The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis


Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms—including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions—are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.


MDR tuberculosis, XDR tuberculosis, and resistance beyond XDR tuberculosis remains a major threat to global tuberculosis control because of the increasing burden it creates on health-care systems, economies, and societies, the threat to health-care workers in tuberculosis-endemic countries, the high mortality, and the unsustainably high costs of treating drug-resistant tuberculosis. Additionally, the development of totally drug-resistant or programmatically incurable tuberculosis has raised several ethical and medicolegal challenges. The global epidemiology of drug-resistant tuberculosis shows a worrying increase in the prevalence and incidence of drug-resistant tuberculosis in several countries and regions. Also, the proportion of cases of tuberculosis that are MDR and fluoroquinolone-resistant or aminoglycoside-resistant—ie, pre-XDR—or that are programmatically incurable has increased greatly. New molecular tools such as next-generation whole-genome sequencing are shedding further light on the transmission, diagnosis, and pathogenesis of drug-resistant tuberculosis.522Particularly, several lines of evidence challenge the traditional view that resistance is acquired through non-adherence promoted by poor programmatic functioning. Although adherence is clearly important for the prevention of drug-resistant tuberculosis, several other factors that promote pharmacokinetic mismatch drive the acquisition of drug-resistant tuberculosis even when adherence is good. However, newer methods to enable whole-genome sequencing directly from sputum and to assess its effect on clinical outcomes are needed.

Furthermore, a paradigm shift is required to take testing from the clinical setting into the community, thus promoting active case finding, and the detection of the undiagnosed and unsuspected cases of community-based drug-resistant tuberculosis. Newer drugs have improved the efficacy of the treatment of MDR and XDR tuberculosis, and therefore the prognosis, but resistance amplification will need to be minimised through strengthening tuberculosis programmes and other innovative approaches to prevent pharmacokinetic mismatch. Novel ways to reduce or eliminate the transmission of drug-resistant tuberculosis and to understand the fundamental biology of transmission are urgently required. These key messages are summarised in panel 11, and timeline-orientated research priorities and goals for drug-resistant tuberculosis are shown in table 15. All these priorities will need to be urgently addressed in tandem with the strengthening of health systems, reduction of poverty, and changing of political will.

Key messages

  • Resistance to antituberculosis drugs is a global problem of considerable public health importance that threatens to derail efforts to eradicate the disease. Advocacy is needed in national and transnational fora to ensure the urgency of the situation is understood and that appropriate funding is made available.

  • Practices for the management of individual patients in settings with a high tuberculosis burden are not sufficient to prevent the emergence, amplification, and spread of drug-resistant tuberculosis. These practices include empirical treatment with standardised second-line drug regimens for people who are found to have rifampicin-resistant tuberculosis.

  • Access to drug resistance testing is scarce in most countries and urgently needs to be expanded to allow curative second-line treatment regimens to be implemented.

  • Knowledge regarding the safe use—including dose and length of treatment—of new and repurposed drugs must be improved through clinical trials.

  • Models of care for people with drug-resistant tuberculosis, including programmatically incurable disease, must ensure that the rights and dignity of individual patients are respected.

  • Assessment of the performance, health effects, and potential economic benefits of molecular tools such as genome sequencing for detecting resistance, must be accelerated to facilitate effective implementation.

  • Greater investment is needed in the development of new drugs and diagnostics.



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