This proposal describes a career development plan and research proposal for Dr. Max O'Donnell, a pulmonologist at Albert Einstein College of Medicine. Working with collaborators and mentors at Einstein and in South Africa, Dr. O'Donnell is establishing himself as a translational investigator in drug-resistant tuberculosis (TB) and HIV research. Nowhere has drug-resistant TB generated more alarm than in South Africa, where synergies between endemic TB and HIV have caused 'explosive'increases in TB incidence and case-fatality rates. The most resistant form of TB, extensively drug resistant tuberculosis (XDR-TB), is increasingly prevalent in South Africa. An important obstacle to improving survival for XDR-TB is lack of a rapid, biomarker to serve as a surrogate outcome in clinical trials and guide clinician's by measuring treatment response. Fluoromycobacteriophage (FMP) assays use genetically modified mycobacteria-specific viruses to quantify viable M tuberculosis (Mtb) using a fluorescence reporter system. Utilizing a novel FMP assay with superior test characteristics, Dr. O'Donnell proposes to measure decrease in Mtb in XDR-TB patients'sputum as a biomarker for treatment response (Aim 1). Among XDR-TB patients who fail to respond to treatment Dr. O'Donnell proposes to use the same assay to rapidly diagnose emergent second-line drug resistance (Aim 2). This research component of this proposal is a result of an ongoing funded collaboration between researchers at Albert Einstein College of Medicine with researchers at the KwaZulu-Natal Research Institute for Research in Tuberculosis and HIV/AIDS (K-RITH), and the Centre for AIDS Programme of Research in South Africa (CAPRISA). The training component of this proposal involves developing the applicant as a TB molecular epidemiologist including training in the mentor's laboratory, coursework, seminars, lectures, and specific training in drug-resistant TB microbiology. Unique features include co-mentoring from a renowned TB basic scientist, TB epidemiologist, and translational researcher with additional support from career development committee with extensive TB and career development experience. This is an innovative approach with the potential to make substantial impact in our ability to rationally manage drug-resistant tuberculosis, rapidly evaluate the comparative efficacy of different drug regimens, and rapidly diagnose emergent drug-resistance among TB patients on treatment. This research will form the basis for a prospective study of the application of clinical biomarkers for treatment outcome in drug-resistant tuberculosis that will be proposed in an R01 grant application before the end of the K award.
In order to accelerate the development of new antimycobacterial agents and improve treatment outcomes for patients with drug-resistant tuberculosis (TB), we are developing a TB biomarker to rapidly predict treatment response and diagnose new drug-resistance. By improving treatment outcomes we may improve survival, decrease patients'infectivity and reduce community spread of drug-resistant tuberculosis strains, particularly in HIV endemic settings.
|O'Donnell, M R; Daftary, A; Frick, M et al. (2016) Re-inventing adherence: toward a patient-centered model of care for drug-resistant tuberculosis and HIV. Int J Tuberc Lung Dis 20:430-4|
|O'Donnell, Max R; Pym, Alexander; Jain, Paras et al. (2015) A Novel Reporter Phage To Detect Tuberculosis and Rifampin Resistance in a High-HIV-Burden Population. J Clin Microbiol 53:2188-94|
|OÊ¼Donnell, Max R; Pillay, Melendhran; Pillay, Manormoney et al. (2015) Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa. J Acquir Immune Defic Syndr 69:536-43|
|Cummings, M J; O'Donnell, M R (2015) Inverting the pyramid: increasing awareness of mycobacterial sepsis in sub-Saharan Africa. Int J Tuberc Lung Dis 19:1128-34|
|Cohen, Keira A; Abeel, Thomas; Manson McGuire, Abigail et al. (2015) Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal. PLoS Med 12:e1001880|
|Padayatchi, N; Gopal, M; Naidoo, R et al. (2014) Clofazimine in the treatment of extensively drug-resistant tuberculosis with HIV coinfection in South Africa: a retrospective cohort study. J Antimicrob Chemother 69:3103-7|
|Daftary, Amrita; Padayatchi, Nesri; O'Donnell, Max (2014) Preferential adherence to antiretroviral therapy over tuberculosis treatment: a qualitative study of drug-resistant TB/HIV co-infected patients in South Africa. Glob Public Health 9:1107-16|
|Hicks, R M; Padayatchi, N; Shah, N S et al. (2014) Malnutrition associated with unfavorable outcome and death among South African MDR-TB and HIV co-infected children. Int J Tuberc Lung Dis 18:1074-83|
|OÊ¼Donnell, Max R; Wolf, Allison; Werner, Lise et al. (2014) Adherence in the treatment of patients with extensively drug-resistant tuberculosis and HIV in South Africa: a prospective cohort study. J Acquir Immune Defic Syndr 67:22-9|
|O'Donnell, Max R; Padayatchi, Nesri; Kvasnovsky, Charlotte et al. (2013) Treatment outcomes for extensively drug-resistant tuberculosis and HIV co-infection. Emerg Infect Dis 19:416-24|
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