Drug resistance mechanisms and drug susceptibility testing for tuberculosis

Abstract

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.

Contemporary Concise Review 2018: Respiratory infections and tuberculosis

“…Molecular diagnostic tools are increasingly utilized to diagnose TB and detect drug resistance for both pulmonary and extrapulmonary diseases . In a study by Christopher et al , Xpert MTB/RIF assay on the thoracoscopic biopsy gave a substantially higher yield of 45% than biopsy culture (39%), pleural fluid culture (17%) or pleural fluid Xpert MTB/RIF (14%) among 73 patients with TB confirmed by histopathology on thoracoscopic biopsy.…”

“…Unlike other bacterial infections, a single critical concentration that inhibits the growth of 99% of phenotypically wild type strains is used to classify phenotypic susceptibility or resistance to TB drugs . However, this may not reflect the achievable serum drug level or clinical response of a mutant strain .…”

“…Unlike other bacterial infections, a single critical concentration that inhibits the growth of 99% of phenotypically wild type strains is used to classify phenotypic susceptibility or resistance to TB drugs . However, this may not reflect the achievable serum drug level or clinical response of a mutant strain . Clinical breakpoint (minimal inhibitory concentration at or below which the relevant strain is likely to respond to treatment) may be more informative for isoniazid, rifampicin, fluoroquinolones and other drugs that can be used at higher doses.…”

“…Clinical breakpoint (minimal inhibitory concentration at or below which the relevant strain is likely to respond to treatment) may be more informative for isoniazid, rifampicin, fluoroquinolones and other drugs that can be used at higher doses. The target drug coverage of commercial rapid molecular tests suitable for direct application to clinical specimens is still too limited to guide the formulation of individualized treatment regimens for MDR‐/rifampicin‐resistant (RR‐)TB . Whole‐genome sequencing holds promise for revolutionizing the predictive power of genotypic drug susceptibility test, but cost, throughput, facility requirement, background noises and replicative errors are important hurdles to overcome before its direct application to clinical specimens …”

Epidemiological cut-offs for Sensititre susceptibility testing of Mycobacterium tuberculosis: interpretive criteria cross validated with whole genome sequencing

“…Universal drug susceptibility testing (DST) is highlighted as an important component of the World Health Organizations (WHO) End TB strategy 3 . The increased availability of molecular tests that effectively detect resistance associated variants (RAVs) in the 81 bp hotspot of the rpoB gene which almost universally confers resistance to rifampicin has been very successful 4 . However, for other drugs, genetic targets and markers are less well defined and testing is not ideal for resistance determination.…”