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.