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.     

结核病耐药现状及疗效分析

目的 分析宜昌市结核病耐药现状及不同类型结核患者的治疗效果.方法 对2002年1月至2009年12月的肺结核患者痰结核分枝杆菌培养阳性的标本进行药敏试验,分类统计耐药情况及不同类型、不同管理方式结核患者的治疗效果.结果 宜昌市肺结核总耐药率为33.4％(耐多药率为16.0％),其中:初治组肺结核耐药率18.8％ (162/860),耐多药率为7.1％ (61/860);复治组耐药率为46.6％ (442/949),耐多药率为24.0％ (61/860);初始耐药率20.1％ (292/1454),耐多药率为7.1％ (104/1454),获得性耐药率为87.9％(312/355),耐多药率为52.1％( 185/355).宜昌市初、复治肺结核的治愈率分别为94.2％(810/860)和90.3％( 857/949),差异无统计学意义(P＞0.05);初、复治耐多药肺结核的治愈率分别为72.5％(148/204)和60.8％(87/143),差异有统计学意义(P＜0.05).其中,初治耐多药肺结核完全与不完全管理治愈率分别为79.3％(99/125)、64.5％ (51/79),差异有统计学意义(P＜0.05);复治耐多药肺结核完全与不完全管理治愈率分别为66.7％ (60/90)、47.2％(25/53),差异有统计学意义(P＜0.05).结论 宜昌市初始及获得性耐药率均高于全国平均水平,治疗失败的病例应根据药敏试验结果选择方案.必须加强对耐多药结核(尤其是复治耐多药结核)病例的化疗管理,对于此类患者采取完全管理方式治疗,可以明显提高其治愈率.     

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...     

Drug-resistant tuberculosis in the WHO European Region: An analysis of surveillance data

To review the latest information about levels of anti-tuberculosis (TB) drug resistance in the European Region of the World Health Organization (WHO) and time-trends in multidrug-resistant TB (resistance to isoniazid and rifampicin; MDR-TB) over the past fifteen years.We analysed data on drug resistance among new and previously treated TB cases reported from 1997 to 2012. Data are collected in surveys of representative samples of TB patients or from surveillance systems based on diagnostic drug susceptibility testing.A total of 15.7% (95% confidence limits (CI): 9.5–21.9) of new and 45.3% (95%CI: 39.2–51.5) of previously treated TB cases are estimated to have MDR-TB in the Region. Extensively drug-resistant TB (MDR-TB and resistance to fluoroquinolones and second-line injectables; XDR-TB) had been reported by 38 of the 53 countries of the region (72%). The proportion of MDR-TB cases with XDR-TB is 11.4% (95%CI: 8.6–14.2). Between 1997 and 2012, population rates of MDR-TB declined in Estonia, Latvia and Germany and increased in the United Kingdom, Sweden and Tomsk Oblasts of the Russian Federation.Surveillance of drug resistance has been strengthened in the WHO European Region, which has the highest proportions of MDR-TB and XDR-TB ever reported globally. More complete data are needed particularly from the Russian Federation.     

Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms

One-third of the world's population is infected with Mycobacterium (M.) tuberculosis. Tuberculosis continues to be the most common infectious cause of death and still has a serious impact, medically, socially and financially. Multidrug-resistant tuberculosis (MDR-TB), caused by tubercle bacilli that are resistant to at least isoniazid and rifampin, is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients for whom treatment has failed have a high risk of death. Drugs used to treat tuberculosis are classified into first-line and second-line agents. First-line essential anti-tuberculosis agents are the most effective, and are a necessary component of any short-course therapeutic regimen. The drugs in this category are isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin. Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit severe reactions much more frequently. These drugs include para-aminosalicylic acid (PAS), ethionamide, cycloserine, amikacin and capreomycin. New drugs, which are yet to be assigned to the above categories, include rifapentine, levofloxacin, gatifloxacin and moxifloxacin. Recently there has been much development in the molecular pharmacology of anti-tuberculosis drugs. This review summarizes information for isoniazid, rifampicin, ethambutol, pyrazinamide, and fluoroquinolones, and describes their resistance mechanisms.     

