Drug resistance of Mycobacterium tuberculosis]

Drug resistance of Mycobacterium tuberculosis was followed up within a period of 1986 to 1989. There was a tendency to stabilization of resistance to streptomycin (42 per cent), tubazid (45.2 per cent) and ethionamide (up. to 1.4 per cent). Resistance to kanamycin slowly increased (by 3 to 6 per cent every year). Resistance to rifampicin markedly increased (almost 15 times). Resistance to ethambutol decreased (10 times). It was shown that the drug resistance could be lowered by using the drug combinations.     

Drug resistance of strains of Mycobacterium tuberculosis isolated in Brazil.

Tuberculosis remains a serious public health problem, worsened by an increased frequency of multidrug-resistant Mycobacterium tuberculosis. We report here a retrospective study of resistance to antituberculosis drugs of 170 strains of M. tuberculosis isolated from the state of Rio Grande do Sul, Brazil. The frequency of resistance to at least one drug was 34%, while 22% were resistant to more than one drug. Among the strains isolated from patients without a history of previous treatment for tuberculosis, patients with positive serology for HIV and patients with previous treatment for tuberculosis, the resistance to at least one drug was 14, 27 and 73%, respectively. Multidrug-resistant tuberculosis, defined as resistant to at least rifampicin (RMP) and isoniazid (INH), was found in the groups of patients without previous treatment, HIV co-infected and with previous treatment for tuberculosis at 10, 17 and 44%, respectively. With the purpose of evaluating whether the sensitivity test to INH and RMP would be a good marker to indicate resistance to other antituberculosis drugs, sensitivity tests were performed with four more drugs in 32 strains, initially classified as resistant to INH, RMP or both. Of 18 strains resistant to INH and RMP simultaneously, 89% showed resistance to four more drugs.     

Drug resistance among Mycobacterium tuberculosis strains isolated in Taiwan during 1975.

455 strains of Mycobacterium tuberculosis were isolated from patients with history of treatment in Taiwan Provincial Tuberculosis Control Bureau and tested for resistance against various antituberculosis agents including streptomycin (SM), paraaminosalicylic acid (PAS), isoniazid (INH), cycloserine (CS), prothionamide (1321TH), kanamycin (KM), ethambutol (EMB), and rifampicin (RFP). In vitro resistance to SM and INH was more frequently found than others and the resistance to a single drug was more common than multiple resistance.     

结核分枝杆菌耐氟喹诺酮类药物的分子机制研究进展

结核病是由结核分枝杆菌(Mycobacterium tuberculosis)通过空气传播引起人类感染的慢性传染病,耐药结核分枝杆菌的流行是目前结核病防治的世界难题。氟喹诺酮类药物是人工合成药物,应用于耐药结核的临床治疗中,在治疗中起着核心的作用。但近年来,氟喹诺酮类药物的抗性菌株不断出现,愈发增加了结核病治疗的困难与治疗失败风险。在临床中氟喹诺酮药物的靶点比较清楚,是结核分枝杆菌的DNA旋转酶。目前发现结核分枝杆菌耐氟喹诺酮类药物的机制主要包括药物靶点DNA旋转酶的关键氨基酸改变、药物外排泵系统、细菌细胞壁厚度的增加以及喹诺酮抗性蛋白MfpA介导的DNA旋转酶活性调控。其中在氟喹诺酮靶标DNA旋转酶功能活性改变的耐药机制方面,编码DNA旋转酶基因突变一直是研究的热点,但近年来发现DNA旋转酶的调控蛋白MfpA以及DNA旋转酶的修饰在细菌耐药性中起着重要的作用,相关机制还亟待发现。本文综述了当前结核分枝杆菌耐氟喹诺酮类药物的作用机制,旨在为研发精准诊断技术和药物发掘提供科学理论基础和参考。     

Drug resistance and IS6110‐RFLP patterns of Mycobacterium tuberculosis in patients with recurrent tuberculosis in northern Thailand

