Totally drug‐resistant tuberculosis and adjunct therapies

The first cases of totally drug‐resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as ‘resistance to all first‐ and second‐line drugs used to treat TB’. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR‐TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late‐stage clinical evaluation (e.g. delamanid, bedaquiline, SQ109 and sutezolid). ‘Repurposed’ antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options.     

青海省耐多药肺结核病危险因素的病例对照研究

目的探讨导致耐多药肺结核病的危险因素,从而为预防和控制耐多药结核病提供依据。方法采用非匹配病例对照研究的方法,以青海省第四人民医院2013年1月-2014年6月的住院肺结核患者为样本框,痰罗氏培养结果为结核分枝杆菌复合群,药敏试验证实异烟肼和利福平同时耐药的患者为病例组;异烟肼和利福平均敏感的患者为对照组。对患者的姓名、年龄、性别、民族、婚姻状况、职业、住房、吸烟史、饮酒、既往治疗是否规律、病例分类(为初治或复治患者)、病变累及肺野数、肺内空洞数、病程、住房通风情况等相关因素做统计分析。结果采取logistic回归方法进行分析,最终耐多药肺结核发生的主要危险因素为复治病人患耐药的风险是初治的5.24倍,95%CI(2.005-14.648);病变范围3个肺野数的患者患耐药的风险是≤3个肺野的0.177倍,95%CI(0.062-0.506);空洞数每上升一个等级,患耐药的风险是原来的7.686倍,95%CI(4.524-13.058)。结论加强对肺结核病例的管理,良好的治疗策略,做好基础DOTS工作,积极发现和治愈初复治结核病人,并针对其他危险因素采取措施对降低耐多药结核病疫情有重要意义。     

Drug‐resistant tuberculosis: Past,present, future

In a population of Mycobacterium tuberculosis, random chromosomal mutation that results in genetic resistance to anti‐tuberculosis (TB) drugs occurs at a relatively low frequency. Anti‐TB drugs impose selection pressure so that mycobacterial mutants gradually outnumber susceptible bacilli and emerge as the dominant strains. Resistance to two or more anti‐TB drugs represents cumulative results of sequential mutation. The fourth report on global anti‐TB drug resistance provides the latest data on the extent of such problem in the world. The median prevalence of multi‐drug‐resistant TB (MDR‐TB) in new TB cases was 1.6%, and in previously treated TB cases 11.7%. Of the half a million MDR‐TB cases estimated to have emerged in 2006, 50% were in China and India. The optimal duration of any given combination of anti‐TB drugs for treatment of MDR‐ and extensively drug‐resistant TB (XDR‐TB) has not been defined in controlled clinical trials. Standardized treatment may be feasible for MDR‐TB patients not previously treated with second‐line drugs, but a different strategy needs to be applied in the treatment of MDR‐TB patients who have received second‐line drugs before. Unfortunately, the reliability of drug susceptibility testing of most second‐line anti‐TB drugs is still questionable. Drug‐resistant TB is not necessarily less virulent. Findings from modelling exercise warned that if MDR‐TB case detection and treatment rates increase to the World Health Organization target of 70%, without simultaneously increasing MDR‐TB cure rates, XDR‐TB prevalence could increase exponentially. Prevention of development of drug resistance must be accorded the top priority in the era of MDR‐/XDR‐TB.     

Management of difficult multidrug‐resistant tuberculosis and extensively drug‐resistant tuberculosis: Update 2012

Multidrug‐resistant (MDR) tuberculosis (TB) denotes bacillary resistance to at least isoniazid and rifampicin. Extensively drug‐resistant (XDR) TB is MDR‐TB with additional bacillary resistance to any fluoroquinolone and at least one second‐line injectable drugs. Rooted in inadequate TB treatment and compounded by a vicious circle of diagnostic delay and improper treatment, MDR‐TB/XDR‐TB has become a global epidemic that is fuelled by poverty, human immunodeficiency virus (HIV) and neglect of airborne infection control. The majority of MDR‐TB cases in some settings with high prevalence of MDR‐TB are due to transmission of drug‐resistant bacillary strains to previously untreated patients. Global efforts in controlling MDR‐TB/XDR‐TB can no longer focus solely on high‐risk patients. It is difficult and costly to treat MDR‐TB/XDR‐TB. Without timely implementation of preventive and management strategies, difficult MDR‐TB/XDR‐TB can cripple global TB control efforts. Preventive strategies include prompt diagnosis with adequate TB treatment using the directly observed therapy, short‐course (DOTS) strategy and drug‐resistance programmes, airborne infection control, preventive treatment of TB/HIV, and optimal use of antiretroviral therapy. Management strategies for established cases of difficult MDR‐TB/XDR‐TB rely on harnessing existing drugs (notably newer generation fluoroquinolones, high‐dose isoniazid, linezolid and pyrazinamide with in vitro activity) in the best combinations and dosing schedules, together with adjunctive surgery in carefully selected cases. Immunotherapy may also have a role in the future. New diagnostics, drugs and vaccines are required to meet the challenge, but science alone is insufficient. Difficult MDR‐TB/XDR‐TB cannot be tackled without achieving high cure rates with quality DOTS and beyond, and concurrently addressing poverty and HIV.     

