PI: HEYSELL, SCOTT K Project: 1K23AI099019-01 Title: Clinical Impact of Anti-TB Drug Levels and M. Tuberculosis Susceptibility Accession Number: 3398392 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== Worldwide tuberculosis (TB) treatment failure occurs in up to 20% of individuals despite multidrug therapy. In Virginia we have found diabetes to be a significant risk factor for delayed response. At our collaborative site in Tanzania, patients with multidrug-resistant (MDR)-TB are at increased risk of death compared to those with drug-susceptible TB. In both settings we have found low serum drug levels to TB medications, however the best use of serum drug levels in managing TB remains unclear. To inform this problem we have developed a TB drug activity assay that is performed with a patient's plasma or serum while on TB therapy and their autologous TB isolate that allows a metric of both drug levels and relative resistance of the isolate. In this proposal, therefore, we will compare (1) drug levels, (2) M. tuberculosis drug susceptibility (MIC), and (3) the TB drug activity assay to relevant treatment outcomes in patients at risk of poor treatment failure- diabetics in Virginia and those with MDR-TB in Tanzania. The proposal leverages an existing state TB control initiative of early drug level monitoring and dose adjustment in diabetics, and will further establish a cohort of MDR-TB patients at Kibong'oto National TB Hospital, the Tanzanian referral hospital for MDR-TB. Active funding and infrastructure for all aspects of the proposal exist through an NIH R01 for TB susceptibility, an NIH/Fogarty UVA-Tanzania Training Grant, and the Virginia Department of Health. My career development plan includes mentorship, graduate level coursework, and publication benchmarks in diagnostic development, field research, TB pharmacology, and MDR-TB cohort design. Completion of this proposal will allow me to become an independent investigator in these fields. PROJECT NARRATIVE Tuberculosis (TB) treatment failure occurs despite multidrug therapy. Currently there are not practical tools for measurement of drug activity in many TB-endemic/ resource-limited settings. The proposed project will study two populations at-risk of treatment failure: those with diabetes and those with multidrug-resistant TB. Completion of these studies will inform the use of three potential methodologies: drug levels, M. tuberculosis drug MICs, and a novel TB drug activity assay which can be performed in settings capable of TB culture.

Public Health Relevance

Tuberculosis (TB) treatment failure occurs despite multidrug therapy. Currently there are not practical tools for measurement of drug activity in many TB-endemic/ resource-limited settings. The proposed project will study two populations at-risk of treatment failure: those with diabetes and those with multidrug-resistant TB. Completion of these studies will inform the use of three potential methodologies: drug levels, M. tuberculosis drug MICs, and a novel TB drug activity assay which can be performed in settings capable of TB culture.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI099019-02
Application #
8512655
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Lacourciere, Karen A
Project Start
2012-07-15
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$129,870
Indirect Cost
$9,620
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Reynolds, Jonathan; Heysell, Scott K (2014) Understanding pharmacokinetics to improve tuberculosis treatment outcome. Expert Opin Drug Metab Toxicol 10:813-23
Banu, Sayera; Rahman, S M Mazidur; Khan, M Siddiqur Rahman et al. (2014) Discordance across several methods for drug susceptibility testing of drug-resistant Mycobacterium tuberculosis isolates in a single laboratory. J Clin Microbiol 52:156-63
Mpagama, Stellah G; Ndusilo, Norah; Stroup, Suzanne et al. (2014) Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis. Antimicrob Agents Chemother 58:782-8
Thomas, T A; Heysell, S K; Houpt, E R et al. (2014) Outbreak of pyrazinamide-monoresistant tuberculosis identified using genotype cluster and social media analysis. Int J Tuberc Lung Dis 18:552-8
Heysell, Scott K; Thomas, Tania A; Sifri, Costi D et al. (2013) 18-Fluorodeoxyglucose positron emission tomography for tuberculosis diagnosis and management: a case series. BMC Pulm Med 13:14
Mpagama, Stellah G; Houpt, Eric R; Stroup, Suzanne et al. (2013) Application of quantitative second-line drug susceptibility testing at a multidrug-resistant tuberculosis hospital in Tanzania. BMC Infect Dis 13:432
Zhdanova, Svetlana; Heysell, Scott K; Ogarkov, Oleg et al. (2013) Primary multidrug-resistant Mycobacterium tuberculosis in 2 regions, Eastern Siberia, Russian Federation. Emerg Infect Dis 19:1649-52
Mpagama, Stellah G; Heysell, Scott K; Ndusilo, Nora D et al. (2013) Diagnosis and interim treatment outcomes from the first cohort of multidrug-resistant tuberculosis patients in Tanzania. PLoS One 8:e62034