分支杆菌139例耐药情况分析

目的通过分析139例分支杆菌培养及药敏资料,探讨分支杆菌耐药情况。方法收集2011年5月20日～2012年7月31日我院结核病区139例结核病患者痰结核培养及药物敏感(包括异烟肼、利福平、链霉素、乙胺丁醇、左氧氟沙星、卡那霉素,对氨基水杨酸7种抗结核药物)试验数据,分析其耐药情况。结果对7种药物全敏感43例(30.9%,43/139),耐药96例(69.1%,96/139)。单耐药24例(17.3%,24/139),多耐药27例(19.4%,27/139),耐多药(MDR)45例(32.4%,45/139),广泛耐药(XDR)10例(7.2%,10/139)。耐药率:INH(47.48%)>PAS(46.04%)>RFP(38.13%)>S(26.62%)>Km(20.14%)>Lfx(19.42%)>EMB(16.55%)。对一线药品均敏感57例(41%,57/139),对一线药品均耐药82例(59%,82/139)。对二线药品均敏感62例(44.6%,62/139),对二线药品均耐药77例(55.4%,77/139)。结论分支杆菌感染耐药情况严重,应重视及加强分支杆菌培养分析,根据药敏及时调整,减少无效治疗。     

Drug-resistant and multidrug-resistant tubercle bacilli

Drug resistant (DR) and multidrug resistant (MDR) tuberculosis (TB) is a consequence of human activity and did not exist before chemotherapeutic drugs were introduced. Monotherapy with various drugs in sequence or other inadequate drug regimens have strongly contributed to the creation of MDR-TB. Such TB strains are mainly prevalent in regions with weak national TB programmes or poor socio-economic environments. Strains may also spread in some communities such as poorly administered prisons. From these and other sources, MDR-TB may spread in the population from which travellers might transfer strains between countries and continents. Therefore an effective surveillance of the resistance pattern of TB bacilli is a demanding task in all countries. In this review some aspects of epidemiology, diagnosis and mechanisms of DR in TB are discussed. MDR-TB is an important international problem of increasing significance for the whole global community.     

Whole-genome sequencing in drug susceptibility testing of Mycobacterium tuberculosis in routine practice in Lyon,France

Rapid and correct determination of Mycobacterium tuberculosis (MTB) drug susceptibility is a challenge for tuberculosis (TB) management. Phenotypic drug susceptibility testing (DST) remains the reference method but is time consuming. In this study, genotypic prediction of the first-line drug susceptibility profile obtained by whole-genome sequencing (WGS) was compared with that obtained by phenotypic DST and the line probe assay (LPA). All MTB strains isolated from patients during routine practice at the mycobacteria laboratory of Lyon University Hospital, France, between November 2016 and July 2019 were included (n = 274). Isolates were tested for the first-line drugs using phenotypic DST (Mycobacteria Growth Indicator Tube) and for genotypic prediction of the susceptibility profile with LPA and WGS. Considering phenotypic DST as the reference, WGS predicted resistance to rifampicin, isoniazid, ethambutol and pyrazinamide with sensitivities of 100%, 100%, 100% and 93.8%, respectively, and susceptibility to these drugs with specificities of 99.6%, 100%, 98.5% and 100%, respectively. Performance of the LPA was poorer, with sensitivity of 83.3% for rifampicin and 85.7% for isoniazid resistance. Five isolates were classified as susceptible according to phenotypic DST (1 for rifampicin, 4 for ethambutol) while WGS detected resistance mutations in rpoB and embB genes. WGS, used under appropriate quality-control conditions, has good performance to predict the resistance profile for the four first-line drugs and can correct phenotypic DST results. This study highlights the need for future guidelines recommending WGS as the initial tool in routine practice in areas where the prevalences of TB and drug-resistant MTB are low.     

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.     

