皮肤型结核治疗的研究进展

随着结核病呈现流行趋势,皮肤结核也有上升趋势研究进展,由于不断出现的耐药结核病、耐多药结核病、获得性免疫缺陷综合征（HIV）的流行及结核持留菌的问题,使得有效控制结核病面临更大的挑战。传统的抗结核治疗疗程长,副作用大,使病人的依从性差,很难达到满意效果。皮肤结核的治疗也存在这个问题,因此研究开发新型抗结核药物及原有药物的新型用法,实现对皮肤结核的有效控制迫在眉睫。本文针对目前皮肤结核的治疗方案及有关新型药物做如下综述。     

抗结核新药的临床应用:新希望与新挑战

<正>耐药结核病是我国乃至全球面临的重大公共卫生挑战^[1-2]。由于对一线抗结核药物治疗方案中的核心药物利福平和异烟肼耐药，耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)全球治疗成功率仅为54%；可见，开发新型抗结核药物对于提高耐药结核病患者的治疗转归具有重要价值^[2-3]。近年来，一系列新型抗结核药物的上市为耐药患者的临床治疗带来了新希望。如何科学合理应用抗结核新药，减少耐药发生，最大程度发挥其杀灭耐药结核分枝杆菌的作用成为其临床推广的关键因素。     

耐药结核病的流行和监测

20世纪抗结核病药物相继问世，使结核病的治愈成为可能，但随之出现了结核分枝杆菌的耐药性。染色体自发突变导致对某种抗结核病药物耐药的发生频率为10^-6～10^18，由于不同药物耐药的突变位点不同，同时使用3种抗结核药的同时耐药频率为10^-18-10^20。因此，联用3种有效的抗结核药物时，发生抗结核药物耐药的概率极少。从这一点出发，可以认为耐药的发生是结核分枝杆菌基因突变被人为放大的结果。不合理的用药、治疗管理不善、药物供应不足和质量不佳以及间断用药等，刺激结核分枝杆菌发生耐药性，即获得性耐药（acquired drug resistance）；随后，耐药结核分枝杆菌在人群中传播，发生耐药结核分枝杆菌感染，即原发耐药（primary drug resistance）；耐多药结核病（MDR-TB）是指至少同时对异烟肼和利福平耐药的结核病。     

结核分支杆菌耐药性的研究进展

结核分支杆菌耐药是指原来对于抗结核药物敏感的结核分支杆菌变得不敏感或产生了耐受性,它是结核病防治工作中遇到的一个棘手和重要的问题。随着人们对结核病的认识不断提高,结核病在治疗过程中遇到的新的问题和挑战也越来越多,结核菌耐药菌株越来越强和多耐药结核菌的不断增多     

抗结核药物的临床应用进展

自南非2006年发现53例广泛耐药结核病爆发流行后，WHO在2006年9月宣布了一个强化结核病控制措施、有效防治广泛耐药结核病全球行动计划。广泛耐药结核病（XDR-TB）是指在耐多药结核病的基础上出现对任何氟喹诺酮类药物以及三种二线注射药物（硫酸卷曲霉素、卡那霉素和阿米卡星）中至少一种具耐药性的结核。因此，XDR-TB通常是在MDR-TB的基础上发展而来；其根本原因在于不合理使用二线抗结核药物，以及对耐多药结核病治疗缺乏管理或管理不善所导致。现将有关抗结核药物的临床应用进展综述如下。     

《WHO耐药结核病治疗指南(2016更新版)》药物分类要点

2015年11月,世界卫生组织(WHO)召集了多学科的结核耐药结核病专家,对耐药结核病的治疗策略进行了更新,并推出《WHO耐药结核病治疗指南(2016更新版)》,该指南对传统利福平耐药结核病(RR-TB)与耐多药结核病(MDR-TB)个体化方案中的抗结核药物进行重新分组和分类,即将药物分为A、B、C、D4组,其中A、B、C组为核心二线抗结核药物,D组为非核心附加药物,具体内容如下。     

抗结核药物基因组学研究进展

结核病是由结核分枝杆菌感染引起的传染性疾病,主要依靠化学药物进行治疗。抗结核药物基因组学主要关注药物基因组学在抗结核治疗中的应用。抗结核药物基因组学领域研究的深入开展有助于为结核病的个体化治疗铺平道路。本综述主要介绍了目前国内外在抗结核药物基因组学领域包括人类基因组学的研究方法、药物基因组学与抗结核药物代谢、药物基因组学与抗结核药物致肝损伤,以及药物基因组学与结核分枝杆菌耐药的研究进展,并对抗结核药物基因组学面临的挑战进行了探讨。     

