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The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing.
mBio. 2017 08 29; 8(4)MBIO

Abstract

The Xpert MTB/RIF assay (Xpert) is a rapid test for tuberculosis (TB) and rifampin resistance (RIF-R) suitable for point-of-care testing. However, it has decreased sensitivity in smear-negative sputum, and false identification of RIF-R occasionally occurs. We developed the Xpert MTB/RIF Ultra assay (Ultra) to improve performance. Ultra and Xpert limits of detection (LOD), dynamic ranges, and RIF-R rpoB mutation detection were tested on Mycobacterium tuberculosis DNA or sputum samples spiked with known numbers of M. tuberculosis H37Rv or Mycobacterium bovis BCG CFU. Frozen and prospectively collected clinical samples from patients suspected of having TB, with and without culture-confirmed TB, were also tested. For M. tuberculosis H37Rv, the LOD was 15.6 CFU/ml of sputum for Ultra versus 112.6 CFU/ml of sputum for Xpert, and for M. bovis BCG, it was 143.4 CFU/ml of sputum for Ultra versus 344 CFU/ml of sputum for Xpert. Ultra resulted in no false-positive RIF-R specimens, while Xpert resulted in two false-positive RIF-R specimens. All RIF-R-associated M. tuberculosis rpoB mutations tested were identified by Ultra. Testing on clinical sputum samples, Ultra versus Xpert, resulted in an overall sensitivity of 87.5% (95% confidence interval [CI], 82.1, 91.7) versus 81.0% (95% CI, 74.9, 86.2) and a sensitivity on sputum smear-negative samples of 78.9% (95% CI, 70.0, 86.1) versus 66.1% (95% CI, 56.4, 74.9). Both tests had a specificity of 98.7% (95% CI, 93.0, 100), and both had comparable accuracies for detection of RIF-R in these samples. Ultra should significantly improve TB detection, especially in patients with paucibacillary disease, and may provide more-reliable RIF-R detection.IMPORTANCE The Xpert MTB/RIF assay (Xpert), the first point-of-care assay for tuberculosis (TB), was endorsed by the World Health Organization in December 2010. Since then, 23 million Xpert tests have been procured in 130 countries. Although Xpert showed high overall sensitivity and specificity with pulmonary samples, its sensitivity has been lower with smear-negative pulmonary samples and extrapulmonary samples. In addition, the prediction of rifampin resistance (RIF-R) in paucibacillary samples and for a few rpoB mutations has resulted in both false-positive and false-negative results. The present study is the first demonstration of the design features and operational characteristics of an improved Xpert Ultra assay. This study also shows that the Ultra format overcomes many of the known shortcomings of Xpert. The new assay should significantly improve TB detection, especially in patients with paucibacillary disease, and provide more-reliable detection of RIF-R.

Authors+Show Affiliations

Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA chakraso@njms.rutgers.edu allandda@njms.rutgers.edu.Cepheid Inc., Sunnyvale, California, USA.Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.Cepheid Inc., Sunnyvale, California, USA.Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.Cepheid Inc., Bothell, Washington, USA.Cepheid Inc., Sunnyvale, California, USA.Public Health Research Institute, Rutgers, New Jersey Medical School, Newark, New Jersey, USA.Foundation for Innovative New Diagnostics, Geneva, Switzerland.Foundation for Innovative New Diagnostics, Geneva, Switzerland.National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia.P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.National Reference Laboratory, Republican Scientific and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.Emerging Bacterial Pathogens Unit, San Raffaele Scientific Institute, Milan, Italy.Emerging Bacterial Pathogens Unit, San Raffaele Scientific Institute, Milan, Italy.Department of Preventive Medicine and Community Health, Rutgers, New Jersey Medical School, Newark, New Jersey, USA.Foundation for Innovative New Diagnostics, Geneva, Switzerland.Cepheid Inc., Sunnyvale, California, USA.Cepheid Inc., Sunnyvale, California, USA.Cepheid Inc., Sunnyvale, California, USA.Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA chakraso@njms.rutgers.edu allandda@njms.rutgers.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28851844

