北京基因型结核分枝杆菌的流行及与二线抗结核药物耐药性的相关性

目的探讨北京市北京基因型MTB的流行风险因素及其与二线抗结核药物耐药性的相关性。方法收集北京各区县MTB菌阳临床株1140例,采用比例法进行药敏试验;采用间隔区寡核苷酸分型(Spoligotyping)方法鉴定北京基因型与非北京基因型MTB;使用SPSS 22.0统计学软件,采用χ2检验或Fisher精确概率检验方法对实验数据进行统计学分析。结果在1140株MTB临床分离株中,北京基因型941株(82.5%),非北京基因型199株;北京基因型菌株来源的患者中男性663例(70.5%),非北京基因型菌株来源的患者中男性124例(62.3%),两者比较差异有统计学意义[P=0.021,OR(95%CI):1.442(1.048~1.985)];北京基因型菌株来源的患者中流动人口441例(46.9%),非北京基因型菌株来源的患者中流动人口78例(39.2%),两者比较差异有统计学意义[P=0.048,OR(95%CI):1.368(1.001~1.869)];北京基因型菌株来源的患者中年龄≥65岁的患者129例(13.7%),非北京基因型菌株来源的患者中40例(20.1%),二者比较差异有统计学意义[P=0.021,OR(95%CI):0.631(0.426~0.936)];北京基因型菌株中对左氧氟沙星(Levofloxacin,Lfx)、阿米卡星(Amikacin,Am)、卷曲霉素(Capreomycin,Cm)、对氨基水杨酸(Para-aminosalicylic,PAS)的耐药率分别为5.5%(52/941)、1.3%(12/941)、3.2%(30/941)和3.0%(28/941),非北京基因型菌株对以上4种药物的耐药率分别为10.6%(21/199)、8.5%(17/199)、12.6%(25/199)和11.6%(23/199),二者对4种药物的耐药率比较差异均有统计学意义(均P<0.05);北京基因型菌株中耐多药(MDR)菌株58株(6.2%),非北京基因型菌株中MDR菌株19株(9.5%),两者比较差异无统计学意义(P>0.05)。结论北京基因型MTB在北京广泛流行且在男性人群和流动人口中的比例较高;与非北京基因型菌株相比,北京基因型菌株对Lfx、Am、Cm及PAS的耐药率低,但MDR-TB患者的比例无显著差异。     

宁波地区流动人口耐多药肺结核二线抗结核药物耐药状况及耐药基因突变特征分析

目的 了解宁波地区流动人口耐多药肺结核(multidrug-resistant Mycobacterium tuberculosis,MDR-TB)患者临床分离菌株二线抗结核药物耐药状况及耐药基因突变特征。方法 以2017—2019年浙江省宁波地区结核病耐药监测收集的133例MDR-TB患者作为研究对象(流动人口占42.11%,56/133;户籍人口占57.89%,77/133),采用1%比例法对患者临床分离菌株进行卡那霉素(kanamycin,KAN)、阿米卡星(amikacin,AMK)、卷曲霉素(capreomycin,CAP)、氧氟沙星(ofloxacin,OFX)、左氧氟沙星(levofloxacin, LVX)5种二线抗结核药物的耐药检测。同时采用PCR DNA直接测序法检测rrs、tlyA、eis、gidB、gyrA、gyrB 6个二线抗结核药物耐药相关基因的突变特征。结果 56株流动人口MDR-TB 患者临床分离菌株KAN 耐药率(7.14%,4/56),AMK耐药率(5.36%,3/56),CAP耐药率(1.79%,1/56),OFX耐药率(28.57%,16/56),LVX耐药率(33.93%,19/56)与77株户籍人口患者临床分离菌株KAN 耐药率(7.79%,6/77),AMK耐药率(6.49%,5/77),CAP耐药率(3.90%,3/77),OFX耐药率(31.37%,24/77),LVX耐药率(25.97%,20/77)比较差异无统计学意义(X²_KAN=0.020,P=0.888; X²_AMK =0.074,P=0.786; X²_CAP =0.036,P=0.850; X²_OFX =0.104,P=0.747; X²_XLV =0.990,P=0.320)。56株流动人口MDR-TB 患者临床分离菌株准广泛耐药率(Pre-XDR)(33.93%,19/56),广泛耐药率(XDR-TB)(3.57%,2/56)与77株户籍人口患者临床分离菌株准广泛耐药率(Pre-XDR)(24.68%,19/77),广泛耐药率(XDR-TB)(7.79%,6/77)比较差异无统计学意义(X²_Pre-XDR=1.360,P=0.243;X²_XDR-TB=0.411,P=0.521)。56株流动人口MDR-TB患者临床分离菌株rrs突变率(8.93%,5/56)、tlyA突变率(1.79%,1/56)、eis突变率(3.57%,2/56)、gidB突变率(5.36%,3/56)、gyrA突变率(39.29%,22/56)和gyrB突变率(3.57%,2/56)与77例户籍人口患者临床分离菌株rrs突变率(5.19%,4/77)、tlyA突变率(11.69%,9/77)、eis突变率(0.00%,0/77)、gidB突变率(2.60%,2/77)、gyrA突变率(31.17%,24/77)和gyrB突变率(2.60%,2/77)比较差异无统计学意义(X²_rrs=0.247、X²_tlyA=3.259、X²_eis=0.901、X²_gidB=0.133、X²_gyrA=0.944、X²_gyrB=0.000,均P>0.05)。6个基因的突变类型中,rrs 2种、tlyA 1种、eis 2种、gidB 2种,gyrA 5种、gyrB 4种,均以点突变为主。结论 尽管本地区流动人口MDR-TB患者临床分离菌株二线抗结核药物耐药形势较为严峻,但流动人口可能不是MDR-TB二线抗结核药物耐药防控的重点人群。     

