Whole Genome Sequencing of Drug Resistant Tuberculosis in India: Genotype-Phenotype Correlation, Clinical Impact of Resistance, and Sequencing Directly from Sputum

印度耐药结核病的全基因组测序：基因型-表型相关性、耐药性的临床影响以及直接从痰中测序

• 批准号: 10187512
• 负责人: Jeffrey Tornheim
• 金额: $ 19.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187512
• 关键词: Adult; Antibiotics; Bioinformatics; Biological Assay; Cause of Death; Cessation of life; Clinical; Clinical Investigator; Clinical Pharmacology; Clinical Trials; Cohort Studies; Communicable Diseases; Country; Coupled; Cycloserine; Cytolysis; DNA; DNA sequencing; Data; Data Analyses; Databases; Diagnosis; Disease Progression; Dose; Drug Combinations; Drug Exposure; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Drug usage; Ethionamide; Extreme drug resistant tuberculosis; Failure; Fellowship; Frequencies; Future; Generations; Genetic; Genotype; Goals; Growth; Hospital Referrals; India; Injectable; Institutional Review Boards; Intermediate resistance; Isoniazid resistance; K-Series Research Career Programs; Knowledge; Laboratories; Linezolid; Longitudinal Studies; Longitudinal cohort; Measures; Mentors; Mentorship; Methods; Minimum Inhibitory Concentration measurement; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Outcome; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phenotype; Physicians; Plasma; Positioning Attribute; Predictive Value; Predisposition; Privatization; Prospective cohort; Quinolones; Regimen; Relapse; Reporting; Research; Resistance; Resources; Rifampicin resistance; Rifampin; Risk; Sampling; South African; Specimen; Sputum; Standardization; Supervision; Symptoms; Testing; Time; Training; Translating; Treatment Protocols; Treatment outcome; Tuberculosis; United States National Institutes of Health; Universities; Use of New Techniques; Work; adolescent patient; base; biomarker evaluation; biomedical referral center; career; clinical application; clinical diagnostics; cohort; cost; design; disease transmission; drug standard; experience; fluoroquinolone resistance; genome sequencing; global health; human DNA; improved; individualized medicine; insight; isoniazid; medical specialties; mutant; novel; patient oriented; patient oriented research; personalized approach; precision drugs; prospective test; rapid diagnosis; resistance gene; resistance mutation; resistant strain; side effect; skill acquisition; tool; translational scientist; treatment program; tuberculosis drugs; tuberculosis treatment; whole genome; working group

Project Summary / Abstract Tuberculosis (TB) is the primary infectious disease killer worldwide, with 25% of global cases in India and 12% of India's multidrug-resistant TB (MDR-TB, resistant to rifampin and isoniazid) in Mumbai. Reliance on standardized treatment regimens means drug susceptibility testing (DST) is not performed for most Indian TB patients at diagnosis, resulting in delayed use of effective drugs, and poor outcomes for 45% of MDR-TB patients. In a prospective cohort of MDR-TB patients cared for at the specialty referral center where this K23 will be conducted, the average patient reports 6 months between symptom onset and MDR-TB treatment. Four of these are after diagnosis, but before comprehensive resistance testing is completed. This is time during which disease progression and transmission continue, while patients receive drugs that don't help and many suffer significant side effects. MDR-TB treatment programs need rapid, comprehensive DST, which can be achieved in India through whole genome sequencing (WGS). This K23 Mentored Patient-Oriented Career Development Award will allow the recipient to develop a research career pursuing more comprehensive, rapid diagnosis through the combination of WGS and minimum inhibitory concentration (MIC) testing of patient samples in a clinical cohort. This scientific plan will evaluate DST for MDR-TB through an assessment of WGS of cultured TB specimens as a method of second-line DST in comparison to MIC-based DST and standard DST methods; an assessment of the impact of low-level resistance identified by MIC, hetero-resistance identified by WGS, and pharmacokinetic parameters on longitudinal outcomes in a cohort of MDR-TB patients; and an assessment WGS of Mycobacterium tuberculosis DNA directly from sputum as an alternative to culture-based WGS for DST. These aims are nested in an IRB-approved longitudinal cohort of 200 adult and adolescent patients initiating treatment for MDR-TB at a private multispecialty referral hospital in Mumbai. This mentored research will train the applicant to generate and analyze data optimizing DST for TB and shortening time to individualized therapy for MDR-TB. The applicant is an Infectious Diseases-trained physician at Johns Hopkins University with a longstanding commitment to patient-oriented research in resource-limited settings. He has spent 2 years developing a clinical cohort of MDR-TB patients in Mumbai, where he has lived through an NIH Fogarty Global Health Fellowship. His long-term goals are to develop expertise in the interpretation and clinical application of WGS data to MDRTB with the ultimate goal of translating WGS into a useful clinical diagnostic tool. This K23 will facilitate skill development in the generation, analysis, and interpretation of WGS, MIC, and pharmacokinetic data. Training will include formal coursework, supervised data analysis, laboratory work, and mentorship by a team with expertise in cohort studies, bioinformatics, WGS, mycobacteriology, clinical pharmacology, and MDR-TB treatment. Collectively, the activities of this K23 will provide a pathway to an independent career as a clinical investigator able to design, test, and disseminate novel personalized approaches to the therapy of MDR-TB.