The decline of high drug resistance rate of pulmonary Mycobacterium tuberculosis isolates from a southern Taiwan medical centre, 1996-2000

To investigate the anti-tuberculosis drug resistance pattern of pulmonary tuberculosis isolates in southern Taiwan, we performed a hospital-based surveillance at a southern Taiwan medical centre from 1996 to 2000. The combined drug resistance rates to at least one of four first-line agents (isoniazid, rifampicin, ethambutol, streptomycin) was 52.4%, and to both isoniazid and rifampicin was 11.4%, indicating high resistance rates compared with those reported in the World Health Organization (WHO)/International Union Against Tuberculosis and Lung Disease (IUATLD) global project and in northern Taiwan. The resistance rates to two second-line drugs, cycloserine, and kanamycin, were 75.7 and 23.7%, respectively. A significant decreasing trend in resistance rates to all tested drugs except streptomycin was observed during the 5-year period. The resistance rates in 1996 and 2000 were 43.1 and 16.4% for isoniazid, 23.4 and 9.5% for rifampicin, 23.4 and 12.1% for ethambutol, 92.7 and 50.9% for pyrazinamide. The combined drug resistance rate may not be the most accurate tool as it includes previously treated cases that may inflate the resistance rate and cases without a history of treatment. However, the observation of trends in the susceptibility of pulmonary tuberculosis with the increasing percentages of tuberculosis patients receiving the complete treatment course and the decreasing percentages of cases lost to follow-up in Kaohsiung after the institution of new governmental regulations for case management in 1997, suggest that such intervention programs are useful.     

微孔药敏检测法检测耐多药结核病 33例耐药分析

目的 探讨MicroDSTTM(微孔药敏检测法)微孔板法检测结核分枝杆菌的耐药情况分析.方法 用MicroDSTTM微孔板法对贵阳市公共卫生救治中心2018年1月至2019年11月期间部分用比例法药敏试验随机筛选的33例耐多药结核病(MDR-TB)阳性菌株进行16种抗结核药药物敏感性检测.结果 异烟肼、利福平耐药率与比例法比较符合率为97.0％(32/33)、93.9％(31/33);对16种药总耐药率33％(174/528);一线总耐药率70.5(93/132)、二线总耐药率20.5(81/396).结论 微孔板法检测的MDR-TB病人筛选率与比例法具有较高符合率、且本地区MDR-TB病人的耐药情况较严重,应加强药物监测,选择有效药物化疗,而MicroDSTTM微孔板法的推广使用有利于MDR-TB诊断和药物筛选.     

Tb drug resistance: is it really a threat to Africa?

In most of the world and particularly in Eastern Europe, China and India, drug resistance is increasingly seen as a major threat to tuberculosis (TB) control and even to public health and health security. What about in Africa? The conditions for creation of drug resistance exist in most, if not all, African countries, as a result of underinvestment in basic TB control, poor management of anti-TB drugs and virtual absence of infection control measures. The severity of drug resistance is increasing--following outbreaks all over the world of multi-drug resistant TB (MDR) in the 1990's, extensive drug resistant (XDR) TB has now been found in 37 countries, including South Africa. (MDR is, in essence, resistance to the most powerful first-line drugs, and XDR-TB is TB resistant to the most powerful second-line drugs as well.) Worse still, the impact of XDR-TB is magnified among those with HIV infection, giving rise to a remarkably high mortality, and exposing significant weaknesses in both HIV and TB control. In particular, the lack of laboratories capable of carrying out culture and drug susceptibility testing severely limits the capacity of countries even to detect the problem in Africa. This paper analyses the threat of TB drug resistance to health and to TB control in Africa, and puts forward measures to diminish this threat.     

