• Yingda L Xie, Soumitesh Chakravorty, Derek T Armstrong, Sandra L Hall, Laura E Via, Taeksun Song, Xing Yuan, Xiaoying Mo, Hong Zhu, Peng Xu, Qian Gao, Myungsun Lee, Jongseok Lee, Laura E Smith, Ray Y Chen, Joon Sung Joh, YoungSoo Cho, Xin Liu, Xianglin Ruan, Lili Liang, Nila Dharan, Sang-Nae Cho, Clifton E Barry, Jerrold J Ellner, Susan E Dorman, and David Alland.
• From the Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (Y.L.X., L.E.V., R.Y.C., C.E.B.), and Johns Hopkins University School of Medicine, Baltimore (D.T.A., S.E.D.) - both in Maryland; the Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark (S.C., L.E.S., N.D., D.A.); Boston Medical Center and Boston University School of Medicine, Boston (S.L.H., J.J.E.); the International Tuberculosis Research Center, Changwon (T.S., M.L., J.L., S.-N.C.), and the National Medical Center (J.S.J.), Seoul Metropolitan Seobuk Hospital (Y.C.), and the Department of Microbiology, College of Medicine, Yonsei University (S.-N.C.), Seoul - all in South Korea; Henan Provincial Chest Hospital (X.Y., X.M., X.L., X.R., L.L.) and Sino-U.S. Tuberculosis Research Collaboration (H.Z.), Zhengzhou, and Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Science, Fudan University, Shanghai (P.X., Q.G.) - all in China; and the Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa (C.E.B.).
• N. Engl. J. Med. 2017 Sep 14; 377 (11): 1043-1054.

BackgroundFluoroquinolones 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.MethodsWe 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.ResultsAmong 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.ConclusionsThis 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 .).

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