结核分枝杆菌药物作用机理及耐药机制研究进展

结核病（Tuberculosis,TB）是由结核分枝杆菌（Mycobacterium tuberculosis,MTB）引起的慢性、严重致死性传染病，也是当下仅次于新冠病毒肺炎的第二大单一传染源致死原因。伴随着抗生素滥用和抗结核药物的不规范使用，多耐药（multidrug-resistant,MDR）、泛耐药（extensively drug-resistant,XDR）和全耐药（totally drug-resistant,TDR）结核病的出现已成为全世界范围内结核病疫情消灭的障碍。据世界卫生组织统计，我国仍是全球结核病高负担国家之一，也是MDR结核病流行严重的国家之一。传统药物已无法满足现阶段结核病的控制，抗结核药物新靶点的发现和新型抗结核药物的研发已迫在眉睫。本文对传统和目前新研发的抗结核药物的作用机制进行了阐述，着重介绍了已知耐药机制的新进展，以期为开发新的抗结核药物提供新思路，降低结核病对社会的危害。     

抗结核药物的研究进展

近年来,每年约有180万人死于结核病,结核病已经成为全球性的公众健康问题。耐药结核杆菌的出现和结核艾滋病双重感染已成为结核病治疗的主要挑战。因此,研制新的抗结核药物显得尤为迫切。鉴于如此迫切形势,研究人员专注于抗结核药物的研发,发现了许多具有抗结核菌活性的候选药物,其中有一些已经进入临床试验。本文对几类新型抗结核药物的化学结构、作用机制、构效关系、代谢、抗结核活性以及临床应用进行了综述。     

中医药防治肺结核研究进展

全球结核病疫情急剧恶化,虽然西医抗结核药物不断更新,对结核病的防治起到了重要的作用,但有些结核病不适应抗结核药的治疗,且所用的化学治疗药物价格昂贵、不良反应突出。中医药在防治肺结核中积累了较为丰富的经验,体现了不可忽视的优势作用。对肺结核古今文献及中医防治肺结核的经验进行总结,以期中西医互补,取长补短,优化对肺结核的治疗提供文献资料。     

结核分枝杆菌耐药特征及新型抗结核药物研究进展

近年来耐药结核病流行呈日益严重趋势,已成为严重威胁人类健康的重大公共卫生和社会问题.及早发现并应用规范药物治疗对控制其蔓延意义重大.本文对常用抗结核药物耐药现状、耐药机制和新型抗结核药物进行了总结,以期为结核病的预防及临床抗结核药物的合理应用提供参考和借鉴.     

中医药防治肺结核研究进展

全球结核病疫情急剧恶化，虽然西医抗结核药物不断更新，时结核病的防治起到了重要的作用，但有些结核病不适应抗结核药的治疗，且所用的化学治疗药物价格昂贵、不良反应突出。中医药在防治肺结核中积累了较为丰富的经验，体现了不可忽视的优势作用。对肺结核古今文献及中医防治肺结核的经验进行总结，以期中西医互补，取长补短，优化对肺结核的治疗提供文献资料。     

新型抗结核药物的研究进展

近年来,引起结核病的结核分枝杆菌对传统的抗结核药产生了持留性和耐药性,造成了结核病的临床治疗效果不佳,本文从天然来源的新型抗结核药物及化学合成和半合成的新型抗结核药物两方面阐述了新型抗结核药物的进展情况,为临床合理应用抗结核药提供了参考依据.     

中药在耐多药结核分支杆菌感染中的应用前景

目的耐多药结核分枝杆菌(MDR-TB)感染是造成结核病重新流行的重要原因之一。中药在难治性结核病的治疗中有独到的优势,从天然药物中选择和研究抗结核新药具有重要意义。本文对近年来关于中药单方和复方抗结核机制的研究做了简单回顾,并对其在MDR-TB感染中的应用前景进行了评估。     

新型抗结核药物的研究概况

近年来,耐药结核患者逐渐增多,结核病治疗面临严峻挑战,新型抗结核药物研发愈加迫切,倍受关注。其中利福霉素类及其衍生物、氟喹诺酮类、新型大环内脂类等到中成药及其他药物已进入临床试验。该文就这些新型药物的作用机制、试验结果、临床疗效进行总结,尤其对利福布丁、莫西沙星、PA-824、TMC-207、利奈唑胺及PNU-100480进行重点介绍,以期为临床医师治疗结核病提供参考。     

