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. 2017 Oct 15;65(8):1364-1370.
doi: 10.1093/cid/cix556.

Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study

Maha R Farhat  1   2 , Karen R Jacobson  3 , Molly F Franke  4 , Devinder Kaur  5 , Megan Murray  4   6 , Carole D Mitnick  4   7
Affiliations

Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study

Maha R Farhat et al. Clin Infect Dis. .

Abstract

Background: Molecular diagnostics that rapidly and accurately predict fluoroquinolone (FQ) resistance promise to improve treatment outcomes for individuals with multidrug-resistant (MDR) tuberculosis (TB). Mutations in the gyr genes, though, can cause variable levels of in vitro FQ resistance, and some in vitro resistance remains unexplained by gyr mutations alone, but the implications of these discrepancies for treatment outcome are unknown.

Methods: We performed a retrospective cohort study of 172 subjects with MDR/extensively drug-resistant TB subjects and sequenced the full gyrA and gyrB open reading frames in their respective sputum TB isolates. The gyr mutations were classified into 2 categories: a set of mutations that encode high-level FQ resistance and a second set that encodes intermediate resistance levels. We constructed a Cox proportional model to assess the effect of the gyr mutation type on the time to death or treatment failure and compared this with in vitro FQ resistance, controlling for host and treatment factors.

Results: Controlling for other host and treatment factors and compared with patients with isolates without gyr resistance mutations, "high-level" gyr mutations significantly predict poor treatment outcomes with a hazard ratio of 2.6 (1.2-5.6). We observed a hazard of death and treatment failure with "intermediate-level" gyr mutations of 1.3 (0.6-3.1), which did not reach statistical significance. The gyr mutations were not different than culture-based FQ drug susceptibility testing in predicting the hazard of death or treatment failure and may be superior.

Conclusions: FQ molecular-based diagnostic tests may better predict treatment response than traditional drug susceptibility testing and open avenues for personalizing TB therapy.

Keywords: MDR-TB; MIC; fluoroquinolones; gyr; outcome.

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References

    1. World Health Organization Global tuberculosis report 2016 Available at: http://www.who.int/tb/publications/global_report/en/. Accessed 5 January 2017.
    1. Hillemann D, Rüsch-Gerdes S, Richter E. Feasibility of the GenoType MTBDRsl assay for fluoroquinolone, amikacin-capreomycin, and ethambutol resistance testing of Mycobacterium tuberculosis strains and clinical specimens. J Clin Microbiol 2009; 47:1767–72. - PMC - PubMed
    1. Boehme CC, Nabeta P, Hillemann D et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010; 363:1005–15. - PMC - PubMed
    1. Farhat MR, Jacobson KR, Franke MF et al. Gyrase mutations are associated with variable levels of fluoroquinolone resistance in Mycobacterium tuberculosis. J Clin Microbiol 2016; 54:727–33. - PMC - PubMed
    1. Safi H, Lingaraju S, Amin AG et al. Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-arabinose biosynthetic and utilization pathway genes. Nat Genet 2013; 45. doi:10.1038/ng.2743. - PMC - PubMed

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