Abstract
BackgroundIsoniazid (INH) represents the cornerstone for the treatment of cases infected with Mycobacterium tuberculosis (MTB) strains. Several molecular mechanisms have been shown to be the major causes for INH resistance, while the dynamic change of mutations conferring INH resistance among MTB strains during the past decade is still unknown in China.MethodsIn this study, we carried out a comparative analysis of the INH minimal inhibitory concentration (MIC) distribution, and investigate the dynamic change of molecular characteristics among INH-resistant MTB strains between 2005 and 2015.ResultsThe proportion of INH resistance (39.0%, 105/269) in 2015 was significantly higher than in 2005 (30.0%, 82/273; P = 0.03). Among 269 isolates collected in 2015, 76 (28.3%, 76/269) exhibited high-level INH-resistance (MIC≥32 mg/L), which was significantly higher than that in 2005 (20.5%, 56/273, P = 0.04). In addition, a significantly higher percentage of INH-resistant isolates carried inhA promoter mutations in 2015 (26.7%) versus that in 2005 (14.6%, P = 0.04), while no significant difference was observed in the rates of isolates containing katG mutations between 2005 (76.8%) and 2015 (70.5%, P = 0.33). Notably, the proportion of MTB isolates with inhA mutations (26.7%, 28/105) for patients who had previous exposure to protionamide (PTH) was higher than that for patients who had no previous exposure to PTH (21.4%, 6/28).ConclusionsIn conclusion, our results demonstrated that the proportion of INH-resistant MTB isolates significantly increased during the last decade, which was mainly attributed to an increase of high-level INH-resistant MTB. In addition, prior exposure to PTH may be associated with the increased frequency of INH-resistant tuberculosis strains with inhA mutations in China.
Highlights
Isoniazid (INH) represents the cornerstone for the treatment of cases infected with Mycobacterium tuberculosis (MTB) strains
Approximately 85% of all clinical INH-resistant isolates have the mutations in the two genes, the contribution of these two major mechanisms in INH resistance differ from one geographic region to another, indicating the genetic diversity of INH-resistant MTB strains circulating in various regions [5, 13, 14]
Factors associated with the increased prevalence of INHresistant TB A total of 542 MTB isolates were enrolled in this study, including 273 isolates (50.4%) collected in 2005 and 269 isolates (49.6%) collected in 2015
Summary
Isoniazid (INH) represents the cornerstone for the treatment of cases infected with Mycobacterium tuberculosis (MTB) strains. Resistance to isoniazid is a complex process, and several genes, including katG, inhA, ahpC, kasA and ndh, involve in resistance to INH in MTB [9,10,11] Of these targets, two molecular mechanisms have been shown to be the major causes for INH resistance: mutations in katG and mutations in the promoter region of inhA [11]. Multiple studies have shown that katG mutations are the most frequent genetic substitutions conferring INH resistance, especially in high-level INH resistant strains [12] In the latter situation, mutations in the promoter region of inhA gene stimulate the overexpression of InhA, the target protein of INH, and cause INH resistance, which are usually associated with low-level resistance [12]. Approximately 85% of all clinical INH-resistant isolates have the mutations in the two genes, the contribution of these two major mechanisms in INH resistance differ from one geographic region to another, indicating the genetic diversity of INH-resistant MTB strains circulating in various regions [5, 13, 14]
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