Drug‐resistant tuberculosis: An update on disease burden,diagnosis and treatment

The emergence of antimicrobial resistance against Mycobacterium tuberculosis , the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug‐resistant tuberculosis (MDR‐TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR‐TB achieved a successful outcome. For many years, patients with drug‐resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR‐TB through drug‐specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor‐made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high‐burden/resource‐limited settings. More recently, MDR‐TB treatment outcomes have dramatically improved with the use of bedaquiline‐based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure‐rates, and may substantially decrease the duration of MDR‐TB treatment necessary to achieve relapse‐free cure.     

Extensively drug‐resistant tuberculosis (XDR‐TB) among health care workers in South Africa

Objective To determine the clinical profile and outcomes of health care workers (HCWs) with extensively drug resistant tuberculosis (XDR‐TB) in the Eastern and Western Cape Provinces of South Africa. Method Retrospective case record review of 334 patients with XDR‐TB reported during the period 1996–2008 from Western and Eastern Cape Province, Cape Town, South Africa. Case records of HCWs with XDR‐TB were analysed for clinical and microbiological features, and treatment outcomes. Results From 334 case records of patients with XDR‐TB, 10 HCWs were identified. Eight of ten were HIV‐uninfected, and four of 10 had died of XDR‐TB despite treatment. All 10 HCWs had received an average of 2.4 courses of TB treatment before being diagnosed as XDR‐TB. Conclusions In the Eastern and Western Cape provinces of South Africa XDR‐TB affects HCWs, is diagnosed rather late, does not appear to be related to HIV status and carries a high mortality. There is an urgent need for the South African government to implement WHO infection control recommendations and make available rapid drug susceptibility testing for HCWs with suspected multidrug‐resistant (MDR)/XDR‐TB. Further studies to establish the actual risk and sources of infection (nosocomial or community) are required.     

北京市朝阳区肺结核患者耐药状况及相关因素分析

目的了解朝阳区当前结核病耐药状况及相关影响因素,为今后结核病防治工作提供参考依据。方法将2006—2007年朝阳区结防所登记的所有初治及复治痰结核分枝杆菌培养阳性的病例作为研究对象,采用绝对浓度间接法对4种抗结核药物异烟肼(H)、利福平(R)、链霉素(S)及乙胺丁醇(E)进行疗前药物敏感试验。结果430株结核分枝杆菌总耐药率为15.6%（67/430）,耐多药率3.0%（13/430）;初始耐药率为12.3%（47/381）,耐多药率1.8%（7/381）;获得性耐药率为40.8%（20/49）,耐多药率12.2%（6/49）。复治组耐药率及耐多药率均显著高于初治组,差异有统计学意义（P<0.001）。4种抗结核药物的总体耐药率顺位由高到低依次为S（12.6%）、H（8.4%）、R（5.8%）、E（0.9%）;初始耐药率顺位为S（10.0%）、H(6.3%)、R(3.7%)、E(0.8%);获得性耐药率顺位为S（32.7%）、H(24.5%)、R(22.4%)、E(2.0%)。初始耐药以耐单药为主,获得性耐药以耐2种药为主。经多因素非条件logistic回归分析,化疗史是影响耐药的主要因素,复治患者耐药率明显高于初治患者（OR=4.9,95%, CI为2.6～9.4,P<0.001）,而不同年龄、不同性别、有无空洞、有无糖尿病对耐药率的影响差异无统计学意义（P>0.05）。复治患者既往治疗用药不规律是造成耐药的主要原因（OR=5.8,95%, CI为1.5～23.5,P<0.05）。结论朝阳区肺结核患者的耐药率处在全国较低水平。抓好初治病人的治疗管理,减少不规律用药,是控制耐药的关键。     

产生耐多药结核病50例的危险因素分析

目的探讨产生耐多药结核病的危险因素。方法病例组为50例耐多药结核患者,对照组为50例非耐药结核患者,采用卡方检验和非条件Logistic回归进行分析。结果卡方分析有统计学意义(P0.05)的变量有体重指数(BMI)、居住地、饮酒、服药规律性、结核病史、肺结核空洞病灶;非条件logistic回归分析有统计学意义的变量有饮酒、服药规律性、结核病史和肺结核空洞病灶,OR值分别为0.211、0.442、2.468、6.150。结论不规律服药、结核病史和肺结核空洞病灶是产生耐多药结核病的危险因素,应采取相对应措施控制产生耐多药结核病。     

湘潭农村居民结核潜伏感染现状及影响因素研究

目的 了解湖南省湘潭农村居民结核感染现状及其影响因素,为农村居民结核病防控提供科学的数据支撑。方法 采取整群随机抽样方法,抽取湘潭县中路铺镇6个自然村为研究现场,以这6个村5岁及以上常住人群为研究对象,采用γ-干扰素释放试验(IGRA)检测其结核分枝杆菌感染情况,运用单因素和多因素研究方法探讨其影响因素。结果 本研究应检人数5 440人,实检4 913人,受检率为90.3%。 受检人群潜伏感染率为26.0%(1 276/4 913),其中男性为29.8%(660/2 216),女性22.8%(616/2 697),差异有统计学意义(χ²=30.502,P<0.001);不同年龄组QuantiFERONTB Gold In-Tube (QFT)阳性率的差异有统计学意义(χ²=297.531,P<0.001),年龄越大结核分枝杆菌潜伏感染率越高。非条件二分类logistic回归分析显示:吸烟人群(OR=1.684,95%CI=1.462~1.939)、年龄46~60岁(OR=2.076,95%CI=1.748~2.465)、年龄>60岁(OR=3.152,95%CI=2.655~3.741);BMI<18.5 kg/m²:(OR=1.792,95%CI=1.397~2.300)、BMI 24~27.9 kg/m²:(OR=2.037,95%CI=1.563~2.656)、BMI≥28 kg/m²:(OR=2.597,95%CI=1.899~3.551)、有结核密切接触史(OR=1.214,95%CI=1.021~1.442)是结核潜伏感染的影响因素。结论 湘潭农村居民结核分枝杆菌感染率较高,感染的重点人群为老年人、吸烟人群、BMI异常人群以及有结核密切接触史的人群,需对以上重点人群采取针对性的措施。     

Influence of glutathione S‐transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug‐induced hepatotoxicity in a Caucasian population

Objectives: Genetic variations in enzymes of isoniazid metabolism confer an increased risk for antituberculosis drug‐induced hepatotoxicity in Asian populations. The present study was aimed at investigating the possible association of antituberculosis drug‐induced hepatotoxicity with polymorphisms at the glutathione S‐transferase (GST) gene in a Caucasian population. Methods: A prospective case–control study was nested in a cohort of patients with active tuberculosis who were treated with a combination of isoniazid, rifampicin and pyrazinamide. Cases constituted patients with antituberculosis drug‐induced hepatotoxicity (n=35), and controls constituted patients without any evidence of this complication (n=60). Homozygous null polymorphisms at GST loci M1 and T1 were analysed from genomic DNA from all participants. Results: The GSTT1 homozygous null polymorphism was significantly associated with antituberculosis drug‐induced hepatotoxicity [odds ratio (OR) 2.60, 95% confidence interval (CI) 1.08–6.24, P=0.03]. No significant association was observed between the GSTM1 homozygous null polymorphism and antituberculosis drug‐induced hepatotoxicity (OR 0.73, 95% CI 0.31–1.73, P=0.48). Conclusion: The GSTT1 homozygous null polymorphism may be a risk factor of antituberculosis drug‐induced hepatotoxicity in Caucasians.     

Inflammation and tuberculosis: host‐directed therapies

Tuberculosis (TB) is an airborne infectious disease that kills almost two million individuals every year. Multidrug‐resistant (MDR) TB is caused by strains of Mycobacterium tuberculosis (M. tb) resistant to isoniazid and rifampin, the backbone of first‐line antitubercular treatment. MDR TB affects an estimated 500 000 new patients annually. Genetic analysis of drug‐resistant MDR‐TB showed that airborne transmission of undetected and untreated strains played a major role in disease outbreaks. The need for new TB vaccines and faster diagnostics, as well as the development of new drugs, has recently been highlighted. The major problem in terms of current TB research and clinical demands is the increasing number of cases of extensively drug‐resistant and ‘treatment‐refractory’ TB. An emerging scenario of adjunct host‐directed therapies is intended to target pulmonary TB where inflammatory processes can be deleterious and lead to immune exhaustion. ‘Target‐organ‐saving’ strategies may be warranted to prevent damage to infected tissues and achieve focused, clinically relevant and long‐lasting anti‐M. tb cellular immune responses. Candidates for such interventions may be biological agents or already approved drugs that can be ‘re‐purposed’ to interfere with biologically relevant cellular checkpoints. Here, we review current concepts of inflammation in TB disease and discuss candidate pathways for host‐directed therapies to achieve better clinical outcomes.     

Epidemiological perspective of drug resistant extrapulmonary tuberculosis

Tuberculosis(TB) remains one of the leading infectious diseases causing significant morbidity and mortality worldwide. Although, pulmonary TB is the most common presentation and is the main transmissible form of the disease, extrapulmonary TBalso significantly contributes to the burden of disease and can cause severe complications and disabilities. At present, the most serious issue with TB control programme is emergence of multi and extensively drug resistant Mycobacterium tuberculosis strain worldwide. As the number of drug resistant pulmonary TB is increasing around the world, the number of drug resistant TB with extrapulmonary manifestations are also on rise. However, there is surprisingly scant information in medical literatures on prevalence and impact of extrapulmonary drug-resistant TB. Here, we appraise the recent epidemiological studies that underpin the status and impact of drug resistance in TB cases with extrapulmonary manifestations.