户区的既定临床基础设施上。在那里，对多达9种药物耐药的MDR突变体产生了继发性病例。具体目的是：（1）检测耐多药和耐异烟肼支原体的家庭内传播。结核菌株与药物敏感菌株相比。(2)评估社会人口统计学和临床混杂因素以及风险修饰因素（如年龄、性别、合并症、HIV感染、营养状况和卡介苗接种）对这些关联的影响。(3)测量特定耐药突变和表型之间的相关性，包括（i）多药耐药，（ii）临床表现和（iii）传播性。(4)测量真实复发率与再感染率。这些目标将通过一项为期4年的前瞻性队列研究和分子流行病学方法来实现。超过11，000例患者（包括至少500例感染性MDR结核病患者）及其暴露的家庭接触者将沿着入组。该项目将建立在美国和秘鲁研究者多学科团队、马萨诸塞州公共卫生部和秘鲁卫生部之间的既定合作基础上;它将允许招募和纵向随访持续暴露于MDR、耐药和药敏M的大型人群。结核菌株研究结果将指导结核病诊断和治疗的基础研究。

DESCRIPTION (provided by applicant): The overarching goal of this project is to provide new knowledge about the transmission dynamics of multidrug- resistant (MDR) M. tuberculosis in a high tuberculosis-burden area in Peru. A better understanding of the epidemiology and natural history of MDR tuberculosis in a high-exposure population is very significant because it will change our capacity to contain the spread of MDR tuberculosis in the United States and elsewhere. Mutations that lead to antibiotic resistance are often assumed to reduce bacterial fitness in the absence of antibiotics; this is referred to as the fitness "cost" of resistance. Recent studies suggest specific drug-resistance- conferring mutations that minimize the fitness cost of antibiotic resistance may favor the emergence of highly transmissible MDR mutants. The emergence of such M. tuberculosis strains threatens global tuberculosis control because these strains are much more difficult and expensive to treat than drug-sensitive strains. In the 1990s, MDR tuberculosis outbreaks in the U.S. were associated with high mortality. The existence of highly transmissible MDR strains may create an opportunity for the intentional spread of this disease through bioterrorism. The proposed study will build on an established clinical infrastructure in the urban shantytowns in northern Lima, Peru, where tuberculosis is hyperendemic. There, MDR mutants resistant to as many as nine drugs have produced secondary cases. Specific aims are: (1) To measure the within-household transmission of MDR and isoniazid- resistant M. tuberculosis strains compared to drug-sensitive strains. (2) To assess the impact of socio- demographic and clinical confounders and risk modifiers such as age, sex, co-morbidity, HIV infection, nutritional status, and BCG vaccination on these associations. (3) To measure associations among specific resistance mutations and phenotypes including (i) multi-drug resistance, (ii) clinical presentations, and (iii) transmissibility. (4) To measure the rate of true relapse versus re-infection. These aims will be achieved using a prospective four-year enrollment cohort study and molecular epidemiologic methods. Over 11,000 patients, including at least 500 with infectious MDR tuberculosis, will be enrolled along with their exposed household contacts. This project will build on an established collaboration among a multidisciplinary team of U.S. and Peruvian investigators, the Massachusetts Department of Public Health, and the Ministry of Health of Peru; it will permit the enrollment and longitudinal follow-up of a large cohort of persons with sustained exposure to MDR, drug-resistant, and drug- sensitive M. tuberculosis strains. Results will serve to guide basic research in tuberculosis diagnostics and therapeutics.