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.     

Control of anti-tuberculosis drug resistance in Botswana.

SETTING: Botswana, where in 2000 the prevalence of human immunodeficiency virus (HIV) infection among adults was 38%, and the tuberculosis (TB) rate was 591/100,000. A 1995-1996 survey demonstrated low levels of anti-tuberculosis drug resistance. OBJECTIVE: Because TB drug resistance may increase rapidly in HIV-infected populations, a second survey was undertaken in 1999 to determine any increase in anti-tuberculosis drug resistance. DESIGN: Sputum specimens positive for acid-fast bacilli from patients without prior TB treatment (new patients), and all sputum specimens from patients reporting prior TB treatment (retreatment patients) were collected nationwide. Specimens were cultured for Mycobacterium tuberculosis and tested for resistance to isoniazid, rifampicin, ethambutol, and streptomycin. RESULTS: From January to May 1999, 783 patients were consecutively enrolled from all districts. Of these, 483 (61.7%) were male, the median age was 33 years, and 82% were new patients. Drug resistance occurred in 6.3% of new patients (95 % confidence interval [CI] 4.6-8.6) and 22.8% of retreatment patients (95% CI 16.5-30.1). Resistance to at least isoniazid and rifampicin was found in 0.5% of new (95% CI 0.1-1.3) and 9.0% of retreatment patients (95% CI 5.1-14.5). CONCLUSION: Anti-tuberculosis drug resistance remains relatively low in Botswana, probably as a result of a well-functioning TB program. Periodic surveys will be essential to adequately determine any significant trend.     

MGIT 960系统行二线抗结核药物敏感性试验的实用性评价

目的 评价全自动BACTEC MGIT 960系统在结核分枝杆菌二线抗结核药物（second-line anti-TB drugs,SLD）药敏试验中的实用性。 方法 本实验纳入患者435例。该纳入患者均通过痰涂片抗酸染色（萋-尼法）镜检,L-J固体和MGIT 960系统液体培养及鉴定,共筛查出阳性菌株212例。212例阳性菌株分别进行一线抗结核药物异烟肼（INH）、利福平（RFP）、链霉素（S）和乙胺丁醇（EMB）的耐药性试验,其中耐药菌株（所有耐药株）118例。以118例耐药株作为SLD药敏试验实验株,应用L-J和MGIT 960两种方法分别进行卷曲霉素（Cm）、卡那霉素（Km）、氧氟沙星（Ofx）和乙硫异烟胺（Eto）的药物敏感性试验,并计算出两方法药敏试验所需的时间和符合率;L-J和MGIT960两种培养方法的比较采用配对设计的卡方检验;两种方法检测结果的一致性用Kappa值检验判别。 结果 MGIT 960系统药敏试验所需时间平均10.0 d（1183/118）,L-J固体培养法所需时间平均28.5 d（3360/118）,两者相差18.5 d。MGIT 960与L-J培养法的SLD Cm、Km、Ofx和Eto敏感及耐药符合率和一致性检验Kappa值分别为88.1%（104/118）和0.520;95.8%（113/118）和0.815;91.5%（108/118）和0.824;71.2%（84/118）和0.375。 结论 MGIT 960系统液体培养法常用SLD药敏试验与金标准（L-J培养）比较除Eto外符合率高、一致性好;该方法检测快速、准确,具有很强的实用性,可作为结核分枝杆菌快速培养和药敏试验的新方法。     

Acquired anti-tuberculosis drug resistance in Yaounde, Cameroon.

