DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa ; Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, Basel, Switzerland.
PLoS One. 2013 Aug 23;8(8):e70919. doi: 10.1371/journal.pone.0070919. eCollection 2013.
South Africa shows one of the highest global burdens of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). Since 2002, MDR-TB in South Africa has been treated by a standardized combination therapy, which until 2010 included ofloxacin, kanamycin, ethionamide, ethambutol and pyrazinamide. Since 2010, ethambutol has been replaced by cycloserine or terizidone. The effect of standardized treatment on the acquisition of XDR-TB is not currently known.
We genetically characterized a random sample of 4,667 patient isolates of drug-sensitive, MDR and XDR-TB cases collected from three South African provinces, namely, the Western Cape, Eastern Cape and KwaZulu-Natal. Drug resistance patterns of a subset of isolates were analyzed for the presence of commonly observed resistance mutations.
Our analyses revealed a strong association between distinct strain genotypes and the emergence of XDR-TB in three neighbouring provinces of South Africa. Strains predominant in XDR-TB increased in proportion by more than 20-fold from drug-sensitive to XDR-TB and accounted for up to 95% of the XDR-TB cases. A high degree of clustering for drug resistance mutation patterns was detected. For example, the largest cluster of XDR-TB associated strains in the Eastern Cape, affecting more than 40% of all MDR patients in this province, harboured identical mutations concurrently conferring resistance to isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, ethionamide, kanamycin, amikacin and capreomycin.
XDR-TB associated genotypes in South Africa probably were programmatically selected as a result of the standard treatment regimen being ineffective in preventing their transmission. Our findings call for an immediate adaptation of standard treatment regimens for M/XDR-TB in South Africa.
南非的耐多药（MDR）和广泛耐药（XDR）结核病（TB）负担位居全球之首。自 2002 年以来，南非采用标准化联合疗法治疗 MDR-TB，该方案在 2010 年以前包含氧氟沙星、卡那霉素、乙胺丁醇、乙硫异烟胺和吡嗪酰胺。自 2010 年以来，乙硫异烟胺已被环丝氨酸或特拉唑嗪取代。目前尚不清楚标准化治疗对 XDR-TB 获得的影响。
我们从南非三个省份（西开普省、东开普省和夸祖鲁-纳塔尔省）采集了随机抽样的 4667 例药物敏感、MDR 和 XDR-TB 患者分离株，对其进行了基因特征分析。对部分分离株的耐药模式进行了分析，以检测常见耐药突变的存在情况。
我们的分析结果表明，在南非的三个相邻省份，不同的菌株基因型与 XDR-TB 的出现之间存在很强的关联性。从药物敏感到 XDR-TB，XDR-TB 中主要存在的菌株比例增加了 20 多倍，占 XDR-TB 病例的 95%以上。我们检测到耐药突变模式高度聚类。例如，在东开普省最大的 XDR-TB 相关菌株簇中，该省超过 40%的所有 MDR 患者同时携带了导致异烟肼、利福平、吡嗪酰胺、乙胺丁醇、链霉素、乙硫异烟胺、卡那霉素、阿米卡星和卷曲霉素耐药的相同突变。
南非的 XDR-TB 相关基因型可能是由于标准治疗方案无效而在临床上被选择出来的。我们的研究结果呼吁南非立即调整 M/XDR-TB 的标准治疗方案。
