Molecular Determinants of Ethionamide Resistance in Clinical Isolates of Mycobacterium tuberculosis

Background: Ethionamide and prothionamide are now included in group C of the WHO recommended drugs for the treatment of tuberculosis resistant to rifampicin and multidrug-resistant tuberculosis. The clinical relevance of ethionamide and prothionamide has increased with the wide spread of resistant tuberculosis. Methods: We retrospectively analyzed 349 clinical isolates obtained between 2016 and 2020. The susceptibility to ethionamide was tested using both the Bactec(TM) MGIT(TM) 960 system and the Sensititre(TM) MYCOTB plate. Results: The MIC of ethionamide increases with the total resistance of the isolates in a row from susceptible to XDR strains. A significant part of the isolates have a MIC below the breakpoint: 25%, 36%, and 50% for XDR, pre-XDR, and MDR strains. Sensitivity and specificity of detection of mutations were 96% and 86% using MGIT resistance as a reference. Conclusions: Phenotypic methods for testing ethionamide are imperfectly correlated, and the isolates with MIC of 5 mg/L have the intermediate resistance. A significant proportion of resistant TB cases are susceptible and eligible for ethionamide treatment. Resistance could be explained using only analysis of loci ethA, P-fabG1, and inhA for most isolates in the Moscow region. The promoter mutation P-fabG1 c(-15)t predicts resistance to ethionamide with high specificity but low sensitivity.

Automated summary

Ethionamide susceptibility testing methods are imperfectly correlated in drug-resistant tuberculosis, and a significant proportion of resistant TB cases are susceptible to ethionamide treatment.