耐多药结核病的分子机制研究进展

耐药结核病尤其耐多药结核病的发生和流行是当前结核病疫情回升的主要原因之一,成为结核病控制的重要障碍.本文从耐多药结核病的发展现状出发,归纳了各种耐单药结核病、耐多药结核病已有的分子机制研究,从耐多药结核病发病治疗现状、分子生物学、耐多药检测技术角度指出了目前国内外耐多药结核病已有的分子机制研究成果,在此基础上对耐多药结核病发病的分子机制规律的研究前景予以了展望.     

耐多药结核病的分子机制研究进展

耐药结核病尤其耐多药结核病的发生和流行是当前结核病疫情回升的主要原因之一,成为结核病控制的重要障碍.本文从耐多药结核病的发展现状出发,归纳了各种耐单药结核病、耐多药结核病已有的分子机制研究,从耐多药结核病发病治疗现状、分子生物学、耐多药检测技术角度指出了目前国内外耐多药结核病已有的分子机制研究成果,在此基础上对耐多药结核病发病的分子机制规律的研究前景予以了展望.     

耐多药结核病耐药分子机制的研究

目的 研究耐多药结核分支杆菌耐药的分子机理，建立快速检测耐药基因的分子药敏试验方法。方法 通过ＰＣＲ和ＰＣＲ－ＳＳＣＰ分析结构分支杆菌耐多药临床分离株的ｒｐｏＢ、ｒｐｓＬ、ｋａｔＧ基因和ｉｎｈＡ调节序列。结果 ＰＣＲ分析耐药基因的敏感性为１－０ｐｇＤＮＡ；除ｒｐｏＢ基因引物ＰＣＲ扩增为属特异性外，余耐药基因引物ＰＣＲ扩增都具有较高的的特异性。２０株耐多药分离株中，９０％有２种以上耐药遗传标志改变，     

耐多药结核病的预防

耐多药结核病（MDR—TB）是指至少同时对异烟肼和利福平产生耐药的结核分枝杆菌引起的结核病。由于这类患者同时耐至少两种最有效的抗结核病药物，不仅治疗困难，还有可能不可治愈而持续传播耐多药结核菌，增加原发性MDR—TB发病的可能性，造成严重的流行病学和公共卫生隐患。WHO估计全球每年有30万MDR—TB新病例，而我国2000年耐多药率已达10．7％，其中初始耐多药率为7．6％，获得性耐多药率为17．1％。近年来一些省市报道的耐多药率还远远超过该水平，辽宁省和河南省已分别居于西太区9个耐药监测国家和地区的第1和第2位，被WHO称为两个MDR—TB的“热点省”，我国的耐多药结核病问题已经引起了我国和世界范围的关注。紧抓“初治”这个根本环节，采取多种积极措施，预防耐多药结核病的产生，已经成为控制结核病及耐药结核病在我国流行的迫切任务之一。     

应用结核病DNA疫苗治疗小鼠耐多药结核病的研究

目的 研究结核分枝杆菌Ag85A质粒DNA疫苗单独或联合药物治疗小鼠耐多药结核病的效果,为建立耐多药结核病的免疫治疗新策略和新方案奠定基础.方法 用结核分枝杆菌高耐利福平、低耐异烟肼临床分离株HB361尾静脉注射17～19 g的6～8周龄雌性BALB/C小鼠后,将小鼠随机分为6组,每组10只.感染后第2天开始,分别用pVAX1载体(A组)、利福平(B组)、吡嗪酰胺(C组)、Ag85A质粒DNA疫苗(D组)、Ag85A质粒DNA疫苗联合利福平(E组)、Ag85A质粒DNA疫苗联合吡嗪酰胺(F组)治疗60 d.治疗结束后4周,分别取肺、肝和脾观察病理改变,称取重量,做菌落计数.结果 小鼠感染4周后,肺内菌量达到1.5×107 CFU,脾内菌量达到1.1×106 CFU.A、B组小鼠死亡率均为10%,其余各组小鼠均存活.治疗结束后4周,肺组织病理显示,各治疗组肺组织病变均有不同程度减轻,病变局限,可见正常的肺泡结构,肺泡轮廓相对清晰.与A组比较,C、D、E、F组肺组织菌落数分别减少了1.18、1.35、1.38、1.08 logs,脾脏菌落数分别减少了0.91、1.00、1.26、1.03 logs(P＜0.01).结论 结核分枝杆菌Ag85A质粒DNA疫苗单独或联合药物治疗小鼠耐多药结核病均有显著疗效.Ag85A质粒DNA疫苗与抗结核药物联合治疗是治疗耐多药结核病的最有前途的免疫策略.     

