抗结核药物药代动力学/药效学的研究及进展

结核病治疗需要联合使用多种药物且治疗时间较长,迫切需要研发抗结核新药。抗结核新药的研发成果十分有限,对现有药物体内外的药代动力学/药效学(pharmacokinetic/pharmacodynamic,PK/PD)进行研究,优化抗结核药物的使用,对提高疗效,减少耐药结核病的发生至关重要。作者主要对PK/PD研究方法及抗结核药物PK/PD特点进行综述,为临床优化抗结核药物治疗方案提供参考。     

抗结核药治疗药物监测临床应用专家共识

治疗药物监测(therapeutic drug monitoring,TDM)是通过测定患者体内的药物暴露、药理标志物或药效指标,利用定量药理模型,以药物治疗窗为基准,指导制订适合患者的个体化给药方案。抗结核治疗过程中,存在药物浓度个体差异大、不良反应多等问题,可能导致治疗失败、耐药和复发。进行抗结核药物TDM,可以优化药物治疗方案,提高药物疗效,降低不良反应。为推进中国结核病TDM规范化,保证TDM的科学性、伦理性、合法性,使患者最大程度获益,经有关结核病临床和基础研究领域的专家反复讨论,就抗结核药物TDM的意义、适应证、检测方法、实施流程及TDM的质量控制等,制订了《抗结核药治疗药物监测临床应用专家共识》。     

抗结核药物致药物热34例浅析

结核病是由结核杆菌引起的传染病，规则应用抗结核药物是治疗的主要手段，但口服抗痨药物也可以引起药物热，且易与原发病致发热相混淆，造成诊断困难。现将本院2000～2005年34例抗结核药物致药物热的临床资料进行回顾性分析，探讨结核患化疗过程中抗痨药物与发热的关系，以提高对抗结核药物致热的认识。[第一段]     

肺结核患者抗结核药物治疗不良反应

目的探讨肺结核在抗结核药物治疗过程中发生的不良反应。方法对247例行抗结核药物治疗的肺结核患者出现不良反应进行分类分析。结果不良反应主要表现为肝肾功能损害,消化道症状和中枢神经症状等;年龄超过50岁者不良反应发生率明显高于年龄低于50岁者(P<0.05)。结论肺结核患者使用抗结核药治疗应加强督导和随访,定期复查肝肾功能,及时有效处理药物不良反应。     

抗结核药物致药物热28例临床分析

目的 探讨抗结核药物临床应用中出现药物热的情况。方法 回顾性分析28例抗结核药物引起药物热患者的临床资料。结果 抗结核药物引起的药物热，多出现于用药后2个月以内，占96．4％（27／28），其中以链霉素最常见。结论 在结核病人的化疗过程中尤其是用药后2个月内出现发热的患者，应考虑到药物热的可能，避免误诊，漏诊。     

抗结核药物致药物热28例临床分析

目的　探讨抗结核药物临床应用中出现药物热的情况。方法 回顾性分析28例抗结核药物引起药物热患者的临床资料。结果 抗结核药物引起的药物热,多出现于用药后2个月以内,占96.4% (2728),其中以链霉素最常见。结论 在结核病人的化疗过程中尤其是用药后2个月内出现发热的患者,应考虑到药物热的可能,避免误诊,漏诊。     

糖皮质激素联合四联抗结核药物治疗老年结核性脑膜炎的疗效及对脑脊液细胞学的影响

目的探讨糖皮质激素联合四联抗结核药物治疗老年结核性脑膜炎(TBM)的疗效及对脑脊液(CSF)细胞学的影响。方法该院收治的老年TBM患者107例随机分为观察组52例和对照组55例,均给予2异烟肼(H)+利福平(R)+乙胺丁醇(E)+吡嗪酰胺(Z)/4异烟肼(H)+利福平(R)方案抗结核治疗,观察组在此基础上给予糖皮质激素治疗。治疗3个月后,比较两组患者的临床疗效及症状改善情况,记录两组发热及意识障碍恢复时间,检测治疗前后两组CSF指标白细胞(WBC)、葡萄糖、氯化钠(Na Cl)及蛋白质(Pro)含量变化,记录治疗过程中不良反应的发生情况。结果观察组发热及意识障碍恢复时间均较对照组缩短(P<0.05),临床症状改善较对照组显著(P<0.05);观察组总有效率显著高于对照组(P<0.05);治疗后两组CSF中WBC、Pro水平均较治疗前降低,Na Cl、葡萄糖均较治疗前升高,且观察组各指标水平变化均较对照组明显(均P<0.05),两组不良反应发生率比较无统计学差异(P>0.05)。结论糖皮质激素与四联抗结核药物联用治疗老年TBM能显著提高疗效,缓解临床症状,可通过改善炎性状态、减轻CSF细胞学损伤而发挥治疗作用,不良反应少,值得临床推广。     

2010年度北京市海淀医院抗结核药物的临床应用分析

目的 了解北京市海淀医院抗结核药物的临床应用情况,以便对综合性医院合理应用抗结核药物方案提供参考依据。方法 利用北京市海淀医院计算机信息系统统计2010年度该院各一线抗结核药物使用的总量、金额及用药天数,计算出用药频度（DDDs）、日均费用（DDC）和药物利用指数（DUI）,进行合理用药评价。从2010年度17321例住院患者中检索出使用过一线抗结核药的患者62例,并对这62例患者病历中抗结核药的用药原因、用药方案、用法用量进行分析。结果 北京市海淀医院抗结核一线药物主要有利福平、异烟肼、乙胺丁醇、吡嗪酰胺、硫酸链霉素,5种药物全年总费用合计1988.05元。利福平、乙胺丁醇和吡嗪酰胺的DUI值小于1,分别是0.85、0.86和0.96。使用一线抗结核药62例患者中有48例患者为抗结核治疗用药,其中确诊及临床诊断结核病初治患者32例,抗结核治疗化疗方案选择HRZE方案的比例为43.8%（14/32）,抗结核治疗方案中加用了二线抗结核药左氧氟沙星的比例为79.2%（38/48）。结论 北京市海淀医院抗结核药物用量较少,临床使用规范化比例低,个别药给药剂量不足,今后有待加强对结核病规范化治疗的学习及培训。     

抗痨药致药物性肝炎103例临床分析

目的：探计抗结核药致药物性肝炎的临床特点与防治方法。方法：回顾性调查分析2001年1月至2003年6月以来本院住院肺结核患者在抗结核治疗中出现肝损害的临床相关因素及特征。结果：抗结核药致药物性肝炎与患者年龄、性别、结核病类型、有无乙肝病毒感染等相关，治疗预后较好。结论：抗结核治疗中不可避免出现肝损害．应早期发现，早期治疗，预后一般良好。     

利奈唑胺治疗耐药肺结核致药物超敏反应综合征1例并文献复习

本文报道1例利奈唑胺治疗耐药肺结核致药物超敏反应综合征(DIHS)病例, 并复习相关文献。患者应用利奈唑胺1个月后出现发热伴皮疹、多发淋巴结肿大、血液系统异常及肝脏损害, 骨髓穿刺涂片及病理均提示骨髓中嗜酸性粒细胞明显增多, 支持DIHS诊断。及时停用致敏药物, 并早期足量应用糖皮质激素, 患者恢复较好。二线抗结核药物致DIHS发生率较低, 但病情凶险, 早期症状不典型, 易误诊、漏诊。抗结核治疗期间出现发热伴皮疹、血液系统异常、淋巴结肿大及多脏器功能损伤时, 需高度警惕DIHS并及时处理, 以免贻误最佳治疗时期。     

145株非结核分枝杆菌对10种药物的耐药性分析

目的了解我院非结核病患者分离的非结核分枝杆菌对10种药物的耐药状况。方法用MB/Bact 240分枝杆菌培养仪和改良罗氏管对患者的多种标本进行分枝杆菌分离培养鉴定,对分离到的分枝杆菌采用绝对浓度法对10种抗结核药物,利福平、异烟肼、乙胺丁醇、链霉素,利福喷丁、丙硫异烟肼、氧氟沙星、卷曲霉素、卡那霉素和对氨基水扬酸进行药物敏感性试验。结果 1722例患者的标本非结核分枝杆菌培养阳性145株,对10种药总耐药率97.2%（141/145）,单耐药率最高为异烟肼、链霉素和对氨基水扬酸,最低为氧氟沙星。结论非结核分枝杆菌耐药情况十分严重,应加强抗结核药物的耐药性监测;根据药敏试验选择科学有效的化疗方案。     

含药凝胶介入治疗耐多药空洞肺结核的初步临床研究

目的　评价经纤支镜灌注含药凝胶治疗耐多药肺结核的临床疗效和安全性。方法 治疗组用纤支镜灌注含药凝胶治疗和抗结核药物治疗,对照组用抗结核药物治疗。观察治疗效果。结果治疗 6月后,治疗组痰菌阴转率 73.1%,病灶治疗有效率 85.4%,空洞治疗有效率 81%,明显高于对照组 51.3%,56.7%和 51.4%(P＜0.05 ),治疗组痰菌阴转时间 36.3d,比对照组 61.8d明显缩短(P＜0.01 )。治疗组无严重不良反应。结论 经纤支镜含药凝胶灌注治疗耐多药肺结核疗效优于单纯药物治疗,是治疗耐多药肺结核病的一种有效、安全的方法。     

Management of adverse effects with antituberculosis chemotherapy

Tuberculosis has now become a curable disease with chemotherapy. So it is natural that the present issues in tuberculosis management are focused on how to complete standard chemotherapy. In this context, management of adverse effects constitutes an essential part of antituberculosis chemotherapy, as well as directly observed therapy. In this symposium, discussions were held about three major subjects on this issue. First, hepatotoxicity develops frequently and has sometimes fatal outcome, which makes it the most problematic adverse effect. "Management of hepatotoxicity during antituberculosis chemotherapy" was published by the Japanese Society for Tuberculosis (JST) in 2006. Dr. Shinsho Yoshiba evaluated this recommendation and pointed out that the criteria for discontinuation of drug based on AST, ALT and bilirubin levels is too sensitive and the concept of predicting fulminant hepatic failure (FHF) is lacking. He stressed the importance of monitoring serum prothrombin time for predicting FHF. Next, allergic drug reaction such as fever or skin rash often causes distress, although rarely fatal. As isoniazid (INH) and rifampicin (RFP) are key drugs for the cure, readministration of these drugs is often attempted by desensitization therapy. "Recommendation about desensitization therapy of antituberculosis drugs" was also published by JST in 1997. Dr. Yoshihiro Kobashi reported high success rates of 79 percent for INH and 75 percent for RFP according to this recommendation. He also reported correlated factor with the success, such as the longer period from the discontinuation to the desensitization therapy and lower doses of drugs at starting desensitization. Finally, we sometimes experience transient worsening of radiographical findings and general symptoms during antituberculosis chemotherapy. This is presumed to be due to allergic reaction to dead bacilli without requiring discontinuation of the drug. Differential diagnosis includes drug-induced pneumonia requring discontinuation and true worsening of pulmonary tuberculosis due to drug resistance requiring change in therapy. Dr. Masanori Akira reported that presence of ground-glass attenuation and/or consolidation by HRCT suggests transient worsening or drug-induced pneumonia, whereas presence of centrilobular nodules and/or tree-in bud suggests true worsening. We believe that these findings from the symposium will add useful information for management of adverse effects and be helpful for implementation of antituberculosis chemotherapy. (1) Hepatotoxicity of antituberculosis drugs: Shinsho YOSHIBA (Sempo Tokyo Takanawa Hospital) Antituberculosis drugs are sometimes hepatotoxic. Doctors who are responsible for the treatment of patients with tuberculosis should always be aware of their hepatotoxicity, because it seldom leads to fulminant hepatic failure. The Japanese Society for Tuberculosis proposed criteria based on the levels of AST, ALT and bilirubin for the prevention of such grave hepatic injury in 2006. In recent years attempts have been made to predict fulminant hepatic failure (FHF) before patients develop coma. Yoshiba's formula using prothrombin time, etiology, cholinesterase and bilirubin is widely accepted as useful to predict FHF. Introduction of the formula to this area is recommended. (2) Desensitization therapy for allergic reactions of antituberculous drugs: Yoshihiro KOBASHI, Mikio OKA (Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School) We evaluated the usefulness of desensitization therapy for patients showing allergic reactions of INH and RFP according to the guideline proposed by the Japanese Society for Tuberculosis. Adverse reactions were 22 patients with drug eruption, 22 with drug fever and 6 with drug fever plus eruption. The clinical effect of desensitization therapy was good in 27 out of 36 patients for RFP (75%), and in 19 out of 24 patients for INH (79%). The comparative study between patient group with success desensitization therapy and that with failure desensitization therapy was not a significant difference except for initiation period of desensitization therapy. (3) The imaging features of early transient radiographic progression, true worsening of TB, and drug induced pneumonitis during TB treatment: Masanori AKIRA (Department of Radiology, NHO Kinki-chuo Chest Medical Center) HRCT findings of the new lesions in the early transient radiographic progression are enlargement or confluence of the original lesions, development of areas of ground-glass attenuation and/or consolidation ipsilateral to the original lesion, and development of areas of ground-glass attenuation and/or consolidation in the subpleural region contralateral to the lesion. These CT findings may suggest a local hypersensitivity reaction to drug or massive dead tubercle bacilli per se. In contrast, CT findings of patients with multiple drug-resistant tuberculosis and true progression are centrilobular nodules, tree-in-bud appearance, nodules, and cavitation. These CT findings may suggest a bronchogenic spread from the original tuberculous lesions.     

A case of severe adult-onset Still' s disease presenting with pleuropericarditis]

Adult-onset Still' s disease (AOSD) is an uncommon rheumatic disease characterized by high spiking fever, arthritis, an evanescent skin rash and variety of systemic symptoms, though initial onset of pleuropulmonary manifestation is relatively rare and could be responsible for a delay in diagnosis. We report a case of AOSD presenting with pleuritis with concomitant pericardial effusion. A 42-year-old Japanese man was admitted with a spiking fever of 40 degrees C, hyperleucocytosis (21.6 x 10(9)/l), and a high titer of C-reactive protein (16.84mg/dl). Chest X-ray film and computed tomography showed bilateral pleural effusion and massive pericardial effusion which both required tube drainage. Analyses of fluids revealed that both were exudative and sterile, and pleural biopsy showed nonspecific inflammation with mild fibrosis. Neither antibiotics nor antituberculosis drugs were effective. Rash, hepatosplenomegaly, polyarthritis, pharyngitis and right hypochondralgia were accompanied by serum hyperferritinemia. After exclusion of the possibility of infection, other connective tissue disease and malignancy, a diagnosis of AOSD was made. Improvement was not observed with nonsteroidal anti-inflammatory drug and corticosteroid therapy. Double filtration plasmapheresis (DFPP) following steroid pulse therapy alleviated the symptoms and the laboratory data immediately and corticosteroids could be tapered. DFPP is a safe therapeutic procedure and can be an alternative for refractory AOSD.     

589株结核分枝杆菌对10种药物的耐药性分析

目的了解深圳市第三人民医院结核病患者结核分枝杆菌对10种药物的耐药情况。方法用MB/Bact 240分枝杆菌培养仪和改良罗氏管对患者的多种标本进行分枝杆菌分离培养鉴定,对分离到的结核分枝杆菌采用绝对浓度法对10种抗结核药物,利福平（RFP）、异烟肼（INH）、乙胺丁醇（EMB）、链霉素（SM）,利福喷丁（RFT）、丙硫异烟肼（TH）、氧氟沙星（OFL）、卷曲霉素（CPM）、卡那霉素（KM）和对氨基水扬酸（PAS）进行药敏试验。结果 1722例患者的标本结核分枝杆菌培养阳性589株,阳性率为34.2%（589/1722）,589株结核分枝杆菌对10种药总耐药率38%（224/589）,单耐药率最高为SM（17.1%）,最低为PAS（3.4%）;55株MDR-TB对另外8种药物耐药率最高为RFT（94.5%）,最低为KM（20%）和PAS（20%）,对10种药物全耐者有3株（0.5%）。结论结核菌耐药情况仍然十分严重,应加强抗结核药物的耐药性监测;根据药敏试验结果选择科学有效的化疗方案。     

Drug Fever Due to Favipiravir Administration for the Treatment of a COVID-19 Patient

A 55-year-old Japanese man was hospitalized with the novel coronavirus disease 2019 (COVID-19). On the 14th day after the start of favipiravir administration, the patient developed a fever with a temperature of 38.1℃. His pulse rate also became elevated to 128 bpm, so relative bradycardia was not suspected. Since he was in good overall health and no concomitant symptoms and signs were apparent, we considered it to be drug fever due to favipiravir. After the completion of favipiravir treatment, the patient''s temperature normalized within 24 hours. We herein report this case of drug fever caused by favipiravir.     

A case of miliary tuberculosis with prolonged high fever for more than 2 months under antituberculous therapy

A 28 year-old male was admitted to our hospital with persistent cough and high fever. He was diagnosed to have miliary tuberculosis by the transbronchial lung biopsy specimen and tuberculous choroidal lesions in the ocular fundus. Antituberculosis therapy was immediately started. In spite of the fact that the bacilli were sensitive to the antituberculosis drugs used and he had no other complications, high fever persisted and lasted for more than 2 months. When tuberculosis is suspected, and antituberculosis treatment is tried to observe its clinical response, the presence of similar cases mentioned above should be taken into consideration.     

Sparfloxacin in the treatment of drug resistant tuberculosis or intolerance of first line therapy.

Patients with multiresistant tuberculosis (TB) and patients with intolerance of first line antituberculosis drugs present a major treatment problem. Sparfloxacin is highly active against mycobacteria, but the use is restricted by side effects and the contribution to antituberculosis therapy is unclear. A prospective study has therefore been performed to analyse the efficacy and tolerability of sparfloxacin in cases of resistant TB or intolerance of first line therapy. Between April 1993 and April 1999, 30 TB patients (28 with pulmonary TB and two with lymph node TB) were treated with combinations of sparfloxacin and at least two other drugs at the Chest Hospital Heckeshorn, Berlin. Sixteen patients were infected by resistant mycobacteria (one single drug resistance (SDR), one polyresistance, and 14 multidrug resistances (MDR); 14 males (age range 23-53 yrs), 2 females (68-74 yrs)). Twelve patients (11 males, one female, 27-80 yrs) had not tolerated first line antituberculosis drugs. Two additional male patients had continuous proof of Mycobacterium tuberculosis in sputum without resistance during therapy The duration of sparfloxacin therapy during hospitalization ranged 2.5-4 months. Twenty-five patients completed therapy and were cured according to this study's definition. Although sparfloxacin was generally well tolerated, five mild phototoxic reactions and six moderate prolongations of the electrocardiographic QT-interval (30-40 ms compared to baseline < or = 450 ms) were registered without clinical symptoms in the patient group. In summary, sparfloxacin proved an effective and safe alternative antituberculosis drug for complicated tuberculosis.     

Antituberculosis drugs and hepatotoxicity

Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity.     

A case of anaphylactoid purpura associated with nephrosis followed by pulmonary tuberculosis

A 54-year old man was admitted to our hospital because of high fever, productive cough and purpura in both legs in June 2005. Urinalysis showed microscopic hematuria and proteinuria. Chest radiograph showed consolidation of right upper field. Because acid-fast bacilli and polymerase chain reaction test for Mycobacterium tuberculosis were positive in bronchial lavage fluid, we made a diagnosis of pulmonary tuberculosis, and prescribed antituberculosis therapy with isoniazid, rifampicin, ethambutol and pyrazinamide. In addition, anaphylactoid purpura was diagnosed by skin biopsy. In July 2005, renal function was deteriorated and nephrosis appeared. We treated with corticosteroid in addition to antituberculosis therapy. His symptoms and renal dysfunction improved. We report a rare case of an anaphylactoid purpura following occurence of pulmonary tuberculosis.