Remarks

• Priority should be given to those at a higher risk of resistance to medications used for the treatment of RR-TB, including individuals who:
• continue to be smear or culture positive after 2 months or more of treatment or have experienced treatment failure;
• have previously had TB treatment, including with the new and repurposed drugs;
• are in contact with a person known to have resistance to TB drugs, including the new and repurposed drugs; or
• have pre-XDR-TB with resistance to fluoroquinolones.
• As above, this recommendation is conditional because of the lack of data on health benefits, the variable certainty of evidence on diagnostic accuracy, the fact that accuracy is suboptimal for certain drugs, and limited and variable evidence on costs, cost–effectiveness and feasibility of implementation.

Implementation considerations Although the evidence that is available supports the use of targeted NGS to detect drug resistance after TB diagnosis, to guide clinical decision-making for DR-TB treatment, the following factors need to be considered when implementing these tests:

• Regulatory approval from national regulatory authorities or other relevant bodies is required before implementation of these diagnostic tests.
• In its current format, targeted NGS is a high complexity test that is most suitable for centralized laboratories equipped with specialized skills and infrastructure.
• Targeted NGS tests do not replace existing rapid tests that are more accessible and easier to perform for detecting resistance to rifampicin, isoniazid and fluoroquinolones. However, if targeted NGS can be performed rapidly, it can be considered as an alternative initial option for prioritized populations. Those who will benefit most from these tests are individuals who require rapid and comprehensive DST but have limited access to phenotypic DST.
• Priority should be given to samples with a high bacillary load as determined by initial bacteriological tests (e.g. semiquantitative high/medium or smear-positive grading). In situations where the bacillary load is low (e.g. semiquantitative low/very low/trace or smearnegative grading), the recommendations still hold, although rates of indeterminate results are likely to be higher; therefore, phenotypic DST is likely still required for samples with a low bacillary load.
• Similarly, the recommendations apply to children, adolescents and PLHIV populations because these populations have a higher frequency of samples with low bacterial load.
• The recommendation is based on data obtained from sputum and BAL specimens, and can be extrapolated to other lower respiratory tract samples (e.g. endotracheal aspirates). However, further research is needed to evaluate the use of these tests on alternative sample types for diagnosing pulmonary TB in children (e.g. nasopharyngeal and stool samples) and diagnosing extrapulmonary TB.
• Since sensitivity for bedaquiline, linezolid and clofazimine resistance is suboptimal, consideration of the pretest probability is important in interpreting the targeted NGS results for these drugs. Further testing of samples with a susceptible result (using culturebased phenotypic DST) would be warranted, particularly when the risk of resistance is high. Since specificity is high, a result that indicates resistance may be used to guide the therapy, particularly among those at risk for resistance. In the case of pretomanid, the basis for resistance has not been fully elucidated; hence, culture-based DST is also required for this drug.