DST/NRF Centre of Excellence for Biomedical TB Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Health Science, Stellenbosch University, Stellenbosch, South Africa.
J Antimicrob Chemother. 2012 May;67(5):1088-93. doi: 10.1093/jac/dks033. Epub 2012 Feb 22.
To compare mutations in the quinolone resistance-determining region of the gyrA gene and flanking sequences with the MICs of ofloxacin and moxifloxacin for Mycobacterium tuberculosis.
The presence of mutations in 177 drug-resistant M. tuberculosis isolates was determined by DNA sequencing and the MICs quantified by MGIT 960.
Single nucleotide polymorphisms were detected at codons 94 (n = 30), 90 (n = 12), 91 (n = 3), 89 (n = 1), 88 (n = 1) and 80 (n = 1). Four isolates with double mutations D94G plus A90V (n = 2) and D94G plus D94N (n = 2) reflect mixed populations. Agreement between genotypic and phenotypic susceptibility was high (≥97%) for both drugs. Mutant isolates had an MIC(50) of 8.0 mg/L and an MIC(90) of >10 mg/L for ofloxacin compared with an MIC(50) and MIC(90) of 2.0 mg/L for moxifloxacin. Codons 94 and 88 were linked to higher levels of fluoroquinolone resistance compared with codons 90, 91 and 89. The MIC distributions for the wild-type isolates ranged from ≤0.5 to 2.0 mg/L for ofloxacin and from ≤0.125 to 0.25 mg/L for moxifloxacin. However, 96% of the isolates with genetic alterations had MICs ≤2.0 mg/L for moxifloxacin, which is within its achievable serum levels.
This study provides quantitative evidence that the addition of moxifloxacin to extensively drug-resistant tuberculosis (XDR-TB) regimens based on a clinical breakpoint of 2.0 mg/L has merit. The use of moxifloxacin in the treatment of multidrug-resistant tuberculosis may prevent the acquisition of additional mutations and development of XDR-TB.
比较结核分枝杆菌 gyrA 基因喹诺酮耐药决定区及其侧翼序列的突变与氧氟沙星和莫西沙星 MIC 的关系。
通过 DNA 测序确定 177 株耐药结核分枝杆菌分离株中的突变情况，并通过 MGIT 960 定量 MIC。
在密码子 94（n = 30）、90（n = 12）、91（n = 3）、89（n = 1）、88（n = 1）和 80（n = 1）处检测到单核苷酸多态性。有 4 株分离株存在双重突变 D94G 加 A90V（n = 2）和 D94G 加 D94N（n = 2），反映了混合群体。两种药物的基因型和表型药敏一致性均较高（≥97%）。与氧氟沙星的 MIC（50）为 8.0mg/L 和 MIC（90）>10mg/L 相比，突变分离株的 MIC（50）和 MIC（90）分别为 2.0mg/L 和>10mg/L。与密码子 90、91 和 89 相比，密码子 94 和 88 与氟喹诺酮耐药水平较高相关。野生型分离株的 MIC 分布范围为氧氟沙星≤0.5-2.0mg/L，莫西沙星≤0.125-0.25mg/L。然而，96%的遗传改变分离株的莫西沙星 MIC 值≤2.0mg/L，这在其可达到的血清水平范围内。
本研究提供了定量证据，表明在基于临床折点 2.0mg/L 的广泛耐药结核病（XDR-TB）方案中添加莫西沙星是有价值的。在治疗耐多药结核病时使用莫西沙星可能会阻止获得额外的突变和发展为 XDR-TB。