Citation

Chakravorty, Soumitesh, et al. "The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium Tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing." MBio, vol. 8, no. 4, 2017.
Chakravorty S, Simmons AM, Rowneki M, et al. The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing. mBio. 2017;8(4).
Chakravorty, S., Simmons, A. M., Rowneki, M., Parmar, H., Cao, Y., Ryan, J., Banada, P. P., Deshpande, S., Shenai, S., Gall, A., Glass, J., Krieswirth, B., Schumacher, S. G., Nabeta, P., Tukvadze, N., Rodrigues, C., Skrahina, A., Tagliani, E., Cirillo, D. M., ... Alland, D. (2017). The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing. MBio, 8(4). https://doi.org/10.1128/mBio.00812-17
Chakravorty S, et al. The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium Tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing. mBio. 2017 08 29;8(4) PubMed PMID: 28851844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing. AU - Chakravorty,Soumitesh, AU - Simmons,Ann Marie, AU - Rowneki,Mazhgan, AU - Parmar,Heta, AU - Cao,Yuan, AU - Ryan,Jamie, AU - Banada,Padmapriya P, AU - Deshpande,Srinidhi, AU - Shenai,Shubhada, AU - Gall,Alexander, AU - Glass,Jennifer, AU - Krieswirth,Barry, AU - Schumacher,Samuel G, AU - Nabeta,Pamela, AU - Tukvadze,Nestani, AU - Rodrigues,Camilla, AU - Skrahina,Alena, AU - Tagliani,Elisa, AU - Cirillo,Daniela M, AU - Davidow,Amy, AU - Denkinger,Claudia M, AU - Persing,David, AU - Kwiatkowski,Robert, AU - Jones,Martin, AU - Alland,David, Y1 - 2017/08/29/ PY - 2017/8/31/entrez PY - 2017/8/31/pubmed PY - 2018/4/26/medline KW - Xpert MTB/RIF Ultra KW - diagnosis KW - sensitive KW - tuberculosis JF - mBio JO - mBio VL - 8 IS - 4 N2 - The Xpert MTB/RIF assay (Xpert) is a rapid test for tuberculosis (TB) and rifampin resistance (RIF-R) suitable for point-of-care testing. However, it has decreased sensitivity in smear-negative sputum, and false identification of RIF-R occasionally occurs. We developed the Xpert MTB/RIF Ultra assay (Ultra) to improve performance. Ultra and Xpert limits of detection (LOD), dynamic ranges, and RIF-R rpoB mutation detection were tested on Mycobacterium tuberculosis DNA or sputum samples spiked with known numbers of M. tuberculosis H37Rv or Mycobacterium bovis BCG CFU. Frozen and prospectively collected clinical samples from patients suspected of having TB, with and without culture-confirmed TB, were also tested. For M. tuberculosis H37Rv, the LOD was 15.6 CFU/ml of sputum for Ultra versus 112.6 CFU/ml of sputum for Xpert, and for M. bovis BCG, it was 143.4 CFU/ml of sputum for Ultra versus 344 CFU/ml of sputum for Xpert. Ultra resulted in no false-positive RIF-R specimens, while Xpert resulted in two false-positive RIF-R specimens. All RIF-R-associated M. tuberculosis rpoB mutations tested were identified by Ultra. Testing on clinical sputum samples, Ultra versus Xpert, resulted in an overall sensitivity of 87.5% (95% confidence interval [CI], 82.1, 91.7) versus 81.0% (95% CI, 74.9, 86.2) and a sensitivity on sputum smear-negative samples of 78.9% (95% CI, 70.0, 86.1) versus 66.1% (95% CI, 56.4, 74.9). Both tests had a specificity of 98.7% (95% CI, 93.0, 100), and both had comparable accuracies for detection of RIF-R in these samples. Ultra should significantly improve TB detection, especially in patients with paucibacillary disease, and may provide more-reliable RIF-R detection.IMPORTANCE The Xpert MTB/RIF assay (Xpert), the first point-of-care assay for tuberculosis (TB), was endorsed by the World Health Organization in December 2010. Since then, 23 million Xpert tests have been procured in 130 countries. Although Xpert showed high overall sensitivity and specificity with pulmonary samples, its sensitivity has been lower with smear-negative pulmonary samples and extrapulmonary samples. In addition, the prediction of rifampin resistance (RIF-R) in paucibacillary samples and for a few rpoB mutations has resulted in both false-positive and false-negative results. The present study is the first demonstration of the design features and operational characteristics of an improved Xpert Ultra assay. This study also shows that the Ultra format overcomes many of the known shortcomings of Xpert. The new assay should significantly improve TB detection, especially in patients with paucibacillary disease, and provide more-reliable detection of RIF-R. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/28851844/The_New_Xpert_MTB/RIF_Ultra:_Improving_Detection_of_Mycobacterium_tuberculosis_and_Resistance_to_Rifampin_in_an_Assay_Suitable_for_Point_of_Care_Testing_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=28851844 DB - PRIME DP - Unbound Medicine ER -