title: High proportion of fluoroquinolone-resistant Mycobacterium tuberculosis isolates with novel gyrase polymorphisms and a gyrA region associated with fluoroquinolone susceptibility.
abstract: Fluoroquinolone resistance in Mycobacterium tuberculosis can be conferred by mutations in gyrA or gyrB. The prevalence of resistance 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 diagnosed in Tennessee from 2002 to 2009 were screened for phenotypic ofloxacin resistance (>2 μg/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 with M. tuberculosis H37Rv. 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-resistant M. tuberculosis isolates did not have previously described resistance mutations, which has implications for genotypic diagnostic tests.
authors.affiliation: University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Devasia
authors.forename: Amondrea
authors.initials: A
authors.lastname: Blackman
authors.forename: Svetlana
authors.initials: S
authors.lastname: Eden
authors.forename: Haijing
authors.initials: H
authors.lastname: Li
authors.forename: Fernanda
authors.initials: F
authors.lastname: Maruri
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shintani
authors.forename: Charles
authors.initials: C
authors.lastname: Alexander
authors.forename: Anne
authors.initials: A
authors.lastname: Kaiga
authors.forename: Charles W
authors.initials: CW
authors.lastname: Stratton
authors.forename: Jon
authors.initials: J
authors.lastname: Warkentin
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Tang
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Sterling
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D003062:Codon; D027081:DNA Gyrase / Q000235:genetics*; D004252:DNA Mutational Analysis; D024881:Drug Resistance, Bacterial; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics*; D011110:Polymorphism, Genetic; D014397:Tuberculosis, Pulmonary / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003062:Codon; D024841:Fluoroquinolones; D027081:DNA Gyrase