抗结核药物研究进展

自20世纪80年代以来,随着耐药结核病（尤其是耐多药结核病）以及结核病与HIWAIDS并发导致的结核病疫情的再度上升,结核病已经成为全球重大公共卫生问题和社会问题。然而,近四十余年来,几乎没有新作用机制的抗结核药物问世,现有的抗结核药物的耐药越来越严重,迫切需要新的作用机制的抗结核药物的出现。经过近二十年的不懈努力,逐渐开发了一些具有潜在抗结核作用的新药,这些很有前途的新药已经进入临床试验的各个阶段,为抗结核药物治疗带来新的希望。处于临床试验不同阶段的抗结核药物见表1。     

抗结核药物不良反应和护理

结核病化疗是治疗和控制结核病的主要手段,但因抗结核药物的副作用而导致患者的治疗依从性下降并不少见.针对抗结核药物可能出现的副作用,采取相应的护理措施是非常重要的.     

利福霉素的研究新进展

结核病是由结核分枝杆菌引起的一种慢性感染性疾病,以肺结核最常见.而随着近年来耐药结核的增多,抗结核药物的研究已经越来越引起社会的关注.利福霉素作为抗结核治疗的先驱药物之一,一直在临床上发挥着重要的作用.该篇综述简述了利福霉素的生产与结构改造、耐药现状、耐药机制、新的适应症和新的剂型5个方面的研究现状,为药物开发、临床应用提供了一些参考信息.     

初、复治患者结核分枝杆菌临床分离株对抗结核药物耐药性的分析

目的 了解专科医院初复治患者的结核分枝杆菌耐药率及耐药谱。方法 研究随机选取了来自首都医科大学附属北京胸科医院的500株涂片阳性的初复治肺结核患者痰标本,分离培养后对15种抗结核药物包括利福平异烟肼（INH）、利福平（RFP）、链霉素（Sm）、乙胺丁醇（EMB）、括吡嗪酰胺（PZA）、阿米卡星（Am）、卡那霉素（Km）、卷曲霉素（Cm）、氧氟沙星（Ofx）、左氧氟沙星（Lfx）、莫西沙星（Mfx）、对氨基水杨酸（PAS）、丙硫异烟胺（Pto）、利奈唑胺（Lzd）、乙硫异烟胺（Eto）通过MEGIT 960进行药物敏感试验。结果 实验纳入的500例结核分枝杆菌样本,菌种鉴定结果显示71株为NTM,另外有12株培养污染。其余417例菌株进行4种一线抗结核药物（包括INH、RFP、Sm、EMB）的耐药表型实验,耐药率为47.2%（95% CI：42.5%~52.0%）,MDR耐药率为28.2%（95% CI：24.4%~33.1%）。复治病例的总耐药率和MDR耐药率的病例发生率均显著高于初治患者（P=0.000）。417株结核分枝杆菌在完成4种一线抗结核耐药表型实验后,采用数字表法按照一定比例筛选了全敏感和耐药株共150例,进行后续11种抗结核药物（包括PZA、Am、Km、Cm、Ofx、Lfx、Mfx、PAS、Pto、Lzd、Eto）的耐药表型实验,5例发生污染,剩余145例结核分枝杆菌对PZA、Am、Km、Cm、Ofx、Lfx、Mfx的复治患者耐药率均显著高于初治患者（P < 0.05）,对于PAS、Pto、Lzd、Eto 4种药物,初复治患者间差异无统计学意义（P > 0.05）。结论 本研究发现初复治患者结核分枝杆菌耐药率较高,应进一步加强结核病患者管理。     

抗结核新靶点及相关药物的研究进展

肺结核是一种由结核分枝杆菌（Mycobacterium tuberculosis）感染引起的,严重威胁人类健康的传染病。近年来,多药耐药和广泛耐药型结核杆菌的出现给该疾病的控制带来了巨大挑战,在新趋势下,迫切需要作用于新靶点的抗结核药物诞生。本文从结核杆菌细胞生长涉及的必需生物过程、结核杆菌致病和耐药机制3个角度出发,系统综述了抗结核领域新靶点及相关药物的研究进展。     

Update on the treatment of tuberculosis and latent tuberculosis infection

Henry M. Blumberg, MD; Michael K. Leonard, Jr, MD; Robert M. Jasmer, MD

JAMA. 2005;293:2776-2784.

