Fluoroquinolone resistance in patients with multidrug-resistant tuberculosis

描述（由申请人提供）：尽管有治疗结核病的药物，但2011年仍有140万人死于结核病。虽然世界上大多数发达地区的结核病发病率有所下降，但南非和其他地区一直无法实现结核病控制。抗药性结核分枝杆菌菌株的发展和传播、人类免疫缺陷病毒（艾滋病毒）感染的持续蔓延以及严重的资源限制是南非面临的一些复杂问题。 M.结核病的发生是由于细菌基因组的自发突变。当单一药物用于治疗时，当给予或提供的多药治疗方案不足时，或当患者不坚持治疗时，选择突变菌株。这些耐药菌株可以传播给其他人。对两种最重要的一线药物异烟肼和利福平（定义为耐多药[MDR]结核病）的耐药性，其次是对关键二线药物（氟喹诺酮类和注射剂;定义为广泛耐药[XDR]结核病）的额外耐药性，导致治疗结局逐渐恶化。氟喹诺酮类药物是成功治疗耐多药结核病的关键;氟喹诺酮类药物耐药性的发展与不良结局相关。 目前的提案旨在描述耐多药结核病患者中氟喹诺酮类耐药的发生率和结局，特别关注在耐多药结核病诊断时具有氟喹诺酮类敏感分离株，但尽管坚持治疗仍发生氟喹诺酮类耐药的患者。这个问题在南非的程度及其对临床结果的影响尚不清楚。我们将首先描述频率， 其氟喹诺酮耐药性出现在正在治疗MDR结核病的患者中。然后，我们将确定氟喹诺酮类耐药发展的风险因素，以及氟喹诺酮类耐药对临床结局的影响。研究人群将从2007年至2011年西开普省的南非国家卫生实验室服务数据库中抽取。将采用分子流行病学技术来表征与氟喹诺酮耐药相关的突变，并区分同一菌株中出现的耐药性和氟喹诺酮耐药菌株的外源性再感染。 拟议的研究将提供新的洞察力的范围和风险因素氟喹诺酮耐药结核病的人口与高负担的艾滋病毒以及耐多药和广泛耐药结核病。这些结果将允许实施战略，以防止氟喹诺酮耐药性的发展，并保护这类药物的有效抗结核治疗。

DESCRIPTION (provided by applicant): Despite the availability of drugs that can cure tuberculosis, 1.4 million people died of tuberculosis in 2011. Although tuberculosis incidence has declined in most developed areas of the world, South Africa and other regions have been unable to achieve tuberculosis control. The development and transmission of drug-resistant Mycobacterium tuberculosis strains, continued spread of human immunodeficiency virus (HIV) infection, and significant resource limitations are a few of the complexities that have converged in South Africa. The development of drug-resistance in M. tuberculosis occurs due to spontaneous mutations in the bacterial genome. Mutant strains are selected when single drugs are used for treatment, when insufficient multidrug treatment regimens are administered or supplied, or when patients do not adhere to their treatment. These drug-resistant strains can then be transmitted to other people. Resistance to the two most important first-line drugs, isoniazid and rifampin (defined as multidrug-resistant [MDR] tuberculosis), followed by additional resistance to critical second-line drugs (fluoroquinolones and injectable agents; defined as extensively drug-resistant [XDR] tuberculosis), results in progressively worse treatment outcomes. Fluoroquinolones are critical for the successful treatment of MDR-TB; development of fluoroquinolone resistance is associated with poor outcomes. The current proposal seeks to characterize the incidence and outcomes of fluoroquinolone resistance in patients who have MDR tuberculosis, with particular attention to patients who have fluoroquinolone-susceptible isolates at the time of MDR tuberculosis diagnosis, but who develop fluoroquinolone resistance despite adherence to treatment. The extent of this problem in South Africa, and its effect on clinical outcomes, are unknown. We will first describe the frequency with which fluoroquinolone resistance emerges among patients being treated for MDR tuberculosis. We will then determine risk factors for the development of fluoroquinolone resistance, followed by the effect of fluoroquinolone resistance on clinical outcomes. The study population will be drawn from the South African National Health Laboratory Service database in the Western Cape Province from 2007 to 2011. Molecular epidemiologic techniques will be employed to characterize mutations associated with fluoroquinolone resistance and distinguish between emergence of resistance in the same strain and exogenous reinfection with a fluoroquinolone-resistant strain. The proposed studies will provide new insight into the scope and risk factors fo fluoroquinolone-resistant tuberculosis in a population with a high burden of HIV as well as MDR and XDR tuberculosis. The results will allow for implementation of strategies to prevent the development of fluoroquinolone resistance and protect this class of drugs for effective anti-tuberculosis therapy.