Multidrug resistant to extensively drug resistant tuberculosis: What is next?

Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbitidy of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD)-susceptibility testing, invention of newer antitubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB.     

复治肺结核患者结核分枝杆菌L型培养结果分析

目的：了解复治肺结核患者的结核分枝杆菌L型培养情况,探讨结核分枝杆菌L型阳性与耐多药的关系。方法：选择180例肺结核患者的痰标本进行结核分枝杆菌培养和结核分枝杆菌L型培养,同时对110例复治组中培养阳性的标本行耐药监测。结果：复治组的L型阳性率为43．6％,初治组的L型阳性率为15．7％,复治组显著高于初治组（P〈0．01）;菌阳复治组的L型阳性率50％,菌阴复治组的L型阳性率39．4％,菌阳组明显高于菌阴组（P〈0．05）;L型菌阳性患者的耐药率显著高于L型菌阴性组（P〈0．05）。结论：结核分枝杆菌L型阳性是引起结核病复发、耐药的重要原因;MDR-TB与结核分枝杆菌L型感染有关。     

抗结核药物及其耐药相关突变位点的研究进展

结核病是结核分枝杆菌复合物引起的传染性疾病,致死率、致残率高,在全球传染病中居第2位。近年来耐药结核病所占比例逐年升高,成为消灭结核病面临的巨大挑战之一。传统的耐药诊断方法基于培养,费时费力,所需技术要求高;而现有分子检测方法仅能检测少量抗结核药物的少数耐药基因。因此,更好地理解抗结核药物的耐药机制有助于全面耐药诊断。本文对临床中使用频率较高的11类一线和二线抗结核药物及其相应耐药相关基因、突变位点的研究进展进行总结,尤其是对环丝氨酸、利奈唑胺、氯法齐明等二线药物的近期研究做了系统描述,为全面耐药诊断、精准治疗指导、新药研发及耐药机制深入研究提供了前期工作基础。     

Molecular detection, identification and drug resistance detection in Mycobacterium tuberculosis

This minireview presents recent developments in molecular methods for the diagnosis of tuberculosis, including detection, identification and determination of drug resistance of Mycobacterium tuberculosis . Tuberculosis remains one of the major causes of global death from a single infectious agent. This situation is worsened by the HIV/AIDS pandemic because one-third of HIV/AIDS patients are coinfected with M. tuberculosis . Also of great concern is the emergence of drug-resistant tuberculosis because there are almost no treatment options available for patients affected by highly resistant strains of M. tuberculosis . Advances in molecular biology techniques and a better knowledge of the molecular mechanisms of drug resistance have provided new tools for the rapid diagnosis of tuberculosis. Several nucleic acid amplification technologies have been developed and evaluated. New molecular approaches are being introduced continuously. This minireview will also comment on the future perspectives for the molecular diagnosis of tuberculosis and the feasibility for the implementation of these newer techniques in the clinical diagnostic laboratory.     

结核分枝杆菌潜伏感染诊断方法的新进展

每年有超过8百万人感染结核,其中绝大部分没有发展为活动性结核病,而是表现为潜伏性结核感染。大多数活动性结核病是潜伏感染的结核杆菌重新被激活所致,因此结核潜伏感染者成为结核患者的重要来源。及早诊断和治疗结核潜伏感染者是控制结核传播的最有效手段之一。我们较要综述了目前国内外结核潜伏感染的诊断方法及其新进展。     

Clinical and epidemiological profiles of individuals with drug-resistant tuberculosis

Drug-resistant tuberculosis (TB) is a growing global threat. Approximately 450,000 people developed multidrug-resistant TB worldwide in 2012 and an estimated 170,000 people died from the disease. This paper describes the sociodemographic, clinical-epidemiological and bacteriological aspects of TB and correlates these features with the distribution of anti-TB drug resistance. Mycobacterium tuberculosis (MT) cultures and drug susceptibility testing were performed according to the BACTEC MGIT 960 method. The results demonstrated that MT strains from individuals who received treatment for TB and people who were infected with human immunodeficiency virus were more resistant to TB drugs compared to other individuals (p < 0.05). Approximately half of the individuals received supervised treatment, but most drug-resistant cases were positive for pulmonary TB and exhibited positive acid-fast bacilli smears, which are complicating factors for TB control programs. Primary healthcare is the ideal level for early disease detection, but tertiary healthcare is the most common entry point for patients into the system. These factors require special attention from healthcare managers and professionals to effectively control and monitor the spread of TB drug-resistant cases.     