SETTING: Tuberculosis centre of H?pital Jamot, Yaounde, Cameroon. OBJECTIVES: To determine the prevalence of acquired resistance (ADR) to the main anti-tuberculosis drugs, and to identify risk factors associated with its occurrence in Yaounde. DESIGN: A total of 111 previously treated adults admitted consecutively to the tuberculosis centre with sputum smear-positive pulmonary tuberculosis between June 1996 and July 1997 were included in the study. Information on potential risk factors for ADR was obtained from each patient, and human immunodeficiency virus (HIV) serostatus was determined. Drug susceptibility testing to the main anti-tuberculosis drugs was performed on cultures of Mycobacterium tuberculosis complex isolated from sputum samples of each patient by the indirect proportion method. All patients whose isolates tested resistant to at least one anti-tuberculosis drug were defined as having ADR. RESULTS: Growth of M. tuberculosis complex was obtained from sputum specimens of 98 (88.3%) of the 111 patients studied; 57 (58.2%) of these were resistant to at least one anti-tuberculosis drug. Resistance to isoniazid was the most common (54.1%), followed by resistance to rifampicin (27.6%), streptomycin (25.5%) and ethambutol (12.2%). Multidrug resistance was observed in 27 (27.6%) of the cases. In a multivariate logistic regression analysis, ADR was significantly associated only with monotherapy use in previous tuberculosis treatment(s) (P = 0.03). CONCLUSION: The rate of ADR of M. tuberculosis is quite high in Yaounde. Acquired resistance to rifampicin alone or in combination with isoniazid is also high. Monotherapy in previous anti-tuberculosis treatment(s) is a significant predictor of ADR in previously treated patients in Yaounde. These results underscore the urgent need for the re-establishment of a tuberculosis control programme, using the DOTS strategy, in Cameroon.     

抗结核药物贝达喹啉的耐药情况及其耐药机制研究进展

随着耐多药结核病(multidrug-resistant tuberculosis, MDR-TB)和广泛耐药结核病(extensively drug-resistant tuberculosis, XDR-TB)菌株的增多,结核分枝杆菌(Mycobacterium tuberculosis,MTB)的耐药性成为全球亟待解决的问题。贝达喹啉(bedaquiline, Bdq)作为近50年来首个明确用于MDR-TB治疗的新药,其耐药问题受到逐步关注。笔者对Bdq的耐药特征和耐药基因突变等研究进展进行综述,旨在更好指导临床用药,提高患者的治疗成功率,减少耐药的发生。     

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。     

High levels of resistance to second-line anti-tuberculosis drugs among prisoners with pulmonary tuberculosis in Georgia.

SETTING: Penitentiary system of Georgia. OBJECTIVE: To determine the prevalence of resistance to second-line drugs among prisoners with pulmonary tuberculosis (PTB). DESIGN: Retrospective evaluation of resistance to second-line drugs in tuberculosis (TB) patients treated from 2001 to 2003. RESULTS: The overall observed prevalence of multidrug-resistant TB (MDR-TB) was 14.4% (39/270). The lowest resistance was found for ofloxacin (OFX), which was 2.2% (6/270) overall and 5.1% (2/39) among MDR patients. Isolates from four non-MDR patients who had never received anti-tuberculosis treatment were found to be resistant to OFX. Resistance to kanamycin and capreomycin occurred simultaneously only among MDR patients and was observed in 17/39 cases (43.6%). High rates of resistance to > or =2 second-line drugs (18/39, 46.2%) and > or =3 second-line drugs (10/39, 25.6%) were observed among all MDR-TB patients, reaching respectively 59.3% and 29.6% among previously treated MDR-TB cases. Only one patient was found to be resistant to four second-line drugs. No extensively drug-resistant TB (XDR-TB) according to the latest definition was detected. CONCLUSION: Our findings reveal a serious threat to the TB control efforts in the study population.     

