Anti-tuberculosis drugs adverse reactions: a review of the Iranian literature

Introduction: Tuberculosis (TB) treatment, in particular therapy for multidrug-resistant TB (MDR-TB), is associated with toxicities and adverse drug reactions (ADRs).

Areas covered: This paper reviews Iranian literature reporting ADRs which occurred during tuberculosis treatment. English language papers were sourced from PubMed, ScienceDirect, Wiley, Ovid and Proquest, with Google Scholar searched for Persian language articles. Reported ADRs, proportion of patients with ADRs, risk factors and determinants, as well as the characteristics of the studies were reviewed. 21 articles were included; about 60% of them were in English and three included patients with MDR-TB. The ratio of ADR per capita was 1.9 (in 6 studies) and 33.63% of patients developed an ADR (in 7 studies). Hepatitis (2.5 – 45.3%) was reported in nearly all of the studies. The mean time from initiation of medication to development of hepatitis ranged from 4.67 to 25.25 days (in 6 studies). Most cases of mortality were due to hepatotoxicity. Except for comorbidities and female gender, other risk factors such as HIV and length of hospitalization were only reported in one article.

Expert opinion: The pattern of ADRs in Iranian articles was found to be similar to many other studies in the present review. We suggest that future studies resolve the confounding factors in this area that are mentioned in this review.     

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.     

Beijing genotype of Mycobacterium tuberculosis is significantly associated with linezolid resistance in multidrug-resistant and extensively drug-resistant tuberculosis in China

Linezolid (LNZ) is a promising antimicrobial agent for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). To investigate the efficacy of LNZ among MDR-TB and XDR-TB in China, the LNZ susceptibility of 158 MDR-TB isolates from the national drug resistance survey was determined by the minimum inhibitory concentration method. The 158 MDR-TB isolates were also sequenced in the 23S rRNA, rplC and rplD genes conferring LNZ resistance and were typed using spoligotyping to identify the Beijing genotype of Mycobacterium tuberculosis. Overall, the prevalence of LNZ-resistant isolates was 10.8% (17/158) among MDR-TB isolates circulating in China. Beijing genotype was significantly associated with LNZ resistance in MDR-TB and XDR-TB (odds ratio = 4.66, 95% confidence interval 1.03–21.16; P = 0.033). In addition, a higher frequency of LNZ-resistant isolates was observed among XDR-TB strains (60%) compared with the MDR (5.6%; P < 0.001) and pre-XDR groups (12.2%; P = 0.004). Mutations in 23S rRNA and rplC were responsible for only 29.4% of LNZ-resistant M. tuberculosis among MDR-TB isolates, and a novel non-synonymous substitution His155Asp in rplC was first identified to be contributing to low-level LNZ resistance (2 μg/mL) in M. tuberculosis. The unsatisfactory correlation between mutant genotypes highlights the urgent need to investigate another mechanism for LNZ resistance that has not yet been described.     

耐药结核病的流行和监测现状

结核分枝杆菌的耐药性已成为全球关注的重大公共卫生挑战。根据世界卫生组织(World Health Organization, WHO)的统计,我国是全球22个结核病(tuberculosis, TB)高负担国家之一,也是全球27个耐多药结核病(multi-drug resistant TB, MDR-TB)高负担国家之一。耐药结核病(drug resistant TB, DR-TB)是中国结核病防治工作的三大挑战之一,如若耐药结核病的流行不能得到有效控制,将会影响我国“2035年终止结核病流行目标”的顺利实现。结核病耐药性监测对于指导合理使用抗生素起着至关重要的作用,耐药监测是评估结核病防治规划实施效果的有效指标。1994年,WHO和国际防痨及肺部疾病联合会(International Union Against Tuberculosis and Lung Disease, UNION)共同开展了一项全球性的结核病耐药性监测项目,我国除参与该项目外,同时积极开展了多次全国结核病流行病学调查,并成功开展了全国结核病耐药性基线调查,为制定科学防治结核病的策略措施提供重要参考依据。     

The safety and tolerability of the second-line injectable antituberculosis drugs in children

ABSTRACT

Introduction: A growing number of children globally are being treated for multidrug-resistant tuberculosis (MDR-TB). The second-line injectable antituberculosis medications amikacin, kanamycin and capreomycin, traditionally a mainstay of MDR-TB treatment, cause important adverse effects including permanent sensorineural hearing loss, nephrotoxicity, electrolyte abnormalities, injection pain and local injection site complications.

Areas covered: To characterize the safety and tolerability of the second-line injectables in children treated for MDR-TB, we reviewed data on the mechanism of injectable associated adverse effects, risk factors for their development, and the incidence of injectable-associated adverse effects in adults and children treated for MDR-TB.

