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Specific gyrA gene mutations predict poor treatment outcome in MDR-TB. / Rigouts, L.; Coeck, N.; Gumusboga, M.; de Rijk, W. B. ; Aung, K J M; Hossain, M A; Fissette, K.; Rieder, H L; Meehan, C. J.; de Jong, B. C.; Van Deun, A.

In: Journal of Antimicrobial Chemotherapy, Vol. 71, No. 2, 2016, p. 314-323.

Research output: Contribution to journalA1: Web of Science-article

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@article{ce32ee3d26ef45c6971f3a6dd883d8d6,
title = "Specific gyrA gene mutations predict poor treatment outcome in MDR-TB",
abstract = "OBJECTIVES: 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.",
keywords = "B110-medical-informatics, Tuberculosis, Drug Resistance, Fluoroquinolines, Treatment outcome",
author = "L. Rigouts and N. Coeck and M. Gumusboga and {de Rijk}, {W. B.} and Aung, {K J M} and Hossain, {M A} and K. Fissette and Rieder, {H L} and Meehan, {C. J.} and {de Jong}, {B. C.} and {Van Deun}, A.",
note = "{\circledC} The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.",
year = "2016",
doi = "10.1093/jac/dkv360",
language = "English",
volume = "71",
pages = "314--323",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "2",

}

RIS

TY - JOUR

T1 - Specific gyrA gene mutations predict poor treatment outcome in MDR-TB

AU - Rigouts, L.

AU - Coeck, N.

AU - Gumusboga, M.

AU - de Rijk, W. B.

AU - Aung, K J M

AU - Hossain, M A

AU - Fissette, K.

AU - Rieder, H L

AU - Meehan, C. J.

AU - de Jong, B. C.

AU - Van Deun, A.

N1 - © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

PY - 2016

Y1 - 2016

N2 - OBJECTIVES: 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.

AB - OBJECTIVES: 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.

KW - B110-medical-informatics

KW - Tuberculosis

KW - Drug Resistance

KW - Fluoroquinolines

KW - Treatment outcome

U2 - 10.1093/jac/dkv360

DO - 10.1093/jac/dkv360

M3 - A1: Web of Science-article

C2 - 26604243

VL - 71

SP - 314

EP - 323

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 2

ER -

ID: 1359538