Fluoroquinolones; particularly later-generation agents such as gatifloxacin and moxifloxacin, have excellent in vitro and in vivo activity against Mycobacteriumtuberculosis. Clinical trials are underway to assess the role of fluoroquinolones as first-line therapy for tuberculosis. These agents currently play a critical role in the treatment of multidrug-resistant tuberculosis (MDR-TB; resistance to at least isoniazid and rifampin). One potential difficulty with using fluoroquinolones to treat tuberculosis is their widespread use for the treatment of several other bacterial infections such as pneumonia and urinary tract infections. We have shown in preliminary work that fluoroquinolone treatment of community-acquired non-tuberculous infections is a risk factor for fluoroquinolone resistance in newly-diagnosed tuberculosis. However, the extent of fluoroquinolone resistance in M. tuberculosis is unknown because fluoroquinolone susceptibility testing of M. tuberculosis is not routinely performed. The risk factors for fluoroquinolone-resistant tuberculosis are also not completely understood. Fluoroquinolone resistance in M. tuberculosis can occur due to a single base-pair mutation in DMA gyrase. However, genetic mutations have not been identified in all fluoroquinolone-resistant M. tuberculosis isolates reported to date. Better characterization of the genetic mutations associated with fluoroquinolone resistance in M. tuberculosis would extend our understanding of the development of fluoroquinolone resistance and allow for its rapid identification. We will determine the proportion of newly diagnosed tuberculosis cases with fluoroquinolone resistance in two large, well-characterized study populations, and assess for trends in fluoroquinolone resistance over time. We will also identify the clinical risk factors associated with fluoroquinolone resistance, and characterize the relationship between phenotypic fluoroquinolone resistance and genetic mutations in M. tuberculosis. A better understanding of the prevalence, trends, and risk factors for fluoroquinolone resistance in M. tuberculosis would clarify whether fluoroquinolones are indeed a viable option for the first-line treatment of tuberculosis, and how best to preserve their usefulness against tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063200-03
Application #
7367845
Study Section
Special Emphasis Panel (ZRG1-IRAP-Q (01))
Program Officer
Parker, Tina M
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$365,542
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Eilertson, Brandon; Maruri, Fernanda; Blackman, Amondrea et al. (2016) A novel resistance mutation in eccC5 of the ESX-5 secretion system confers ofloxacin resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 71:2419-27
Van Der Heijden, Y F; Maruri, F; Holt, E et al. (2015) A comparison of interview methods to ascertain fluoroquinolone exposure before tuberculosis diagnosis. Epidemiol Infect 143:960-5
Eilertson, Brandon; Maruri, Fernanda; Blackman, Amondrea et al. (2014) High proportion of heteroresistance in gyrA and gyrB in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother 58:3270-5
van der Heijden, Yuri F; Maruri, Fernanda; Blackman, Amondrea et al. (2013) Fluoroquinolone susceptibility in Mycobacterium tuberculosis after pre-diagnosis exposure to older- versus newer-generation fluoroquinolones. Int J Antimicrob Agents 42:232-7
van der Heijden, Y F; Maruri, F; Blackman, A et al. (2012) Fluoroquinolone exposure prior to tuberculosis diagnosis is associated with an increased risk of death. Int J Tuberc Lung Dis 16:1162-7
Blackman, A; May, S; Devasia, R A et al. (2012) Microcolonies in fluoroquinolone agar proportion susceptibility testing of Mycobacterium tuberculosis: an indicator of drug resistance. Eur J Clin Microbiol Infect Dis 31:2177-82
Maruri, Fernanda; Sterling, Timothy R; Kaiga, Anne W et al. (2012) A systematic review of gyrase mutations associated with fluoroquinolone-resistant Mycobacterium tuberculosis and a proposed gyrase numbering system. J Antimicrob Chemother 67:819-31
Devasia, Rose; Blackman, Amondrea; Eden, Svetlana et al. (2012) High proportion of fluoroquinolone-resistant Mycobacterium tuberculosis isolates with novel gyrase polymorphisms and a gyrA region associated with fluoroquinolone susceptibility. J Clin Microbiol 50:1390-6
Devasia, Rose A; Blackman, Amondrea; May, Carolyn et al. (2009) Fluoroquinolone resistance in Mycobacterium tuberculosis: an assessment of MGIT 960, MODS and nitrate reductase assay and fluoroquinolone cross-resistance. J Antimicrob Chemother 63:1173-8
Devasia, Rose A; Blackman, Amondrea; Gebretsadik, Tebeb et al. (2009) Fluoroquinolone resistance in Mycobacterium tuberculosis: the effect of duration and timing of fluoroquinolone exposure. Am J Respir Crit Care Med 180:365-70

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