Sue and Bill Gross School of Nursing, University of California, Irvine.
Botswana-Upenn Partnership, Gaborone, Botswana.
J Infect Dis. 2018 Nov 5;218(12):1974-1982. doi: 10.1093/infdis/jiy480.
Heteroresistant Mycobacterium tuberculosis infections (defined as concomitant infection with drug-resistant and drug-susceptible strains) may explain the higher risk of poor tuberculosis treatment outcomes observed among patients with mixed-strain M. tuberculosis infections. We investigated the clinical effect of mixed-strain infections while controlling for pretreatment heteroresistance in a population-based sample of patients with tuberculosis starting first-line tuberculosis therapy in Botswana.
We performed 24-locus mycobacterial interspersed repetitive unit-variable number tandem-repeat analysis and targeted deep sequencing on baseline primary cultured isolates to detect mixed infections and heteroresistance, respectively. Drug-sensitive, micro-heteroresistant, macro-heteroresistant, and fixed-resistant infections were defined as infections in which the frequency of resistance was <0.1%, 0.1%-4%, 5%-94%, and ≥95%, respectively, in resistance-conferring domains of the inhA promoter, the katG gene, and the rpoB gene.
Of the 260 patients with tuberculosis included in the study, 25 (9.6%) had mixed infections and 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%), respectively, for isoniazid and 21 (8.1%), 0 (0%), and 10 (3.8%), respectively, for rifampicin. In multivariable analysis, mixed infections but not heteroresistant infections independently predicted poor treatment outcomes.
Among patients starting first-line tuberculosis therapy in Botswana, mixed infections were associated with poor tuberculosis treatment outcomes, independent of heteroresistance.
异质性耐药结核分枝杆菌感染（定义为同时感染耐药和敏感株）可能解释了在混合株结核分枝杆菌感染患者中观察到的结核治疗结局较差的更高风险。我们在博茨瓦纳开始一线抗结核治疗的结核患者的基于人群的样本中，通过控制治疗前异质性耐药性，研究了混合感染的临床效果。
我们对基线原发性培养分离物进行了 24 个基因座分枝杆菌插入重复单位-可变数串联重复分析和靶向深度测序，分别检测混合感染和异质性耐药性。药物敏感、微异质性耐药、宏异质性耐药和固定耐药感染定义为在 inhA 启动子、katG 基因和 rpoB 基因的耐药性赋予域中耐药频率<0.1%、0.1%-4%、5%-94%和≥95%的感染。
在研究的 260 例结核患者中，25 例（9.6%）有混合感染，30 例（11.5%）有不良治疗结局。在异烟肼中，分别发现 11 例（4.2%）、2 例（0.8%）和 11 例（4.2%）的微异质性耐药、宏异质性耐药和固定耐药，利福平分别发现 21 例（8.1%）、0 例（0%）和 10 例（3.8%）。多变量分析表明，混合感染而非异质性耐药感染独立预测不良治疗结局。
在博茨瓦纳开始一线抗结核治疗的患者中，混合感染与结核治疗结局不良相关，与异质性耐药无关。
