The clinical effect of mixed-strain Mycobacterium tuberculosis infections and heteroresistance to isoniazid or rifampicin: a retrospective cohort study. Mycobacterium tuberculosis

Background: Heteroresistant Mycobacterium tuberculosis (Mtb) infections (concomitantinfection with drug-resistant and drug-susceptible Mtb) may explain the higher risk ofpoor tuberculosis (TB) treatment outcomes observed among patients with mixed-strainMtb infections. We investigated the clinical effect of mixed infections andheteroresistance among a population-based sample of TB patients starting first-line TBtherapy in Botswana.Methods: We performed 24-locus MIRU-VNTR and targeted deep sequencing onbaseline primary cultured isolates to detect mixed infections and heteroresistance,respectively. Drug sensitive, micro-heteroresistant, macro-heteroresistant, and fixed-resistant infections were defined as <0.1%, 0.1 – 4%, 5% – 94%, and ≥95% frequencyof resistance-associated variants, respectively, in resistance conferring domains ofkatG, inhA promoter, and rpoB genes.Results: Of the 260 TB patients included in the study, 25 (9.6%) had mixed infectionsand 30 (11.5%) had poor treatment outcomes. Micro-heteroresistance, macro-heteroresistance, and fixed resistance were found among 11 (4.2%), 2 (0.8%) and 11(4.2%) for isoniazid and 21 (8.1%), 0 (0%) and 10 (3.8%) for rifampicin, respectively. Inmultivariable analysis, mixed infections, but not heteroresistant infections,independently predicted poor treatment outcomes.Conclusions: Among newly diagnosed TB patients in Botswana, heteroresistant Mtbinfections did not explain the association between mixed infections and poor TBtreatment outcomes.

背景：异质性耐药结核分枝杆菌（Mycobacterium tuberculosis, Mtb）感染指同时感染耐药与药物易感型结核分枝杆菌，该类感染或可解释混合菌株结核分枝杆菌感染患者中观察到的结核病治疗转归不良风险升高现象。本研究针对博茨瓦纳起始一线抗结核治疗的肺结核患者人群样本，探究混合感染与异质性耐药的临床影响。
方法：本研究对基线初代培养分离株分别开展24位点分枝杆菌散在重复单位-可变数目串联重复序列（24-locus MIRU-VNTR）分型与靶向深度测序，以检测混合感染与异质性耐药。将katG、inhA启动子及rpoB基因耐药决定区内耐药相关变异体的频率分别＜0.1%、0.1%~4%、5%~94%、≥95%的感染定义为药物敏感感染、微异质性耐药感染、宏异质性耐药感染及固定耐药感染。
结果：本研究纳入260例肺结核患者，其中25例（9.6%）存在混合感染，30例（11.5%）出现不良治疗转归。异烟肼相关的微异质性耐药、宏异质性耐药、固定耐药检出率分别为4.2%（11例）、0.8%（2例）、4.2%（11例）；利福平相关的上述三类耐药检出率则分别为8.1%（21例）、0%（0例）、3.8%（10例）。多变量分析显示，混合感染而非异质性耐药感染可独立预测不良治疗转归。
结论：在博茨瓦纳新发肺结核患者中，异质性耐药结核分枝杆菌感染无法解释混合感染与结核病不良治疗转归之间的关联。