结核菌耐药的基因及治疗

近年来．随着化疗药物的广泛应用。耐药结核病,尤其是耐多药结核病（MDR-TB）对全球结核病控制造成严重威协。高耐药率和耐多药菌株以及广泛耐药结核病的不断扩散,正日益成为全球结核病控制中的一个重大问题。而我国多耐药结核病疫情属全世界22个高负担国家之一。     

The evolution of extensively drug resistant tuberculosis (XDR-TB): history, status and issues for global control

Tuberculosis (TB) is a devastating disease caused by Mycobacterium tuberculosis that killed an estimated 4000-5000 person each day during 2005. Although infections with drug sensitive strains can be effectively cured with a 6 to 9 month regimen of multiple antibiotics, the inability to deliver and complete appropriate courses of therapy on a global level has led to the selection of resistant strains over the past 50 years. The selection and spread of multiple drug resistant M. tuberculosis continued for decades leading to two operationally distinct forms of the disease, multiple drug resistant (MDR-TB) and extensively drug resistant (XDR-TB). The estimate for MDR-TB and XDR-TB cases for 2005 were 424,000 and 27,000 respectively, and the situation is worst in areas with high incidences of HIV infection. The outcome was predictable based on basic microbiological principles, and the resultant and future epidemic effectively modeled mathematically. This situation was brought to the forefront when an outbreak of XDR-TB occurred in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 and began to spread. Unfortunately, we do not know the true extent of XDR-TB globally. However, all signs point to an emerging epidemic of TB infections that will be difficult, if not impossible to cure. A few new drugs are in clinical trials, but it is too early to know the final outcome; some may fail, and none will be available for several years. The situation will continue to worsen unless more resources are made available to discover and deliver better treatment options.     

喹诺酮抗分枝杆菌活性及其构效关系研究进展

随着耐药结核病(尤其是耐多药结核病)发病率的不断上升以及结核病与AIDS病的并发,结核病疫情再度上升,成为全球重大公共卫生问题。作为二线抗结核病药物,氟喹诺酮类药物具有一定优势,它们在临床治疗耐多药结核病以及对不能耐受一线抗结核病药物的患者治疗中扮演着重要角色。本文综述了近年来喹诺酮(包括氟喹诺酮、6-非氟喹诺酮和非经典喹诺酮)在抗分枝杆菌活性及其构效关系方面的研究进展。     

Drug-resistant tuberculosis in Ethiopia: problem scenarios and recommendation

Tuberculosis (TB) is a major public health problem in Ethiopia. This review is prepared to indicate possible future challenges related to tuberculosis control and it includes previous reports of drug-resistant surveys in Ethiopia. Drug-resistant TB, both initial and acquired, was reported from different regions of the country. In studies from 1984 to 2001, the initial resistance to isoniazid ranges from 2% to 21% and initial resistance to streptomycin ranges from 2 to 20%. Multidrug-resistance (MDR) TB defined as resistance to at least isoniazid and rifampicin was also reported in about 1.2% of new cases and 12% of re-treatment cases. In all studies which included ethambutol susceptibility test, ethambutol resistance is either nil or very low (below 0.5%). All MDR isolates were susceptible to ethambutol. Treatment and re-treatment regimens recommended by the National TB/Leprosy Control Program could be effective on all cases other than those with MDR-TB. MDR-TB is difficult to cure. Therefore, special emphasis should be given to control the spread of MDR-TB. Lack of control efforts may lead to the increased resistance to both first- and second-line drugs. A well supported and controlled special treatment unit, which uses both first-line and second-line drugs is required for a proper management of these cases and for effective control of the spread of MDR-TB. A uniform susceptibility to ethambutol can be taken as an advantage to develop standard low-cost re-treatment regimen for MDR-TB patients.     

