High Proportion of Fluoroquinolone-Resistant Mycobacterium tuberculosis Isolates with Novel Gyrase Polymorphisms and a gyrA Region Associated with Fluoroquinolone

Fluoroquinolone resistance inMycobacterium tuberculosis can be conferred by mutations in gyrA or gyrB. The prevalence of re-sistance mutations outside the quinolone resistance-determining region (QRDR) of gyrA or gyrB is unclear, since such regions are rarely sequenced.M. tuberculosis isolates from 1,111 patients with newly diagnosed culture-confirmed tuberculosis diag-nosed in Tennessee from 2002 to 2009 were screened for phenotypic ofloxacin resistance (>2g/ml). For each resistant isolate, two ofloxacin-susceptible isolates were selected: one with antecedent fluoroquinolone exposure and one without. The complete gyrA and gyrB genes were sequenced and compared withM. tuberculosisH37Rv. Of 25 ofloxacin-resistant isolates, 11 (44%) did not have previously reported resistance mutations. Of these, 10 had novel polymorphisms: 3 in the QRDR of gyrA, 1 in the QRDR of gyrB, and 6 outside the QRDR of gyrA or gyrB; 1 did not have any gyrase polymorphisms. Polymorphisms in gyrA codons 1 to 73 were more common in fluoroquinolone-susceptible than in fluoroquinolone-resistant strains (20 % versus 0%; P 0.016). In summary, almost half of fluoroquinolone-resistantM. tuberculosis isolates did not have previously described re