1994-2004年间韩国抗结核药物的耐药趋势

地点:实施国家结核病控制规划的韩国245个卫生中心及韩国国家结核病协会的结核实验室网络.目的:观察韩国1994-2004年间抗结核药物的耐药趋势和可能的相关因素.设计:评估在给定的时期内,在卫生中心登记治疗的所有结核病人.结果:2004年监测发现的2636名新涂阳病人中,338例(12.8%,95%可信区间[CI]11.5-14.1)显示对任一一种一线抗结核药物耐药:261例耐异烟肼(INH)(9.9%,95%CI8.8-11.0).71例为耐多药(MDR)(2.7%,95%CI2.1-3.3).与先前的监测相比,自1994年以来,新病例中耐药有统计学显著增高的有MDR(P=0.006 75)、任一药物耐药(P=0.03779)、INH耐药(P=0.00313)、利福平耐药(P=0.00176).新病例中,对任意一个二线药物耐药介于0.1%(卷曲霉素)和1.1%(对氨基水杨酸)之间,复治病例中,对任意一个二线药物耐药介于1.1%至3.6%之间.新病例和复治病例中,对卡那霉素和氧氟沙星的耐药率分别为1.4%和2.6%.结论:新病例中耐药具有统计学显著增加.     

Trend of anti-tuberculosis drug resistance in Korea, 1994-2004.

SETTING: The 245 health centres through which the National Tuberculosis Programme (NTP) is implemented in Korea and the TB Laboratory Network of the Korean National Tuberculosis Association. OBJECTIVE: To observe the trend of anti-tuberculosis drug resistance in Korea from 1994 to 2004 and possible related factors. DESIGN: All tuberculosis (TB) patients registered for treatment at the health centres for a given period were assessed. RESULTS: Of 2636 new smear-positive patients from the 2004 survey, 338 cases (12.8%, 95% confidence interval [CI] 11.5-14.1) showed resistance to any of the first-line drugs: 261 with isoniazid (INH) resistance (9.9%, 95%CI 8.8-11.0) and 71 with multidrug resistance (MDR) (2.7%, 95%CI 2.1-3.3). Compared with previous surveys, a statistically significant increase in MDR (P=0.00675), any drug resistance (P=0.03779), any INH resistance (P=0.00313) and any rifampicin resistance (P = 0.00176) has been observed among new cases since 1994. Any resistance to second-line drugs ranged from 0.1% (capreomycin) to 1.1% (para-aminosalicylic acid) among new cases and from 1.1% to 3.6% among retreatment cases. Resistance to kanamycin and ofloxacin was found in 1.4% and 2.6%, respectively, of new and previously treated MDR-TB cases. CONCLUSION: A statistically significant increase in drug resistance was noticed among new cases.     

耐多药肺结核患者抗二线结核药的耐药分析

目的了解耐多药肺结核患者对二线抗结核药物的耐药情况。方法对我院住院的341例耐多药肺结核患者二线抗结核药物的耐药情况进行分析。结果 341例MDR-TB对左氧氟沙星、丙硫异烟胺、力克肺疾、对氨基水杨酸、丁胺卡那霉素、卷曲霉素的总耐药率依次为49.9%、26.4%、24.9%、23.4%、18.5%、15.8%。复治组对二线抗结核药物的耐多药率明显高于初治组,不合理治疗是形成MDR-TB或XDRTB的主要原因。结论耐多药肺结核患者对二线抗结核药物耐药情况严重,要引起重视。     

Paediatric use of second-line anti-tuberculosis agents: a review

Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the imminent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and require treatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely on second-line medications which are less effective and often associated with more pronounced adverse effects than first-line therapy. Despite the fact that most of these agents were discovered many years ago, robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties, adverse effects and drug interactions, especially in children. Children differ from adults in the way that drugs are administered, the manner in which they are metabolised and in the adverse effects experienced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviral therapy is also poorly documented. This article reviews the available second-line drugs currently used in the treatment of MDR-TB in children and discusses medication properties and adverse effects while potential interactions with antiretroviral therapy are explored.     

