氟喹诺酮类药物在耐多药结核病治疗中的应用

自20世纪50年代，结核病的治疗进入化学治疗时代。尤其是短程化疗问世以来，比较有效的抗结核药物的联合治疗使85％以上初治肺结核患者痊愈。但由于耐药结核病，尤其是耐多药结核病（multidrug—resistant tuberculosis，MDR-TB）的出现，迅速成为全球性危机，1994-1997年世界卫生组织／国际结核与肺病联合会（WHO／IUATLD）抗结核药物耐药性监测工作组在35个国家进行了监测。     

非生物因素对抗结核药物性肝损害影响的巢式病例对照研究

化学治疗是目前控制结核病流行的主要方法,我国对肺结核患者的治疗采用统一短程督导化学治疗方案.抗结核药物在发挥治疗作用的同时,也存在着不容忽视的药物不良反应.据报道,抗结核药物性肝损害是最常见也是最严重的不良反应之一[1-3].年龄、性别、HBsAg、肝炎史、糖尿病、营养不良等生物因素对抗结核药物性肝损害的发生有影响[4-5],本研究旨在探讨非生物因素对抗结核药物性肝损害的影响.     

未来理想的抗结核药物与化学治疗方案

结核病的化学治疗至今已经历了70多年的演变,曾经一度非常有效的现代结核病化疗方案目前对于耐多药结核分枝杆菌基本“束手无策”。WHO在2006年提出了至2015年降低50%的结核病患病率和死亡率,至2050年“消除作为公共卫生问题的结核病”的控制目标,实现这一目标的前提必须是新的抗结核药物的研发应用和新的抗结核化学治疗理念的实施。笔者简单回顾抗结核化学治疗的药物与方案的历史,分析现状,对未来理想的抗结核药物与化学治疗方案提出一些设想。     

皮肤型结核治疗的研究进展

随着结核病呈现流行趋势,皮肤结核也有上升趋势研究进展,由于不断出现的耐药结核病、耐多药结核病、获得性免疫缺陷综合征（HIV）的流行及结核持留菌的问题,使得有效控制结核病面临更大的挑战。传统的抗结核治疗疗程长,副作用大,使病人的依从性差,很难达到满意效果。皮肤结核的治疗也存在这个问题,因此研究开发新型抗结核药物及原有药物的新型用法,实现对皮肤结核的有效控制迫在眉睫。本文针对目前皮肤结核的治疗方案及有关新型药物做如下综述。     

贝达喹啉治疗耐药结核病的研究进展

耐药结核病是全球结核病控制规划面临的主要挑战,需要采用二线抗结核药物治疗,但治疗效果并不十分理想,故亟须研究和开发新型抗结核药物。贝达喹啉(bedaquiline)是过去40多年中美国食品药品监督管理局(FDA)批准用于治疗耐药结核病的第一种药物,该药能有效提高耐药结核病的临床疗效及缩短治疗时间。本文综述了贝达喹啉治疗耐药结核病的作用机制、临床试验、不良反应和药物-药物相互作用及耐药机制的研究进展,以提高临床对贝达喹啉的认识。     

耐药结核病的研究进展

耐药结核病是当今世界非常严峻的公共卫生问题,它直接影响着全球结核病疫情的控制。除我们常见的耐多药结核病外,近年来耐药结核病的定义和类型也在不断变化并增加,如超广泛耐药、全耐药等。耐药结核病的诊断主要通过常规的细菌学和核酸检测方法在实验室中确定。部分药物敏感的病例由于对抗结核药物不能耐受而使治疗方案受限,表现为与耐药结核病相同的治疗结果,可称之为"临床耐药结核病"。对耐药结核病的预防主要寄望于现有抗结核药物的个性化使用,用足核心药物异烟肼和利福平是关键。抗结核新药的出现有助于我们控制耐多药结核病,但现阶段仍要注意实施综合疗法,加大病灶局部的抗结核药物浓度,立足于现有药物,个性化治疗耐多药结核病才是正确的道路。     

