Epidemiology of multidrug-resistant tuberculosis in Peru

描述(由申请人提供)：该项目的总体目标是提供有关秘鲁结核病高负担地区耐多药(MDR)结核分枝杆菌传播动力学的新知识。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历史非常重要，因为这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在没有抗生素的情况下会降低细菌的适合度；这被称为耐药性的适合度“成本”。最近的研究表明，将抗生素耐药性的适宜成本降至最低的特定耐药突变可能有利于高传播性MDR突变的出现。这些结核分枝杆菌菌株的出现威胁到全球结核病控制，因为这些菌株比药物敏感菌株更难治疗，成本也更高。在20世纪90年代，耐多药结核病在美国的爆发与高死亡率有关。高度可传播的多药耐药性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。这项拟议的研究将建立在秘鲁利马北部城市棚户区已建立的临床基础设施上，那里的结核病高度流行。在那里，对多达9种药物具有抗药性的多药耐药突变株产生了继发性病例。具体目标是：(1)测量耐多药和异烟肼结核分枝杆菌菌株与药物敏感菌株在家庭内的传播情况。(2)评估社会人口学和临床混杂因素以及年龄、性别、合并症、艾滋病毒感染、营养状况和卡介苗接种等风险修正因素对这些相关性的影响。(3)检测特异性耐药突变和表型之间的关系，包括(I)多药耐药、(Ii)临床表现和(Iii)遗传性。(4)测量真实复发率与再感染率。这些目标将使用前瞻性的四年登记队列研究和分子流行病学方法来实现。超过11000名患者，包括至少500名传染性耐多药结核病患者，将与他们接触过的家庭接触者一起登记。该项目将建立在美国和秘鲁调查人员组成的多学科团队、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；它将允许对持续接触耐多药、耐药和药物敏感结核分枝杆菌菌株的大量人群进行登记和纵向跟踪。研究结果将用于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.