我国二线抗结核药物使用现状调查研究

目的 调查各级结防机构、结核病专科医院和综合医院二线抗结核药物（second-line anti-tuberculosis drugs, SLD）的使用情况,为国家进一步制定合理使用SLD的相关政策提供资料。 方法 采用分层目的 抽样,按照我国东、中、西的地理位置分布,东、中、西部各抽取4个省,共抽取12个省,各省所有地市和县都参与调查。对各级结核病防治机构、结核病专科医院、综合医院和乡镇卫生院（以下总称为“医疗、结防机构”）进行问卷调查,并将调查问卷进行汇总分析。 结果调查4-782个机构,72.6%的机构使用了SLD。省市县乡各级医疗、结防机构,使用SLD的比例依次降低,分别为：省级87.0%,地市级83.4%,县区级72.0%,乡镇级70.3%。不同类型的机构使用SLD的比例也不相同,结核病防治所设在结核、胸、肺科医院以及定点医院（98.7%）、结核病医院和有结核病科的专科病院（100%）、综合医院（99.4%）较高。疾病预防控制中心（简称“CDC”）内设结核病防治所（科）较低（22.9%）。不同的SLD使用的比例也不相同,丁胺卡那霉素（49.6%）、氧氟沙星（42.3%）、 左氧氟沙星（66.2%）和 环丙沙星（39.5%）使用的比例较高。仅有92家（1.9%）医疗、结防机构做一线抗结核药物的药物敏感性试验。影响SLD使用的因素有：地区、机构类型、是否有结核病门诊和病房、结核病床位数、是否做痰涂片、是否做痰培养（P均<0.001）和患者涂阳率（P<0.05）等。药物敏感性试验不是使用SLD的影响因素（P=0.771）。 结论 SLD在各级结防、医疗机构使用很普遍,不同级别、不同类型的机构以及不同SLD的使用存在较大差异,而药物敏感性试验很少开展。国家应制定有关合理使用SLD的政策,促进SLD药物敏感性试验的开展。     

印度既往接受过抗结核治疗患者的一线和二线抗结核药耐药谱

本文对2001-2004年间,全印度2816例复治失败结核病患者的痰培养和药物敏感试验结果,在Chennai的结核病研究中心进行了回顾性分析。其中1498例(53%)被确诊为患有耐多药结核病(MDR-TB),671例(44.8%)至少耐一种二线抗结核药,分别为:490例(32.7%)耐乙硫异烟胺,245例(16.4%)耐氧氟沙星,169例(11.3%)耐卡那霉素;69例(4.6%)为广泛耐药结核病(XDR-TB)。尽管本结果是从高度选择的、不具代表性的患者人群中获得,但耐多药结核病患者中的二线抗结核药耐药率(包括XDR率)如此之高仍值得关注。因此,以高质量的DOTS服务来预防M/XDR-TB的产生,仍是目前的首要任务。此外,也需要尽快扩展在修改后的国家结核病控制规划(RNTCP)下的高质量的规划管理,以及更加规范规划之外对二线抗结核药的使用。     

In vivo experimental drug resistance study in Trypanosoma vivax isolates from tsetse infested and non-tsetse infested areas of Northwest Ethiopia

Ethiopia, particularly in the Northwest region, is affected by both tsetse fly and non-tsetse fly transmitted trypanosomosis with a significant impact on livestock productivity. The control of trypanosomosis in Ethiopia relies on either curative or prophylactic treatment of animals with diminazene aceturate (DA) or isometamidium chloride (ISM), respectively. However, since these two trypanocides have been on the market for more than 40 years, this may have resulted in drug-resistance. Therefore, in vivo drug resistance tests on two Ethiopian isolates of Trypanosoma vivax were completed, one from an area where tsetse flies are present and one from an area where tsetse flies are not present. Twenty four cattle (Bos indicus) aged between 6 and 12 months, purchased from a trypanosome-free area (Debre Brehan: Northcentral Ethiopia) and confirmed to be trypanosome-negative, were randomly assigned into four groups of six animals, which were infected with T. vivax isolated from a tsetse-infested or non-tsetse infested area, and in each case treated with curative doses of DA or ISM. Each animal were inoculated intravenously 3 × 10⁶ trypanosomes from donor animals. Parasitaemia became patent earlier in infections with non-tsetse T. vivax (∼7 days post-infection) than tsetse (∼14 days post-infection). Both groups were treated at the highest peak parasitaemia with DA or ISM and nine cattle, four with non-tsetse T. vivax (two ISM- and two DA-treated) and five with tsetse T. vivax (three ISM- and two DA-treated) showed relapses of parasitaemia. Moreover, treatment did not improve diagnostic host markers of trypanosome infections in these animals. In conclusion, in vivo drug tests indicated the presence of resistant parasites (>20% of treated animals in each group relapsed) against recommended doses of both available trypanocidal drugs.