Fluoroquinolone resistance in patients with multidrug-resistant tuberculosis

描述(申请人提供)：尽管有治疗结核病的药物可用，2011年仍有140万人死于结核病。尽管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。耐药结核分枝杆菌菌株的发展和传播，人类免疫缺陷病毒(HIV)感染的持续传播，以及严重的资源限制，是南非汇聚的几个复杂问题。结核分枝杆菌耐药性的产生是由于细菌基因组的自发突变所致。当单一药物用于治疗时，当给予或供应的多种药物治疗方案不足时，或当患者不坚持治疗时，选择突变菌株。这些抗药性菌株随后可以传播给其他人。对两种最重要的一线药物异烟肼和利福平(定义为多药耐药[MDR]结核病)的耐药性，以及对关键二线药物(氟喹诺酮类和注射用药；定义为广泛耐药[XDR]结核病)的额外耐药性，导致治疗结果日益恶化。氟喹诺酮类药物对耐多药结核病的成功治疗至关重要；对氟喹诺酮类药物耐药性的发展与不良结局有关。目前的建议旨在描述耐多药结核病患者对氟喹诺酮耐药的发生率和结果，特别关注那些在诊断为耐氟喹诺酮结核时具有氟喹诺酮敏感菌株，但尽管坚持治疗仍对氟喹诺酮耐药的患者。这一问题在南非的严重程度及其对临床结果的影响尚不清楚。我们将首先用以下方式描述频率 在接受耐多药结核病治疗的患者中出现了对氟喹诺酮类药物的耐药性。然后，我们将确定氟喹诺酮耐药的危险因素，然后确定氟喹诺酮耐药对临床结果的影响。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。分子流行病学技术将被用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耐药菌株的外源性再感染。拟议的研究将为在艾滋病毒以及耐多药和广泛耐药结核病高负担人群中耐氟喹诺酮结核病的范围和风险因素提供新的见解。这一结果将有助于实施预防氟喹诺酮耐药性发展的战略，并保护这类药物进行有效的抗结核治疗。

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.