Diagnostic Value of the Amplicor PCR Assay for Initial Diagnosis and Assessment of Treatment Response for Pulmonary Tuberculosis

We evaluated the Amplicor PCR assay as an initial diagnostic tool on the basis of clinical diagnosis, and assessed this assay as a follow-up test for patients with pulmonary tuberculosis during chemotherapy. Of the 208 specimens from 155 patients who were bacteriologically and/or clinically diagnosed with active tuberculosis before chemotherapy, 144 were Amplicor PCR-positive (sensitivity, 69.2%), which was equal to the results of culturing. Among 89 specimens which showed positive results by smear and culturing, the Amplicor PCR assay detected 87 (97.8%), whereas among 55 specimens which showed smear-negative but culture-positive results, the Amplicor PCR assay detected 46 (83.6%)(P = 0.003). No false positive results were found in the two systems (specificity, 100%, 120/120). The Amplicor PCR assay was also evaluated as a follow-up test using 926 specimens from 207 patients receiving active tuberculosis chemotherapy. Among 433 specimens which showed Amplicor-PCR positive, 222 (51.3%) were culture-negative. On the other hand, among 233 culture-positive specimens, only 12 (5.2%) were Amplicor PCR-negative. Therefore, this assay is useful for the rapid diagnosis of tuberculosis. The duration of Amplicor PCR-positive after culture-negative conversion was significantly associated with the presence of cavitary lesion, smear-positive specimens before treatment, and smear-positive specimens with negative cultures during chemotherapy.     

Halo-vest辅助下前路手术治疗严重颈椎结核伴后凸畸形

目的：探讨使用halo-vest支具牵引复位并通过前路手术治疗严重颈椎结核并后凸畸形的方法和疗效。方法：通过对2004年10月至2010年9月在我科住院治疗的14例严重颈椎结核并后凸畸形的患者进行回顾性研究。本组患者中男8例,女6例,术前颈椎后凸Cobb角24-42°,平均34°。术前使用四联抗结核药物治疗2-4周,通过Halo-vest支具牵引复位。纠正颈椎后凸畸形后,采用一期前路手术治疗。手术处理包括：结核病灶清除、自体髂骨植骨或钛网植入、颈前路钢板内固定。术后继续抗结核治疗12-24个月。结果：术后随访12-48个月,平均26个月。所有颈椎结核并后凸畸形的患者都能通过halo-vest支具牵引恢复基本的颈椎序列,并能很好地耐受手术。术后患者局部疼痛和全身结核中毒症状明显缓解,神经功能均较术前有所恢复,后凸畸形得到矫正。术后3-6个月植骨融合,无内固定及伤口并发症,无严重halo-vest支具相关并发症,无结核复发。结论：对于严重颈椎结核并后凸畸形的患者,术前通过halo-vest支具牵引复位,可矫正畸形,恢复颈椎正常生理序列,为后期手术治疗创造条件并降低术中复位可能引起的脊髓损伤风险。Halo-vest辅助下的前路手术是治疗严重颈椎结核伴后凸畸形的有效手段。     

结核分枝杆菌蛋白抗原的研究进展

结核病当今世界人类致死的主要疾病之一,早期诊断发现病人、选择敏感的抗结核药物进行有效治疗是控制结核病的关键。而临床上对结核病患者检出率低,漏诊率和误诊率高,结果导致结核耐药的情况越来越严重。简便、快速、准确的免疫学检测方法在诊断结核病中起到了重要的作用。本文对用于免疫学检测的蛋白抗原作一综述。     

Outcomes after Chemotherapy with WHO Category II Regimen in a Population with High Prevalence of Drug Resistant Tuberculosis

Standard short course chemotherapy is recommended by the World Health Organization to control tuberculosis worldwide. However, in settings with high drug resistance, first line standard regimens are linked with high treatment failure. We evaluated treatment outcomes after standardized chemotherapy with the WHO recommended category II retreatment regimen in a prison with a high prevalence of drug resistant tuberculosis (TB). A cohort of 233 culture positive TB patients was followed through smear microscopy, culture, drug susceptibility testing and DNA fingerprinting at baseline, after 3 months and at the end of treatment. Overall 172 patients (74%) became culture negative, while 43 (18%) remained positive at the end of treatment. Among those 43 cases, 58% of failures were determined to be due to treatment with an inadequate drug regimen and 42% to either an initial mixed infection or re-infection while under treatment. Overall, drug resistance amplification during treatment occurred in 3.4% of the patient cohort. This study demonstrates that treatment failure is linked to initial drug resistance, that amplification of drug resistance occurs, and that mixed infection and re-infection during standard treatment contribute to treatment failure in confined settings with high prevalence of drug resistance.     