Emerging therapeutic targets in tuberculosis: post-genomic era

Every minute, somewhere in the world four people die from tuberculosis (TB), yet it has been nearly 40 years since a novel drug was introduced to treat this disease. The ever increasing number of TB cases together with the advent of multi-drug resistant (MDR) TB, has stimulated the search for novel anti-TB agents. An array of novel drug targets is provided by the mycobacterial cell wall, whose integrity is essential for bacterial viability. Over the years researchers have identified potential drug targets that are associated with the synthesis of various cell wall constituents. This classic approach, together with the unravelling of the Mycobacterium tuberculosis genome sequence, has placed TB drug research in an unprecedented position. An entire new set of genetic and bioinformatic tools for probing potential drug targets is now available. As therapies using first-line drugs like isoniazid (INH) or rifampin in combination with second-line drugs, like ethambutol (EMB) still continues, a number of substituted fluoroquinolones are being considered as the new generation of anti-TB drugs for their favourable pharmacokinetic profile and excellent oral bioavailability. In this review, the future of anti-TB drugs is discussed with reflection on the structure and biosynthesis of cell wall constituents that are potential drug targets. The importance and relevance of the M. tuberculosis genome sequence for the development of novel anti-TB drugs, have also been underscored.     

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.     

A structure‐based strategy toward the development of novel candidates for antimycobacterial activity: Synthesis,biological evaluation,and docking study

Bacterial resistance to most of the available antibiotics has stimulated the discovery of novel efficacious antibacterial agents. Bedaquiline is first of its type that has been specifically introduced for the management of MDR‐TB in combination with other drugs. In this study, a series of isoniazid/ethambutol/pyrazinamide/‐quinoline conjugates based on the structures of bedaquiline were designed and synthesized. Biological activity tests revealed that some of isoniazid/ethambutol/quinoline conjugates have useful antibiotic activity against MTB H37Rv (MIC: 2.0–8.0 μg/ml). Furthermore, molecular docking calculations were performed for the most potent inhibitor to show its binding interactions within the active site of the possible target protein. Overall, these compounds represent novel valuable starting point with potent antimycobacterial activity and deserve further structural modifications.     

深圳市2005年、2009年结核菌耐药监测结果

目的了解深圳市结核分枝杆菌耐药情况,为深圳市结核病控制提供科学依据。方法依据（WHO／IUALD）结核病耐药指南,将深圳市2005年和2009年每年3月至8月间所有新涂阳和新登记的复治涂阳的肺结核作为监测对象,对2005年802例、2009年1054例成功分离的结核分枝杆菌菌株,用比例法进行药物敏感实验。结果2005年总耐药率18．3％,初始耐药率17．2％,获得性耐药率31．3％;总耐多药率4．7％,初始和获得性耐多药率分别为3．25％和21．9％;2009年总耐药率17．4％,初始耐药率16％,获得性耐药率39．3％;总耐多药率3．8％,初始和获得性耐多药率分别为3．02％和16．4％。2009年以上各耐药率、各耐多药率与2005年比较,差异元统计学意义,2005年、2009年的获得性耐药率、获得性耐多药率均显著高于初始耐药率、初始耐多药率。结论深圳市耐药结核病的发生率处于较高水平,应该引起高度重视。     

司帕沙星治疗耐多药肺结核疗效观察

评价司帕沙星对耐多药肺结核（ＭＤＲ－ＰＴＢ）的疗效与安全性,将１０４例ＭＤＲ－ＰＴＢ患者随机分为两组,以氧氟沙星作为对照。治疗组５２例均采用３ＳＨＲＺＥ＋ＳＰＬＸ／９ＨＲＥ＋ＯＦＬＸ方案治疗,疗程均为１２个月。疗程结束时,治疗组痰转阴率９２．３１％。明显高于对照组６９．２３％（０．０１〈Ｐ〈０．０５）;治疗２个月时治疗组痰菌转阴率非常显著（Ｐ〈０．０１）,表明司帕沙星是目前氟喹诺酮类中治疗ＭＤＲ－     

