Specific gyrA gene mutations predict poor treatment outcome in MDR TB
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.
The Journal of antimicrobial chemotherapy