卡那霉素治疗的南非广泛耐药结核病患者中耐药率高、缺乏临床获益且预后不佳。
High frequency of resistance, lack of clinical benefit, and poor outcomes in capreomycin treated South African patients with extensively drug-resistant tuberculosis.
作者信息
Pietersen Elize, Peter Jonny, Streicher Elizabeth, Sirgel Frik, Rockwood Neesha, Mastrapa Barbara, Te Riele Julian, Davids Malika, van Helden Paul, Warren Robin, Dheda Keertan
机构信息
Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Department of Science and Technology/National Research Foundation Centre for Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Science, Stellenbosch University, Tygerberg, South Africa.
出版信息
PLoS One. 2015 Apr 24;10(4):e0123655. doi: 10.1371/journal.pone.0123655. eCollection 2015.
BACKGROUND
There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear.
METHODS
We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis.
RESULTS
Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co-amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin.
CONCLUSION
In South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings.
背景
关于广泛耐药结核病（XDR-TB）患者中卷曲霉素耐药的流行病学及与治疗相关的转归的数据有限。相对于最低抑菌浓度（MIC），卷曲霉素可在血清中达到较高浓度，但尽管存在微生物耐药，卷曲霉素是否具有治疗益处仍不明确。
方法
我们回顾了2002年8月至2012年10月在南非两个省诊断为XDR-TB的患者中与卷曲霉素使用相关的药敏谱及转归。对分离株进行卷曲霉素耐药基因分型检测的患者纳入分析。
结果
178例XDR-TB患者中，41%感染了HIV。87%（154/178）的分离株含有赋予卷曲霉素耐药的突变[80%（143/178）rrs A1401G，6%（11/178）为异质性耐药（同时含有rrs A1401G突变和野生型序列）]。既往耐多药结核病（MDR-TB）治疗史、既往使用卡那霉素情况或菌株类型与卷曲霉素耐药无关。92%（163/178）的XDR-TB患者接受了卷曲霉素经验性治疗。卷曲霉素耐药降低了痰培养转阴的几率。在卷曲霉素敏感和耐药患者中，诊断时的体重是生存的唯一独立预测因素（p<0.001）。相比之下，HIV状态和使用阿莫西林/克拉维酸是死亡的独立预测因素（p<0.05）。当分析仅限于分离株对卷曲霉素耐药的患者时，卷曲霉素的使用与生存或培养转阴无关。
结论
在南非，XDR-TB分离株中赋予卷曲霉素耐药的突变频率极高。对于那些存在卷曲霉素耐药的患者，使用卷曲霉素似乎没有治疗益处。这些数据为结核病流行地区XDR-TB的药敏试验及治疗方案设计提供了参考。
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