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

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

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.

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