Expert opinion: Despite a substantial evidence base in adults demonstrating the frequent and potentially serious adverse effects of second-line injectables, important knowledge gaps remain. Improved characterization of the incidence of injectable-associated adverse effects will inform rational guidance on monitoring children with TB on injectables. Eliminating the need for injectables in MDR-TB treatment regimens is a high priority, and will rely on the use of novel antituberculosis TB drugs. Strategies to reduce the risk of adverse effects of injectables, if used, deserve evaluation. This includes evaluation of potentially otoprotective medications N-acetylcysteine or aspirin, high frequency hearing screening for earlier detection of ototoxicity and therapeutic drug monitoring.     

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.     

Current and developing therapies for the treatment of multi drug resistant tuberculosis (MDR-TB) in India

Introduction: India accounts for 25% of the global burden of MDR-TB. In 2016, the India’s Revised National TB Control Programme reported a success rate of 46% among 19,298 MDR-TB patients treated under the programme. This suboptimal treatment outcome warrants an urgent need for newer drugs and newer regimens in the treatment of MDR-TB. India requires new shorter, cheap, safe and effective anti-TB regimen to treat MDR-TB.

Areas covered: We used different search strategies to obtain relevant literature from PubMed, on Indian experiences of developing therapies for the treatment of MDR-TB. Further information from the Central TB Division Government of India on programmatic management of resistant TB was collected.

Expert opinion: In 2016 WHO recommended a shorter MDR-TB regimen of 9–12 months (4–6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E /5 Mfx-Cfz-Z-E) may be used instead of longer regimens. Currently, conducting trials involving newer drugs such as bedaquiline, have been proposed. The regimen will be of a shorter duration containing isoniazid, prothionamide, bedaquiline, levofloxacin, ciprofloxacin, ethambutol and pyrazinamide (STREAM regimen). To successfully treat MDR-TB one requires new classes of antibiotic and newer diagnostic tests. This represents an enormous financial and technical challenge to the programme managers and policy makers.     

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.     

铜陵市2017~2018年初治与复治结核病患者耐药情况分析

目的 分析铜陵市初治与复治结核病耐药现状和特点,掌握结核分支杆菌的耐药谱,为铜陵市结核病疫情制定防控策略提供依据。方法 选取2017~2018年铜陵市耐药监测点的888例初治与复治结核病患者的痰标本进行萋尼氏抗酸染色、结核分支杆菌培养、药物敏感性试验以及菌群鉴定。采用比例法对结核分支杆菌复合群进行药物敏感性试验,并进行统计学分析。结果 在888例初治与复治结核病患者样本中,319例为结核分支杆菌复合群,其中初治结核病患者262例,复治结核病患者57例。总耐药率为19.75%（63/319）,初治结核病患者耐药率为15.65%（41/262）,复治结核病患者耐药率为38.60%（22/57）。总耐多药率为10.66%（34/319）,初治结核病患者耐多药率为6.11%（16/262）,复治结核病患者耐多药率为31.58%（18/57）。8种抗结核药耐药率顺位依次为异烟肼（10.34%）、链霉素（7.52%）、利福平（6.90%）、卷曲霉素（6.90%）、对氨基水杨酸钠（4.70%）、氧氟沙星（3.76%）、卡那霉素（2.82%）、乙胺丁醇（2.19%）。结论 铜陵市初治和复治结核病耐药疫情依然严重,仍需要采取更加有效、全面、及时的干预管理办法,减少结核病耐药性产生。     

山东省耐多药肺结核可疑者筛查情况分析

目的回顾性分析山东省全球基金耐多药肺结核防治项目中可疑者筛查情况,探索并完善耐多药肺结核患者的发现策略。方法在项目地区以耐多药肺结核患者的密切接触者、涂片阳性的慢性和复治失败、初治失败、复发、返回及治疗3个月末痰涂片仍阳性的初治涂阳患者等重点人群为主要筛查对象,进行结核菌培养和药敏试验,分析不同人群中耐多药及广泛耐药肺结核的筛出情况。结果开展培养的4318例涂片阳性的耐多药肺结核可疑者中,培养阳性3315例(82.5%);开展药敏试验的3296例可疑者中,422例(14.3%)被诊断为耐多药肺结核,16例(0.5%)被诊断为广泛耐药肺结核,其中复治失败患者中耐多药及广泛耐药肺结核检出率最高,为64.5%,初治失败患者中耐多药及广泛耐药肺结核检出率较高,为41.2%,新患者中耐多药及广泛耐药肺结核检出率较低,仅为6.6%。结论重点人群筛查是一种高效的耐多药肺结核患者的筛查策略,值得在山东省其他地市推广应用。     

Prevalence of IGRA-positivity and risk factors for tuberculosis among injecting drug users in Estonia and Latvia

