The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The limit of detection for MTB is lower with Xpert Ultra (16 cfu/mL) than with Xpert MTB/RIF (131 cfu/mL).
“The limit of detection for MTB is lower with Xpert Ultra (16 bacterial colony‐forming units (cfu) per mL) than with Xpert MTB/RIF (131 cfu per mL) (Chakravorty 2017).”
From Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults (2021) · cites this paper as Chakravorty 2017
The Results section (‘Sensitivity of Ultra versus that of Xpert’) reports an MTB detection limit of 15.6 CFU/mL for Ultra, consistent with the claimed 16. It reports 112.6 CFU/mL for Xpert, not the claimed 131 CFU/mL, although the claimed value falls within the reported confidence interval. (LLM, conf=0.93)
Experimental — accuracy not yet measuredXpert Ultra trace result corresponds to the lowest bacterial burden for detection of M tuberculosis.
“‘Trace' corresponds to the lowest bacterial burden for detection of M tuberculosis (Chakravorty 2017).”
From Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults (2021) · cites this paper as Chakravorty 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Rapid Molecular Detection of Tuberculosis and Rifampin Resistance
Boehme, C. C., Nabeta, P., Hillemann, D., Nicol, M. P., Shenai, S., Krapp, F., Allen, J., Tahirli, R., Blakemore, R., Rustomjee, R., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907847 · Cited by 2,309 · see citing works
Self-citationXpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults
Steingart, K. R., Schiller, I., Horne, D. J. D. L., Pai, M., Boehme, C. C., & Dendukuri, N. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009593.pub3 · Cited by 1,147 · see citing works
Helb, D., Jones, M., Story, E., Boehme, C., Wallace, E., Ho, K., Kop, J., Owens, M. R., Rodgers, R., Banada, P., et al. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.01463-09 · Cited by 914 · see citing works
Self-citationGagneux, S., & Small, P. M. (2007) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(07)70108-1 · Cited by 705 · see citing works
Denkinger, C. M., Schumacher, S. G., Boehme, C. C., Dendukuri, N., Pai, M., & Steingart, K. R. (2014) · European Respiratory Journal · doi:10.1183/09031936.00007814 · Cited by 527 · see citing works
Self-citationEvaluation of the analytical performance of the Xpert MTB/RIF assay
Blakemore, R., Story, E., Helb, D., Kop, J., Banada, P., Owens, M. R., Chakravorty, S., Jones, M., & Alland, D. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.00128-10 · Cited by 485 · see citing works
Theron, G., Zijenah, L. S., Chanda, D. M., Clowes, P., Rachow, A., Lesosky, M., Bara, W., Mungofa, S., Pai, M., Höelscher, M., et al. (2013) · The Lancet · doi:10.1016/s0140-6736(13)62073-5 · Cited by 434 · see citing works
IS6110, an IS-like element ofMycobacterium tuberculosiscomplex
Thierry, D., Cave, M. D., Eisenach, K. D., Crawford, J. T., Bates, J. H., Gicquel, B., & Guesdon, J. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.1.188 · Cited by 433 · see citing works
Zeka, A. N., Tasbakan, S., & Cavusoglu, C. (2011) · Journal of Clinical Microbiology · doi:10.1128/jcm.05434-11 · Cited by 362 · see citing works
Albert, H., Nathavitharana, R. R., Isaacs, C., Pai, M., Denkinger, C. M., & Boehme, C. C. (2016) · European Respiratory Journal · doi:10.1183/13993003.00543-2016 · Cited by 302 · see citing works