The emergence of drug resistant Mycobacterium tuberculosis has become a global threat to tuberculosis (TB) prevention and control efforts. This study aimed to determine the drug resistance profiles and DNA fingerprints of M. tuberculosis strains isolated from patients with relapsed or retreatment pulmonary TB in Chiang Rai province in northern Thailand. Significant differences in multidrug resistance (MDR) (P = 0.025) and resistance to isoniazid (P = 0.025) and rifampin (P = 0.046) between first and second registrations of patients with retreatment TB were found. However, there were no significant differences in resistance to any drugs in patients with relapsed TB. The rate of MDR‐TB strains was 12.2% among new patients at first registration, 22.5% among patients with recurrence who had previously undergone treatment at second registration and 12.5% at third registration. Two retreatment patients whose initial treatment had failed had developed MDR‐TB with resistance to all TB drugs tested, including rifampin, isoniazid, streptomycin and ethambutol. IS6110‐RFLP analysis revealed that 66.7% (10/15 isolates) of MDR‐TB belonged to the Beijing family. In most cases, IS6110‐RFLP patterns of isolates from the same patients were identical in relapse and retreatment groups. However, some pairs of isolates from retreatment patients after treatment failure had non‐identical IS6110‐RFLP patterns. These results suggest that, after failure and default treatment, patients with retreatment tuberculosis have a significantly greater risk of MDR‐TB, isoniazid and rifampin resistance than do other patients.     

Recent updates on drug resistance in Mycobacterium tuberculosis

Tuberculosis (TB) along with acquired immune deficiency syndrome and malaria rank among the top three fatal infectious diseases which pose threat to global public health, especially in middle and low income countries. TB caused by Mycobacterium tuberculosis (Mtb) is an airborne infectious disease and one-third of the world's population gets infected with TB leading to nearly 1·6 million deaths annually. TB drugs are administered in different combinations of four first-line drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) which form the core of treatment regimens in the initial treatment phase of 6–9 months. Several reasons account for the failure of TB therapy such as (i) late diagnosis, (ii) lack of timely and proper administration of effective drugs, (iii) lower availability of less toxic, inexpensive and effective drugs, (iv) long treatment duration, (v) nonadherence to drug regimen and (vi) evolution of drug-resistant TB strains. Drug-resistant TB poses a significant challenge to TB therapy and control programs. In the background of worldwide emergence of 558 000 new TB cases with resistance to rifampicin in the year 2017 and of them, 82% becoming multidrug-resistant TB (MDR-TB), it is essential to continuously update the knowledge on the mechanisms and molecular basis for evolution of Mtb drug resistance. This narrative and traditional review summarizes the progress on the anti-tubercular agents, their mode of action and drug resistance mechanisms in Mtb. The aim of this review is to provide recent updates on drug resistance mechanisms, newly developed/repurposed anti-TB agents in pipeline and international recommendations to manage MDR-TB. It is based on recent literature and WHO guidelines and aims to facilitate better understanding of drug resistance for effective TB therapy and clinical management.     

Determination of Drug Resistance of Mycobacterium tuberculosis Cultures

A total of 3,303 strains of Mycobacterium tuberculosis were tested for sensitivity to streptomycin (SM), isoniazid (INH), and p-aminosalicylic acid (PAS) by the Steenken modified minimal inhibitory concentration (MIC) test. A simultaneous double blind comparison was carried out on 277 selected strains by the Steenken MIC test and the Canetti proportion method. Agreement between the results for the two tests was 82% for SM, 95% for INH, and 89% for PAS. A small number of strains appeared to be sensitive when tested by one method but resistant by the other. MIC determinations were carried out on 83 strains by using Steenken-Smith, Lowenstein-Jensen, and Middlebrook 7H10 media containing a more extended range of concentrations of the test drugs. The MIC values for both SM and dihydrostreptomycin increased on Steenken-Smith medium compared with the other two. INH did not show any medium effect, whereas PAS showed increased MIC values in 7H10 agar. The significance of the comparisons of the MIC values on the various media is discussed in terms of possible changes in the drug sensitivity testing methods used at present in this laboratory.     