New drugs for tuberculosis

In the last ten years, an unexpected resurgence of tuberculosis (TB) has occurred in industrialised countries; contributing factors are likely to include the spread of HIV infection and increasing waves of immigration. Moreover, multidrug resistant (MDR) strains of Mycobacterium tuberculosis are emerging, rendering older therapies largely ineffective. One approach to circumvent this situation has been the addition of antimicrobials with some in vitro antituberculosis activity, but which are marketed for other infections (particularly some quinolones and the combination of oxicillin-clavulanic acid), to current therapeutic regimens. New drugs, possibly acting on novel targets, are urgently required, as are more specific vaccines.     

抗结核药物最新进展

结核病是病死率仅次于艾滋病的全球第二大感染性疾病。当前结核病的控制面临一系列挑战。世界卫生组织推荐的结核治疗方案疗程长,对敏感菌和耐药菌感染分别需6个月、20个月的持续治疗。现有抗结核一线化疗药仍为四十多年前所开发,品种有限,选择余地小。此外,多耐药结核病(MDR-TB)及广泛耐药结核病(XDR-TB)的流行,严重阻碍了结核病控制的进展。严峻的结核病防治形势急需抗结核新药的出现。近十年来,抗结核化疗新药研发在沉寂多年后取得了较明显进展。本文介绍了近年上市与处于临床及临床前研究阶段的抗结核新药。     

抗结核药物的作用机制及结核分枝杆菌的耐药机理

结核病是一个严重的全球性疾病,随着艾滋病病毒及耐药结核菌的出现及播散成为结核病控制的又一个威胁。虽然我们有结核疫苗及抗结核药物,但控制结核病仍是一件很棘手的事情。多重耐药结核菌的不断出现给结核病的治疗带来很大的困难。为有效控制耐药结核病,我们必须了解结核菌的耐药机理。本文讨论了抗结核药物的作用机制及结核菌的耐药机理。结核菌耐药机理的阐明对耐药菌的快速分子诊断及新药的开发有重要的意义。     

抗结核一线药物及结核分枝杆菌的耐药分子机制

近年来涌现出了耐多药结核病(Multidrug-resistanttuberculosis,MDR-TB)/广泛耐药结核病(Extensively drug-resistant tuberculosis,XDR-TB)。MDR-TB是指由耐异烟肼和利福平两种或以上抗结核药物的结核分枝杆菌引起的结核病。XDR-TB是指不...     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.     

Fluoroquinolones and tuberculosis

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.     

Problems of multidrug- and extensively drug-resistant TB

Worldwide, it is thought that in 2010 around 9 million people developed tuberculosis (TB) and around 1.5 million people died from the disease. Standard therapy (6 months of rifampicin and isoniazid, plus pyrazinamide and ethambutol for the first 2 months) is recommended for newly diagnosed active respiratory TB and is effective if taken correctly. However, its effectiveness can be compromised by a number of factors including poor adherence (e.g. because of the long duration of treatment, occurrence of unwanted effects) or inadequate drug levels for other reasons (e.g. drug-drug interactions, poor quality medicines). These factors also contribute to the development of resistance to one or more of the drugs. Multidrug resistant TB (MDR-TB) is defined as TB with resistance to both rifampicin and isoniazid. Patients with MDR-TB are treated with a combination of first-line and second-line drugs based on the results of drug susceptibility testing. The treatment is longer, less effective, less tolerable, and more expensive than standard therapy, and involves the use of injectable drugs. Extensively drug-resistant TB (XDR-TB; defined as TB with resistance to rifampicin and isoniazid, and to at least one fluoroquinolone and one second-line injectable agent such as amikacin or capreomycin) is now emerging. Here we highlight patient groups at increased risk of MDR- and XDR-TB, and discuss how to investigate, manage and treat them.     

Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care

Infectious diseases are the leading cause of death worldwide. Among them, tuberculosis (TB) remains a major threat to public health, exacerbated by the emergence of multiple drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb). MDR-Mtb strains are resistant to first-line anti-TB drugs such as isoniazid and rifampicin; whereas XDR-Mtb strains are resistant to additional drugs including at least to any fluoroquinolone and one of the second-line anti-TB injectable drugs such as kanamycin, capreomycin, or amikacin. Clinically, these strains have significantly impacted the management of TB in high-incidence developing countries, where systemic surveillance of TB drug resistance is lacking. For effective management of TB on-site, early detection of drug resistance is critical to initiate treatment, to reduce mortality, and to thwart drug-resistant TB transmission. In this review, we discuss the diagnostic challenges to detect drug-resistant TB at the point-of-care (POC). Moreover, we present the latest advances in nano/microscale technologies that can potentially detect TB drug resistance to improve on-site patient care.     

Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps

Global rates of pulmonary tuberculosis (TB) continue to increase. Moreover, resistance of the causative organism Mycobacterium tuberculosis to the two most effective anti-TB medications continue to rise. Now, multi-drug resistant TB (MDR-TB) has progressed to extensively drug resistant TB (XDR-TB) - a M. tuberculosis organism that is resistant to the most effective second line drugs available for the treatment of TB. This review provides detailed, significant evidence that supports the use of an old neuroleptic compound, thioridazine (TZ), for the management of MDR-TB and XDR-TB infections and which has been shown to inhibit efflux pumps of bacteria. The argument has been previously presented but no one seems to be listening - and the disease continues unabated when there is a very good probability that the suggested drug will prove to be effective. When the prognosis is poor, available therapy predictably ineffective and death is inevitable, compassionate therapy with TZ should be contemplated. The risks are small and the rewards great.     

Newly developed drugs invented to treat tuberculosis in clinical trial

Tuberculosis (TB) is a leading cause of morbidity and mortality in more than one-third of the world population. Its impact on global health is a result of decades of neglect for such an important infectious disease, lack of resources for national TB control programs, poor case detection, and inadequate/inappropriate therapy in high-burden countries. The worldwide dissemination of multidrug (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis poses a serious threat to human health due to inadequacy of long and cumbersome tuberculosis (TB) therapy. Treatment regimens consist of at least four drugs with different mechanisms of action. Several new molecules in clinical development hasencouraged the scientific community to discover new drug targets and new drug candidates. Therefore, new drugs are urgently needed to shorten and improve the treatment course in drug resistant TB, and to minimize the occurrence of new infections and death. Nowadays, various new investigational drugs, such as bedaquine (TMC207), nitroimidazoles (PA-824, OPC-67683), diamines (SQ109), oxazolidinones (Linezolid, PNU-100480 (Sutezolid), ADZ5847), pyrroles (LL3858) and fluoroquinolones (moxifloxacin and gatifloxacin), have entered clinical trials and are in progress to be developed for the treatment of MDR-TB. In this perspectivearticle, an overview of the new anti-TB drugs with different structures that are either being clinically used or in advanced stages clinical stages as well as of preclinical development are presented. This review provides snapshots of the efforts that are being made in the development of new drugs as lead anti-TB agents. Finally, it is crucial to improve the connection between research and development institutes, industries, drug control authorities, and international policy-making bodies to deliver efficacious therapies for patients who are suffering from TB.     

Current status and future development of antitubercular chemotherapy

Tuberculosis (TB), which kills more people than any other infectious disease, was declared a global emergency by the World Health Organization in 1993. The emergence of new Mycobacterium tuberculosis strains that are resistant to some or all current antitubercular drugs seriously hampers the control of the disease. Up to 50 million people may be infected with drug-resistant TB, with resistance being caused by inconsistent or partial treatment when patients do not comply with long-term chemotherapy. Resistance is often a corollary to HIV infection. Besides being more fatal, drug-resistant TB is more difficult and more expensive to treat. In addition to this human cost, TB also represents a significant economic burden for developing countries. Therefore, new approaches to the treatment of TB are needed. During the last few years, important efforts have been made in order to elucidate the molecular mechanism of action of antitubercular drugs and understand the genetic basis of acquired drug resistance in M. tuberculosis. The identification of novel targets requires the characterisation of biochemical pathways specific to mycobacteria. Many unique metabolic processes occur during the biosynthesis of cell wall components, including arabinogalactan and mycolic acids. In this review, the mode of action of first- and second-line agents, as well as the potentiality of some promising drugs that are still at an early stage of development will be described. Finally, some of the attractive targets offered by the mycobacterial cell wall for the rational design of new antitubercular drugs for a future and more effective control of the disease will be examined.     