Tuberculosis (TB) has emerged as a global public health epidemic. Despite decreasing numbers of cases in the United States since 1992, TB remains a serious public health problem among certain patient populations and is highly prevalent in many urban areas. The responsibility for prescribing an appropriate drug regimen and ensuring that treatment is completed is assigned to the public health program or the clinician not to the patient. The initial prescribed regimen for the treatment of TB usually consists of 4 drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. The minimum length for the treatment of drug-susceptible TB with a rifampin-based regimen is 6 to 9 months. Providing medications directly to the patient and watching him/her swallow the anti-TB drugs, which is termed directly observed therapy, is recommended for all patients diagnosed with TB and can help ensure higher completion rates, prevent the emergence of drug resistant TB, and enhance TB control. There has been renewed interest in the treatment of those with latent TB infection as a TB-control strategy in the United States for eliminating the large reservoir of individuals at risk for progression to TB. The 2 broad categories of persons who should be tested for latent TB infection are those who are likely to have been recently infected (such as contacts to infectious TB cases) and persons who are at increased risk of progression to TB disease following infection with Mycobacterium tuberculosis (eg, human immunodeficiency virus infection and selected medical conditions; recent immigrants to the United States from high TB-burden countries). The preferred regimen for the treatment of latent TB infection is 9 months of isoniazid. There is now renewed interest in and great need for the development of new drugs to treat TB and latent TB infection.

     

低清除率药物的代谢稳定性预测模型研究进展

药物代谢的稳定性测试是新药发现阶段的关键环节,实现药物的低清除率通常是药物代谢稳定性设计中的重要目标。如何准确评估低清除率药物的代谢稳定性参数,并用体外代谢数据预测人体药动学已经成为新药研发阶段的挑战。传统的肝微粒体模型和悬浮肝细胞模型的孵育时间短,低清除率药物无法产生足够的代谢转化,因此进一步模拟体内环境和延长肝细胞培养时间的新型模型逐渐发展起来。本文重点介绍了新型的低清除率药物代谢稳定性预测模型的原理和优缺点等,包括肝细胞传递式培养模型、单层贴壁肝细胞培养模型、共培养模型和微灌流模型等,同时对模型的发展趋势进行展望,以期为早期先导化合物的代谢稳定性检测提供借鉴和优化。     

Ofloxacin in multidrug resistant tuberculosis

Tuberculosis (TB) is the leading infectious cause of death today and 3.81 million cases occurred in 1997 and 1998. Even today in spite of having four drugs like isoniazid, rifampicin, streptomycin/pyrazinamide and ethambutol for the intensive phase, the total duration of treatment remains six months. Because of the global health problems of TB, the increasing rate of multidrug resistant TB (MDR-TB) and the high rate of co-infection with HIV, the need for effective non-toxic antituberculous agents is essential. Fluoroquinolones have been classified as drugs having low bactericidal activity by the WHO. To date, they have been used for preventive therapy, empirical treatment of patients with TB and retreatment of patients with relapsing TB. In-vitro and in-vivo clinical studies have identified ofloxacin as a promising new agent in the treatment of MDR-TB. Ofloxacin has been advocated by the WHO in case of MDR-TB, when susceptibility to test results are not available before starting the new treatment, in the continuation period (18 months) and if resistance is proven to at least isoniazid and rifampicin.     

Risk factors and drug-resistance patterns among pulmonary tuberculosis patients in northern Karnataka region,India

Background:

India is one of the high tuberculosis (TB)-burden countries in the world. Resistance to anti-tuberculosis (anti-TB) drugs has already become an important and alarming threat in most of the regions worldwide. India ranks second in the world in harbouring multi-drug resistant cases (MDRTB). Prevalence of MDR-TB mirrors the functional state and efficacy of TB control programmes and realistic attitude of the community towards implementation of such programmes. The most important risk factor in the development of MDRTB is improper implementation in the guidelines in the management of TB, and high rate of defaults on the part of the patients. The study was carried out to evaluate the drug resistance pattern to first line anti-TB drugs in Northern Karnataka region, India.

Materials and Methods:

A prospective study was conducted at J. N. Medical College and its associated Hospitals, Belgaum. Between January 2011 and December 2012, 150 sputum samples of suspected pulmonary TB patients based on the history were examined for the AFB culture by Lowenstein-Jensen (LJ) culture technique. A total of two early morning samples were collected for the smear [Ziehl-Neelsen (ZN) staining] and culture methods. It was observed that ZN staining for AFB was positive in 113 patients (75%), while AFB culture by LJ medium yielded growth in 66 cases (44%). Thus, a total of 66 AFB culture-positive samples by LJ medium were subjected for AFB drug-sensitivity testing (DST). DST was done for Isoniazid (INH), Rifampicin (RIF), Pyrazinamide (PZA), Ethambutol (EMB) and Streptomycin (SM) after isolation by using the resistance proportion method.