The road to drug resistance in Mycobacterium tuberculosis

Sequencing of serial isolates of extensively drug-resistant tuberculosis highlights how drug resistance develops within a single patient and reveals unexpected levels of pathogen diversity.Tuberculosis (TB) remains a crucial public health problem, with increasing drug resistance posing a challenge to current control efforts. Treatment regimens for drug-susceptible TB are onerous, requiring a minimum of six months of treatment with four antitubercular drugs. There are patients who develop multi-drug-resistant (MDR), extensively drug-resistant (XDR) and totally drug-resistant (TDR) forms, which are successively more difficult to treat. In these circumstances, treatment regimens involve the use of a larger number of less-effective drugs, which have a narrower therapeutic margin.In many bacteria, drug-resistance determinants are carried on mobile genetic elements. However, in Mycobacterium tuberculosis (Mtb), drug resistance is exclusively associated with point mutations and chromosomal rearrangements. Poor or intermittent therapy has long been thought to be the major explanation for drug resistance, and it is believed that drug-resistant strains develop through the sequential fixation of a small set of mutations, such that the pathogen samples only a small proportion of possible evolutionary paths [1].The application of whole-genome sequencing (WGS) has revealed previously underappreciated levels of genetic diversity within circulating Mtb populations, and the implications of this diversity for transmission and disease outcomes are increasingly being acknowledged. By contrast, mycobacterial heterogeneity within a single host, and any concomitant biological or clinical significance, has been explored but seldom documented.In a study published in this issue of Genome Biology, Eldholm and colleagues apply WGS to investigate the evolution from drug-sensitive to XDR-TB within a single patient [2]. This adds to an emerging body of evidence that suggests that intra-host microbial diversity is substantial and might have significant consequences when inferring transmission. There are few instances, if any, in the literature where this has been investigated in such detail.     

结核分枝杆菌利福平耐药性的研究进展

本旨在阐明结核分枝杆菌耐利福平分离株rpoB基因突变的规律,以及rpoB基因突变与利福平最低抑菌浓度(MIC)的关系。结核分枝杆菌的rpoB基因突变是引起利福平耐药性的主要原因,耐利福平分离株的rpoB基因突变主要集中在507～533位密码子的81bp的区域内,约80％的菌株发生531位或526位密码子突变。不同类型rpoB基因突变的结核分枝杆菌对利福平的耐受性也不同,通常发生531位密码子突变的菌株的MIC≥64μg／ml。     

Drug resistance in patients with pulmonary tuberculosis.

A review of the records of 984 patients admitted to hospital from 1970 through 1973 with bacteriologically proven pulmonary tuberculosis showed bacterial resistance to one or more antituberculosis drugs in 103 (10.5%). Among the patients who had had previous drug treatment for tuberculosis the prevalence of drug resistance was 20% in the Canadian-born patients and 69.4% in the recent immigrants. Among the patients who had had no previous drug treatment the prevalence of drug resistance (primary resistance) was 2.7% in Canadian-born patients but 11.4% in recent immigrants. Because of the higher prevalence of drug resistance among recent immigrants and the finding in recent years that increasingly more tuberculosis patients in Ontario are recent immigrants, drug resistance in this group is likely to assume even more importance in the future.     