结核分枝杆菌耐异烟肼分子机制的研究进展

虽然近几年结核病的增长速度逐步降低,但由于耐多药结核（multidrug-resistant TB,MDR-TB）的持续威胁,以及泛耐药结核（extensively drug-resistant TB,XDR-TB）比例的不断增加[1],对TB的防控仍面临着巨大的困难[2,3]。据世界卫生组织相关报告指出,2008年全球约有MDR-TB病例390000-510000例,占全部结核患者的3.6%,而其中的5.4%为XDR-     

苏州市结核病耐多药情况分析

目的 了解苏州市地区感染结核分枝杆菌(Mycobacterium tuberculosis,MTB)的结核病患者耐多药情况.方法 对2008年9月～2011年5月期间在苏州大学附属传染病医院就诊的肺结核病患者的临床分离株进行菌型鉴定后,用药敏罗氏培养基进行药物敏感性试验,分析结核病患者的耐多药情况.结果 苏州市地区近三年期结核病耐多药发生率总体为10.5％,2010年及2011年度耐多药发生率(18.2％)显著高于2008及2009年度(x2 =19.9,P＜0.01),且复治组耐多药发生率显著高于初治组(x2 =70.5,P＜0.01).结论 苏州大学传染病医院收治的结核病耐多药率呈上升趋势,且复治组高于初治组.     

应用结核病DNA疫苗治疗小鼠耐多药结核病的研究

Objective To establish foundation for new strategy and program on immune therapy of multi-drug resistant tuberculosis (MDR-TB) by studying the therapeutic effects of Mycobacterium tuberculosis Ag85A plasmid DNA vaccine alone or combined with drugs on MDR-TB mice. Methods Sixty 6-8 weeks old female BALB/C mice were injected via tail vein with clinical isolate Mycobacterium tuberculosis HB361 which was highly resistant to rifampin (RFP) and lowly resistant to isoniazid. The mice were randomly divided into six groups, ten mice in each group. From the second day after infection,the mice respectively received pVAX1 vector (group A), RFP (group B), pyrazinamide (PZA) (group C),Ag85A plasmid DNA vaccine (group D), Ag85A plasmid DNA vaccine combined with RFP (group E),Ag85A plasmid DNA vaccine combined with PZA (group F) for sixty days. Four weeks after the end of treatment,the lung, liver and spleen of the mice were taken and their pathological changes, weight and colony count were examined. Results Four weeks after infection, the numbers of bacteria in lung and spleen of the mice reached up to 1.5×107 CFU and 1.1 × 106 CFU,respectively. The death rates of mice in group A and group B were both 10% ,and the mice in other groups were alive. Four weeks after the end of treatment,lung pathology in the treated groups showed that the lung lesions were slight and limited,normal alveolar structure were seen, and the profile of the alveoli was relatively clear. Compared with group A, group C, D, E, F reduced by 1.18,1.35,1.38,1.08 logs on the colony count of lung, and reduced by 0.91,1.00,1.26 and 1.03 logs on the colony count of spleen (P＜0.01), respectively. Conclusions Mycobacterium tuberculosis Ag85A plasmid DNA vaccine alone or combined with drugs has significant therapeutic effects on MDR-TB mice. Ag85A plasmid DNA vaccine combined with anti-tuberculosis drugs is the most promising immunization strategy for treatment of MDR-TB.     