建国70年来结核病化学治疗的历史进程要览

结核病是一种古老的传染病,人类与其进行了长期的、艰苦卓绝的斗争,对结核病化学治疗的历史进程值得回顾与总结。随着中华人民共和国的成立及建国70年来我国各个方面的发展,从20世纪50年代初期第一代抗结核化学治疗药物及化学治疗方案的问世,到如今的抗结核新药的研发、问世,以及具有全新机制的化疗药物及治疗方案(包括预防性治疗)的探索、改进、完善,建国70年来结核病化学治疗的进展无不印证着人类彻底控制结核病的历程。     

结核病控制项目地区耐药结核病两种治疗方案的对比研究

耐药结核病尤其是至少对异烟肼和利福平同时耐药的耐多药结核病（MDR—TB）治疗时间长（疗程约为24个月），治疗药物多（至少需要4种药物，且多为二线抗结核药物），不良反应发生率高，治愈率低，对全球结核病控制工作构成严重威胁。作为全球22个结核病高负担国家之一，我国耐药结核病疫情严峻。据2000年全国结核病流行病学抽样调查结果显示，     

抗结核药物的临床应用进展

自南非2006年发现53例广泛耐药结核病爆发流行后，WHO在2006年9月宣布了一个强化结核病控制措施、有效防治广泛耐药结核病全球行动计划。广泛耐药结核病（XDR-TB）是指在耐多药结核病的基础上出现对任何氟喹诺酮类药物以及三种二线注射药物（硫酸卷曲霉素、卡那霉素和阿米卡星）中至少一种具耐药性的结核。因此，XDR-TB通常是在MDR-TB的基础上发展而来；其根本原因在于不合理使用二线抗结核药物，以及对耐多药结核病治疗缺乏管理或管理不善所导致。现将有关抗结核药物的临床应用进展综述如下。     

耐药结核病的流行简况

结核病是当前危及人类生命的主要杀手。耐药结核病(drug-resistant tuberculosis)尤其是耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)的出现使得结核病流行势态更为严峻。MDR-TB是指结核病患者感染的M.TB体外被证实至少对异烟肼、利福平这2种一线抗结核药物耐药...     

First Susceptibility Testing of Mycobacterium tuberculosis for Second-line Anti-tuberculosis Drugs in Ghana

We performed drug susceptibility testing on first- and second-line drugs in Mycobacterium tuberculosis (M. tuberculosis) for the first time in Ghana to obtain preliminary data on drug-resistant tuberculosis. Of 21 isolates (4 new cases and 17 treated cases), 5 (23.8%) were multi-drug resistant tuberculosis (MDR-TB) and 19 (90.5%) were resistant to at least one drug, but no extensively drug-resistant TB (XDR-TB) was identified. Since the target patients were Category II, IV or smear positive at follow-up microscopy, it is understandable that there were many drug-resistant TB cases. Six isolates were resistant to one or two second-line drugs, but the second-line drugs were not approved in Ghana. It is considered that the bacilli were imported from abroad. Preventing the import of drug-resistant TB bacilli is probably one of best ways to control TB in Ghana.     

Chronic tuberculous empyema with bronchopleural fistula resulting in treatment failure and progressive drug resistance

We treated five patients with a past history of tuberculous pleural infection that led to chronic, quiescent, loculated empyema. Reactivation of TB was associated with formation of BPF and recovery of drug-susceptible Mycobacterium tuberculosis from sputum. All patients had recurrence of positive sputum cultures that yielded tubercle bacilli resistant to drugs they were receiving. The lungs demonstrated gross thickening with calcification of both visceral and parietal pleura. Two patients underwent retreatment chemotherapy followed by decortication-empyemectomy and lung resection surgery; both are now culture-negative for TB. One patient received retreatment chemotherapy but refused surgery; he remains clinically stable with negative sputum cultures. Two other patients' organisms became drug-resistant and they remain sputum-culture positive. We believe that thick, calcified pleural walls limit penetration of drugs into the infected empyema space, resulting in suboptimal drug concentrations and drug resistance. Intensified chemotherapy and surgical intervention should be considered in these cases.     

