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.