应用结核病DNA疫苗治疗小鼠耐多药结核病的研究

Objective To establish foundation for new strategy and program on immune therapy of multi-drug resistant tuberculosis (MDR-TB) by studying the therapeutic effects of Mycobacterium tuberculosis Ag85A plasmid DNA vaccine alone or combined with drugs on MDR-TB mice. Methods Sixty 6-8 weeks old female BALB/C mice were injected via tail vein with clinical isolate Mycobacterium tuberculosis HB361 which was highly resistant to rifampin (RFP) and lowly resistant to isoniazid. The mice were randomly divided into six groups, ten mice in each group. From the second day after infection,the mice respectively received pVAX1 vector (group A), RFP (group B), pyrazinamide (PZA) (group C),Ag85A plasmid DNA vaccine (group D), Ag85A plasmid DNA vaccine combined with RFP (group E),Ag85A plasmid DNA vaccine combined with PZA (group F) for sixty days. Four weeks after the end of treatment,the lung, liver and spleen of the mice were taken and their pathological changes, weight and colony count were examined. Results Four weeks after infection, the numbers of bacteria in lung and spleen of the mice reached up to 1.5×107 CFU and 1.1 × 106 CFU,respectively. The death rates of mice in group A and group B were both 10% ,and the mice in other groups were alive. Four weeks after the end of treatment,lung pathology in the treated groups showed that the lung lesions were slight and limited,normal alveolar structure were seen, and the profile of the alveoli was relatively clear. Compared with group A, group C, D, E, F reduced by 1.18,1.35,1.38,1.08 logs on the colony count of lung, and reduced by 0.91,1.00,1.26 and 1.03 logs on the colony count of spleen (P＜0.01), respectively. Conclusions Mycobacterium tuberculosis Ag85A plasmid DNA vaccine alone or combined with drugs has significant therapeutic effects on MDR-TB mice. Ag85A plasmid DNA vaccine combined with anti-tuberculosis drugs is the most promising immunization strategy for treatment of MDR-TB.     

耐多药结核病流行与控制

一、概念单耐药(monoreslstance):结核病患者感染的结核分枝杆菌对一种以上的一线抗结核药物耐药。多耐药(polyresistance):结核病患者感染的结核分枝杆菌对一种以上的一线抗结核药物耐药(不包括同时耐异烟肼、利福平)。耐多药(multidrugresistance):结核病患者感染的结核杆菌至少对异烟肼、利福平耐药。     

五药联合方案治疗耐多药结核病的疗效分析

目的　评价异烟肼 (H)、对氨基水杨酸钠 (P)、卷曲霉素 (C)、氧氟沙星 (O)或左氧氟沙星 (L V)和丙硫异烟胺 (Th)方案治疗耐多药结核病 (MDR- TB)的疗效。方法　将 85例 MDR- TB随机分为两组 :治疗组 (4 5例 )应用 H、P、C、O或 L V、Th;对照组 (4 0例 )应用 H、丁胺卡那霉素、利福喷丁、吡嗪酰胺和乙胺丁醇。结果　痰菌阴转率 :治疗组 86 .7% ,对照组 5 5 % ,有高度显著性差异 (P<0 .0 1) ;病灶吸收好转率治疗组 6 4 .4 ,对照组 4 0 ,有显著性差异 (P<0 .0 5 ) ;空洞闭合率 :治疗组 6 8.9 ,对照组 4 0 ,有高度显著性差异 (P<0 .0 1)。随访 2年 ,治疗组和对照组总治愈率分别为 84 .4和 5 0 ,有高度显著性差异 (P<0 .0 1)。结论　 H、P、C、O或 L V、Th方案治疗 MDR- TB疗效满意 ,可作为首选方案     

母牛分枝杆菌联合化疗方案治疗耐多药肺结核疗效观察

目的 分析针对耐多药肺结核患者母牛分枝杆菌联合化疗方案对该类患者的临床疗效.方法 取本院2008-2011年收治耐多药肺结核患者85例,根据治疗方法不同随机分为观察组和对照组.两组均采用6MfxAmPaZE/18MfxPaZE化疗方案,观察组同时加用母牛分枝杆菌22.5 μg肌注,1次/周.比较分析两组临床表现、细菌学及影像学表现等.结果 观察组较对照组早期临床症状明显改善,且观察组的早期痰菌阴转情况、影像学吸收均优于对照组.结论 对于耐多药肺结核患者,在应用核心化疗方案基础上联合应用生物制剂免疫调节剂母牛分枝杆菌能促进患者早期症状的改善及病灶的尽快愈合.     