乌体林斯联合化疗治疗耐多药肺结核疗效观察

目的探讨乌体林斯联合化疗治疗耐多药肺结核（MDR-TB）疗效。方法将146例耐多药肺结核患者随机分为乌体林斯加化疗的治疔组（76例）和仅用化疗的对照组（70例）。治疗组采用左氧氟沙星＋吡嗪酰胺＋乙胺丁醇＋利福喷丁＋异烟肼及乌体林斯1.72μg/m l深部肌注,每周2次;对照组单纯用左氧氟沙星＋吡嗪酰胺＋乙胺丁醇＋利福喷丁＋异烟肼方案治疗,疗程均为18个月。结果治疗6个月、12个月、18个月后,治疗组涂阳阴转率分别为67%、82%、92%,对照组涂阳阴转率分别为34%、44%、51%,痰菌阴转率治疗组显著高于对照组（P〈0.05）组。治疗组病灶吸收显著高于对照组。结论乌体林斯能增加肺结核患者的痰菌阴转率,促进病灶吸收好转,可以作为耐药性肺结核的辅助治疗。     

非一线抗结核药物耐药机制及耐药性诊断研究进展

结核病(Tuberculosis, TB)至今仍是世界三大传染疾病之一。2014年,TB导致的死亡人数已经超过HIV。二线抗TB药物是临床治疗耐多药TB(Multidrug-resistant TB, MDR-TB)的主要药物,然而某些MDR-TB患者由于未及时诊断、治疗方案不合理、所处区域医疗条件差等原因,逐渐发展成为广泛耐药TB(Extensively drug-resistant TB, XDR-TB),使治疗更加困难,其死亡率甚至与肺癌接近。目前结核分枝杆菌(Mycobacterium tuberculosis)的耐药性机制研究已经转向非一线药物,如二线、三线和一些新研发的抗TB药物,揭示这些非一线药物的耐药机制对于耐药TB的治疗和新型抗TB药物的研发具有重要意义。本文对目前临床上使用的主要非一线药物的耐药机制研究进行了综述,并对目前常用的TB耐药性诊断方法的优缺点进行了归纳比较。     

Nanotechnology based drug delivery system(s) for the management of tuberculosis

The era of nanotechnology has allowed new research strategies to flourish in the field of drug delivery. Nanoparticle-based drug delivery systems are suitable for targeting chronic intracellular infections such as tuberculosis. Polymeric nanoparticles employing poly lactide-co-glycolide have shown promise as far as intermittent chemotherapy in experimental tuberculosis is concerned. It has distinct advantages over the more traditional drug carriers, i.e. liposomes and microparticles. Although the experience with natural carriers, e.g. solid lipid nanoparticles and alginate nanoparticles is in its infancy, future research may rely heavily on these carrier systems. Given the options for oral as well as parenteral therapy, the very nature of the disease and its complex treatment urges one to emphasize on the oral route for controlled drug delivery. Pending the discovery of more potent antitubercular drugs, nanotechnology-based intermittent chemotherapy provides a novel and sound platform for an onslaught against tuberculosis.     

Recent advancements in the development of anti-tuberculosis drugs

Modern chemotherapy has significantly improved patient outcomes against drug-sensitive tuberculosis. However, the rapid emergence of drug-resistant tuberculosis, together with the bacterium’s ability to persist and remain latent present a major public health challenge. To overcome this problem, research into novel anti-tuberculosis targets and drug candidates is thus of paramount importance. This review article provides an overview of tuberculosis highlighting the recent advances and tools that are employed in the field of anti-tuberculosis drug discovery. The predominant focus is on anti-tuberculosis agents that are currently in the pipeline, i.e. clinical trials.     

结核分枝杆菌外排泵研究进展

结核病是由结核分枝杆菌(Mycobacterium tuberculosis,Mtb)引起的一种传染病。随着多药耐药和广泛耐药结核分枝杆菌的出现,结核病的治疗变得更为艰难。近年来研究发现,结核分枝杆菌存在外排泵是其耐药的原因之一,现已发现结核分枝杆菌的主要易化子超家族(major facilitator superfamily,MFS)、三磷酸腺苷(adenosine-triphosphate,ATP)结合盒超家族(ATP-Binding Cassette,ABC)、耐受小节分裂区家族(resistance-nodulation-division,RND)和小耐多药性家族(small multidrug resistance,SMR)外排泵。但是人们对结核分枝杆菌外排泵介导的耐药现象认识不足,仍缺乏从新药发现角度研发外排泵抑制剂的研究。本文拟对结核分枝杆菌的ABC、MFS、RND和SMR外排泵的结构和功能,以及结核分枝杆菌外排泵抑制剂的研究进展进行综述。     