Clinical and operational value of the extensively drug-resistant tuberculosis definition.

Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance.     

Management of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis: current status and future prospects

Resistance in Mycobacterium tuberculosis arises from man-made selection of genetic mutants that result from spontaneous chromosomal alterations. Thus, drug-resistant tuberculosis (TB) is generally due to inappropriate treatment regimen, poor drug quality, erratic drug supply and poor patient adherence to treatment, reflecting failure in the implementation of an effective TB control programme. Multidrug-resistant TB (MDR-TB) usually denotes bacillary resistance to at least isoniazid and rifampicin. Proper implementation of the directly observed treatment, short-course (DOTS) strategy should achieve a high cure rate for disease and curtail the development of drug resistance. Innovations in reinforcement of this strategy should further facilitate its delivery and enhance its effectiveness. However, established MDR-TB is notoriously difficult to treat, and necessitates the use of alternative specific antituberculosis chemotherapy regimens. These regimens comprise combination use of second-line antituberculosis drugs, that are generally more costly and toxic, and have to be given for longer durations. The fluoroquinolones, better tolerated by patients, have a pivotal role in MDR-TB treatment. Optimal delivery of these treatment regimens mandates a programmatic basis which is now included under the Stop-TB Drug-Resistance Programme(s). The key components embrace political commitment, quality-assured drug susceptibility testing, reliable supply of quality drugs, delivery of chemotherapy under directly observed settings, and a sound recording and reporting system to monitor the individual treatment outcome of patient and overall performance of the TB control programme. Adjunctive surgery in selected MDR-TB patients help to improve their treatment success. Further exploration is required regarding the use of immunotherapy. The recent emergence of extensively drug-resistant TB (XDR-TB), representing MDR-TB with additional bacillary resistance to fluoroquinlones and one or more of the second-line injectable drugs -kanamycin, amikacin and capreomycin, threatens the global control of TB. Given the escalating size of the problem of MDR-TB and XDR-TB worldwide, gigantic instillation of resources is required for control of this formidable challenge, largely through more accurate and rapid drug susceptibility testing (especially for rifampicin and fluoroquinolone), regular drug-resistance surveillance, development of new antituberculosis drugs and other therapeutic modalities, intensive infection control, especially in HIV care settings, as well as strengthening of currently functioning DOTS and Drug-Resistance Programmes.     

The medical and surgical treatment of drug-resistant tuberculosis

Multi drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are burgeoning global problems with high mortality which threaten to destabilise TB control programs in several parts of the world. Of alarming concern is the emergence, in large numbers, of patients with resistance beyond XDR-TB (totally drug-resistant TB; TDR-TB or extremely drug resistant TB; XXDR-TB). Given the burgeoning global phenomenon of MDR-TB, XDR-TB and TDR-TB, and increasing international migration and travel, healthcare workers, researchers, and policy makers in TB endemic and non-endemic countries should familiarise themselves with issues relevant to the management of these patients. Given the lack of novel TB drugs and limited access to existing drugs such as linezolid and bedaquiline in TB endemic countries, significant numbers of therapeutic failures are emerging from the ranks of those with XDR-TB. Given the lack of appropriate facilities in resource-limited settings, such patients are being discharged back into the community where there is likely ongoing disease spread. In the absence of effective drug regimens, in appropriate patients, surgery is a critical part of management. Here we review the diagnosis, medical and surgical management of MDR-TB and XDR-TB.KEYWORDS : Extensively drug-resistant tuberculosis (XDR-TB), surgery, drug resistance     

Survey of drug resistance of Mycobacterium tuberculosis in 3 Mexican states, 1997

