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    Specific gyrA gene mutations predict poor treatment outcome in MDR-TB

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    Publication date
    2016-02
    Author
    Rigouts, L.
    Coeck, N.
    Gumusboga, M.
    de Rijk, W.B.
    Aung, K.J.
    Hossain, M.A.
    Fissette, K.
    Rieder, H.L.
    Meehan, Conor J.
    de Jong, B.C.
    Van Deun, A.
    Show allShow less
    Keyword
    Mutation
    Bangladesh
    Genes
    Ofloxacin
    Tuberculosis
    Treatment outcome
    Multidrug-resistant tuberculosis
    Gatifloxacin
    Moxifloxacin
    Malnutrition-inflammation-cachexia syndrome
    Rights
    (c) 2016 The Author. This is an Open Access article distributed under the Creative Commons CC-BY-NC license (http:// creativecommons.org/licenses/by-nc/4.0/)
    Peer-Reviewed
    Yes
    
    Metadata
    Show full item record
    Abstract
    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. 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. 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. 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.
    URI
    http://hdl.handle.net/10454/17328
    Version
    Published version
    Citation
    Rigouts L, Coeck N, Gumusboga M et al (2016) Specific gyrA gene mutations predict poor treatment outcome in MDR-TB. Journal of Antimicrobial Chemotherapy. 71(2): 314-323.
    Link to publisher’s version
    https://doi.org/10.1093/jac/dkv360
    Type
    Article
    Collections
    Life Sciences Publications

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