The New Xpert MTB/RIF Ultra: Improving Detection of
            <i>Mycobacterium tuberculosis</i>
            and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing

Chakravorty, Soumitesh; Simmons, Ann Marie; Rowneki, Mazhgan; Parmar, Heta; Cao, Yuan; Ryan, Jamie; Banada, Padmapriya P.; Deshpande, Srinidhi; Shenai, Shubhada; Gall, A. A.; Glass, Jennifer S.; Krieswirth, Barry; Schumacher, Samuel G; Nabeta, Pamela; Tukvadze, Nestani; Rodrigues, Camilla; Skrahina, Alena; Tagliani, Elisa; Cirillo, Daniela María; Davidow, Amy L.; Denkinger, Claudia M.; Persing, David H.; Kwiatkowski, Robert; Jones, Martin; Alland, David

doi:10.1128/mbio.00812-17

Cited by 467 publications

(439 citation statements)

References 23 publications

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“…due to silent mutations leading to no wild‐type hybridization patterns) or detection of MTB DNA in culture‐negative patients may lead to discrepancies with current gold standards, thus hindering clinical interpretation of the results obtained with molecular assays . Some of these drawbacks could be overcome by designing the assay to specifically address the detection of synonymous mutations as recently done for the Xpert Ultra; however, this strategy requires a priori knowledge of all the possible silent mutations in the targeted region. Fourth, clear understanding of the relationship between genotype and phenotype and clinical outcome is not always available, and several factors contribute in complicating the clinical interpretation of genetic polymorphisms …”

Section: Discussionmentioning

confidence: 99%

Drug resistance mechanisms and drug susceptibility testing for tuberculosis

et al. 2018

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is the deadliest infectious disease and the associated global threat has worsened with the emergence of drug resistance, in particular multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Although the World Health Organization (WHO) End-TB Strategy advocates for universal access to antimicrobial susceptibility testing, this is not widely available and/or it is still underused. The majority of drug resistance in clinical MTB strains is attributed to chromosomal mutations. Resistance-related mutations could also exert certain fitness cost to the drug-resistant MTB strains and growth fitness could be restored by the presence of compensatory mutations. Understanding these underlying mechanisms could provide an important insight into TB pathogenesis and predict the future trend of MDR-TB global pandemic. This review covers the mechanisms of resistance in MTB and provides a comprehensive overview of current phenotypic and molecular approaches for drug susceptibility testing, with particular attention to the methods endorsed and recommended by the WHO.

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Section: Discussionmentioning

confidence: 99%

Drug resistance mechanisms and drug susceptibility testing for tuberculosis

et al. 2018

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“…Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) has been endorsed by the WHO in high‐incidence countries . Recently, a new version of the test, Xpert MTB/RIF Ultra, has been introduced to the market . The Xpert MTB/RIF Ultra has higher sensitivity than Xpert MTB/RIF in patients with paucibacillary disease and in patients with HIV, though at the expense of a decrease in specificity .…”

Section: Improving Diagnosismentioning

confidence: 99%

Drug‐resistant tuberculosis: An update on disease burden, diagnosis and treatment

et al. 2018

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The emergence of antimicrobial resistance against Mycobacterium tuberculosis, the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug-resistant tuberculosis (MDR-TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR-TB achieved a successful outcome. For many years, patients with drug-resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR-TB through drug-specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor-made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high-burden/resource-limited settings. More recently, MDR-TB treatment outcomes have dramatically improved with the use of bedaquiline-based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure-rates, and may substantially decrease the duration of MDR-TB treatment necessary to achieve relapse-free cure.

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“…Thus, even though results were available rapidly, Xpert missed over one in three cases. The next generation assay Xpert MTB/Rif Ultra has an analytic limit of detection of 15 colony forming units (CFU)/ml, compared to 113 CFU/ml for Xpert 26 . Ultra appears to be significantly more sensitive than Xpert or culture for the diagnosis of TBM (95% versus 45% and 45% respectively, P<0.001) 27 .…”

Section: Discussionmentioning

confidence: 99%

Can improved diagnostics reduce mortality from Tuberculous meningitis? Findings from a 6.5-year cohort in Uganda

Cresswell¹,

Bangdiwala²,

Bahr³

et al. 2018

Wellcome Open Res

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Background: Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa and is notoriously difficult to diagnose. We describe the impact of improved TBM diagnostics over 6.5 years at two Ugandan referral hospitals. Methods: Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert MTB/Rif (Xpert) on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume centrifuged CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen. We compared rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 HIV-infected adults presenting with suspected meningitis underwent lumbar puncture, of which 33% (558/1672) had negative CSF cryptococcal antigen and 12% (195/1672) were treated for TB meningitis. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27) amongst those with a known outcome. Adjusting for definite TBM diagnosis and antiretroviral therapy use, and using imputed data, assuming 50% of those with an unknown outcome died, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three. Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard. Conclusions: As TBM diagnostics have improved, microbiologically-confirmed TBM diagnoses have increased and in-hospital mortality has declined. Yet, mortality due to TB meningitis remains unacceptably high and further measures are needed to improve outcomes from TBM in Uganda.

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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

Cited by 467 publications

References 23 publications

Drug resistance mechanisms and drug susceptibility testing for tuberculosis

Drug resistance mechanisms and drug susceptibility testing for tuberculosis

Drug‐resistant tuberculosis: An update on disease burden, diagnosis and treatment

Can improved diagnostics reduce mortality from Tuberculous meningitis? Findings from a 6.5-year cohort in Uganda

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