抗结核药物贝达喹啉与氯法齐明耐药的研究现状

耐多药/利福平耐药结核病(multidrug-/rifampicin-resistant tuberculosis, MDR/RR-TB)和广泛耐药结核病(extensively drug-resistant tuberculosis, XDR-TB)的出现对世界范围内结核病的控制构成了巨大威胁。由于缺乏有效的药物,MDR-TB患者的治疗成功率仅为59%,XDR-TB患者的治疗成功率不足50%。近年来,新型抗结核药物贝达喹啉(bedaquiline, Bdq)、老药新用药物氯法齐明(clofazimine, Cfz)在MDR/RR-TB和XDR-TB患者中的应用可以明显改善患者的治疗结局。两种药物均通过损害分枝杆菌能量代谢来发挥作用,尽管存在交叉耐药,但在临床治疗中仍然被临床医生联合使用。因此,在临床应用过程中除了需要关注药物的不良反应外,也应关注Bdq和Cfz的耐药情况。笔者旨在总结Bdq和Cfz耐药相关机制,以及临床治疗中Bdq和Cfz耐药性的出现情况,讨论如何延缓Bdq和Cfz获得性耐药的增加和传播。     

耐药结核病综合治疗的回顾与展望

耐药结核病尤其是耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)和广泛耐药结核病(extensively drug-resistant tuberculosis,XDR-TB)的治疗,仍然是结核病控制工作中所面临的主要难题.耐药结核病的治疗费用高、不良反应大、治疗效果差.以化学治疗为主,联合免疫治疗、萎陷疗法、介入治疗、外科手术、中医药和营养支持治疗等可提高耐药结核病的疗效.     

耐药结核病的流行简况

结核病是当前危及人类生命的主要杀手。耐药结核病(drug-resistant tuberculosis)尤其是耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)的出现使得结核病流行势态更为严峻。MDR-TB是指结核病患者感染的M.TB体外被证实至少对异烟肼、利福平这2种一线抗结核药物耐药...     

含贝达喹啉方案治疗艾滋病合并原发广泛耐药肺结核患者一例

<正>艾滋病(acquired immune deficiency syndrome,AIDS)是由人类免疫缺陷病毒(human immunodeficiency virus,HIV)引起的后天性人类免疫缺陷综合征。结核分枝杆菌是AIDS患者较为常见的机会性病原菌。贝达喹啉(bedaquiline,Bdq)是近50年来第一个上市的二芳基喹啉类抗结核新药，2018年世界卫生组织将Bdq列为治疗耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)长程治疗方案的首选药物^[1]。本文报道了国内首例将Bdq用于治疗艾滋病合并原发广泛耐药肺结核患者，现将患者诊治过程报告如下，为广大临床医师诊治该类患者提供思路。     

贝达喹啉治疗耐多药结核病的研究进展

全球耐药结核病疫情严峻,耐多药结核病(MDR-TB)患者治疗成功率较低,成为WHO终止结核病策略目标的障碍。WHO现行的MDR-TB治疗方案循证等级较低且药物毒性大,研发抗结核新药势在必行。贝达喹啉(Bdq)具有独特的作用机制和药代动力学特点,不易与其他抗MDR-TB药物产生交叉耐药,能缩短MDR-TB的痰培养阴转时间,提高痰培养阴转率,有望成为缩短MDR-TB疗程的先行者,但在应用Bdq治疗MDR-TB患者的过程中应警惕其药物毒性。     

耐药结核病的化学治疗药物及其最新研究进展

耐药结核病尤其是耐多药结核病 （multidrug- reisistant tuberculosis,MDR-TB） 和广泛耐药结核病 （extensively drug-resistant tuberculosis,,XDR—TB）是21世纪全球所面临的最为严重的公共卫生问题之一。化学药物仍然是治疗耐药结核病的主要武器。近年来,耐药结核病化学治疗药物方面的研究取得了可喜的成绩,本文就耐药结核病的化学治疗药物及其最新研究进展做一介绍。     

