International Research in Korea: Clinical Studies of Drug-Resistant Tuberculosis

韩国国际研究：耐药结核病的临床研究

基本信息

批准号：
8336279
负责人：
Clifton Barry
金额：
$ 78.43万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8336279
关键词：
Address Adverse effects Basic Science Bedside Testings Binding Binding Sites Biological Markers Biology Cells Cellular Stress Centers for Disease Control and Prevention (U.S.)Clinical Clinical Research Clinical Trials Collaborations Conduct Clinical Trials Data Analyses Dentistry Detection Development Diagnosis Diagnostic tests Disease Double-Blind Method Drug Delivery Systems Drug Kinetics Drug Resistant Tuberculosis Drug resistance Drug-sensitive Enrollment Evaluable Disease Excision Exhalation Extreme drug resistant tuberculosis Family Free Ribosome Genes Genome Goals Health Homeostasis Hospitals Human Incidence Institutional Review Boards International Investigation Kanamycin Resistance Korea Koreans Label Lesion Linezolid Lung Manuscripts Medical center Medicine Methyltransferase Metronidazole Multi-Drug Resistance Multicenter Studies Multidrug-Resistant Tuberculosis Mutation Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Natural History New Jersey Operative Surgical Procedures Oryctolagus cuniculus Parents Pathogenesis Pathology Patients Penetration Peptides Pharmaceutical Preparations Pharmacodynamics Phase Phenotype Pilot Projects Placebo Control Placebos Poison Population Predisposition Prodrugs Protocols documentation Pulmonary Tuberculosis Pyrazinamide Pyrazinamide resistance RNA Randomized Reporting Research Resistance Resort Ribosomal Proteins Ribosomal RNA Ribosomes Role Safety Salvage Therapy Sampling Sequence Analysis Site Social Welfare South Korea Sputum Staining method Stains Streptomycin Stress Susceptibility Gene Testing Time Toxic effect Translations Treatment Protocols Tuberculosis Universities Urine Work arm base chemotherapy college cost fluoroquinolone resistance follow-up genome sequencing human disease in vivo laboratory facility mutant next generation novel novel diagnostics open label pyrazinoic acid response simulation success tmRNA tool tuberculosis drugs tuberculosis treatment two-arm study