耐多药结核病诊治进展

介绍 随着耐药结核菌耐药范围不断扩大,广泛耐药结核病逐渐成为全球健康问题。耐多药结核病治疗难度大、费用高,在许多地区甚至无法治愈[1]。随着HIV流行导致院内耐多药结核病例数量激增,耐多药结核病的流行及二线抗结核药物广泛应用和使用不当,是目前耐多药结核病产生的关键因素。     

耐药结核病治疗药物研究进展

目前结核病仍然是全球十大死因之一,全球耐药结核病的疫情不容乐观。由于抗结核新药的匮乏,耐药结核病治疗非常困难,治疗时间长,成功率低,因此新型抗结核药物的研发非常迫切。近期除了已被世界卫生组织推荐的治疗耐多药肺结核的新药如利奈唑胺、贝达喹啉及德拉马尼外,还有针对结核分枝杆菌的约17种新化合物正处于不同的临床试验阶段。本文将耐药结核病治疗药物研究进展综述如下。     

常用抗结核二线药物耐药机制研究进展

结核病(tuberculosis,TB)仍是全球最严重的传染病之一.随着结核分枝杆菌(Mycobacterium tuberculosis,MTB)对一线抗结核药物耐药性增强,二线抗结核药物如氟喹诺酮类、氨基糖苷类和硫代酰胺类等在临床应用中越来越受到重视.近年来MTB对二线药物耐药性不断增加,使得其耐药机制成为诸多学者的研究热点.常见的耐药机制有MTB基因突变导致耐药、细胞壁结构及通透性改变和药物外排泵等,但仍有部分机制不甚清楚.本文就MTB对常用抗结核二线药物的耐药机制进行综述,为改善结核病的治疗提供理论参考.     

Xpert Mtb/RIF检测技术在结核病诊断中的应用评价

目的 评估Xpert Mtb/RIF检测技术快速诊断肺结核及利福平耐药的可靠性.方法 在4个县（区）级结核病防治机构（湘潭县、岳阳县、绥化市北林区和兰西县）,门诊医生连续纳入2142例初诊肺结核可疑患者,每例患者留取3份痰标本,实验室工作人员对每份标本同时进行涂片镜检、固体培养和Xpert Mtb/RIF（利福平耐药实时荧光定量核酸扩增检测技术）检测,临床医生2个月末对患者完成随访.省级参比实验室对555例培养阳性患者完成比例法利福平药敏试验,国家参比实验室对传统药敏试验和Xpert Mtb/RIF检测结果不一致菌株进行rpoB耐药基因核心区间测序.以随访后临床诊断结果为金标准,比较涂片镜检、固体培养和Xpert Mtb/RIF检测结核分枝杆菌的敏感度.以传统药敏试验结果为金标准,分析Xpert Mtb/RIF检测利福平耐药的效能.结果 以临床诊断结果为金标准,涂片镜检、固体培养和Xpert Mtb/RIF检测结核分枝杆菌的敏感度分别为25.68％（284/1106）、51.44％（555/1079）和58.82％（650/1105）,Xpert Mtb/RIF检测敏感度高于涂片镜检（x2=360.10,P＜0.05）和固体培养试验（x2=50.13,P＜0.05）.以传统药敏试验结果为金标准,XpertMtb/RIF检测利福平耐药的敏感度和特异度分别为87.10％（27/31）和97.95％（477/487）.结论 Xpert Mtb/RIF检测操作简单,检测敏感度高于涂片镜检和固体培养,同时可以诊断患者是否对利福平耐药,在我国县（区）级实验室具有非常好的应用前景.     