BackgroundIllegal drug use and HIV are independent risk factors for tuberculosis (TB) among injecting drug users (IDU). Estonia and Latvia have experienced high rates of TB as well as IDU and HIV outbreaks. There is a lack of knowledge about TB among IDUs in these countries. The purpose of the current study was to estimate the prevalence and risk factors of Mycobacterium tuberculosis (MTB) infection among IDUs in Estonia and Latvia.MethodsParticipants for this cross-sectional study were recruited from syringe exchange programmes using respondent-driven sampling. For assessing infection with MTB interferon-gamma release assay (IGRA) was used.ResultsThe study included 375 participants from Estonia and 313 from Latvia. The prevalence of IGRA-positivity among IDUs was 7.7% in Estonia and 25.6% in Latvia. HIV-prevalence was 62% in Estonia and 23% in Latvia. In both countries, IGRA-positivity rates did not differ between HIV-positive and HIV-negative participants. IGRA-positivity was independently associated with a prior diagnosis of TB in Estonia and with imprisonment (ever within a lifetime) and preceding contact with a TB patient in Latvia.ConclusionOur findings indicate there is an urgent need for a more vigorous approach in providing IDUs with TB screening services.     

结核分枝杆菌感染T细胞斑点试验对淋巴结结核的诊断价值

目的 探讨结核分枝杆菌感染T细胞斑点试验(T-SPOT.TB)对淋巴结结核的诊断价值。方法 将2012年7月至2015年10月安徽省胸科医院收治的134例淋巴结肿大患者分为结核组(95例)和非结核组(39例),另取健康对照组28例,采外周血行T-SPOT.TB检测,对比分析3组T-SPOT.TB的阳性率,敏感度及特异度。结果 结核组、非结核组和健康对照组T-SPOT.TB阳性率分别为85.26%、15.38%和3.57%,结核组患者T-SPOT.TB阳性检测率显著高于其他两组。T-SPOT.TB诊断淋巴结结核的敏感度、特异度、阳性预测值和阴性预测值分别为85.26%、89.55%、92.05%和81.08%。结论 T-SPOT.TB试验可作为淋巴结结核的重要诊断手段。     

Selective drug deposition in lungs through pulmonary drug delivery system for effective management of drug-resistant TB

Introduction: The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) is a major health issue and continues to be a global health concern. Despite significant advancements in treatment modalities, ~1.6 million deaths worldwide occur due to TB infection. This is because of tuberculosis reservoirs in the alveoli making it a challenge for the formulation scientist to target this.

Area covered: This review recent investigations on the forefront of pulmonary drug delivery for managing MDR-TB and XDR-TB. Novel delivery systems like liposomes, niosomes, employing carbohydrate, and -coated molecules via conjugation to selectively deliver the drugs to the lung TB reservoir via pulmonary administration are discussed.

Expert opinion: Poor patient adherence to treatment due to side effects and extended therapeutic regimen leads to drug-resistant TB. Thus, it is essential to design novel strategies this issue by developing new chemical entities and/or new delivery systems for delivery to the lungs, consequently reducing the side effects, the frequency and the duration of treatment. Delivery of drugs to enhance the efficacy of new/existing anti-TB drugs to overcome the resistance and enhance patient compliance is underway.     

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...     

Methadone treatment improves tuberculosis treatment among hospitalized opioid dependent patients in Ukraine

BackgroundUkraine's volatile syndemics of tuberculosis (TB) and HIV among people who inject drugs (PWIDs) introduces numerous treatment challenges for each condition, including high mortality and development of multi-drug resistant TB (MDR-TB).MethodsA prospective, non-randomized 90-day observational study was conducted in six Ukrainian TB treatment sites to assess the effectiveness of integrating methadone maintenance (MMT) with TB treatment using: (1) 90-day TB treatment retention; (2) time to treatment discontinuation; (3) TB medication adherence; and (4) subject disposition, including mortality. Of the 110 participants enrolled, 57 received MMT and 53 did not (non-MMT).ResultsAll of the primary outcomes were significantly better in MMT versus non-MMT groups, including 90-day TB treatment completion (89.5% versus 73.6%; p = 0.031), time to TB treatment discontinuation (p = 0.039) and TB medication adherence (97.1% versus 86.2%; p < 0.001) after controlling for death. The major reasons for treatment non-completion in the non-MMT group included death (N = 3), administrative discharge from the clinic (N = 5), loss to follow-up (N = 2), and arrest (N = 4). Overall, 90-day mortality was high (8.2%). After controlling for covariates differing between the two groups at baseline, the only independent predictor of completing 90 days of TB treatment was receipt of MMT in an integrated treatment setting (AOR = 3.05; 95% CI 1.08–8.66).ConclusionsMMT integrated into inpatient TB treatment significantly improves retention in TB treatment and TB medication adherence among PWIDs. These findings call for policy change to increase the number of MMT sites in TB facilities and make MMT a low-threshold treatment option for opioid dependence in Ukraine.     

