Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis.
Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis.
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DOI：
10.1056/nejmoa1614915
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发表时间：
2017-09-14
期刊：
影响因子：
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通讯作者：
Alland D
中科院分区：
文献类型：
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作者：
Xie YL;Chakravorty S;Armstrong DT;Hall SL;Via LE;Song T;Yuan X;Mo X;Zhu H;Xu P;Gao Q;Lee M;Lee J;Smith LE;Chen RY;Joh JS;Cho Y;Liu X;Ruan X;Liang L;Dharan N;Cho SN;Barry CE 3rd;Ellner JJ;Dorman SE;Alland D
氟喹诺酮类药物和二线注射药物是耐多药结核病治疗方案的支柱，对这些药物的耐药性定义了广泛的耐药结核病。我们评估了直接从痰标本中检测对氟喹诺酮类药物、氨基糖苷类药物和异烟肼耐药的结核分枝杆菌的自动化、试剂盒分子分析的准确性。我们在中国和韩国有结核病症状的成年人中进行了一项前瞻性诊断准确性研究，将调查性试验与表型药敏试验和DNA测序进行比较。进行Xpert MTB/RIF检测和痰培养。结核分枝杆菌分离株进行了表型药敏试验和katG、gyrA、gyrB和RRS基因以及EIS和INHA启动子区域的DNA测序。在308例培养阳性的结核分枝杆菌感染者中，以表型药敏试验为参考标准，异烟肼、氧氟沙星、莫西沙星的敏感性分别为83.3%(95%可信区间，77.1~88.5)、88.4%(95%可信区间，80.2~94.1)、87.6%(莫西沙星)(95%可信区间，79.0~93.7)；莫西沙星的临界浓度为2.0μg/m l时为96.2%(95%CI，87.0~99.5)，卡那霉素为71.4%(95%CI，5 6.7~83.4)，阿米卡星为70.7%(95%CI，5 4.5~83.9)。该方法对除莫西沙星外的所有药物检测表型耐药的特异度均为94.3%或以上(特异度为84.0%[95%CI，78.9~88.3])，但莫西沙星的临界浓度为2.0μg/m l。以DNA测序为参照标准，该方法检测耐药突变的敏感性异烟肼98.1%(95%CI，94.4~99.6)，氟喹诺酮95.8%(95%CI，89.6~98.8)，卡那霉素92.7%(95%CI，80.1~98.5)，阿米卡星96.8%(95%CI，83.3~99.9)，特异度99.6%(95%CI，97.9~100)或以上。这项研究试验准确地检测到与异烟肼、氟喹诺酮类和氨基糖苷类药物耐药有关的结核分枝杆菌突变，有望成为指导结核病患者治疗决策的快速护理点检测方法。(国家过敏与传染病研究所、国家卫生研究院、科技部中国资助；ClinicalTrials.gov编号，NCT02251327。)
Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid. We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M. tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions. Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 μg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 μg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 μg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater. This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; ClinicalTrials.gov number, NCT02251327.)