Jose Vadakunnel Maria, Nehru Vijayalakshmi Jawaharlal, Brammacharry Usharani, Ramachandra Venkateswari, Palavesam Suganthi, Muthukumar Anbazhagi, Mani Balasundaram Revathi, R Sriramkumar S, Pradhabane Gunavathy, Vn Azger Dusthackeer, Subramani Sangeetha, Muthaiah Muthuraj, Soundappan Govindarajan
Institute of Basic Medical Sciences, University of Madras, Chennai, Tamil Nadu, India.
Department of Environmental Science, Central University, Kasaragod, Kerala, India.
BMC Infect Dis. 2025 Feb 27;25(1):284. doi: 10.1186/s12879-025-10655-6.
Although many studies have examined the connection between mutations in the rpoB gene and drug resistance, the impact of common mutations on treatment outcomes for RR-TB is not yet fully understood.
This study explores the relationship between rpoB gene mutations and drug-resistant phenotypes, assesses their role in predicting RR-TB prognosis, and investigates the impact of disputed rpoB mutations in M. tuberculosis on treatment outcomes.
192 rifampicin-resistant isolates were retested for drug susceptibility and gene sequencing. Minimum inhibitory concentrations (MICs) were determined for 98 isolates with disputed rpoB gene mutations. These mutations can cause low-level resistance to rifampicin, leading to inconsistencies in drug susceptibility testing and impacting medication therapy decisions.
Of 192 cases, 116 (60.4%) achieved successful outcomes, while 76 (39.6%) were unsuccessful. Among the 98 isolates tested for phenotypic drug susceptibility testing (DST) based on minimum inhibitory concentration (MIC), 67 (68.4%) showed high-level resistance with a MIC of ≥ 1 µg/mL. In contrast, 31 (31.6%) drug-susceptible tuberculosis isolates exhibited low-level resistance with a MIC of < 1.0 µg/mL. Of the 31 isolates with low-level resistance, 14 (45.2%) had successful treatment outcomes, while 17 (54.8%) did not. Among the 67 isolates with high-level resistance, 41 (61.2%) achieved successful outcomes, whereas 26 (38.8%) did not. In analysing the 14 codons of the Rifampicin Resistance Determining Region (RRDR) of the rpoB gene, the Leu430Pro codon showed the highest odds ratio (OR) of 2.98 (95% CI: 0.96-9.27) with a p-value of 0.0591, indicating statistically not significant. However, this suggests a potential association with rifampicin resistance that requires further investigation, particularly in areas with high drug-resistant tuberculosis prevalence. Other reported variants had lower odds ratios: Asp435Val with 1.23 (95% CI: 0.32-4.75), Asp435Tyr with 1.86 (95% CI: 0.60-5.76), His445Tyr with 1.16 (95% CI: 0.47-2.91), and Ser450Leu with 1.44 (95% CI: 0.81-2.58).
This study indicates that low-level rifampicin mono-resistance in tuberculosis (TB) patients is associated with poor clinical outcomes. A mutation at the Leu430Pro codon showed the highest odds ratio of 2.98 (p-value 0.0591), suggesting a potential association with rifampicin resistance that warrants further research, especially in areas with high drug-resistant TB. It highlights the need for more aggressive treatment strategies for patients with low-level rifampicin resistance, even if they seem solely mono-resistant.
尽管许多研究已探讨rpoB基因突变与耐药性之间的联系，但常见突变对耐多药结核病治疗结果的影响尚未完全明确。
本研究探讨rpoB基因突变与耐药表型之间的关系，评估其在预测耐多药结核病预后中的作用，并研究结核分枝杆菌中存在争议的rpoB基因突变对治疗结果的影响。
对192株耐利福平菌株重新进行药敏试验和基因测序。对98株存在争议的rpoB基因突变的菌株测定最低抑菌浓度（MIC）。这些突变可导致对利福平的低水平耐药，从而导致药敏试验结果不一致，并影响药物治疗决策。
192例患者中，116例（60.4%）治疗成功，76例（39.6%）治疗失败。在基于最低抑菌浓度（MIC）进行表型药敏试验（DST）的98株菌株中，67株（68.4%）表现出高水平耐药，MIC≥1μg/mL。相比之下，31株（31.6%）药敏结核分枝杆菌菌株表现出低水平耐药，MIC<1.0μg/mL。在31株低水平耐药菌株中，14株（45.2%）治疗成功，17株（54.8%）治疗失败。在67株高水平耐药菌株中，41株（61.2%）治疗成功，26株（38.8%）治疗失败。在分析rpoB基因的利福平耐药决定区（RRDR）的14个密码子时，Leu430Pro密码子的优势比（OR）最高，为2.98（95%CI：0.96 - 9.27），p值为0.0591，表明在统计学上无显著意义。然而，这表明其与利福平耐药可能存在关联，需要进一步研究，特别是在耐多药结核病患病率高的地区。其他报道的变异体优势比较低：Asp435Val为1.23（95%CI：0.32 - 4.75），Asp435Tyr为1.86（95%CI：0.60 - 5.76），His445Tyr为1.16（95%CI：0.47 - 2.91），Ser450Leu为1.44（95%CI：0.81 - 2.58）。
本研究表明，结核病患者的低水平利福平单耐药与不良临床结局相关。Leu430Pro密码子处的突变优势比最高，为2.98（p值0.0591），表明其与利福平耐药可能存在关联，值得进一步研究，尤其是在耐多药结核病高发地区。这突出了对低水平利福平耐药患者，即使看起来只是单耐药，也需要采取更积极治疗策略的必要性。
