Liu Yanping, Zhang Yangyi, Lu Xiaoyu, Wu Zheyuan, Li Minjuan, Zhang Rui, Lu Yixiao, Hou Renjie, Ji Yating, Zhang Qingping, Jiang Qi, Li Jing, Jiang Yuan, Wang Yunxia, Yuan Jianhui, Takiff Howard E, Chen Xin, Shen Xin, Yang Chongguang
School of Public Health (Shenzhen), Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Guangdong, People's Republic of China.
Division of TB and HIV/AIDS Prevention, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, People's Republic of China.
Emerg Microbes Infect. 2025 Dec;14(1):2534656. doi: 10.1080/22221751.2025.2534656. Epub 2025 Aug 1.
Mixed infection refers to the presence of multiple strains within one host, while heteroresistance denotes the coexistence of drug-susceptible and drug-resistant strains or genotypes. Mixed infections and heteroresistance with can complicate drug resistance diagnosis, treatment options, and transmission inference. We conducted a population-based genomic epidemiological study of multidrug-resistant tuberculosis (MDR-TB) in Shanghai, China, between January 1, 2005, and December 31, 2018, to evaluate the prevalence and impact of mixed infection and heteroresistance on MDR-TB diagnosis and treatment outcomes. Demographic, clinical, and laboratory data were collected, and factors associated with mixed infections and heteroresistance were identified with multivariable logistic regression analysis. Among the 936 MDR-TB patients in our study, 10.8% (101/936) had mixed infections and 16.5% (154/936) exhibited heteroresistance, which was more frequent with second-line anti-TB drugs ( < 0.01). There was a higher risk of heteroresistance in older patients (≥60 years: aOR 1.91, 95% CI 1.02-3.57), patients with diabetes (2.59, 1.36-4.91), and mixed infections (2.85, 1.67-4.88). Mixed infections and heteroresistance accounted for 22.6% (58/257) of the strains with discrepancies between phenotypic and genotypic drug susceptibility testing (DST). Strains with heteroresistance to EMB had a higher discordance rate than those without (29.1% VS 17.2%, < 0.05). Isolates that were phenotypically susceptible but genotypically resistant harboured minority or low-frequency resistance mutations and were more common in patients with mixed infections and heteroresistance. In summary, mixed infections are significantly associated with heteroresistance, and both mixed infections and heteroresistance can lead to discrepancies between phenotypic and genotypic DST.
混合感染是指在一个宿主体内存在多种菌株，而异质性耐药是指药物敏感菌株与耐药菌株或基因型同时存在。混合感染和异质性耐药会使耐药性诊断、治疗方案及传播推断变得复杂。我们于2005年1月1日至2018年12月31日在中国上海开展了一项基于人群的耐多药结核病（MDR-TB）基因组流行病学研究，以评估混合感染和异质性耐药对MDR-TB诊断及治疗结果的患病率和影响。收集了人口统计学、临床和实验室数据，并通过多变量逻辑回归分析确定了与混合感染和异质性耐药相关的因素。在我们研究的936例MDR-TB患者中，10.8%（101/936）有混合感染，16.5%（154/936）表现出异质性耐药，二线抗结核药物的异质性耐药更为常见（<0.01）。老年患者（≥60岁：调整后比值比1.91，95%置信区间1.02-3.57）、糖尿病患者（2.59，1.36-4.91）和混合感染患者（2.85，1.67-4.88）发生异质性耐药的风险更高。在表型和基因型药物敏感性试验（DST）结果存在差异的菌株中，混合感染和异质性耐药占22.6%（58/257）。对乙胺丁醇有异质性耐药的菌株的不一致率高于无此耐药的菌株（29.1%对17.2%，<0.05）。表型敏感但基因型耐药的分离株携带少数或低频耐药突变，在混合感染和异质性耐药患者中更为常见。总之，混合感染与异质性耐药显著相关，且混合感染和异质性耐药均可导致表型和基因型DST结果出现差异。
