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Background <p>Linezolid is an important drug for the treatment of drug-resistant tuberculosis (DR-TB). Acquired linezolid resistance threatens treatment efficacy. This study aimed to analyze the risk factors and molecular mechanisms of linezolid-acquired resistance in a clinical cohort.</p> Methods <p>We conducted a retrospective study of 61 patients with DR-TB who failed linezolid-containing regimens (2017–2021). Paired baseline and post-treatment <i>Mycobacterium tuberculosis</i> isolates were subjected to linezolid Minimum inhibitory concentration (MIC) testing (Microplate Alamar Blue Assay) and sequencing of <i>rplC</i>, <i>rrl</i> (23&#xa0;S rRNA), and <i>rplD</i>. Acquired resistance was defined as a ≥ 4-fold increase in MIC or the presence of new resistance-conferring mutation. Risk factors were analyzed using logistic regression.</p> Results <p>Acquired linezolid resistance occurred in 31.1% (19/61) of patients. Younger age (&lt; 37.5 years; OR = 1.04/year decrease, <i>p</i> = 0.012) and prolonged therapy (&gt; 14.3 months; OR = 1.07/month, <i>p</i> = 0.004) were the independent risk factors. Sequencing revealed 26 mutation events across the longitudinal isolates; 57.7% (15/26) harbored <i>rplC</i> T460C (Cys154Arg), whereas 38.5% (10/26) had <i>rrl</i> mutations (G2270T, G2814T). A novel <i>rplD</i> A518T (Lys173Ile) mutation emerged concurrently with the <i>rplC</i> T460C mutation. Phenotypic-genotypic discordance occurred in 11.5% (3/26) of resistant isolates, including one strain with MIC elevation (0.25→4.0&#xa0;mg/L) lacking target mutations. Linezolid resistance correlated with prior resistance to clofazimine (kappa = 0.538, <i>p</i> &lt; 0.001), amikacin, and pasiniazid.</p> Conclusions <p>Young age, extended therapy, and ribosomal mutations drive linezolid resistance. Pretreatment susceptibility screening is critical.</p>

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Acquired linezolid resistance in DR-TB: genotype-phenotype discordance and molecular heterogeneity in a retrospective cohort

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月14日

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  • Wenqiang Zhou,
  • Qingfeng Wang,
  • Wenjuan Nie,
  • Wenhui Shi,
  • Yang Yang,
  • Wenjie Qi,
  • Yu Lu,
  • Naihui Chu

摘要

Background

Linezolid is an important drug for the treatment of drug-resistant tuberculosis (DR-TB). Acquired linezolid resistance threatens treatment efficacy. This study aimed to analyze the risk factors and molecular mechanisms of linezolid-acquired resistance in a clinical cohort.

Methods

We conducted a retrospective study of 61 patients with DR-TB who failed linezolid-containing regimens (2017–2021). Paired baseline and post-treatment Mycobacterium tuberculosis isolates were subjected to linezolid Minimum inhibitory concentration (MIC) testing (Microplate Alamar Blue Assay) and sequencing of rplC, rrl (23 S rRNA), and rplD. Acquired resistance was defined as a ≥ 4-fold increase in MIC or the presence of new resistance-conferring mutation. Risk factors were analyzed using logistic regression.

Results

Acquired linezolid resistance occurred in 31.1% (19/61) of patients. Younger age (< 37.5 years; OR = 1.04/year decrease, p = 0.012) and prolonged therapy (> 14.3 months; OR = 1.07/month, p = 0.004) were the independent risk factors. Sequencing revealed 26 mutation events across the longitudinal isolates; 57.7% (15/26) harbored rplC T460C (Cys154Arg), whereas 38.5% (10/26) had rrl mutations (G2270T, G2814T). A novel rplD A518T (Lys173Ile) mutation emerged concurrently with the rplC T460C mutation. Phenotypic-genotypic discordance occurred in 11.5% (3/26) of resistant isolates, including one strain with MIC elevation (0.25→4.0 mg/L) lacking target mutations. Linezolid resistance correlated with prior resistance to clofazimine (kappa = 0.538, p < 0.001), amikacin, and pasiniazid.

Conclusions

Young age, extended therapy, and ribosomal mutations drive linezolid resistance. Pretreatment susceptibility screening is critical.