结核分枝杆菌耐吡嗪酰胺分子机制研究

吡嗪酰胺(PZA)是结核病短程化疗中的一线抗结核药物,由吡嗪酰胺酶转换成为活性形式吡嗪酸而生效。吡嗪酰胺酶由pncA基因编码,pncA基因突变会导致该酶活性丧失,与PZA耐药性产生有关。为了进一步明确PZA耐药性产生的基因学基础和PZA耐药株的pncA基因突变率,对中国100株结核分枝杆菌临床分离株进行了DNA序列测定,其中85株为PZA耐药株,15株为PZA敏感株。PZA耐药株有27%(23/85)发生了pncA基因突变,从而导致吡嗪酰胺酶基本氨基酸序列的改变,突变分布在pncA基因开读框架17-546位的核苷酸。其中有一株突变位于pncA基因的调节区域-11位处。同时发现20%(3/15)pncA敏感株也发生了pncA基因突变。敏感株发生突变可能是由于PZA敏感性实验不准确或存在其它耐药机制。实验表明,pncA基因突变是PZA耐药的主要机制之一,中国PZA耐药临床分离株尚存在其它耐药分子机制。     

AhpC, oxidative stress and drug resistance in Mycobacterium tuberculosis

The Mycobacterium tuberculosis AhpC is similar to a family of bacterial and eukaryotic antioxidant proteins with alkylhydroperoxidase (Ahp) and thioredoxin-dependent peroxidase (TPx) activities. AhpC expression is associated with resistance to the front-line antitubercular drug isoniazid in the naturally resistant organisms E. coli and M. smegmatis. We identified several isoniazid-resistant M. tuberculosis isolates with ahpC promoter mutations resulting in AhpC overexpression. These strains were more resistant to cumene hydroperoxide than were wild-type strains. However, these strains were unchanged in their sensitivity to isoniazid, refuting a role for AhpC in detoxification of this drug. All the isoniazid-resistant, AhpC-overexpressing strains were also deficient in activity of the mycobacterial catalase-peroxidase KatG. KatG, the only known catalase in M. tuberculosis, is required for activation of isoniazid. We propose that compensatory ahpC promoter mutations are selected from KatG-deficient, isoniazid-resistant M. tuberculosis during infections, to mitigate the added burden imposed by organic peroxides on these strains.     

结核分枝杆菌耐药性的分子生物学研究进展

结核病一直是世界性问题,我国其发病情况尤为严重,是亚洲的第二大结核病发病国家。结核病治疗方面常使用抗生素作为首选药物,随着抗菌药的滥用,结核杆菌对多种抗菌药产生耐药性,结核病耐药患者增多,治疗难度增加。因此,结核杆菌耐药分子机制的研究更加重要,新型抗结核药物研制更加迫切。结核分枝杆菌的基因突变是引起耐药的主要分子学依据,因此基于结核分枝杆菌耐药性相关基因的深入探索,对于预防结核病的传播及治疗皆具有深远影响。本文从分子生物学角度分析了近年来结核分枝杆菌耐药性产生的原因及相关研究进展。     

997例结核分枝杆菌的耐药性分析

目的分析结核病患者的耐药性和临床特点为临床治疗提供依据。方法回顾分析厦门大学附属厦门第一医院2011-2013年送检的结核病患者样本及其分离培养出的结核分枝杆菌的耐药性,为临床合理选用抗结核药物提供依据。结果结核病的耐药率相对较低,三年中全部敏感的分别为41.7%、40.1%和42.6%;结核病耐药性较高的药物主要是异烟肼(INH)、利福平(RFP)和链霉素(SM);复治结核病患者的耐药性明显高于初治患者,2011年RFP和EMB(乙胺丁醇)的P值0.05,INH、SM(链霉素)、PAS(对氨基水杨酸)、K(卡那霉素)、LFX(左氧氟沙星)的P值0.01;2012年EMB、PAS、K的P值0.05,INH、RFP、SM、LFX的P值0.01;2013年INH、SM、K的P值0.05,RFP、EMB、PAS、LFX的P值0.01;差异具有统计学意义。结论结核病的耐药性高,尤其是复治患者,临床上应根据药敏结果合理用药,针对不同患者建立不同治疗方案,加强护理及健康教育以提高治愈率。