利福平耐药实时荧光定量核酸扩增检测技术的诊断效果对比研究

目的 评价利福平耐药实时荧光定量核酸扩增检测技术（GeneXpert Mtb/RIF）检测临床标本诊断结核病和耐利福平结核病的效能.方法 2011年1-5月从解放军第三○九医院、广州市胸科医院和河南省疾病预防控制中心3家单位,连续收集门诊就诊的1971例疑似结核病患者的痰标本,进行涂片、金标准培养和金标准比例法传统药敏试验和GeneXpert Mtb/RIF检测.应用SPSS 11.5统计软件对GeneXpert Mtb/RIF与不同检测方法进行敏感度和特异度分析,以P＜0.05为差异有统计学意义.结果 与涂片及培养比较,GeneXpert Mtb/RIF检测1968例（1971例中有3例污染排除）痰标本诊断结核病的敏感度和特异度分别为93.27％（748/802）、91.93％（797/867）和91.60％（1068/1166）、95.55％（1052/1101）;与临床诊断比较,GeneXpert Mtb/RIF检测1945例（1971例中有26例无法定诊）痰标本诊断结核病的敏感度和特异度分别为78.66％（822/1045）、98.67％（888/900）;与金标准传统药敏试验比较,GeneXpert Mtb/RIF检测797例标本诊断耐利福平结核病的敏感度和特异度分别为97.92％（188/192）、100.00％（595/595）.结论 GeneXpert Mtb/RIF是一种检测痰标本诊断结核病及耐利福平结核病的快速简便、自动化、敏感度和特异度较高的分子生物学方法,适用于结核病和耐利福平结核病的临床诊断.     

结核分枝杆菌临床株对利福霉素类药物的耐药特点分析

目的比较分析临床标本结核分枝杆菌(Mycobacterium tuberculosis,Mtb)对利福霉素类药物的耐药特点,为含利福霉素类药物的抗结核治疗方案的改进提供细菌学基础。方法用绝对浓度法检测470份临床标本中Mtb的耐药情况。结果 180份培养阳性的标本中,41份对利福霉素类耐药,对利福平和利福喷汀的耐药水平高度一致,对二者的耐药水平显著高于对利福布汀的耐药水平,对低浓度和高浓度利福布汀耐药的数量差异显著。结论临床标本中的Mtb对利福平和利福喷汀的耐药水平表现出高度一致性,提示利福喷汀不适于作为利福平耐药的后备药物,利福布汀可以作为利福平的后备药物,但服用剂量可能影响治疗效果。     

结核分枝杆菌及利福平耐药核酸扩增检测成本分析

目的 比较固体培养、比例法药敏和结核分枝杆菌及利福平耐药核酸扩增（Xpert Mtb/RIF）(简称“Xpert”)检测在中国基层实验室应用的检测成本。 方法 选取4个县（区）级结核病防治机构收集3次固体培养和Xpert检测成本数据,2个省参比实验室收集3次对硝基苯甲酸（PNB）菌群鉴定和比例法利福平药敏试验成本数据。采用要素法计算每种方法单位检测成本,计算每例患者不同检测方法的检测成本。在不同结核病患病率人群中,以固体培养试验为金标准,比较Xpert检测在不同检测效能下检出1例结核病患者的成本。在不同利福平耐药率的可疑人群中,以传统药敏试验为金标准,比较Xpert检测在不同检测效能下检出1例利福平耐药结核病患者的成本。调整Xpert检测设备和试剂价格后,分析Xpert检测的单位成本。 结果 固体培养、菌群鉴定、利福平药敏试验和Xpert检测的单位检测成本分别为47.87、46.73、82.86和118.62元。传统方法检测每例结核病患者所需成本（2份培养,1份传代,1份PNB鉴定试验）为172.57元。传统方法检测每例耐药结核病患者的平均成本（2份固体培养,1份传代,1份PNB鉴定及药敏试验）为208.84元。当Xpert检测结核病或利福平耐药特异度为85%时,如果检测敏感度大于70%,在结核病患病率或利福平耐药结核病患病率1%～70%的任何人群中,Xpert检出1例结核病或利福平耐药结核病患者的成本均低于传统方法。试剂价格变化对于检测成本的影响远远大于设备价格变化的影响。 结论Xpert检测是一种比传统方法更经济并快速的检测方法,适合在中国基层实验室推广。     

Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia

Mycobacterium tuberculosis (Mtb) infection is difficult to treat because Mtb spends the majority of its life cycle in a nonreplicating (NR) state. Since NR Mtb is highly tolerant to antibiotic effects and can mutate to become drug resistant (DR), our conventional tuberculosis (TB) treatment is not effective. Thus, a novel strategy to kill NR Mtb is required. Accumulating evidence has shown that repetitive exposure to sublethal doses of antibiotics enhances the level of drug tolerance, implying that NR Mtb is formed by adaptive metabolic remodeling. As such, metabolic modulation strategies to block the metabolic remodeling needed to form NR Mtb have emerged as new therapeutic options. Here, we modeled in vitro NR Mtb using hypoxia, applied isotope metabolomics, and revealed that phosphoenolpyruvate (PEP) is nearly completely depleted in NR Mtb. This near loss of PEP reduces PEP-carbon flux toward multiple pathways essential for replication and drug sensitivity. Inversely, supplementing with PEP restored the carbon flux and the activities of the foregoing pathways, resulting in growth and heightened drug susceptibility of NR Mtb, which ultimately prevented the development of DR. Taken together, PEP depletion in NR Mtb is associated with the acquisition of drug tolerance and subsequent emergence of DR, demonstrating that PEP treatment is a possible metabolic modulation strategy to resensitize NR Mtb to conventional TB treatment and prevent the emergence of DR.