项目摘要 /摘要 结核病（TB）是全球主要的传染病杀手，印度有25％的全球病例，12％ 印度在孟买的多药耐药结核病（MDR-TB，对利福平和异尼氏菌素的抗性）。依靠 标准化治疗方案意味着大多数印度结核病未进行药物敏感性测试（DST） 诊断的患者，导致有效药物的使用延迟，而45％的MDR-TB患者的预后不良。 在一个在专业推荐中心受到关注的MDR-TB患者中，该K23将是 进行的，平均患者在症状发作和MDR-TB治疗之间报告了6个月。其中四个 在诊断后，但在完成全面的抵抗测试之前。这是疾病的时候 进展和传播继续，而患者收到无济于事的药物，许多人遭受了重大影响 副作用。 MDR-TB治疗计划需要快速，全面的DST，这可以在印度实现 通过整个基因组测序（WGS）。这款K23指导了以患者为导向的职业发展奖 将允许接收者发展研究职业，以通过 WGS和最低抑制浓度（MIC）在临床队列中的患者样品的结合。 该科学计划将通过评估培养的结核病标本的WG评估MDR-TB的DST 与基于MIC的DST和标准DST方法相比，二线DST的方法；评估 通过MIC鉴定的低水平电阻，WGS鉴定的异质抗性和药代动力学的影响 MDR-TB患者队列中纵向结局的参数；以及评估WGS 直接来自痰的结核分枝杆菌DNA作为DST的基于培养的WGS的替代方案。这些 目标嵌套在IRB批准的200名成人和青少年患者的纵向队列中 在孟买的一家私人多专业转诊医院进行MDR-TB。这项指导的研究将培训申请人 为了生成和分析数据优化TB的数据，并为MDR-TB的个性化治疗时间缩短了时间。 申请人是约翰·霍普金斯大学经过传染病训练的医师 在资源有限的设置中致力于以患者为导向的研究。他花了2年的时间发展临床 Mumbai的MDR-TB患者队列，他通过NIH Fogarty全球健康研究金居住。他的 长期目标是在WGS数据的解释和临床应用中发展专业知识 最终的目标是将WGS转化为有用的临床诊断工具。这个K23将有助于技能 WGS，MIC和药代动力学数据的一代，分析和解释的发展。训练 将包括正式的课程工作，受监督的数据分析，实验室工作以及团队的指导 队列研究，生物信息学，WGS，分枝杆菌，临床药理学和MDR-TB的专业知识 治疗。总体而言，这项K23的活动将为临床的独立职业提供途径 能够设计，测试和传播MDR-TB治疗的新型个性化方法。

项目成果

Swimming against the STREAM: Why STREAM 2 data cannot be easily applied to MDR-TB patients across India.

• DOI: 10.4103/lungindia.lungindia_74_23
• 发表时间: 2023-05
• 期刊: Lung India : official organ of Indian Chest Society
• 作者: Udwadia ZF;Patel JM;Batyala M;Tornheim JA;Rodrigues C
• 通讯作者: Rodrigues C

Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection.

长时间的新冠病毒脑雾和肌肉疼痛与急性感染期间从上呼吸道清除 SARS-CoV-2 RNA 的时间较长有关。

• DOI: 10.1101/2023.01.18.23284742
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Antar,AnnukkaAR;Yu,Tong;Demko,ZoeO;Hu,Chen;Tornheim,JeffreyA;Blair,PaulW;Thomas,DavidL;Manabe,YukariC;OutSMARTStudyGroup
• 通讯作者: OutSMARTStudyGroup

Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India.

• DOI: 10.3389/fphar.2022.1081123
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Resendiz-Galvan, Juan Eduardo;Arora, Prerna R.;Abdelwahab, Mahmoud Tareq;Udwadia, Zarir F.;Rodrigues, Camilla;Gupta, Amita;Denti, Paolo;Ashavaid, Tester F.;Tornheim, Jeffrey A.
• 通讯作者: Tornheim, Jeffrey A.