BACKGROUND: Drug resistance threatens global tuberculosis (TB) control efforts. Population-based estimates of drug resistance are needed to develop strategies for controlling drug-resistant TB in Mexico. OBJECTIVE: To obtain population-based data on Mycobacterium tuberculosis drug resistance in Mexico. METHODS: To obtain drug resistance data, we conducted a population-based study of TB cases in the states of Baja California, Sinaloa, and Oaxaca, Mexico. We performed cultures and drug susceptibility testing on M tuberculosis isolates from patients with newly diagnosed, smear-positive TB from April 1 to October 31, 1997. RESULTS: Mycobacterium tuberculosis was isolated from 460 (75%) of the 614 patients. Levels of resistance in new and retreatment TB cases to 1 or more of the 3 current first-line drugs used in Mexico (isoniazid, rifampin, and pyrazinamide) were 12.9% and 50.5%, respectively; the corresponding levels of multi-drug-resistant TB were 2.4% and 22.4%. Retreatment cases were significantly more likely than new cases to have isolates resistant to 1 or more of the 3 first-line drugs (relative risk [RR], 3.9; 95% confidence interval [CI], 2.8-5.5), to have isoniazid resistance (RR, 3.6; 95% CI, 2.5-5.2), and to have multi-drug-resistant TB (RR, 9.4; 95% CI, 4.3-20.2). CONCLUSIONS: This population-based study of M tuberculosis demonstrates moderately high levels of drug resistance. Important issues to consider in the national strategy to prevent M tuberculosis resistance in Mexico include consideration of the most appropriate initial therapy in patients with TB, the treatment of patients with multiple drug resistance, and surveillance or periodic surveys of resistance among new TB patients to monitor drug resistance trends.     

青岛市五区(市)结核病耐药情况分析

基于青岛市五区(市)结核病耐药性的流行现状和数据进行分析,为制定有针对性的化疗方案和耐药结核病控制策略提供科学依据。     

耐药对肺结核病治疗效果的影响

目的评价耐药对地区肺结核病治疗效果的影响。方法对上海地区2004年2月—9月新登记敏感及耐药肺结核病人1年治疗转归进行分析和比较。结果在全市各区(县)结核病定点医院新登记1597例肺结核病病人中,805例培养阳性,其中731例经菌型鉴定为结核分枝杆菌的病人纳入分析。731例病人的总耐药率为18.7%,耐多药率为6.7%。敏感组治疗成功率达到93.0%,非MDR的耐药病人治疗成功率达到85%以上,MDR组治疗成功率为71.4%。经χ²检验,差别有统计学意义(χ²=83.9968,P<0.01)。在68例治疗不成功的病人中,耐药病人占38.2%;而在30例治疗失败的病人中,耐药病人占60%。复治敏感病人的治疗成功率(92.0%)与初治敏感病人(93.1%)相当,但是复治耐药病人的治疗成功率远低于初治耐药病人。结论(1)上海地区肺结核病病人治疗管理效果良好;(2)耐药是肺结核病治疗失败的重要因素,应加强和改进对耐药结核病的治疗措施;(3)耐药和敏感病人治疗效果存在较大差异,应分别评价。     

Predicting the future trend of drug-resistant tuberculosis in Thailand: assessing the impact of control strategies

The purposes of this study are to predict the future trend of drug-sensitive and resistant tuberculosis (TB) in Thailand, and to assess the impact of different control strategies on the generation of drug resistant TB, through the use of mathematical analysis. We assume that the present status of TB and the emergence of drug-resistant TB in Thailand are the consequence of past epidemics. Control strategies in the model are defined by specifying the value of the effective treatment rate (baseline value = 0.74) and the relative treatment efficacy (baseline value = 0.84). It is predicted that the total number of new TB cases would continue to decrease at the current level of intervention. Although a dramatic decline in the incidence rate of drug-sensitive cases is expected, drug-resistant cases are predicted to increase gradually, so that more than half of the TB strains would not be drug-sensitive after 2020. The prediction is not greatly altered by improving the interventions. They could, however, delay the emergence of drug-resistant strains for a few years. Our study demonstrates it would be impossible to avoid the continued emergence of drug-resistant TB in the future. It is pointed out that there are urgent needs to ensure adequate supervision and monitoring, to insure treatment of 100% of the targeted population with Directly Observed Therapy.