电子支气管镜三联注药联合化疗治疗耐多药肺结核疗效分析

目的：分析针对耐多药肺结核患者的化疗方案联合支气管注药方案对该类患者的临床疗效。方法取本院2008—2011年收治耐多药肺结核患者80例,根据治疗方法不同随机分为观察组和对照组。两组均采用6LfxCmPaZPto/18LfxPaZPto 化疗方案,观察组同时加用支气管镜三联注药治疗2个月。比较两组临床表现、细菌学及影像学表现等。结果观察组及对照组临床表现有效率差别不明显,但观察组的早期痰菌阴转情况、影像学吸收情况均优于对照组。结论对于耐多药肺结核患者,在应用核心化疗方案基础上早期给予局部支气管内电子支气管镜注药治疗能增加患者早期痰菌阴转率,促进病灶吸收。     

Factors predicting treatment success in multi-drug resistant tuberculosis patients treated under programmatic conditions

Background

Treatment success in multi-drug resistant tuberculosis under programmatic conditions has been far from satisfactory. Knowledge of the factors predicting treatment outcome can guide us to take appropriate corrective measures for better results. However, there is a scarcity of data on these predictors in Indian patients. The present study was sought to evaluate association of different patient and disease specific factors with treatment outcome in MDR-TB patients.

经纤支镜灌注治疗耐多药肺结核

目的 探讨经纤支镜灌注治疗耐多药肺结核的治疗价值。方法 将26例耐多药肺结核病患随机分为治疗组和对照组。治疗组强化期采用纤支镜灌注治疗加全身化疗，对照组只进行全身化疗。结果 强化期结束时，经纤支镜灌注治疗组症状明显改善92.86%，痰菌阴转率85.71%，病灶显吸收率78.58%，明显高于单纯化疗组58.33％、50％、33.33%（P＜0.01-0.05）。结论 经纤支镜灌注治疗耐多药肺结核疗效显，且无并发症及明显副反应，值得进一步推广使用。     

经皮肺穿刺注药治疗耐多药空洞型肺结核疗效的Meta分析

目的 系统评价经皮肺穿刺注药治疗耐多药空洞型肺结核的疗效.方法 计算机检索Pubmed、Cochranel Library、CKNI、CMB、Wanfang database、VIP数据库有关经皮肺穿刺注药治疗耐多药空洞型肺结核疗效的临床随机对照试验(randomized controlled trial,RCT),检索时间从建库至2016年4月.由两名研究员按照纳入及排除标准进行文献筛选、资料提取和文献质量评价,应用RevMan 5.3软件进行Meta分析.结果 共纳入15个随机对照试验,涉及1 456例耐多药空洞型肺结核患者.结果显示,经皮肺穿刺注药治疗耐多药空洞型肺结核的痰菌转阴率、空洞闭合率、病灶吸收率均明显高于单纯全身化疗组.结论 经皮肺穿刺注药可显著提高耐多药空洞型肺结核疗效,值得临床进一步研究及推广.     

耐多药肺结核患者肾上腺皮质水平的临床研究

目的　探讨耐多药肺结核患者肾上腺皮质水平的变化规律。方法 采用放射免疫分析法对56例耐多药肺结核患者进行血清皮质醇含量测定,并与无耐药肺结核、正常健康人进行对比。结果 耐多药肺结核患者的皮质醇含量分别为842±168(8AM)、624±62(4PM),均明显高于非耐药肺结核组和正常组。结论 耐多药肺结核患者肾上腺皮质功能较正常人明显增加,且皮质醇分泌仍具有正常节律性。