Despite significant efforts to end tuberculosis (TB), TB is still a leading killer among infectious diseases worldwide, claiming 1.5 million lives and making 10.5 million individuals ill each year (1–3). The hallmark of Mycobacterium tuberculosis (Mtb) pathogenesis is its ability to survive under a range of antimicrobial environments. After invading, recruitment of immune cells at the site of infection causes granuloma formation, a multicellular structure that traps uncleared Mtb. The interior of the granuloma is hypoxic, nutritionally starved, acidic, and filled with biochemical antimicrobial effectors such as reactive oxygen species (ROS) and reactive nitrogen intermediates. Mtb is able to survive under these conditions because it enters a nonreplicating (NR) persistent state (4, 5). The reduced efficacy of a conventional TB treatment method is largely attributed to this Mtb phenotypic heterogeneity ranging from replicating to NR states, a bet-hedging strategy that supports Mtb survival in response to antibiotic treatment and the host immune system (6). Although the precise mechanisms of how Mtb enters the NR state are unclear, the proportion of NR Mtb can be gradually enhanced by intermittent exposure to antibiotics, suggesting that NR Mtb is formed by adaptive strategies, to avoid irreversible antimicrobial damage (7). Indeed, our recent reports showed that the tolerance to antibiotics of NR Mtb was largely attributed to metabolic shifts including functional depletion of metabolic processes such as glycolipid biosynthesis, the canonical TCA cycle, and electron transport chain (ETC) activities that are required for Mtb replication (8–11). Conventional TB drugs kill Mtb by inhibiting the very processes that become dispensable for NR Mtb viability, thus rendering NR Mtb resistant to treatment.During the course of infection, activated macrophages release antimicrobial effectors such as ROS. Recent metabolomics studies using NR Mtb collected under hypoxia or in vitro biofilm culture achieved drug tolerance by remodeling its trehalose metabolism by switching trehalose-carbon flux toward the biosynthesis of central carbon metabolism (CCM) intermediates while decreasing the flux to the biosynthesis of cell wall glycolipids (8, 9). This caused accumulation of intermediates in the early portion of glycolysis (GL) such as glucose 6-phosphate (Glc-P) and fructose 1,6-bisphosphate (FBP), and near complete depletion of phosphoenolpyruvate (PEP), a metabolite in the low portion of GL (8). We separately showed that NR Mtb under hypoxia also altered the TCA cycle by shifting the carbon flux through the glyoxylate shunt to secure succinate. A portion of synthesized succinate was secreted through the membrane to maintain membrane potential (ΔΨm) and ATP levels in the absence of ETC terminal electron acceptors (10, 12). The accompanied bypassing of the oxidative branch of the TCA cycle enabled NR Mtb to avoid overproduction of NADH (the first substrate of the ETC) and ROS.There is high demand for new TB treatment methods that can quickly eradicate NR Mtb, since the existing arsenal of TB drugs no longer provides effective protection against NR Mtb and drug resistant (DR) TB (13). This ineffectiveness is compounded by antibiotics with reduced penetration efficacy through the NR Mtb cell wall as compared to that of its replicating counterparts (14, 15). Since NR Mtb survival does not rely on the metabolic networks that are targets of conventional TB drugs, novel approaches killing NR Mtb are needed and may include blocking NR Mtb metabolic remodeling and increasing the penetration of TB drugs. Recent reports indicated that agents that restore NR Mtb membrane bioenergetics caused an increase in drug uptake (16). Thus, we hypothesized that metabolic activities altered in NR Mtb play a role in NR Mtb drug tolerance, and reagents that prevent NR Mtb metabolic remodeling can render NR Mtb sensitive to conventional TB drugs.Our metabolomics profile of NR Mtb collected under hypoxia showed accumulation of intermediates in GL and the reductive branch of the TCA cycle, with reciprocal depletion of PEP and oxidative branch intermediates of the TCA cycle such as α-ketoglutarate (αKG). Accumulating GL intermediates included FBP, which is known to allosterically enhance pyruvate kinase (Pyk), thereby helping deplete PEP in NR Mtb (17, 18). PEP depletion also caused an increase in the pyruvate to PEP ratio, which is known to regulate TCA cycle gene expression (19, 20). Thus, PEP depletion may affect multiple cellular metabolic processes that are involved in NR Mtb metabolic remodeling.PEP is the ester derived from the enol of pyruvate and phosphate and is an important intermediate in multiple metabolic networks (21). PEP has the high energy phosphate bond that is involved in GL and the TCA cycle in all organisms. In GL, PEP is formed by the action of the enzyme enolase. Subsequent conversion from PEP to pyruvate by Pyk generates ATP via substrate level phosphorylation. PEP is also formed from oxaloacetate (OAA) after decarboxylation and accompanied hydrolysis of GTP. This is catalyzed by PEP carboxykinase (PckA), which is the rate-limiting step in gluconeogenesis (22, 23). PEP is an enol source that bridges the glycan and peptide of nascent peptidoglycan (PG) biosynthesis for bacterial cell wall construction (24, 25). Separately, PEP initiates the shikimate pathway by condensing with erythrose 4-phosphate, thereby biosynthesizing chorismate, dihydrofolate, and aromatic amino acids. Thus, multiple bacterial metabolic processes are presumably affected by intrabacterial PEP availability. Furthermore, PEP can penetrate the cell membrane and transfer its high-energy phosphate group to ADP and replenish ATP levels (26). Taken together, PEP is functionally linked to multiple metabolic processes, all of which play an essential role for Mtb replication.In the present study, we identified that growth arrest and drug tolerance of NR Mtb are largely attributed to defects in PEP anabolic and catabolic activities. We used isotope metabolomics to show that PEP depletion led to a down-regulation in the activities of the oxidative branch of the TCA cycle and an increase in the carbon flux toward the biosynthesis of triacylglycerol (TAG), which caused a depletion in NADH levels and ETC activities. Down-regulation of ETC activities directly affected membrane bioenergetics and drug uptake, rendering NR Mtb drug tolerant. In parallel, PEP depletion also led to a down-regulation of multiple metabolic pathways required for replication including folate metabolism, aromatic amino acid metabolism, and PG biosynthesis. PEP supplementation was sufficient to partly restore growth and drug susceptibility of NR Mtb even under hypoxia. Finally, we showed that PEP depletion caused emergence of DR mutations. This study demonstrates that the catalytic depletion of PEP is a trigger for the formation of NR Mtb, thereby implying that PEP supplementation can potentially block NR Mtb metabolic remodeling and be a therapeutic option to kill NR Mtb and prevent the emergence of DR.     

