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: 7183481
• 负责人: TIMOTHY R STERLING
• 金额: $ 37.22万
• 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/7183481
• 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; 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

DESCRIPTION (provided by applicant): Fluoroquinolones; particularly later-generation agents such as gatifloxacin and moxifloxacin, have excellent in vitro and in vivo activity against Mycobacterium tuberculosis. 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-MTb; 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 DNA 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.

描述（由申请人提供）：氟喹诺酮类；尤其是后期代剂，例如gatifloxacin和moxifloxatin，具有极好的体外和体内活性，对结核分枝杆菌。正在进行临床试验，以评估氟喹诺酮作为结核病的一线治疗的作用。这些药物目前在治疗多药耐药性结核病（MDR-MTB；对至少异烟肼和利福平的抗性）中起着至关重要的作用。使用氟喹诺酮类治疗结核病的一个潜在困难是它们广泛用于治疗其他几种细菌感染，例如肺炎和尿路感染。我们在初步工作中表明，氟喹诺酮治疗社区获得的非通联感染是新诊断的结核病中氟喹诺酮类抗性的危险因素。然而，由于未常规地进行结核分枝杆菌的氟喹诺酮易感性测试，因此未知结核分枝杆菌中的氟喹诺酮耐药性的程度尚不清楚。氟喹诺酮耐药性结核病的危险因素也不完全了解。氟喹诺酮在结核分枝杆菌中的耐药性可能是由于DNA回旋酶中的单个碱基对突变而发生的。然而，迄今为止报道的所有耐氟喹诺酮类结核分离株尚未鉴定出遗传突变。在结核分枝杆菌中与氟喹诺酮抗性相关的遗传突变的更好表征将扩展我们对氟喹诺酮类抗性发展的理解，并允许其快速鉴定。我们将确定在两个大型特征良好的研究人群中具有氟喹诺酮耐药性的新诊断的结核病病例的比例，并评估了氟喹诺酮抗性的趋势。我们还将确定与氟喹诺酮耐药性相关的临床危险因素，并表征结核分枝杆菌中表型氟喹诺酮抗性与遗传突变之间的关系。更好地了解结核分枝杆菌中氟喹诺酮类抗性的患病率，趋势和危险因素将阐明氟喹诺酮类药物是否确实是一线治疗结核病的可行选择，以及如何最好地保留其对结核病的有用性。