Fluoroquinolone Resistance in M. Tuberculosis

结核分枝杆菌对氟喹诺酮类药物的耐药性

• 批准号: 7367845
• 负责人: TIMOTHY R STERLING
• 金额: $ 36.55万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367845
• 关键词: Animal Model; Bacterial Infections; Base Pairing; Clinical; Clinical Trials; Communities; DNA Gyrase; Data; Development; Diagnosis; Diarrhea; Dose; Fluoroquinolones; Future; Gatifloxacin; Gene Mutation; General Population; Generations; Genes; Genetic; HIV Infections; Human; Immunosuppression; In Vitro; Infection; Measures; Minimum Inhibitory Concentration measurement; Moxifloxacin; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Multiple drug resistant Mycobacteria Tuberculosis; Mutation; Mycobacterium tuberculosis; Newly Diagnosed; Numbers; Osteomyelitis; Outcome; Pharmaceutical Preparations; Phase; Play; Pneumonia; Population Study; Predisposition; Prevalence; Rate; Reporting; Research Personnel; Resistance; Rifampin; Risk; Risk Factors; Role; Tennessee; Testing; Therapeutic immunosuppression; Time; Tuberculosis; Urinary tract infection; Work; base; fluoroquinolone resistance; improved; in vivo; isoniazid; quinolone resistance; success; treatment duration; trend; tuberculosis treatment

Fluoroquinolones; particularly later-generation agents such as gatifloxacin and moxifloxacin, have excellent in vitro and in vivo activity against Mycobacteriumtuberculosis. Clinical trials are underway to assess the role of fluoroquinolones as first-line therapy for tuberculosis. These agents currently play a critical role in the treatment of multidrug-resistant tuberculosis (MDR-TB; resistance to at least isoniazid and rifampin). One potential difficulty with using fluoroquinolones to treat tuberculosis is their widespread use for the treatment of several other bacterial infections such as pneumonia and urinary tract infections. We have shown in preliminary work that fluoroquinolone treatment of community-acquired non-tuberculous infections is a risk factor for fluoroquinolone resistance in newly-diagnosed tuberculosis. However, the extent of fluoroquinolone resistance in M. tuberculosis is unknown because fluoroquinolone susceptibility testing of M. tuberculosis is not routinely performed. The risk factors for fluoroquinolone-resistant tuberculosis are also not completely understood. Fluoroquinolone resistance in M. tuberculosis can occur due to a single base-pair mutation in DMA gyrase. However, genetic mutations have not been identified in all fluoroquinolone-resistant M. tuberculosis isolates reported to date. Better characterization of the genetic mutations associated with fluoroquinolone resistance in M. tuberculosis would extend our understanding of the development of fluoroquinolone resistance and allow for its rapid identification. We will determine the proportion of newly diagnosed tuberculosis cases with fluoroquinolone resistance in two large, well-characterized study populations, and assess for trends in fluoroquinolone resistance over time. We will also identify the clinical risk factors associated with fluoroquinolone resistance, and characterize the relationship between phenotypic fluoroquinolone resistance and genetic mutations in M. tuberculosis. A better understanding of the prevalence, trends, and risk factors for fluoroquinolone resistance in M. tuberculosis would clarify whether fluoroquinolones are indeed a viable option for the first-line treatment of tuberculosis, and how best to preserve their usefulness against tuberculosis.

氟喹诺酮类；尤其是后期代理，例如gatifloxacin和Moxifloxatin，具有极好的 对结核分枝杆菌的体外和体内活性。正在进行临床试验以评估角色 氟喹诺酮作为结核病的一线疗法。这些代理商目前在 治疗多药耐药性结核病（MDR-TB；至少抗异念珠菌和利福平）。一 使用氟喹诺酮类治疗结核病的潜在困难是它们在治疗中的广泛用途 在其他几种细菌感染中，例如肺炎和尿路感染。我们显示了 氟喹诺酮治疗社区获得的非通联感染的初步工作是一种风险 新诊断的结核病中氟喹诺酮耐药性的因素。但是，氟喹诺酮的程度 结核分枝杆菌的耐药性尚不清楚，因为氟喹诺酮易感性测试是结核分枝杆菌的 不常规执行。氟喹诺酮抗肺结核的危险因素也不是完全 理解。结核分枝杆菌中的氟喹诺酮抗性可能是由于单个碱基对突变而发生的 DMA回旋酶。然而，在所有耐氟喹诺酮类药物中尚未鉴定遗传突变。 迄今为止报告的结核病分离株。更好地表征与 结核分枝杆菌中的氟喹诺酮抗性将扩大我们对 氟喹诺酮耐药性并允许其快速识别。我们将确定新的比例 在两项大型，良好的研究中，已诊断出患有氟喹诺酮耐药性的结核病病例 人群，并评估氟喹诺酮抗性的趋势。我们还将确定临床 与氟喹诺酮抗性相关的危险因素，并表征表型之间的关系 结核分枝杆菌中的氟喹诺酮耐药性和遗传突变。更好地理解 结核分枝杆菌中氟喹诺酮耐药性的患病率，趋势和危险因素将阐明是否是否阐明 氟喹诺酮确实是结核病一线治疗的可行选择，以及如何最好的选择 保留其对结核病的有用性。