氟喹诺酮类抗菌药物抗结核作用研究进展

从20世纪80年代开始,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艾滋病的相互结合,使结核病疫情再度上升,成为全球重大公共卫生问题和社会问题。WHO于1996年推荐早期氟喹诺酮环丙沙星、氧氟沙星和司帕沙星作为二线抗结核药物,与其他抗结核药物联合使用治疗耐多药结核病以及对不能耐受一线抗结核药物的患者使用。经过10余年临床实践的检验,这类药物的抗结核疗效已获得普遍肯定,但由于广泛使用以及不合理用药,结核分枝杆菌已对该类药物出现耐药性。近年上市的某些新氟喹诺酮类抗菌药(如莫西沙星和加替沙星)其抗结核活性显著增强。研究发现,这2个8-甲氧基氟喹诺酮的体内活性堪与异烟肼(活性最强的一线抗结核药物)媲美,而用莫西沙星替代标准治疗方案中的异烟肼,其疗程可缩短2个月。然而,由于伦理学等原因,这类药物同传统抗结核药物一样也无法进行单药的现代临床试验,因此其抗结核作用的基础研究在指导临床医师合理用药等方面显得尤为重要。本文从作用机制和耐药机制、构效关系、药动学性质和临床研究(早期杀菌活性)以及单药和联合给药时的体内外活性等方面较全面地综述了近年来氟喹诺酮类抗菌药抗结核作用研究进展。     

T细胞酶联免疫斑点试验及结核蛋白芯片试验对淋巴结核的诊断价值

目的 分析T细胞酶联免疫斑点试验（T-SPOT.TB）及结核蛋白芯片试验在诊断淋巴结核中价值。方法 选取安徽省胸科医院2014年1月至2017年5月确诊为淋巴结核的患者30例为研究组,选取非淋巴结核患者30例为对照组,对两组患者进行T-SPOT.TB及结核蛋白芯片试验,分析试验阳性率、敏感度及特异度。结果 研究组结核蛋白芯片试验阳性率为60.00%,T-SPOT.TB试验阳性率为90.00%,两组差异有统计学意义（P<0.05）。研究组联合检测双阳性率高于对照组,对照组联合检测双阴性率高于研究组,差异有统计学意义（P<0.05）。T-SPOT.TB敏感度为90.90%、特异度93.75%,结核蛋白芯片试验敏感度为71.42%、特异度83.33%。T-SPOT.TB和结核蛋白芯片敏感度差异有统计学意义（P<0.05）。结论 T-SPOT.TB在淋巴结核的诊断中应用价值较高与结核蛋白芯片联合试验可以提高准确率。     

Synthetic investigational new drugs for the treatment of tuberculosis

Introduction: Tuberculosis (TB) is a major global health concern. And while there are treatments already on the market, there is a demand for new drugs that are effective and safe against Mycobacterium tuberculosis, which reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multidrug-resistant TB (MDR-TB).

Area covered: This review covers promising novel investigational TB drugs that are currently under development. Specifically, the authors review the efficacy of novel agents for the treatment of TB in preclinical, phase I and phase II clinical trials. The authors also review the safety and tolerability profiles of these drugs.

Expert opinion: Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB in combination with moxifloxacin and pyrazinamide. Linezolid shows marked efficacy in the treatment of MDR-TB and extensively drug-resistant TB (XDR-TB), but the drug is known to cause significant adverse drug reactions, including peripheral neuropathy, optic neuropathy and myelosuppression. These adverse reactions must be considered prior to prescribing long-term usage of this drug.     

六安市某县结核病细菌学检测及耐药相关因素分析

目的 了解六安市某县结核病耐药状况及相关因素,为制订全市耐药结核病控制策略提供参考依据。 方法 随机抽取我市辖区1县(区),将2013年1月至12月所有登记肺结核病例作为研究对象,进行痰涂片镜检、细菌培养、药敏实验及菌种鉴定,并分析相关影响因素。 结果 结核分枝杆菌总耐药率(单耐药率)为25%(37/148),耐多药率为8.1%(12/148),广泛耐药率为2.03%(3/148);非结核分枝杆菌总耐药率(单耐药率)为100%(5/5) 耐多药率为80%(4/5),广泛耐药率为80%(4/5);单因素及多因素分析显示,复治是单耐药及耐多药结核病的危险因素,20～50岁年龄是耐多药结核病的独立危险因素。涂片阳性率为16.27%(95/584),痰培养阳性率为26.20%(153/584)。 结论 六安市某县结核病耐药疫情形势严峻,需加强对初治病例及青壮年病例的管理,提高其治疗依从性和治疗成功率,减少耐药结核发生。同时需加强结核病的细菌学检测工作,提高菌阳肺结核和耐药结核分枝杆菌的发现率。