Self-administered, standardized regimens for multidrug-resistant tuberculosis in South Korea.

SETTING: National Masan Tuberculosis Hospital, Masan, South Korea, a 430-bed tertiary referral hospital specializing in tuberculosis. OBJECTIVE: To evaluate the treatment outcomes of standardized, empiric regimens for multidrug-resistant tuberculosis (MDR-TB). DESIGN: A retrospective analysis of the hospital records of 142 patients with MDR-TB who had failed short-course chemotherapy. Between 1 January 1998 and 30 June 2000, patients were started on one of two standardized, empiric regimens based on previous treatment history. Drug susceptibility testing of the infecting strain was not used to modify the treatment regimen. Treatment was continued for at least 18 months after conversion to a negative culture. RESULTS: Sixty-three patients (44.1%) were cured and discharged from treatment after at least 18 months of negative cultures; 18 (12.7%) failed treatment, 41 (28.9%) defaulted, four died (2.8%), and 15 (10.6%) were transferred to another institution. One patient is still on treatment. Resistance to ofloxacin was the only risk factor related to poor outcome (death or failure) in univariate or multiple logistic regression analysis. CONCLUSIONS: High levels of resistance to second-line drugs are likely a cause of poor outcome of MDR-TB therapy in Korea. Directly observed therapy and other methods to increase patient compliance should be considered nationwide, as they may improve MDR-TB treatment outcomes.     

Low levels of second-line drug resistance among multidrug-resistant Mycobacterium tuberculosis isolates from Rwanda.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) has become a therapeutic problem in many parts of the world, necessitating the inclusion of second-line anti-tuberculosis drugs in specific treatment regimens. METHODS: We studied the susceptibility of 69 MDR Mycobacterium tuberculosis isolates from Rwanda to second-line drugs by the BACTEC 460 method. RESULTS: The results showed that 62 (89.9%) were resistant to rifabutin while a low rate (4.3%) of resistance was registered for ofloxacin; there was one case (1.4%) of resistance each for para-aminosalicylic acid, kanamycin, ethionamide, and clarithromycin. CONCLUSIONS: This information is important for devising an appropriate treatment regimen for MDR-TB patients in order to stop the spread of MDR strains and contain the acquisition of additional drug resistance in Rwanda.     

全基因组测序预测深圳市耐多药结核分枝杆菌的耐药性分析

目的 通过全基因组测序技术分析深圳市耐多药结核分枝杆菌(MDR-MTB)的耐药性检测情况,为MDR-TB患者的治疗及防控提供科学依据。方法 选取2013—2017年存储于深圳市慢性病防治中心结核病实验室并成功复苏的420株MDR-MTB临床分离株,对其提取DNA后进行全基因组测序。使用内部Perl脚本分析原始数据,参考MTB耐药基因数据库、耐药决定突变数据库及无害突变数据库确定相关基因突变以判断菌株对异烟肼、利福平、链霉素、乙胺丁醇、氟喹诺酮类、吡嗪酰胺、乙硫异烟胺、对氨基水杨酸、卡那霉素、阿米卡星、卷曲霉素、利奈唑胺、贝达喹啉和氯法齐明的耐药情况,同时绘制菌株耐药情况弦图,以及准广泛耐药MTB(pre-XDR-MTB)及XDR-MTB菌株耐药情况热图。结果 全基因组测序从420株菌株中检出23株XDR-MTB菌株(5.48%)和97株pre-XDR-TB菌株(23.10%);其中,所有菌株除对异烟肼、利福平全部耐药外,对链霉素的耐药率最高,达67.86%(285/420),其次为乙胺丁醇(66.19%,278/420)、氟喹诺酮(28.57%,120/420)、吡嗪酰胺(28.33%,119/420)、乙硫异烟胺(13.33%,56/420),对氨基水杨酸(7.38%,31/420)、卡那霉素(6.67%,28/420)、阿米卡星(5.48%,23/420)、卷曲霉素(5.48%,23/420)、利奈唑胺(0.24%,1/420),但未见对贝达喹啉和氯法齐明耐药。全基因组测序发现菌株有212种基因突变类型,以katG-315-S/T(81.43%,342/420)、rpoB-450-S/L(58.57%,246/420)、rpsL-43-K/R(65.96%,188/285)、embB-306-M/V(32.37%,90/278)突变居多。结论 全基因组测序预测深圳市MDR-MTB临床分离株中的pre-XDR-MTB比例较高,对一线抗结核药品及氟喹诺酮类药品的耐药率较高,临床实践中应结合药敏试验结果谨慎使用;而对乙硫异烟胺、氯法齐明、对氨基水杨酸等二线抗结核药品的耐药率较低,考虑这些药品可作为MDR-TB患者治疗方案的组成部分。     

Surveillance of Mycobacterium tuberculosis drug resistance in Hong Kong, 1986-1999, after the implementation of directly observed treatment.