Self-citationLawn, S. D., Brooks, S. V., Kranzer, K., Nicol, M. P., Whitelaw, A. C., Vogt, M., Bekker, L., & Wood, R. (2011) · PLoS Medicine · doi:10.1371/journal.pmed.1001067 · Cited by 278 · see citing works
Ioannidis, P., Papaventsis, D. C., Karabela, S., Nikolaou, S., Panagi, M., Raftopoulou, E., Konstantinidou, E., Μαρίνου, Ι., & Kanavaki, S. (2011) · Journal of Clinical Microbiology · doi:10.1128/jcm.00718-11 · Cited by 152 · see citing works
Repetitive DNA sequences as probes for Mycobacterium tuberculosis
Eisenach, K. D., Crawford, J. T., & Bates, J. H. (1988) · Journal of Clinical Microbiology · doi:10.1128/jcm.26.11.2240-2245.1988 · Cited by 151 · see citing works
Rufai, S. B., Kumar, P., Singh, A., Prajapati, S., Balooni, V., & Singh, S. (2014) · Journal of Clinical Microbiology · doi:10.1128/jcm.03005-13 · Cited by 148 · see citing works
Zetola, N. M., Shin, S. S., Tumedi, K. A., Moeti, K., Ncube, R. T., Nicol, M. P., Collman, R. G., Klausner, J. D., & Modongo, C. (2014) · Journal of Clinical Microbiology · doi:10.1128/jcm.02489-13 · Cited by 142 · see citing works
van Soolingen, D., Hermans, P. W., de Haas, P. E., & van Embden, J. D. (1992) · Journal of Clinical Microbiology · doi:10.1128/jcm.30.7.1772-1777.1992 · Cited by 139 · see citing works
Theron, G., Peter, J., Calligaro, G., Meldau, R., Hanrahan, C. F., Khalfey, H., Matinyenya, B., Muchinga, T. E., Smith, L., Pandie, S., et al. (2014) · Scientific Reports · doi:10.1038/srep05658 · Cited by 121 · see citing works
Sohn, H., Aero, A. D., Menzies, D., Behr, M., Schwartzman, K., Alvarez, G. G., Dan, A., McIntosh, F., Pai, M., & Denkinger, C. M. (2014) · Clinical Infectious Diseases · doi:10.1093/cid/ciu022 · Cited by 95 · see citing works
Self-citationWilliamson, D. A., Basu, I., Bower, J. E., Freeman, J. T., Henderson, G., & Roberts, S. (2012) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2012.06.013 · Cited by 81 · see citing works
Boyles, T. H., Hughes, J. A., Cox, V., Burton, R., Meintjes, G., & Mendelson, M. (2014) · The International Journal of Tuberculosis and Lung Disease · doi:10.5588/ijtld.13.0853 · Cited by 66 · see citing works
Köser, C. U., Feuerriegel, S., Summers, D., Archer, J. A. C., & Niemann, S. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01641-12 · Cited by 65 · see citing works
Molecular Differentiation ofMycobacterium tuberculosisStrains without IS6110Insertions
Lok, K. H., Benjamin, W. H., Kimerling, M. E., et al. (2002) · Emerging infectious diseases · doi:10.3201/eid0811.020291 · Cited by 59 · see citing works
Chakravorty, S., Kothari, H., Aladegbami, B., et al. (2012) · Journal of Clinical Microbiology · doi:10.1128/jcm.00143-12 · Cited by 47 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Bahr, N. C., Nuwagira, E., Evans, E. E., Cresswell, F. V., Bystrom, P. V., Byamukama, A., Bridge, S. C., Bangdiwala, A. S., Meya, D. B., Denkinger, C. M., et al. (2018) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(17)30474-7 · Cited by 308 · see citing works
Self-citationXpert <sup>®</sup> MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance
Kohli, M., Schiller, I., Dendukuri, N., Dheda, K., Denkinger, C. M., Schumacher, S. G., & Steingart, K. R. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd012768.pub2 · Cited by 245 · see citing works
Self-citationKohli, M., Schiller, I., Dendukuri, N., Yao, M., Dheda, K., Denkinger, C. M., Schumacher, S. G., & Steingart, K. R. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd012768.pub3 · Cited by 215 · see citing works