On the spread and control of MDR-TB epidemics: An examination of trends in anti-tuberculosis drug resistance surveillance data

BackgroundMultidrug resistant tuberculosis (MDR-TB) poses serious challenges for tuberculosis control in many settings, but trends of MDR-TB have been difficult to measure.MethodsWe analyzed surveillance and population-representative survey data collected worldwide by the World Health Organization between 1993 and 2012. We examined setting-specific patterns associated with linear trends in the estimated per capita rate of MDR-TB among new notified TB cases to generate hypotheses about factors associated with trends in the transmission of highly drug resistant tuberculosis.Results59 countries and 39 sub-national settings had at least three years of data, but less than 10% of the population in the WHO-designated 27-high MDR-TB burden settings were in areas with sufficient data to track trends. Among settings in which the majority of MDR-TB was autochthonous, we found 10 settings with statistically significant linear trends in per capita rates of MDR-TB among new notified TB cases. Five of these settings had declining trends (Estonia, Latvia, Macao, Hong Kong, and Portugal) ranging from decreases of 3% to 14% annually, while five had increasing trends (four individual oblasts of the Russian Federation and Botswana) ranging from 14% to 20% annually. In unadjusted analysis, better surveillance indicators and higher GDP per capita were associated with declining MDR-TB, while a higher existing absolute burden of MDR-TB was associated with an increasing trend.ConclusionsOnly a small fraction of countries in which the burden of MDR-TB is concentrated currently have sufficient surveillance data to estimate trends in drug-resistant TB. Where trend analysis was possible, smaller absolute burdens of MDR-TB and more robust surveillance systems were associated with declining per capita rates of MDR-TB among new notified cases.     

Current status and future development of antitubercular chemotherapy

Tuberculosis (TB), which kills more people than any other infectious disease, was declared a global emergency by the World Health Organization in 1993. The emergence of new Mycobacterium tuberculosis strains that are resistant to some or all current antitubercular drugs seriously hampers the control of the disease. Up to 50 million people may be infected with drug-resistant TB, with resistance being caused by inconsistent or partial treatment when patients do not comply with long-term chemotherapy. Resistance is often a corollary to HIV infection. Besides being more fatal, drug-resistant TB is more difficult and more expensive to treat. In addition to this human cost, TB also represents a significant economic burden for developing countries. Therefore, new approaches to the treatment of TB are needed. During the last few years, important efforts have been made in order to elucidate the molecular mechanism of action of antitubercular drugs and understand the genetic basis of acquired drug resistance in M. tuberculosis. The identification of novel targets requires the characterisation of biochemical pathways specific to mycobacteria. Many unique metabolic processes occur during the biosynthesis of cell wall components, including arabinogalactan and mycolic acids. In this review, the mode of action of first- and second-line agents, as well as the potentiality of some promising drugs that are still at an early stage of development will be described. Finally, some of the attractive targets offered by the mycobacterial cell wall for the rational design of new antitubercular drugs for a future and more effective control of the disease will be examined.     