含贝达喹啉方案治疗儿童准广泛耐药结核病二例

<正>耐药结核病是一项全球公共卫生危机,全球儿童耐多药结核病(multidrug-resistant tuberculosis, MDR-TB)每年发病人数约2.5～3.5万例,其中21%的MDR-TB患儿可能死于MDR-TB[1]。儿童耐药结核病的危害是巨大的,但我国儿童耐药结核病治疗经验相对缺乏,且部分抗结核药物限制在儿童中使用。贝达喹啉是近50年来第一个上市的二芳基喹啉类抗结核新药,其在成人耐药结核病治疗中的良好作用已得到证实,     

重庆地区耐多药和泛耐药结核病耐药性分布十年数据初步分析

耐多药结核病(multi-drug resistant tuberculosis,MDR-TB)是指至少同时对异烟肼和利福平耐药结核菌感染所致的结核病,是近10多年来全球结核病疫情上升的主要原因之一.2006年以来出现了泛耐药结核病(extensively drug-resistant tuberculosis,XDR-TB)的报道.2006年世界卫生组织(WHO)定义,XDR-TB是指在符合MDR-TB的同时,对喹诺酮类中的任一种药物耐药,以及对下述3种注射用二线抗结核药(卷曲霉素、卡那霉素和阿米卡星)中至少一种耐药.     

耐药结核病分子诊断技术研究进展

结核病（tuberculosis,TB）是严重危害人类健康的慢性传染病,是目前传染病中威胁人类健康的头号杀手。耐药结核菌株的产生和播散,尤其是耐多药菌株的出现,已成为新世纪结核病控制的三大难题之一。耐药结核病尤其是耐多药结核病（multidrug resistant tuberculosis,MDR-TB）和广泛耐药结核病（extensively drug-resistant tuberculosis,XDR-TB）.     

耐多药结核病——预防和控制的关键步骤

<正>耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)被定义为,由至少对异烟肼(isoniazid)和利福平(rifampicirn)治疗耐药的结核分枝杆菌(Mycobacterium tuberculosis)引起的疾病。广泛耐药结核病(extensively drug-resistant,tuberculosis,XDR-TB)是指导疾病的多重耐药菌株还对使用任     

重庆市耐多药结核分枝杆菌对贝达喹啉和德拉马尼的药物敏感性研究

目的 分析重庆市耐多药结核分枝杆菌(multidrug-resistant Mycobacterium tuberculosis,MDR-TB)对贝达喹啉(bedaquiline,Bdq)和德拉马尼(delamanid,Dlm)的药物敏感性,以期为临床上Bdq和Dlm的合理使用提供参考。方法 收集2017年11月至2018年11月间经重庆市公共卫生医疗救治中心鉴定为MDR-TB的菌株,采用微孔板法测定Bdq和Dlm的最低抑菌浓度(minimum inhibitory concentration, MIC),并对相关结果进行分析。结果 所收集的111例MDR-TB临床分离株进行Bdq的药敏检测结果显示, MIC₅₀和MIC₉₀分别为0.016 mg/L和0.125 mg/L;109例MDR-TB菌株的Dlm药敏结果显示,MIC₅₀和MIC₉₀分别为0.016 mg/L和0.063 mg/L。各有5株菌株对Bdq和Dlm耐药,耐药率分别为4.50%和4.59%。不同耐药情况分组对Bdq和Dlm的耐药率与MDR-TB菌株对Bdq和Dlm的耐药率之间差异无统计学意义(P>0.05)。结论 重庆市大部分MDR-TB菌株对这两种新的抗结核药物非常敏感,但不应忽视原发耐药,在制定临床治疗方案时,仍需重视对新药的药敏检测。     

卷曲霉素抗结核作用及耐药机制的研究进展

卷曲霉素(Capreomycin, CPM)是治疗耐多药结核病的二线注射类药物。随着临床上越来越多的使用,CPM耐药问题正逐步浮现,其作用及耐药机制尚未明确。本文针对卷曲霉素治疗结核病的作用机制、耐药机制及相关基因突变的研究进展进行综述,以供研究者参考。     

Second-line drug resistance in multidrug-resistant tuberculosis cases of various origins in the Netherlands