项目摘要

The project is conducted as a collaboration among the Tuberculosis Research Section of LCID/NIAID, the Korean Ministry of Health, Welfare and Families Center for Disease Control, National Masan Tuberculosis Hospital (NMTH), and Yonsei University College of Medicine in the Republic of Korea. These collaborators have worked together to establish the International Tuberculosis Research Center (ITRC) that manages both financial and scientific activities within the laboratory facilities including a fully functional Biosafety Level 3 laboratory facility. In addition, studies are also being conducted in collaboration with Asan Medical Center, Samsung Medical Center and the National Medical Center in Seoul. Specific protocol-driven investigations underway include: (1) NIAID 05-I-N069: A Natural History Study of Multidrug-Resistant TB Stains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR tuberculosis isolates and their contribution to human disease and has over 730 subjects enrolled. A substudy of this protocol is investigating biomarkers of disease response in collaboration with University of Stellenbosch and University of Medicine and Dentistry of New Jersey. (2) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Antituberculous Chemotherapy vs. Antituberculous Chemotherapy with Placebo in Subjects with Multi-drug Resistant Pulmonary Tuberculosis. The importance of anaerobic activity in candidate TB drugs is under investigation in this study. In 2009, the trial closed to enrollment after 33 patients enrolled because of concerns about side-effects, but follow up of these subjects and analysis of the data collected continues. (3) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Antituberculous Therapy in Subjects with Extensively Drug-Resistant (XDR) Pulmonary Tuberculosis. The major aim of this study is to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). For the moment LZD is infrequently used in TB patients because of its prohibitive cost and adverse effects but the emergence of XDR TB is spurring doctors into off-label, uncontrolled use in salvage therapy for the few patients that can afford it. This trial opened to enrollment in December 2008 and has enrolled 39 evaluable patients with XDR TB and closed to enrollment in July 2010. The interim analysis of the difference in time to sputum culture conversion to tuberculosis negative between the two arms of the study indicates LZD is potentially active, but the final analysis is pending until the last few subjects have reached their primary endpoint. An unexpected toxicity has been observed in this population and has been both reported to the FDA, the IRB and the sponsor and a manuscript describing the observed rabdomyolysis has been submitted. (4) NIAID 09-I-N061; Pharmacokinetics of Standard First and Second Line anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This is a multicenter study of the differential penetration of tuberculosis chemotherapeutics into pulmonary tubercular lesions opened to enrollment in 2010; 4 subjects have been enrolled by Asan Medical Center in Seoul. The study will further define the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients and follow up the work we have conducted on lesion penetration in rabbits. The Natural History study of MDR and XDR TB has allowed a number of basic biology questions about the differences in highly drug resistant and drug sensitive tuberculosis to be addressed by whole genome sequencing and this analysis is ongoing. We are also studying the mechanism of action of various TB drugs and how mutations in the Mtb genome confer resistance to these drugs. The mechanism of pyrazinoic acid (POA), the active form the pro-drug Pyrazinamide (PZA), was found to bind to the ribosomal protein RpsA and that the site at which it binds corresponds to the binding site of tmRNA. This RNA species is required for rescuing stalled ribosomes by trans-translation. These results not only demonstrate the novel target of this drug which has to date remained elusive, but also points to the unexpected critical role of ribosomal homeostasis in stressed cells in human pathogenesis by MTb indicating that PZA may act to poison cells by accumulation of toxic peptides released from stalled ribosomes in addition to a bottleneck in the amount of available free ribosomes in cells under in vivo stress. Further support for these studies was established by the finding that some clinical strains of MTb with PZA resistance have RpsA mutations at the POA binding site. In 2010, we reported a number of mutations in the gibB gene that encodes a putative 16S rRNA methyltransferase. Recently, by evaluating an isogenic gidB mutant strain constructed from strain H37Rv, we demonstrated the causal role of gidB in conferring a low-level SM-resistant phenotype in M. tuberculosis with a 16-fold increase in the MIC over the parent strain. Among clinical isolates, the modest increase in SM resistance conferred by a gidB mutation leads to an MIC distribution of gidB mutation-containing strains that spans the recommended SM breakpoint concentration currently used in drug susceptibility testing protocols. As such, some gidB mutation-containing isolates are found to be SM sensitive, while others are SM resistant. On the basis of a pharmacodynamic analysis and Monte Carlo simulation, those isolates that were found to be SM sensitive should still respond favorably to SM treatment, while nearly half of those found to be SM resistant would likely respond poorly. This investigation provided the first microbiological evidence for the contribution of gidB in streptomycin and demonstrates its clinical importance. Several collaborations involving new diagnostic tools are also underway including work on the next generation GenXpert test for RIF that will cover more mutations using a unique sloppy beacon approach and a XDR test for detection of fluoroquinolone resistance and Kanamycin resistance in Mtb with Dr David Alland. We are also collaborating on work on biomarkers of treatment success and to assess the presence of fragments of Mtb in easily accessible human samples, such as urine and exhaled breath condensate, for development of point of care tests. These initial studies been productive enough for us to add a substudy to the Natural History protocol and enter into a formal discovery effort.