OBJECTIVE: To study changing trends in TB epidemiology with emphasis on drug resistance rates in various age groups from 1986-1999. DESIGN: Laboratory-based data on drug susceptibility testing against streptomycin (SM), isoniazid (NH), rifampicin (RMP) and ethambutol (EMB) had been collected continuously in a centralised TB laboratory in Hong Kong. Epidemiological parameters such as sex, age and drug resistance rates in new and retreatment cases were measured and analysed for longitudinal trends. RESULTS: Of 48 924 non-duplicate isolates from new TB cases, 7045 (14.4%) were resistant to one or more drugs, 5773 (11.8%) were resistant to SM and/or INH while 881 (1.8%) were multidrug-resistant (MDR-TB). Of 3857 isolates from retreatment patients, 1176 (30.5%) were resistant to one or more drugs, 616 (16.0%) were resistant to SM and/or [NH, and 467 (12.1%) were MDR-TB. For isolates from new cases, significant declines were observed in the resistance rates against any drug, SM alone, INH alone, SM+INH and INH+RMP. For retreatment isolates, significant declines were also observed in resistance to any drug and INH+RMP. In both new and retreatment cases, isolates from patients aged over 65 years showed significantly lower drug resistance (any drug and INH+RMP) compared with other age groups (16-34 years and 35-65 years). CONCLUSION: With successful implementation of DOTS over a 14-year period, laboratory-based surveillance data showed significant declines in drug resistance, including MDR-TB. This has occurred amidst demographic changes associated with a generally ageing population as well as highly mobile sectors that are in constant exchange with highly endemic areas.     

Second-line drug susceptibilities of Thai multidrug-resistant Mycobacterium tuberculosis isolates.

The emergence of multidrug-resistant tuberculosis (MDR-TB) is increasing and is exacerbated by the human immunodeficiency virus (HIV) epidemic. The standard short-course regimen used for the treatment of tuberculosis is likely to be ineffective against MDR-TB, leading to the need for second-line drugs. In such situations, drug susceptibility testing (DST) is necessary to select an appropriate treatment regimen. In this study, DST of 99 MDR-TB strains isolated in Thailand was performed using a drug-impregnated disc method. The results showed that 94.95% of the strains were susceptible to amikacin and kanamycin, 90.91% to ciprofloxacin and ofloxacin, 85.86% to para-aminosalicylic acid, and 78.79% to ethionamide.     

Management of multidrug-resistant tuberculosis and patients in retreatment.

Retreatment of tuberculosis involves the management of entities as diverse as relapse, failure, treatment after default, and poor patient adherence to the previous treatment. The emergence of conditions for selection of resistance (failure and partial abandonment) is a matter of great concern. The development of a retreatment regimen for tuberculosis requires consideration of certain basic premises. The importance of a comprehensive and directed history of drugs taken in the past, and the limited reliability of susceptibility tests to many of these drugs, should be kept in mind. Taking this into account, and possessing a thorough knowledge of all anti-tuberculosis medications, it is possible to cure almost all patients with an appropriate retreatment regimen including a minimum of three or four drugs not previously used. Nonetheless, the treatment of these patients is so complex that it should only be carried out by experienced staff. Concern about treating tuberculosis patients with drug resistance varies greatly depending on the available resources. High-income countries should provide individual treatment regimens adapted to each patient; however, in other settings, restricted resources could justify the implementation of standardised therapeutic guidelines with second-line drugs in order to facilitate management and reduce costs.     

Additional drug resistance in Mycobacterium tuberculosis isolates from resected cavities among patients with multidrug-resistant or extensively drug-resistant pulmonary tuberculosis

The pathogenesis of increasing drug resistance among patients with multidrug-resistant or extensively drug-resistant tuberculosis undergoing treatment is poorly understood. Increasing drug resistance found among Mycobacterium tuberculosis recovered from cavitary isolates compared with paired sputum isolates suggests pulmonary cavities may play a role in the development of worsening tuberculosis drug resistance.     

Emergence of multidrug-resistant tuberculosis in a community-based directly observed treatment programme in rural South Africa.

