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Jarlier, Vincent
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article
Molecular Investigation of Resistance to Second-Line Injectable Drugs in Multidrug-Resistant Clinical Isolates of <i>Mycobacterium tuberculosi</i> s in France
Abstract
<jats:title>ABSTRACT</jats:title><jats:p>The second-line injectable drugs (SLID, i.e., amikacin, kanamycin, capreomycin) are key drugs for the treatment of multidrug-resistant tuberculosis. Mutations in<jats:italic>rrs</jats:italic>region 1400,<jats:italic>tlyA</jats:italic>, and<jats:italic>eis</jats:italic>promoter are associated with resistance to SLID, to capreomycin, and to kanamycin, respectively. In this study, the sequencing data of SLID resistance-associated genes were compared to the results of phenotypic drug susceptibility testing by the proportion method for the SLID in 206 multidrug-resistant clinical isolates of<jats:named-content content-type="genus-species">Mycobacterium tuberculosis</jats:named-content>collected in France. Among the 153 isolates susceptible to the 3 SLID, 145 showed no mutation, 1 harbored T1404C and G1473A mutations in<jats:italic>rrs</jats:italic>, and 7 had an<jats:italic>eis</jats:italic>promoter mutation. Among the 53 strains resistant to at least 1 of the SLID, mutations in<jats:italic>rrs</jats:italic>accounted for resistance to amikacin, capreomycin, and kanamycin for 81%, 75%, and 44% of the isolates, respectively, while mutations in<jats:italic>eis</jats:italic>promoter were detected in 44% of the isolates resistant to kanamycin. In contrast, no mutations in<jats:italic>tlyA</jats:italic>were observed in the isolates resistant to capreomycin. The discrepancies observed between the genotypic (on the primary culture) and phenotypic drug susceptibility testing were explained by (i) resistance to SLID with MICs close to the critical concentration used for routine DST and not detected by phenotypic testing (<jats:italic>n</jats:italic>= 8, 15% of SLID-resistant strains), (ii) low-frequency heteroresistance not detected by sequencing of drug resistance-associated genes on the primary culture (<jats:italic>n</jats:italic>= 8, 15% of SLID-resistant strains), and (iii) other resistance mechanisms not yet characterized (<jats:italic>n</jats:italic>= 7, 13% of SLID-resistant strains).</jats:p>