Results:

A total of 66 AFB culture-positive specimens, 20 (30.3%) cases were sensitive to all the five drugs while 46 (69.7%) cases showed resistance to one or more drugs. Among these, the resistance to rifampicin was highest (80.4%), while resistance to isoniazid, pyrazinamide, ethambutol and streptomycin were observed to be 60%, 58.7%, 52.1% and 63%, respectively. It was also observed that, resistance to all five drugs was highest (39.18%). MDR isolates were obtained in 52.2% of the cases. Illiteracy, low socio-economic status, previous history of TB and alcoholism were found to have statistically significant association for the development of MDR.

Conclusions:

The prevalence of drug resistance in the present study was observed to be 69.7%. More than half of the cases were multi-drug resistant. The most common resistant pattern observed in this study was resistance to all the first-line drugs. Therefore, during initiation of new case proper explaining and completion of the treatment is very important to avoid the development of future drug resistance in the society.     

T-SPO T.TB 技术在潜伏结核感染者免疫抑制剂治疗中的临床应用

目的：探讨 T‐SPOT ．TB 技术在潜伏结核感染（LTBI）者免疫抑制剂治疗中的筛查效果,为预防和控制 LTBI 提供新的依据。方法应用 T‐SPOT ．TB 试剂盒对162例需要应用免疫抑制的患者进行结核分枝杆菌特异性 T 细胞的检测;同时对所有病例做结核菌素皮肤试验（TST ）;对其中28例 T‐SPOT ．TB 技术筛查阳性患者应用抗 TNF‐α生物制剂治疗前均给予预防性抗结核药物治疗4个月并随访1年。结果 T‐SPOT ．TB 阳性率为36．4％,确诊率为94．9％;TST 阳性率为28．4％,确诊率为69．6％。 T‐SPOT ．TB 阳性率和确诊率与 TST 相比,差异有统计学意义（P＜0．05）;通过对28例 T‐SPOT ．TB 技术筛查阳性,给予预防性抗结核药物治疗4个月的患者1年的随访,结果无一例结核病发生。结论 T‐SPOT ．TB 技术在检测 LTBI 敏感性强、特异性高,是快速诊断结核感染的有效手段;在应用免疫抑制剂对 LTBI 的筛查诊断中具有重要临床价值。     

结核分枝杆菌对一线口服抗结核药物耐药机制及检测方法的研究进展

结核病一直是危害人类健康的一个难题,20世纪90年代化疗药物的出现使结核病的治愈率达到95%以上,并一度认为结核病是可以控制并在全球消失的。然而,结核病的近况并不容乐观,甚至在全球部分地区出现了结核危机,尤其是结核分枝杆菌对一线口服抗结核药的耐药问题日益严重,致化疗的有效率下降。现就目前结核菌的耐药情况,一线口服抗结核药物的耐药机制及关于耐药结核菌快速检测方法、技术的新进展予以综述。     

Challenges of Childhood TB/HIV Management in Malawi

The diagnosis and management of childhood tuberculosis (TB) are major challenges in countries such as Malawi with high incidence of TB and human immunodeficiency virus (HIV) infection. Diagnosis of TB in children often relies only on clinical features but clinical overlap with the presentation of HIV and other HIV-related lung disease is common. The tuberculin skin test (TST), the standard marker of M. tuberculosis infection in immune competent children, has poor sensitivity in HIV-infected children and is not usually available in Malawi. HIV test should be routine in children with suspected TB as it improves clinical management. HIV-infected children are at increased risk of developing active disease following TB exposure which justifies the use of isoniazid preventive therapy (IPT) once active disease has been excluded but this is difficult to implement and appropriate duration of IPT is unknown. HIV-infected children with active TB experience higher mortality and relapse rates on standard TB treatment compared to HIV-uninfected children, highlighting the need for further research to define optimal treatment regimens. HIV-infected children should also receive appropriate supportive care including cotrimoxazole prophylaxis and anti-retroviral treatment (ART) if indicated. There are concerns about concurrent use of some anti-TB drugs such as rifampicin with some ARTs.