结核分枝杆菌乙胺丁醇耐药机制的研究进展

耐多药结核病的出现和流行对结核病的防控造成了严重威胁。乙胺丁醇(Ethambutol, EMB)是一线抗结核药物,常与异烟肼、利福平等联合应用,还可用于耐药结核病的治疗。但近年来EMB耐药形势严峻,我国复治结核病患者中EMB耐药率已达17.2%,并呈上升趋势;耐多药结核病患者中,EMB耐药率约为51.3%~66.7%,情况不容乐观。明确EMB耐药的产生机制对于有效防控EMB耐药率的上升、充分发挥EMB的作用十分重要,因此本文对结核分枝杆菌EMB的耐药现状、EMB的作用机制及其耐药产生机制方面的研究进展进行了综述。     

结核分枝杆菌基因组学与基因组进化

在后基因组时代,特别是在新的测序理论和设备大发展的背景下,一些重大传染性致病微生物基因组序列正在被逐一测定,并且随后的基因功能注释,蛋白质三维结构重建等工作也正在开展,以期对致病微生物的生物学特性、诊断策略和治疗方法等有突破性的认识.作为对人类健康一直存在严重威胁的结核分枝杆菌,其基因组在进化中所发生的各种遗传事件对其生物学性质、致病能力和抗药性等各方面有重要作用.本文旨在阐述结核分枝杆菌的起源及其基因组特征,论述其基因组进化的研究进展.     

HIV and tuberculosis in India

The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time. The World Health Organization (WHO) reports 9.2 million new cases of TB in 2006 of whom 7.7% were HIV-infected. Tuberculosis is the most common opportunistic infection in HIV-infected patients as well as the leading cause of death. Further, there has been an increase in rates of drug resistant tuberculosis, including multi-drug (MDRTB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. The diagnosis of TB is based on sputum smear microscopy, a 100-year old technique and chest radiography, which has problems of specificity. Extra-pulmonary, disseminated and sputum smear negative manifestations are more common in patients with advanced immunosuppression. Newer diagnostic tests are urgently required that are not only sensitive and specific but easy to use in remote and resource-poor settings. Treatment of HIV-TB co-infection is complex and associated with high pill burden, overlapping drug toxicities, risk of immune reconstitution inflammatory syndrome (IRIS) and challenges related to adherence. From a programmatic point of view, screening of all HIV-infected persons for tuberculosis and vice-versa will help identify co-infected patients who require treatment for both infections. This requires good coordination and communication between the TB and AIDS control programs, in India.     

新型抗结核药物研发：微生物非常规培养与沉默基因激活策略

由结核分枝杆菌感染引起的结核病是人类重要传染病之一。临床上结核菌耐药性日趋严重,不断出现的耐多药及广泛耐药结核病患者,使现有的一线至五线药物不能满足结核病防控需求。微生物来源的天然产物是药物先导化合物的重要来源。环境中存在大量常规培养条件下未培养微生物,同时微生物基因组中也存在大量未被表达的"沉默代谢途径"。运用各种方法对未培养微生物进行再培养,同时激活微生物的沉默代谢途径,进而获得潜在的新型抗生素药物已成为目前研究热点。文中系统阐述了近年来获取天然化合物所采用的微生物非常规培养技术及沉默代谢途径激活策略,同时总结了利用这两种方法获得的新型抗结核天然产物,并展望了这些方法在抗结核药物进一步研发中的应用前景。     

Current strategies in TB immunotherapy

Currently available chemotherapy for the treatment of pulmonary tuberculosis (TB) is far from ideal, requiring multiple anti-tuberculous drugs to be taken in combination for extended time periods. This long duration of therapy, coupled with the side effects of current regimens, often results in poor patient adherence, treatment failure and the associated emergence of drug resistance with major financial implications. Thus, the development of novel, shorter treatment regimens is an urgent objective of anti-tuberculous drug discovery. Immunotherapy is an area that merits more consideration than it has previously received, not least, as it could potentially avoid the problem of pathogen resistance. However, this must be undertaken with caution, as at least part of the disease pathology is a consequence of the host immune response. Thus, the protective, and not the harmful, aspects of immunity must be stimulated. Various attempts at utilizing immunotherapy as an adjunct to chemotherapy are reviewed with particular emphasis on the evidence from human studies, including the modulation of cytokine levels, administration of environmental mycobacteria and antibody therapy, in order to modulate or enhance the host immune response to Mycobacterium tuberculosis.