title: The clinical relevance of Mycobacterial pharmacogenetics.
abstract: Current anti-tuberculosis (anti-TB) drug sensitivity testing methods provide a dichotomous readout: isolates are reported as either drug susceptible or drug resistant. This report demonstrates that rapid molecular methods may provide information concerning both the level of resistance and cross-resistance to other anti-TB drugs that is important for optimal clinical management. Specific mutations detected by the Hain GenoType MTBDRplus test, recently approved by the World Health Organization (WHO) for rapid TB diagnosis and drug resistance testing, could inform the decision of whether to include high dose isoniazid (INH) when treating patients with INH mono-resistant TB, MDR-TB or XDR-TB. The presence of mutations in the inhA gene or promoter region generally confers low level INH resistance that can be overcome by high dose INH. The same mutations also confer resistance to ethionamide indicating little benefit from its inclusion in second line treatment regimens in such cases. This information has high clinical relevance since inhA mutations account for a large proportion of INH resistance, and optimized therapy regimens are crucial to improve patient outcomes and reduce the spread of drug resistant TB. This hypothesis needs to be tested in well controlled clinical and pharmacokinetic studies.
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Stellenbosch University, Tygerberg 7505, South Africa. rw1@sun.ac.za
authors.forename: R M
authors.initials: RM
authors.lastname: Warren
authors.forename: E M
authors.initials: EM
authors.lastname: Streicher
authors.forename: N C
authors.initials: NC
authors.lastname: Gey van Pittius
authors.forename: B J
authors.initials: BJ
authors.lastname: Marais
authors.forename: G D
authors.initials: GD
authors.lastname: van der Spuy
authors.forename: T C
authors.initials: TC
authors.lastname: Victor
authors.forename: F
authors.initials: F
authors.lastname: Sirgel
authors.forename: P R
authors.initials: PR
authors.lastname: Donald
authors.forename: P D
authors.initials: PD
authors.lastname: van Helden
mesh_terms: D000465:Algorithms; D000995:Antitubercular Agents / Q000097:blood* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics; D002374:Catalase / Q000235:genetics; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007538:Isoniazid / Q000097:blood* / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; D002374:Catalase; C480353:katG protein, Mycobacterium tuberculosis; C085257:InhA protein, Mycobacterium; D007538:Isoniazid