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Ethionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in theMycobacterium tuberculosis population. ETH resistance inM. tuberculosis is phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in theinhA promoter and in the following genes:katG ,ethA ,ethR ,mshA ,ndh , andinhA . We sequenced the above genes in 64M. tuberculosis isolates (n = 57 ETH-resistant MDR-TB isolates;n = 3 ETH-susceptible MDR-TB isolates; andn = 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% inkatG , 72% inethA , 45.6% inmshA , 8.7% inndh , and 33.3% ininhA or its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations inkatG ; one had a mutation inethA , and another, inmshA andinhA . Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations inmshA gene unrelated to the resistance. Mutations not previously reported were found in theethA ,mshA ,katG , andndh genes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in theM. tuberculosis isolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

antimicrobial agents and chemotherapy

Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates