Drug treatment of tuberculosis--1992.

The impact of the acquired immunodeficiency syndrome (AIDS) pandemic has made tuberculosis an increasing worldwide problem, and the effectiveness of modern chemotherapy has been blunted by the high incidence of primary drug resistance, especially in developing countries. The prospect of finding new and highly effective drugs similar to isoniazid or rifampicin is dim, yet the maximum benefits from the existing drugs which are highly effective have not been received. A 6-month regimen of isoniazid plus rifampicin, supplemented by pyrazinamide during the first 2 months, for treatment of uncomplicated tuberculosis is highly effective and the regimen of choice. Ethambutol should be added if the risk of isoniazid resistance is increased. A regimen of isoniazid, rifampicin, pyrazinamide and streptomycin for 4 months provides effective defence against smear-negative pulmonary tuberculosis. Re-treatment of multiple drug-resistant tuberculosis remains a difficult therapeutic problem. At least 3 drugs that the patient has never previously received, and that are effective according to laboratory susceptibility testing, must be used. Preventive therapy against tuberculosis is accomplished with isoniazid for 6 to 12 months, although rifampicin plus isoniazid for 3 months has been used in the United Kingdom with success. In a mouse model, rifampicin plus pyrazinamide for 2 months is more effective than isoniazid for 6 months as preventive treatment. Patient noncompliance with medication remains the biggest problem in tuberculosis control, and is a complex issue. It can only be resolved by multiple approaches. Intermittent directly observed short course chemotherapy is a major, but not the only, possible solution.     

Therapeutic problems in the management of elderly patients with tuberculosis.

Adverse reactions to antituberculous drugs are more common in the elderly. With the increasing numbers of elderly people and the higher incidence of tuberculosis in this age group, clinicians will encounter more therapeutic problems in the use of antituberculous drugs than in younger patients. Existing studies regarding pharmacological and non-pharmacological factors which may predispose to increased adverse effects in the elderly are reviewed. Reduced clearances of isoniazid and rifampicin at steady state, possible increase in free drug concentration of drugs normally bound to albumin, possible differences in disposition of toxic metabolites such as hydrazine, concomitant administration of both isoniazid and rifampicin, poor nutrition and severity of the disease in the elderly may be contributing factors. Further studies in these areas should provide clearer guidelines on whether dosages or drug combinations should be modified in elderly patients with tuberculosis.     

利福平注射液经纤维支气管镜治疗支气管结核疗效观察

目的探讨常规全身抗结核治疗联合利福平经纤支镜注射介入治疗支气管结核的疗效。方法对80例支气管结核分别行纤维支气管镜注入利福平注射液,异烟肼+阿米卡星,单纯口服抗结核药物3组治疗结果进行对比分析。结果经纤支镜注射利福平介入治疗支气管结核,较纤维支气管镜注入异烟肼+阿米卡星和单纯口服抗结核药物有显著差异。结论通过纤维支气管镜于病灶处注入利福平注射液治疗支气管结核起效快、效果佳、不良反应少,对减少支气管狭窄、肺不张、毁损肺的发生,提高患者的生存质量有积极的意义。     

儿童结核患者抗结核药物血药浓度影响因素及其安全性分析

目的 监测儿童结核患者抗结核药物的血药浓度,探讨血药浓度影响因素,并评价其安全性,指导临床合理用药。方法 回顾性分析浙江省中西医结合医院40例儿童结核患者接受异烟肼、利福平、吡嗪酰胺、乙胺丁醇治疗后的血药浓度监测结果、不良反应以及药物使用前后各生化指标变化情况。结果 儿童结核患者中异烟肼、利福平、吡嗪酰胺、乙胺丁醇的血药浓度达标率分别为48.15%、34.88%、73.81%、18.52%。其中,日剂量与异烟肼(P=0.0250)和利福平(P=0.0212)浓度呈正相关;年龄也是影响异烟肼(P=0.0430)和利福平(P=0.0057)浓度的因素之一,血清白蛋白(P=0.0475)和性别(P=0.0087)分别与利福平和吡嗪酰胺血药浓度相关。药物不良反应主要表现为肝功能异常(5/40,12.50%)和皮疹(4/40,10%),抗结核药物治疗前后谷草转氨酶(aspartate aminotransferase,AST)、谷丙转氨酶(alanine aminotransferase,ALT)、尿酸水平有所升高。结论 异烟肼、利福平、乙胺丁醇在儿童结核患者中的血药浓度达标率较低,患儿抗结核治疗可能与AST、ALT、尿酸升高相关。在抗结核治疗期间进行血药浓度和肝肾功能监测有助于提高药物治疗安全性和实施个体化治疗。     

Recent developments in the treatment of tuberculosis

The history of chemotherapy of tuberculosis commenced in 1944 with the discovery of streptomycin. Currently, short-course chemotherapy comprising rifampicin, isoniazid, pyrazinamide and ethambutol/streptomycin administered under directly observed settings for 6 months (initially all four drugs followed by the former two drugs), constitutes the cornerstone treatment for pulmonary tuberculosis. Multi-drug resistant tuberculosis requires alternative chemotherapy, ideally in the form of individualised regimens, for management. To improve on the duration of chemotherapy for drug-susceptible tuberculosis and to achieve better treatment for multi-drug resistant tuberculosis as well as latent tuberculosis infection, there arises a genuine need for new drugs. The quest for new agents is, however, impeded by obstacles. Hopefully, tackling these through collaborative public-private partnerships on an international scale will lead to a fruitful outcome.     

Recent developments in the treatment of tuberculosis

The history of chemotherapy of tuberculosis commenced in 1944 with the discovery of streptomycin. Currently, short-course chemotherapy comprising rifampicin, isoniazid, pyrazinamide and ethambutol/streptomycin administered under directly observed settings for 6 months (initially all four drugs followed by the former two drugs), constitutes the cornerstone treatment for pulmonary tuberculosis. Multi-drug resistant tuberculosis requires alternative chemotherapy, ideally in the form of individualised regimens, for management. To improve on the duration of chemotherapy for drug-susceptible tuberculosis and to achieve better treatment for multi-drug resistant tuberculosis as well as latent tuberculosis infection, there arises a genuine need for new drugs. The quest for new agents is, however, impeded by obstacles. Hopefully, tackling these through collaborative public-private partnerships on an international scale will lead to a fruitful outcome.     

荧光PCR熔解曲线法在结核分枝杆菌耐药基因检测中的应用

目的探讨气管镜刷检物实时荧光PCR熔解曲线耐药法检测对复治结核病耐药早期诊断的价值,同时根据支气管刷检深部痰液结核菌耐药检测结果,进一步分析指导可疑耐药结核病治疗,规范临床合理用药,为耐药结核病的诊断及治疗提供科学依据。方法纳入160例结核分枝杆菌(MTB)患者为本研究对象。每例患者采用同一标本进行绝对浓度法和熔解曲线法耐药基因检测,观察熔解曲线法对利福平、异烟肼的检测敏感度、特异度、准确度。结果同一标本应用两种方法检测时,绝对浓度法检出利福平21例耐药,139例敏感;检出异烟肼68例耐药,92例敏感。熔解曲线法检出利福平17例耐药,139例敏感,4例未检出结果;检出异烟肼61例耐药,99例敏感。熔解曲线法对利福平的检测准确度为96.15%、敏感度为87.50%、特异度为98.39%;对异烟腓的检测准确度为95.00%、敏感度为88.57%、特异度为96.80%。两种检验方法对利福平及异烟肼的耐药及敏感率比较,差异均无统计学意义(P>0.05)。结论荧光PCR熔解曲线法能够快速检测出MTB对药物的耐药基因检测,而且有良好的敏感度和特异度,有效节约时间、安全高效,是临床检验及诊治耐药结核的有效手段。     

The influence of antituberculosis drugs on the plasma level of verapamil

Summary The influence of antituberculosis drugs on the plasma level of verapamil was studied after its oral and intravenous administration. Six patients who had been treated for at least 6 months with a combination of rifampicin, ethambutol and isoniazid received a single oral dose of 40 mg verapamil. As compared to untreated subjects, the antituberculosis drugs greatly reduced the bioavailability of the calcium antagonist. Studies in patients in whom treatment with ethambutol and isoniazid had been discontinued revealed that the effect was due to rifampicin. The drugs for tuberculosis had no influence on the plasma level of verapamil when it was given intravenously. The findings can be explained by the induction of verapamil metabolizing liver enzymes in patients treated with rifampicin.Some of the results were presented at the Joint Meeting of the Belgian, Dutch and German Pharmacological and Toxicological Societies in Aachen [1]     

Subchronic Toxicity of Human Immunodeficiency Virus and Tuberculosis Combination Therapies in B6C3F1 Mice

Combination therapy with anti-HIV drugs and opportunistic infectiondrugs is a common practice in treatment of AIDS patients. Althoughtoxic effects of most individual therapies are known, the toxicpotential of most combination therapies has not been established.To understand the toxic consequences of combination therapies,the commonly used anti-HIV drug 3'-azido-3'-deoxythymidine (AZT)and tuberculosis infection therapies pyra-zinamide, isoniazid,and rifampicin were evaluated by 13-week gavage studies in B6C3F1mice, either alone or AZT in combination with one of the antituberculosisdrugs. The doses include AZT 100, 200, and 400; pyrazinamide1000 and 1500; isoniazid 50,100, and 150; and rifampicin 100,200, and 400 mg/kg/day. AZT alone caused hematopoietic toxicitywith dose-related bone marrow suppression, macrocytic anemia,and thrombocytosis. Pyrazinamide or isoniazid alone at the dosestested did not cause significant toxicity. Rifampicin alonecaused hematopoietic toxicity and possibly mild hepatic toxicity.Pyrazinamide below 10 times the therapeutic dose when givenwith AZT did not increase the hemato-logical toxicity of AZT.Isoniazid markedly increased the hematological toxicity of AZTand contributed to mortality at 3 to 4 times the therapeuticdose combinations. Administration of rifampicin with AZT atthe calculated therapeutic doses resulted in toxicity of fargreater magnitude than that caused by AZT or rifampicin alone.Combination treatment with AZT and rifampicin caused severeanemia with mortality at 2 to 4 times the therapeutic dose combinations.However, AZT did not enhance the hepatotoxicity of rifampicin.Increased hematopoietic toxicity of AZT when given in combinationwith the above antituberculosis drugs may be due to changesin the metabolism of AZT. Results of these studies indicatethat toxicological effects of combination therapies could beconsiderably more severe than and different from the toxicityof individual therapies.     

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.     

抗结核药致药物性肝损伤危险因素的Logistic回归分析

目的： 探讨抗结核药致药物性肝损伤的危险因素,降低抗结核药物性肝损伤发生率。方法： 选取2004年1月-2014年12月在本院住院治疗的结核病患者,将结核治疗期间出现肝损伤的160例患者设为观察组,未发生药物性肝损伤的1 394例设为对照组,采用回顾性研究方法分析性别、年龄、吸烟史、饮酒史、乙肝（丙肝）史、营养不良、糖尿病、贫血、呼吸系统疾病、心血管疾病、结核药种类和剂量等因素对抗结核药致药物性肝损伤发生的影响。结果： 从单因素Logisitc回归分析结果来看,性别、心血管疾病,结核药中异烟肼、利福平、对氨基水杨酸异烟肼、左氧氟沙星是发生药物性肝损伤的危险因素,多因素Logisitc回归分析显示女性、患有心血管疾病、服用异烟肼、利福平、对氨基水杨酸异烟肼或左氧氟沙星为抗结核药物性肝损伤的危险因素,并且DILI发生率随着结核药剂量增大而增大。结论： 女性（OR=0.661,95%CI 0.464~0.943,P=0.022）、合并心血管疾病（OR=2.017,95%CI 1.109~3.666,P=0.021）、异烟肼（OR=1.544,95%CI 1.235~1.929,P=0.000）、利福平（OR=1.391,95%CI 1.110~1.743,P=0.004）、对氨基水杨酸异烟肼（OR=2.461,95%CI 1.517~3.993,P=0.000）和左氧氟沙星（OR=1.695,95%CI 1.155~2.487,P=0.007）是结核治疗中致DILI高危因素。具有上述高危因素的患者应采取勤监测,早发现、早治疗的措施,抗结核药应按照说明书推荐剂量给药,以减少ATDILI发生,改善结核患者的临床症状,减轻患者负担。     

Synergic activity of fluoroquinolones and linezolid against Mycobacterium tuberculosis

We evaluated the in vitro activity against Mycobacterium tuberculosis of the combination of fluoroquinolones and linezolid with classical drugs. The combination of isoniazid with fluoroquinolones had synergic activity in nine of the ten isoniazid-susceptible strains. We also found synergism between rifampicin and linezolid in five of the 15 strains susceptible to rifampicin. The clinical significance of these findings should be evaluated.     

抗结核药血药浓度监测及临床疗效与安全性分析

目的:建立测定抗结核药血药浓度的方法,并观察其临床疗效与安全性。方法:选择我院2007年8月-2010年12月164例结核病住院患者,采用高效液相色谱(HPLC)法分别测定患者连续服药1个月后异烟肼、利福平、吡嗪酰胺的血药浓度,分析不同血药浓度的临床疗效及肝损害情况。结果:异烟肼、利福平、吡嗪酰胺的血药浓度高于正常浓度范围者分别占9.1%、12.8%、24.4%,低于正常浓度范围者分别占54.3%、9.8%、6.7%。临床疗效以完全改善和明显改善者居多,占92.1%。药物性肝损害多发生在用药后1个月内,以老年人多见。49例肝损害患者中血药浓度高于正常者占73.5%。结论:HPLC法可用于抗结核药血药浓度监测,其结果是临床调整用药剂量的重要依据,对结核病患者合理用药具有重要意义。     

Pharmacokinetic factors in the modern drug treatment of tuberculosis.

Tuberculosis is increasing in prevalence throughout the world, particularly in sub-Saharan Africa, Asia and Latin America. This resurgence can partly be attributed to increasing poverty, particularly in developing countries, and the human immunodeficiency virus (HIV) pandemic. However, there is also increasing concern at the development of multidrug-resistant tuberculosis caused by the misuse of the agents available. The modern treatment of patients with tuberculosis should start, in most cases, with 4 first-line agents in order to minimise the risk of drug resistance developing. A6-month drug regimen is usually satisfactory for pulmonary and nonpulmonary tuberculosis, although not for patients with tuberculous meningitis, in whom a longer course of treatment is required. Coinfection with HIV may produce an atypical clinical and radiological presentation, but the treatment regimen is essentially similar to other situations. Several of the first-line agents, in particular rifampicin (rifampin) and isoniazid, are likely to cause clinically significant drug interactions and/or toxicity, particularly in patients with HIV infection. Consideration of the pharmacodynamic and pharmacokinetic interactions between the host, the mycobacterium and the drug may contribute to the development of pharmacokinetically optimised regimens that make best use of the existing range of antituberculosis drugs. However, such idealised regimens need to be tested in prospective clinical trials. The use of therapeutic drug monitoring in selected groups of patients may improve outcomes, avoid drug toxicity and reduce the development of multidrug-resistant tuberculosis. The management of multidrug-resistant tuberculosis requires a high level of clinical expertise and such patients should start on at least 5 drugs to which the organism is thought to be susceptible. Up to 50% of patients with tuberculosis may not adhere to their drug regimen, resulting in persisting infectiousness, relapse or the development of drug resistance. Directly observed treatment with antituberculosis drugs, combined with a serious commitment to tuberculosis control, is required if we are to combat this increasing epidemic.     

