title: Specific gyrA gene mutations predict poor treatment outcome in MDR-TB.
abstract: OBJECTIVE
  Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second-line treatment outcomes in M. tuberculosis patients treated with fourth-generation fluoroquinolones.
  
  
  METHODS
  We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs.
  
  
  RESULTS
  The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4-13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs.
  
  
  CONCLUSIONS
  Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective.
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium Biomedical Sciences, University of Antwerp, Antwerp, Belgium lrigouts@itg.be.
authors.forename: L
authors.initials: L
authors.lastname: Rigouts
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Coeck
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Gumusboga
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: W B
authors.initials: WB
authors.lastname: de Rijk
authors.affiliation: Damien Foundation, Dhaka, Bangladesh.
authors.forename: K J M
authors.initials: KJ
authors.lastname: Aung
authors.affiliation: Damien Foundation, Dhaka, Bangladesh.
authors.forename: M A
authors.initials: MA
authors.lastname: Hossain
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Fissette
authors.affiliation: Epidemiology Department, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.
authors.forename: H L
authors.initials: HL
authors.lastname: Rieder
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: C J
authors.initials: CJ
authors.lastname: Meehan
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium Department of Medicine, Division of Infectious Diseases, New York University, New York, NY, USA Vaccinology Department, Medical Research Council Unit, Fajara, The Gambia.
authors.forename: B C
authors.initials: BC
authors.lastname: de Jong
authors.affiliation: Mycobacteriology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium International Union Against Tuberculosis and Lung Disease, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Van Deun
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use*; D001459:Bangladesh; D027081:DNA Gyrase / Q000235:genetics*; D024841:Fluoroquinolones / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000302:isolation & purification; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D027081:DNA Gyrase