High Frequency of Resistance, Lack of Clinical Benefit, and Poor Outcomes in Capreomycin Treated South African Patients with Extensively Drug-Resistant Tuberculosis

BackgroundThere 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.MethodsWe 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.ResultsOf 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=ConclusionIn 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】目前关于广泛耐药结核病（XDR-TB, Extensively Drug-Resistant Tuberculosis）患者合并卷曲霉素（capreomycin）耐药的流行病学特征及治疗相关转归的数据十分有限。卷曲霉素的血清浓度远高于最低抑菌浓度（MIC, Minimum Inhibitory Concentration），但即便存在微生物学耐药，卷曲霉素是否仍能发挥治疗益处，目前仍不明确。【方法】本研究回顾分析了2002年8月至2012年10月间，南非两个省份确诊的广泛耐药结核病患者的药敏谱及使用卷曲霉素后的治疗转归。本分析纳入了经基因检测确认存在卷曲霉素耐药的患者。【结果】178例广泛耐药结核病患者中，41%合并人类免疫缺陷病毒（HIV, Human Immunodeficiency Virus）感染。87%（154/178）的菌株分离株携带可介导卷曲霉素耐药的突变[其中80%（143/178）为rrs A1401G突变，6%（11/178）为异质性耐药，即同时携带rrs A1401G突变与野生型序列]。既往耐多药结核病（MDR-TB, Multidrug-Resistant Tuberculosis）治疗史、既往使用卡那霉素，以及菌株分型均与卷曲霉素耐药无显著关联。92%（163/178）的广泛耐药结核病患者接受了经验性卷曲霉素治疗。卷曲霉素耐药会降低痰培养转阴的概率。在所有患者中，诊断时的体重是唯一独立的生存预测因素（原文p值未完整标注）。【结论】在南非，广泛耐药结核病分离株中携带卷曲霉素耐药相关突变的比例极高。对于存在卷曲霉素耐药的患者，使用卷曲霉素似乎未带来明确的治疗益处。本研究数据可为结核病高负担地区的广泛耐药结核病药敏检测及治疗方案设计提供参考依据。