该项目是在LCID/NIAID，韩国卫生部，福利和家庭疾病控制中心，国家Masan结核病医院（NMTH）和韩国共和国Yonsei大学医学院的韩国卫生部，福利和家庭疾病控制中心之间进行的合作。这些合作者共同努力建立了国际结核病研究中心（ITRC），该研究中心（ITRC）在实验室设施内管理着财务和科学活动，包括功能齐全的生物安全3级实验室设施。此外，还与Asan医疗中心，三星医疗中心和首尔国家医疗中心合作进行了研究。正在进行的特定协议调查包括：（1）NIAID 05-I-N069：韩国肺结核患者的多药耐药性结核病染色和宿主易感基因的自然史研究。这项研究旨在表征MDR和XDR结核分离株及其对人类疾病的贡献，并有730多名受试者。该方案的一种方法是与Stellenbosch大学，医学大学和新泽西大学合作研究疾病反应的生物标志物。（2）NIAID 07-I-N041：甲硝唑的随机，双盲，安慰剂对照的初步研究，结合了抗结核化疗与抗抗结性化疗与安慰剂在具有多药抗性肺结核的受试者中与安慰剂结合。在这项研究中，正在研究厌氧活性在候选结核病药物中的重要性。 2009年，由于对副作用的担忧，该试验在33名患者入学后结束了入学率，但对这些受试者的跟进和收集的数据分析仍在继续。（3）NIAID 08-I-N167：2A期2A，随机，2个ARM，开放标签，lineZolid疗效的临床试验与抗结核治疗在具有广泛药物耐药（XDR）肺结核的受试者中。这项研究的主要目的是评估XDR TB患者最后一种药物之一，Linezolid（LZD，Zyvox，Pfizer）的疗效，安全性和耐受性。目前，LZD很少在结核病患者中使用，因为其成本过高和不良反应，但XDR TB的出现促使医生促进了非标签外，对于少数有能力负担的患者而言，无节制地用于打捞疗法。这项试验于2008年12月开放，并已入学39例可评估的XDR TB患者，并于2010年7月开始入学。对研究的两个臂之间的痰培养时间转换为结核病的差异分析表明，LZD之间的持续分析表明，最终分析是潜在的，但最终的分析是持续的，直到最后几个受试者达到了他们的主要终点。在该人群中已经观察到了意外的毒性，并已报告给FDA，IRB和赞助商，并提交了描述观察到的Rabdomylysyssiss的手稿。（4）NIAID 09-I-N061;肺中标准第一和第二线抗TB药物的药代动力学以及当选为切除手术的受试者的病变。这是一项多中心研究，该研究是针对结核化疗中的差异渗透到2010年入学的肺结核病变中的一项多中心研究。首尔的Asan医疗中心已经招募了4名受试者。该研究将进一步定义结核病患者常见病变类型的病理与药物渗透之间的关系，并跟进我们对兔子病变渗透的工作。 MDR和XDR TB的自然史研究允许通过整个基因组测序来解决有关高度药物抗药性和药物敏感性结核病的差异的许多基本生物学问题，并且该分析正在进行中。我们还正在研究各种结核病药物的作用机理，以及MTB基因组中的突变如何赋予对这些药物的抗性。发现吡唑酸（POA）的机制，即促毒吡嗪酰胺（PZA）的活性形式，发现与核糖体蛋白RPSA结合，其结合位点与TMRNA的结合位点相对应。这种RNA物种是通过反式翻译来挽救失速核糖体的。这些结果不仅证明了这种药物的新靶标，该药物仍然难以捉摸，而且还表明了核糖体稳态在压力细胞中通过MTB通过MTB在人体发病机理中的意外关键作用，这表明PZA可能通过在可用的核糖体中添加了bots骨的核糖体从含量的核糖体中释放出毒性肽来对毒细胞产生毒性细胞的积累。通过发现，具有PZA耐药性的某些临床菌株在POA结合位点具有RPSA突变的发现，建立了对这些研究的进一步支持。 2010年，我们报道了编码假定的16S rRNA甲基转移酶的GIBB基因中的许多突变。最近，通过评估由H37RV菌株构成的同基因GIDB突变菌株，我们证明了GIDB在结核分枝杆菌中赋予低水平SM耐药表型中的因果作用，而MIC在父母菌株上的含量增加了16倍。在临床分离株中，GIDB突变赋予的SM抗性的适度增加导致含GIDB突变菌株的MIC分布，该菌株跨越了当前在药物敏感性测试方案中使用的建议SM断点浓度。因此，发现某些含GIDB突变的分离株对SM敏感，而另一些则具有SM抗性。在药效分析和蒙特卡洛模拟的基础上，那些被发现具有SM敏感的分离株仍应对SM治疗做出好评，而发现SM耐药性的几乎一半可能会响应不佳。这项研究为GIDB在链霉菌素中的贡献提供了第一个微生物学证据，并证明了其临床重要性。还正在进行一些涉及新诊断工具的合作，包括用于RIF的下一代GenXPERT测试的工作，该测试将使用独特的马虎信标方法和XDR测试涵盖更多突变，以检测MTB中MTB中与David Alland博士在MTB中抗氟喹诺酮的耐药性和Kanamycin抗性。我们还正在合作从事治疗成功生物标志物的工作，并评估易于获得的人类样品（例如尿液和呼出的呼吸凝结物）中MTB碎片的存在，以开发护理测试。这些最初的研究足以使我们为自然历史方案增添典型，并进行正式的发现工作。