Fluoroquinolones for the treatment of pulmonary tuberculosis

Tuberculosis (TB) continues to be a significant problem globally. Treatment includes a multiple drug regimen with isoniazid, rifampicin (rifampin), pyrazinamide and ethambutol. Often, one of these medications needs to be replaced as a result of adverse events or because Mycobacterium tuberculosis develops resistance against one these first-line agents. Fluoroquinolones, particularly the newer ones, possess good in vitro (levofloxacin, gatifloxacin, moxifloxacin) and in vivo (gatifloxacin and moxifloxacin) bactericidal activity against M. tuberculosis, making them attractive agents for the treatment of pulmonary TB.All relevant clinical trials, cohort studies and case reports investigating the clinical efficacy and tolerability of fluoroquinolones when used for the treatment of pulmonary TB were evaluated for this review. Specifically, efficacy and safety in the following indications were investigated: (i) first-line treatment of drug-sensitive pulmonary TB; (ii) first-line treatment for multi-drug resistant (MDR) TB; and (iii) treatment of patients with drug intolerance. Twenty-seven articles met our inclusion criteria; nine articles presented data from randomised, controlled or cohort studies. Seven studies used fluoroquinolones as first-line agents in drug-sensitive TB (1469 patients), 15 studies used fluoroquinolones to treat MDR-TB (1025 patients) and six studies (951 patients) investigated the use of fluoroquinolones in patients intolerant to other TB medications.In patients with susceptible M. tuberculosis strains, substitution with a fluoroquinolone did not have an effect on cure or radiological improvement at 8 weeks or failure at 12 months. Substitution of older fluoroquinolones into a regimen, especially ciprofloxacin, resulted in a higher rate of relapse and a longer time to sputum-culture conversions. The use of fluoroquinolones in patients with MDR-TB is supported by some trials where others show a lack of improvement in efficacy of a regimen.Our review of the literature does not support the use of older fluoroquinolones, especially ciprofloxacin, as substitute agents for drug-sensitive or drug-resistant TB. However, newer fluoroquinolones, such as moxifloxacin, may be a reasonable alternative based on results from one large clinical trial. Fluoroquinolones have an important role as substitute agents for those who are intolerant of first-line TB agents.     

Drug-resistant tuberculosis: an insurmountable epidemic?

Drug-resistant tuberculosis has brought back the spectre of pre-antibiotic days. WHO surveillance data from 2007 showed multi-drug-resistant tuberculosis (MDR-TB)—tubercle bacillus resistant to both isoniazid and rifampicin accounting for 4.8% of all new and subsequent cases of tuberculosis. India and China—the two most populated countries of the world, house the maximum number of drug-resistant tuberculosis cases. In eastern European and central Asian countries, more than 6% of new TB cases are MDR-TB, whereas the number is <3% in the countries of the western world. Extensively drug-resistant tuberculosis (XDR-TB) has emerged with the prospect of tuberculosis becoming an incurable disease. A surveillance spreading over the six continents showed 10% of MDR-TB cases were also XDR-TB. The fact that tuberculosis is the most common opportunistic infection among HIV-infected patients in developing countries makes the challenge almost insurmountable. The mortality of HIV and MDR-TB co-infected patients is exceedingly high. The absence of guidelines for treatment of drug-resistant tuberculosis and of infrastructure for delivery of DOT program and rapid laboratory diagnostic facilities, including drug susceptibility testing for both first and second-line drugs, and lack of trained human resource in most of the developing world account for the emergence and perpetuation of this menacing problem. WHO along with partnership with Green Light Committee and individual national governments has started DOT plus program to control this global epidemic.     

A Note on Derivatives of Isoniazid,Rifampicin, and Pyrazinamide Showing Activity Against Resistant Mycobacterium tuberculosis

Drug‐resistant tuberculosis (DR‐TB) is a serious problem that impedes the success of the TB control program. Of note, multidrug‐resistant (MDR)‐TB and extensively drug‐resistant (XDR)‐TB have certainly complicated the scenario. One of the possible strategies to overcome drug resistance in an economic and simple manner would involve modification of existing anti‐TB drugs to obtain derivatives that can work on resistant TB bacilli. These may have improved half‐life and increased bioavailability, be more efficacious, and serve as cost‐effective alternatives, as compared to new drugs identified through conventional methods of drug discovery and development. Although extensive literature is available on the activity of various derivatives of first‐line drugs (isoniazid, rifampicin and pyrazinamide) on drug‐susceptible Mycobacterium tuberculosis (MTB), reports on the activity of derivatives on resistant MTB are very limited, to our knowledge. In light of this, the present review aims to provide a concise report on the derivatives of first‐line drugs that have the potential to overcome the resistance to the parental drug and could thus serve as effective alternatives.