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Heteroresistance in tuberculosis: are we missing drug-resistant bacteria hiding in plain sight?
  1. Mirae Park1,
  2. Giovanni Satta2,
  3. Pranabashis Haldar3
  1. 1 Respiratory Medicine, Imperial College Healthcare NHS Trust, London, UK
  2. 2 University College London Centre for Clinical Microbiology, London, UK
  3. 3 Department of Respiratory Sciences, NIHR Respiratory BRC, Glenfield Hospital, University of Leicester, Leicester, UK
  1. Correspondence to Dr Mirae Park, Respiratory Medicine, Imperial College Healthcare NHS Trust, London, UK; mirae.park{at}

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) remains the dominant cause of death from a bacterial infectious disease.1 Sustained global efforts to meet the ambitious elimination targets of WHO’s END-TB strategy have had a limited impact so far. This reflects the complex and multifaceted challenge posed, with multidrug resistant (MDR)-TB representing a significant and growing problem. In 2021, there were an estimated 450 000 new cases of MDR-TB, a 3.1% increase from 2020.1 Furthermore, only 36% of this population accessed treatment, due in part to the challenges of recognising drug resistance.

While culture-based methods have historically provided the gold standard for drug susceptibility testing, they are limited by the prolonged turnaround time which can extend from weeks to months due to dependence on the slow growth rate of MTB. In patients with unrecognised drug-resistant TB, antituberculous therapy may therefore be ineffective or suboptimal, worsening morbidity and prognosis and promoting the development of further drug resistance. Technological advances over the past 15 years have led to a steady transition towards more rapid diagnostic molecular methods that focus on identifying the presence of gene mutations associated with resistance. These include automated platforms for targeted PCR that provide screening at scale, coupled with whole genome sequencing (WGS) for coverage at depth and scope to identify emerging mutations of clinical significance. In 2017, the UK became the first country to systematically implement WGS into the routine diagnostic workflow of mycobacterial infection, achieving clinically impactful improvements in the reporting time of genotypic drug-resistance mutations.2 As data accumulate globally, our understanding of genotypic correlates of phenotypic resistance3 is evolving, supporting wider WGS adoption. However, this transition carries potential risks and …

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