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

被引:79
作者
Rigouts, L. [1 ,2 ]
Coeck, N. [1 ,2 ]
Gumusboga, M. [1 ]
de Rijk, W. B. [1 ]
Aung, K. J. M. [3 ]
Hossain, M. A. [3 ]
Fissette, K. [1 ]
Rieder, H. L. [4 ]
Meehan, C. J. [1 ]
de Jong, B. C. [1 ,5 ,6 ]
Van Deun, A. [1 ,7 ]
机构
[1] Inst Trop Med, Dept Biomed Sci, Mycobacteriol Unit, B-2000 Antwerp, Belgium
[2] Univ Antwerp, Biomed Sci, B-2020 Antwerp, Belgium
[3] Damien Fdn, Dhaka, Bangladesh
[4] Univ Zurich, Biostat & Prevent Inst, Dept Epidemiol, Zurich, Switzerland
[5] NYU, Dept Med, Div Infect Dis, 550 1St Ave, New York, NY 10016 USA
[6] MRC Unit, Vaccinol Dept, Fajara, Gambia
[7] Int Union TB & Lung Dis, Paris, France
基金
欧洲研究理事会;
关键词
RESISTANT MYCOBACTERIUM-TUBERCULOSIS; IN-VITRO ACTIVITY; FLUOROQUINOLONE RESISTANCE; DNA GYRASE; MOLECULAR CHARACTERIZATION; PYRAZINAMIDE RESISTANCE; MOXIFLOXACIN; LEVOFLOXACIN; OFLOXACIN; GATIFLOXACIN;
D O I
10.1093/jac/dkv360
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
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 mutantsaEuroS+aEuroS94Ala) [ORaEuroS=aEuroS4.3 (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.
引用
收藏
页码:314 / 323
页数:10
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