单耐氧氟沙星的结核分枝杆菌耐药机制研究

目的探讨单耐氧氟沙星的结核分枝杆菌中耐药相关基因突变及外排泵基因风坦两种不同耐药机制的作用。方法从国家结核病参比实验室2007年全国耐药基线调查菌株库中挑选单耐氧氟沙星的菌株17株。采用直接测序法检测利福平耐药相关基因删似和gyrB突变情况。提取gyrA和gyrB无突变菌株的RNA后反转录并采用Real—timePCR方法检测20个药物外排泵基因的表达量，对比菌株最低抑菌浓度（MIC）试验结果，筛选可能与氧氟沙星药物外排泵的相关基因，并选用大肠埃希菌为模式生物构建表达载体，检测过表达目的外排泵蛋白的大肠埃希菌对氧氟沙星的耐药程度加以验证。结果在17株单耐氧氟沙星的菌株中，有4株（4／17）检测到gyrA突变，其中包括90位点突变1株及94位点突变3株，上述突变均表现为高浓度耐药，其MIC均不低于4μg/ml。在gyrA和gyrB未突变菌株中，通过real-timePCR检测发现在高浓度耐药的2株菌株中，Rv0933和Rv2938的转录水平显著高于其他低浓度耐药菌株，较对照株H37Rv转录水平高16倍和5倍。在对照组和转入pEASY-E1-Rv2938的大肠埃希菌中MIC均小于0．125μg／ml，而转入pEASY-E1-Rv0933的大肠埃希菌的MIC为2μg／ml。结论本研究结果显示，gyrA耐药决定区基因突变与氧氟沙星高浓度耐药相关，PstB可能是氧氟沙星特异性的药物外排泵基因，其高水平表达与氧氟沙星高浓度耐药相关。     