Alarming drug-resistance rates for tuberculosis in Süreyyapaşa Hospital, Turkey

The susceptibility patterns to 'classic' tuberculous pleuritis can reflect the circulating strains in a society. The records of patients with 'classic' tuberculous pleuritis were reviewed retrospectively. Eighty-six patients were selected who were hospitalized between January 1990 and April 1994. Pleural fluid and tissue samples of patients were cultured in Lowenstein-Jensen medium. The isolated strains were subjected to drug susceptibility testing based on the absolute concentration method. We obtained 40 positive cultures in 86 patients with 'classic' tuberculous pleuritis. The resistance rate was 75% to one or more drugs, 27.5% to two drugs, 15% to three drugs, and 10% to four drugs. The resistance rates to isoniazid, rifampicin, streptomycin, and ethambutol were 32.5, 55,42.5 and 32.5%, respectively. The resistance to isoniazid + rifampicin was 7.5%. Our findings indicate that the resistance rates for 'classic' tuberculous pleuritis are considerably high, reflecting the currently circulating resistance patterns in our region. The best regimen for new tuberculous cases and the appropriate regimens for drug-resistant cases should be designed and conducted by a nationwide institution.     

沧州市结核分枝杆菌间隔区寡核苷酸分型研究

Objective To identify the genetic polymorphism and molecular epidemiological characteristics of Mycobacterium tuberculosis (TB) clinical isolates in Cangzhou, and explore the association between genotypes and drug resistance phenotypes. Methods Mycobacterium tuberculosis isolates were collected from TB patients treated in the Cangzhou Infectious Disease Hospital, and corresponding clinical data were also collected. The genomic DNA was extracted. Spacer oligonucleotide typing (spoligotyping) was applied to genotype the isolates. Drug susceptibility testing of first- line anti- TB drugs (streptomycin, isoniazid, rifampin, ethambutol) was performed using the BACTECTMMGITTM960 liquid medium. Cluster analysis was done by BioNumerics 5.0. Data was analyzed by Graphpad Prism 5.0 software. Results Of the 154 patients, 109 were male and 45 were female. And 121 patients were treated for the first time, 33 were retreatment, 34 had smoking history, 12 were complicated with diabetes mellitus. Fourty-eight strains (31.2%) were resistant to at least one of streptomycin, inoniazid, rifampicin and ethambutol. Initial drug resistance rate was 22.3% and acquired drug resistance rate was 63.6%. The drug resistance rate was significantly higher in retreatment patients than that of new cases. The Beijing family strain accounted for 91.6% of all isolates and the non- Beijing family strain accounted for 8.4% . There were no significant differences in gender, treatment history, smoking history and diabetes history between patients with the Beijing genotype and patients with non- Beijing genotype. Conclusion Mycobacterium tuberculosis in Cangzhou exhibits high genetic diversity. The Beijing genotype is the predominant no association with drug resistance.     

Mycobacterium tuberculosis resistance to antitubercular agents in Antananarivo in 2000

In 1991, the National Tuberculosis control Program (NTP) of Madagascar adopted the short treatment course and the Directly Observed Treatment Strategy (DOTS), according to the recommendations of the OMS/UICTMR. Development of M. tuberculosis primary resistance to the four antituberculosis drugs (streptomycin [S], rifampicine [R], isoniazid [H], ethambutol [E]) is an indicator of the NTP efficiency. We report results from a five-year survey among patients with new smear positive pulmonary tuberculosis. Acquired resistance is assessed among recurrent cases. During the first survey, carried out in 1994-1995 in four large cities, multidrug resistance (MDR) rate to the major antituberculosis drug H and R was low, 0.25% for primary MDR and 5% for acquired MDR. No primary MDR was found in Antananarivo; on the other hand, acquired resistance rate was the highest there (22%). Because of logistical reasons, the second survey (1999-2000) was only carried out in the capital, Antananarivo. Results obtained among 789 new patients with smear positive pulmonary tuberculosis and 79 recurrents cases in 9 diagnostic centres showed low primary and acquired resistance of 11.1% to any drug. Primary resistance to one drug was 10.6%, mainly due to streptomycin 8.5%. MDR rates are comparable with those observed in 1994-1995: 0.1% for primary MDR and 4% for acquired MDR. These results show that ten years after the new NTP implementation, only a few MDR strains are circulating in Antananarivo, which suggests that NTP has been effective.