我院结核病患者利福平和异烟肼血药浓度监测结果分析

目的:提高临床对抗结核药血药浓度监测工作的重视程度。方法:回顾性分析我院2005年8月～2008年12月结核病患者利福平和异烟肼的血药浓度监测结果。结果:共收集并测定241例利福平和53例异烟肼患者服药后2h的血药浓度。利福平血药浓度低于正常浓度范围者占10.4%,高于正常浓度范围者占31.9%;异烟肼血药浓度低于正常浓度范围者占71.7%,高于正常浓度范围者占15.1%。结论:抗结核药血药浓度监测结果是临床调整用药剂量的重要依据,对结核病患者合理用药具有重要意义。     

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.     

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...     

Comparative bioavailability of rifampicin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels

Fixed dose combination (FDC) formulations became popular in the treatment of tuberculosis (TB) because of the better patient compliance, reduced risk of monotherapy and emergence of drug resistance in contrast to treatment with separate formulations of two to four first-line drugs. However, its successful implementation in national programs is limited by probable bioinequivalency of rifampicin if present in FDC form. In this regard, World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. Hence, bioequivalence study of four drug FDC tablet was conducted using 22 healthy male volunteers according to WHO recommended protocol to determine bioavailability of rifampicin, isoniazid and pyrazinamide compared to standard separate combination at the same dose level. The study was designed as two period, two treatment crossover experiment with a washout period of 1 week. Bioequivalence of rifampicin was estimated by plasma and urinary method for both rifampicin and its active metabolite, des-acetyl rifampicin whereas isoniazid and pyrazinamide were estimated from plasma. Mean concentration time profiles and all the pharmacokinetic parameters of rifampicin, isoniazid and pyrazinamide from FDC tablet were comparable to individual formulations and passed the bioequivalence test with power of the test above 95%. Further, bioequivalence of both rifampicin and isoniazid shows that in vitro interaction of rifampicin and isoniazid is clinically insignificant. Thus, it was concluded that FDC formulation is bioequivalent for rifampicin, isoniazid and pyrazinamide and ensures the successful treatment of TB without compromising therapeutic efficacy of any of these components of anti-TB therapy.     

Short-course therapy for tuberculosis

The discovery of rifampicin was the turning point away from the standard long term treatment for tuberculosis of 18 to 24 months and towards a 6-month curative programme. Rifampicin has proven to be highly effective and vital to short-course tuberculosis therapy, but its disadvantage is its cost. This makes it relatively unavailable where it is most needed, i.e. in countries where tuberculosis is still rampant, but which are economically underdeveloped. In such areas other needs take precedence over a chronic and non-spectacular medical condition like tuberculosis. During the past 10 years pyrazinamide has been 'rediscovered' and restudied, and when used in combination with rifampicin has been shown to play an important role in short-course chemotherapy. Its contribution to efficacy does not appear to extend beyond the first 2 months of therapy, and it should be discontinued after 2 months. This relatively short administration period helps to minimise adverse reactions to the drug. The main measure of success in short-course chemotherapy is the relapse rate, and this has been higher, sometimes unacceptably so, in regimens where bacteriostatic drugs were substituted for bactericidal ones. In conclusion, isoniazid, rifampicin and pyrazinamide in combination may be deemed essential to an effective short-course regimen of 6 months' duration. Curtailing the duration of treatment to less than 6 months in smear-positive tuberculosis results in high relapse rates and thus is not acceptable. Several studies have been undertaken varying the drug combinations, the dosages and the drug administration routines (i.e. whether daily followed by intermittent or intermittent throughout), in an effort to arrive at the simplest, most effective, least toxic and most economical all-round treatment programme. Such studies are still in progress. When recommended dosage regiments are followed, the incidence of adverse reactions is low with short-course therapy, and in only 5% or less of patients is it necessary to withdraw one or more drugs.