耐多药肺结核患者二线药敏试验结果分析

目的了解2006和2007年北京市耐多药病例菌株耐二线药物状况,为制定耐多药病例治疗方案提供依据。方法采用绝对浓度法对确定的43例耐多药菌株进行二线抗结核药物敏感试验。结果43例MDR-TB中XDR-TB占2.3%,耐LFX14%,耐AK,PAS,Pto均为9.3%,耐CM2.3%。69.8%的耐多药菌株对二线药敏感。结论对于耐多药病例,进行二线药敏试验,有利于耐多药结核病标准化方案和个体方案的制定。     

安徽省192例HIV阳性结核病患者的治疗转归分析

目的 了解安徽省AIDS高流行县（区）通过积极的干预措施,对HIV与Mtb双重感染患者结核病治愈率和病死率的影响。方法 收集分析安徽省AIDS高流行的7个县（区）2006年10月1日至2009年6月30日发现的199例Mtb与HIV双重感染患者抗结核疗程结束后的转归情况。结果 Mtb与HIV双重感染患者中进行抗病毒治疗者135例,抗结核治疗者192例,181例接受了全程督导,疗程结束后1年内结核病治愈48例,完成疗程113例,迁出4例,死于结核病4例,死于非结核病21例,治疗失败1例,丢失1例。Mtb与HIV双重感染患者的治疗成功率为83.9％（161/192）,总病死率13.0％（25/192）,其中因结核病死亡率2.1％（4/192）。结论 各级结核病防治机构与艾滋病防治机构合作,积极发现Mtb与HIV双重感染并进行及时的抗结核和抗病毒治疗,能有效提高Mtb与HIV双重感染患者的结核病治愈水平,降低病死率。     

厦门市肺结核耐药流行情况及相关因素分析

目的了解近年来厦门市肺结核患者耐药现状,分析影响耐药结核病产生的因素,以期为制定本地区行之有效的结核病防控措施提供科学的参考依据。方法采用横断面调查,对2011年7月1日至2012年6月30日在厦门市各结核病定点医院门诊登记的所有痰涂片阳性的肺结核患者共776例进行调查。收集患者的基本情况和诊疗信息。收集痰标本培养,培养阳性菌株采用比例法进行药物敏感性试验（异烟肼、利福平、链霉素、乙胺丁醇等）;采用对硝基苯甲酸（PNB）培养法鉴定结核分枝杆菌复合群。排除痰菌培养阴性,菌株污染和非结核分枝杆菌感染47例,最终获得药物敏感性试验结果的729例。利用SPSS18．0软件中非条件logistic回归模型分析结核病耐药发生的可能影响因素。结果厦门市总耐药率为27．2％（198／729）,总耐多药率为9．7％（71／729）,初治耐药率为23．4％（134／573）,复治耐药率为41．0％（64／156）,初治耐多药率为7．3％（42／573）,复治耐多药率为18．6％（29／156）;对四种抗结核药物的耐药率最高的为异烟肼16．5％（120／729）,最低的为乙胺丁醇6．9％（50／729）;复治患者的耐药率显著高于初治患者（X2值为19．286,P〈0．01）,是耐药结核病的危险因素（OR=2．154,95％CI=1．467-3．163,Wald X^2=15．319,P〈0．001）。结论厦门市耐药结核病疫情不容乐观,复治化疗史是耐药结核病产生的重要影响因素。     

颗粒显色指示技术快速检测结核分枝杆菌对吡嗪酰胺耐药性的价值

目的 探讨颗粒显色指示技术快速测定结核分枝杆菌（Mycobacterium tuberculosis,Mtb）对吡嗪酰胺耐药性的临床应用价值。方法 应用颗粒显色指示法测定102株Mtb对吡嗪酰胺耐药性,并与美国BD公司BACTEC MGIT-960分枝杆菌检测系统结果进行比较。 结果 颗粒显色指示法测定102株Mtb临床分离株,结果对吡嗪酰胺敏感70株、耐药32株,BACTEC MGIT-960法测定结果敏感69株、耐药33株;两法测定均敏感67株、均耐药30株。如以BACTEC MGIT-960法药敏结果为判断标准,则颗粒显色指示法测定吡嗪酰胺耐药性的敏感度为90.9%(30/33),特异度为97.1%（67/69),阳性预测值为93.8%(30/32),阴性预测值为95.7%(67/70),准确性为95.1%(97/102)。结论 颗粒显色指示技术快速测定Mtb吡嗪酰胺耐药性简便快速,操作不需特殊仪器设备,具有很高的临床应用价值。