SETTING: The Netherlands. OBJECTIVE: To investigate the frequency of resistance to second-line drugs among multidrug-resistant tuberculosis (MDR-TB) cases and its correlation with patients' geographic origin. DESIGN: Retrospective laboratory database study of multidrug-resistant Mycobacterium tuberculosis complex strains isolated in the Netherlands between January 1993 and October 2007. RESULTS: We found 153 patients with MDR-TB, of whom 18 (12%) were native Dutch. Complete second-line drug susceptibility testing was performed for 131 MDR-TB patients. Resistance to second-line drugs was noted in primary samples of 28 (21%) MDR-TB patients. Resistance to a single second-line drug was most frequent (24/28 [86%]; 9 to prothionamide [PTH], 6 to para-aminosalicylic acid, 4 to amikacin [AMK], 4 to ciprofloxacin and 1 to cycloserine). Four MDR-TB patients had strains resistant to multiple second-line drugs; two were extensively drug-resistant M. bovis. In MDR-TB patients of European and Central Asian origin, resistance to second-line drugs was most frequent and involved the widest range of drugs. PTH resistance was frequent among African and American MDR-TB patients, while AMK resistance was frequent among South-East Asians. CONCLUSION: Resistance to second-line drugs is infrequent among MDR-TB patients in the Netherlands. Most second-line drug resistance is recorded among immigrants, with substantial differences in second-line drug resistance in MDR-TB patients originating from different geographical areas.     

结核分枝杆菌环丝氨酸药物敏感性及耐药机制研究

目的 检测耐多药结核病(MDR-TB)临床分离株的环丝氨酸最低抑菌浓度(MIC),并从基因水平进行环丝氨酸耐药机制的研究,为环丝氨酸的快速耐药测定提供理论依据。方法 采用Middlebrook 7H9液体培养基,在96孔板中对140株MDR-TB和37株敏感结核分枝杆菌(MTB)临床分离株进行环丝氨酸药敏试验,筛选出对环丝氨酸耐药及敏感的菌株,再对Ald、Alr、ddlA基因进行突变位点及基因表达量的分析。结果 MDR-TB对环丝氨酸的耐药率仅为4.28%,初步将MIC≥32 μg/mL的结核分枝杆菌菌株判定为对环丝氨酸耐药;Ald、Alr、ddlA基因位点突变与结核分枝杆菌对环丝氨酸耐药无明显相关性,环丝氨酸耐药菌株在Alr基因位点处基因表达量明显高于敏感菌株。结论 目前临床的MDR-TB患者对环丝氨酸的耐药率较低,使用环丝氨酸治疗MDR-TB是一种有效的选择。尚未发现明确的环丝氨酸耐药突变位点,但Alr基因的过表达与MTB环丝氨酸耐药高度相关,可能是其耐药的新机制。     

Pattern of drug resistance among patients of pulmonary tuberculosis

BackgroundDrug resistant tuberculosis (DR-TB), particularly multidrug resistance (MDR-TB) and extensive drug resistance (XDR-TB) pose a serious threat to public health. This study aimed to identify drug resistance in pulmonary tuberculosis patients and to see their association with diabetes, human immunodeficiency virus (HIV), previous history of tuberculosis (TB) and family history of TB.MethodSputum specimens obtained from 11,874 pulmonary tuberculosis patients were subjected to smear microscopy, cartridge based nucleic acid amplification test (CBNAAT) and liquid culture (LC). Smear positive isolates were subjected to first line Line probe assay (FL-LPA) for isoniazid and rifampicin resistance. FL- LPA positive isolates were subjected to second line Line probe assay (SL-LPA) for fluoroquinolones and second line injectable drug resistance.ResultOut of 11,874 microbiologically confirmed cases of pulmonary tuberculosis, 976 (8.2%) had a drug resistant tuberculosis. Five patterns of drug resistance were identified monoisoniazid; 394 (3.32%), rifampicin; 461 (3.88%) (monorifampicin; 383 (3.22%)), multidrug; 73 (0.61), extensivedrug; 11 (0.09) and others; 37 (0.31). Previous history of tuberculosis was significantly associated with rifampicin resistance and MDR-TB. Family history of tuberculosis contact was strongly associated with rifampicin resistance, MDR-TB and XDR-TB.ConclusionThere has been an increasing trend in drug resistance in the recent years, particularly in retreatment cases. This study highlights the pattern of drug resistance and need to detect resistance among all tuberculosis cases, in order to interrupt transmission and control this emerging epidemic.     