Self-citationDonovan, J., Thu, D. D. A., Phu, N. H., Dung, V. T. M., Quang, T. P., Nghia, H. D. T., Oanh, P. K. N., Nhu, T. B., Chau, N. V. V., Ha, V. T. N., et al. (2020) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(19)30649-8 · Cited by 154 · see citing works
Methods for Rapid Diagnosis of Meningitis Etiology in Adults
Poplin, V., Boulware, D. R., & Bahr, N. C. (2020) · Biomarkers in Medicine · doi:10.2217/bmm-2019-0333 · Cited by 119 · see citing works
Cresswell, F. V., Tugume, L., Bahr, N. C., Kwizera, R., Bangdiwala, A. S., Musubire, A. K., Rutakingirwa, M., Kagimu, E., Nuwagira, E., Mpoza, E., et al. (2020) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(19)30550-x · Cited by 124 · see citing works
Perez-Risco, D., Rodriguez-Temporal, D., Valledor-Sanchez, I., & Alcaide, F. (2018) · Journal of Clinical Microbiology · doi:10.1128/jcm.00659-18 · Cited by 103 · see citing works
Wang, G., Wang, S., Jiang, G., Yang, X., Huang, M., Huo, F., Ma, Y., Dai, G., Li, W., Chen, X., et al. (2019) · Journal of Infection · doi:10.1016/j.jinf.2019.02.010 · Cited by 76 · see citing works
Fehr, J., Konigorski, S., Olivier, S., Gunda, R., Surujdeen, A., Gareta, D., Smit, T., Baisley, K., Moodley, S., Moosa, Y., et al. (2021) · npj Digital Medicine · doi:10.1038/s41746-021-00471-y · Cited by 74 · see citing works
Gouda, K., Das, U., & Dhangadamajhi, G. (2021) · Indian Journal of Tuberculosis · doi:10.1016/j.ijtb.2021.01.005 · Cited by 20 · see citing works
Saavedra, B., Mambuque, E., Nguenha, D., Gomes, N., Munguambe, S., García, J. I., Izco, S., Acacio, S., Murias-Closas, A., Cossa, M., et al. (2021) · European Respiratory Journal · doi:10.1183/13993003.00257-2021 · Cited by 25 · see citing works
- Authors
- 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., Davidow, A., Denkinger, C. M., Persing, D., Kwiatkowski, R., Jones, M., & Alland, D.
- Affiliations
- Rutgers New Jersey Medical School (US)
- Cepheid (United States) (US)
- FIND (CH)
- National Center for Tuberculosis and Lung Disease (GE)
- P. D. Hinduja Hospital and Medical Research Centre (IN)
- Republican Scientific and Practical Centre of Pulmonology and Tuberculosis (BY)
- IRCCS Ospedale San Raffaele (IT)
- Corresponding author
- Chakravorty, Soumitesh
- Alland, David
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2017-09-06
- Volume
- 8
- Issue
- 4
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC5574709
- OpenAlex
- W2753668595
- Cited by
- 668
- References
- 23
- Citations by year
- 2026: 61 · 2025: 95 · 2024: 85 · 2023: 88 · 2022: 61 · 2021: 65 · 2020: 85 · 2019: 67 · 2018: 52 · 2017: 7
- FWCI
- 44.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- HHS | National Institutes of Health (AI111397)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- Xpert MTB/RIF Ultra, Xpert MTB/RIF, Mycobacterium tuberculosis, rifampicin resistance, rpoB mutations, point-of-care testing, tuberculosis diagnosis, detection limit, sensitivity and specificity, Mycobacterium bovis BCG, nucleic acid amplification
- MeSH terms
- Point-of-Care Testing, Antibiotics, Antitubercular, Bacterial Proteins, Humans, Mutation, Mycobacterium tuberculosis, Rifampin, DNA-Directed RNA Polymerases, Sensitivity and Specificity, Sputum, Tuberculosis, Tuberculosis, Pulmonary, Polymerase Chain Reaction, Molecular Diagnostic Techniques, Limit of Detection
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
