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.

Figure 1.

Overview of patients and M. tuberculosis complex isolates included. DF, Damien Foundation; ITM, Institute of Tropical Medicine; OFX, ofloxacin; GAT, gatifloxacin; MXF, moxifloxacin; KAN, kanamycin.

Figure 2.

Censored regression analysis for MICs of the fourth-generation FQs (gatifloxacin or moxifloxacin) versus ofloxacin. OFX, ofloxacin; GAT, gatifloxacin; MXF, moxifloxacin. Gatifloxacin and moxifloxacin are right censored above an MIC of 4 mg/L. Bubble sizes are proportional to case density, using the square root of the case number in the stratum.

Figure 3.

Cumulative percentage of isolates in relation to the gatifloxacin MIC, stratified by absence (WT) or presence of any QRDR mutation in the gyrAB genes (11 heterogeneous populations excluded).