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。     

Impact of extensive drug resistance on treatment outcomes in non-HIV-infected patients with multidrug-resistant tuberculosis.

BACKGROUND: Recently, serious concerns about extensively drug-resistant tuberculosis (XDR-TB), which shows resistance to second-line anti-TB drugs in addition to isoniazid and rifampicin, have been raised. The aim of this study was to elucidate the impact of extensive drug resistance on treatment outcomes in non-human immunodeficiency virus (HIV)-infected patients with multidrug-resistant tuberculosis (MDR-TB). METHODS: Patients who received the diagnosis of and treatment as having MDR-TB at Seoul National University Hospital (Seoul, Republic of Korea) between January 1996 and December 2005 were included. The definition of XDR-TB was TB caused by bacilli showing resistance to both isoniazid and rifampicin and also showing resistance to any fluoroquinolone and to at least 1 of the following 3 injectable anti-TB drugs: capreomycin, kanamycin, and amikacin. To identify the impact of extensive drug resistance on treatment outcomes, univariate comparison and multiple logistic regression were performed. RESULTS: A total of 211 non-HIV-infected patients with MDR-TB were included in the final analysis. Among them, 43 patients (20.4%) had XDR-TB. Treatment failure was observed in 19 patients (44.2%) with XDR-TB, whereas treatment of 46 patients (27.4%) with non-XDR-TB failed (P=.057). The presence of extensive drug resistance (adjusted odds ratio [OR], 4.46; 95% confidence interval [CI], 1.35-14.74) and underlying comorbidity (adjusted OR, 2.62; 95% CI, 1.00-6.87) were independent risk factors for treatment failure. However, a higher level of albumin was inversely associated with treatment failure (adjusted OR, 0.87; 95% CI, 0.77-0.97). CONCLUSION: The presence of extensive drug resistance, the presence of comorbidity, and hypoalbuminemia were independent poor prognostic factors in non-HIV-infected patients with MDR-TB.     

甘肃省临夏州、甘南州、定西市结核病耐药监测结果分析

目的了解甘肃省临夏回族自治州、甘南藏族自治州、定西市结核分枝杆菌的耐药现状及耐多药情况,为甘肃省少数民族及贫困地区结核病防治提供科学依据。方法依据(WHO/ IUATLD)结核病耐药监测指南,将调查地区1年连续新发涂阳病人和同期新登记的复治涂阳病人作为监测病例,对成功分离的909例结核分枝杆菌菌株,用绝对浓度间接法进行药物敏感性实验。结果总耐药率26.0%,初始耐药率21.0%,获得性耐药率50.0%;耐多药率10.1%,其中初始耐多药率为7%,获得性耐多药率为24.1%;耐利福平菌株中有70.8%是耐多药（MDR-TB）菌株。结论甘肃省少数民族结核分枝杆菌的耐药的发生率较高,耐药现状应引起卫生主管部门及各级结核病防治机构的重视。     

住院肺结核病人结核菌耐药性的动态观察

目的　分析和评价住院肺结核病人的耐药动态,为今后的结防工作提供参考依据。方法 收集本院不同年代(1982～1983,1990～1991和1997～1998年)住院病例,进行耐药率的分析。结果 原发耐药率分别为24.6%,35.1%和38.3%,原发耐多药率分别为3.5%,6.1%和12.3%。获得性耐药率分别为81.0%,65.8%和74.4%;获得性耐多药率分别为11.5%,16.6%和34.9%。原发耐药率、原发和获得耐多药率有逐年增长的趋势,获得性耐药率变化不大。结论 控制耐药的关键是实施NTP,统一化疗方案,广泛实施DOTS,做好耐药监测评价工作。