OBJECTIVE: Although little studied in developing countries, multidrug-resistant tuberculosis (MDR-TB) is considered a major threat. We report the molecular epidemiology, clinical features and outcome of an emerging MDR-TB epidemic. METHODS: In 1996 all tuberculosis suspects in the rural Hlabisa district, South Africa, had sputum cultured, and drug susceptibility patterns of mycobacterial isolates were determined. Isolates with MDR-TB (resistant to both isoniazid and rifampicin) were DNA fingerprinted by restriction fragment length polymorphism (RFLP) using IS6110 and polymorphic guanine-cytosine-rich sequence-based (PGRS) probes. Patients with MDR-TB were traced to determine outcome. Data were compared with results from a survey of drug susceptibility done in 1994. RESULTS: The rate of MDR-TB among smear-positive patients increased six-fold from 0.36% (1/275) in 1994 to 2.3% (13/561) in 1996 (P = 0.04). A further eight smear-negative cases were identified in 1996 from culture, six of whom had not been diagnosed with tuberculosis. MDR disease was clinically suspected in only five of the 21 cases (24%). Prevalence of primary and acquired MDR-TB was 1.8% and 4.1%, respectively. Twelve MDR-TB cases (67%) were in five RFLP-defined clusters. Among 20 traced patients, 10 (50%) had died, five had active disease (25%) and five (25%) were apparently cured. CONCLUSIONS: The rate of MDR-TB has risen rapidly in Hlabisa, apparently due to both reactivation disease and recent transmission. Many patients were not diagnosed with tuberculosis and many were not suspected of drug-resistant disease, and outcome was poor.     

Using treatment failure under effective directly observed short-course chemotherapy programs to identify patients with multidrug-resistant tuberculosis.

SETTING: Public ambulatory care centers in three districts of northern metropolitan Lima, Peru. OBJECTIVE: To document drug resistance patterns of isolates of Mycobacterium tuberculosis from patients identified as treatment failures under a model tuberculosis (TB) control program based on directly observed, short-course chemotherapy (DOT-SCC). DESIGN: Case series. RESULTS: In a referred, consecutive sample of 173 patients identified as treatment failures on DOT-SCC, 160 (92.5%) had culture-positive TB. Of those 160, 150 (93.8%) had active, pulmonary multidrug-resistant TB (MDR-TB, resistance to at least isoniazid [INH] and rifampicin [RIF]). Sixty of the 150 (40.0%) had isolates resistant to at least INH, RIF, ethambutol (EMB) and pyrazinamide (PZA), the initial first-line empiric treatment regimen used locally. Forty-four (29.3%) had isolates resistant to at least INH, RIF, EMB, PZA and streptomycin (SM), the first retreatment regimen. This series of patients had isolates resistant to a mean of 4.5 of the ten drugs tested. The local profile of multidrug resistance is very different from that obtained from national data from Peru. CONCLUSION: In this setting, treatment failure on DOT-SCC is strongly predictive of active MDR-TB. Because of existing local drug resistance patterns in northern Lima, 89.3% of MDR-TB patients identified as treatment failures will receive ineffective therapy with two or fewer secondary TB drugs if they are given the five-drug empiric retreatment regimen endorsed by the World Health Organization. Further short-course chemotherapy for these patients would only serve to amplify ominous existing drug resistance patterns.     

结核分枝杆菌耐药机制

耐多药结核病和广泛耐药结核病在人类免疫缺陷病毒感染时代的不断增长是有效结核病控制的主要威胁。来自染色体自发突变的结核分枝杆菌耐药概率很低。疾病治疗过程中由于不稳定的药品供应、不合理的治疗方案以及差的患者依从性等人为选择因素导致临床耐药结核病大量发生。已经阐明主要的一线和二线药物包括利福平、异烟肼、吡嗪酰胺、乙胺丁醇、氨基糖甙类和氟喹诺酮类的耐药分子机制。结核分枝杆菌菌株耐药性与毒性／传染性之间的关系需要进一步研究。理解结核分枝杆菌耐药机制将有助于快速分子诊断工具的发展并且可能进一步指导结核病治疗的新药的研制。     

肝硬化合并轻微型肝性脑病的临床特点以及相关影响因素分析

[摘要]　目的　观察肝硬化合并轻微型肝性脑病（minimal hepatic encephalopathy, MHE）的临床特点,以及相关临床指标与MHE发生风险的关系。方法?选取87例肝硬化患者,每例患者均进行数字连接试验-A（number connection test-A, NCT-A）测试,测试结果超过正常值上限的患者确定为MHE组,否则为非MHE组。同时收集患者病史及血常规、肝功能、血氨、凝血功能等临床指标,并计算肝功能Child-Pugh评分,通过Logistic回归分析MHE发生的危险因素。结果?87例肝硬化患者中,49例（56.3%）NCT-A异常,诊断为MHE。统计学分析发现MHE组血氨水平明显高于非MHE组（P＜0.05）,但MHE组的血氨水平与NCT-A异常程度无明显相关性。MHE组中,失代偿期肝硬化患者比例、既往发生显性肝性脑病的患者比例、肝功能Child-Pugh评分B&C级患者比例显著高于非MHE组（P均＜0.05）;MHE组年龄偏低,具有更高的TBIL、氨基转移酶水平,而血ALB、CHE、PTA等较非MHE组均显著下降（P均＜0.05）。单因素Logistic回归分析发现,年龄偏低、失代偿期肝硬化、Child-Pugh分级高、血氨水平高、CHE水平低、TBIL水平高、PTA降低均是MHE发生的危险因素（P均 ＜0.05）;多因素Logistic回归分析发现,TBIL水平高是判断MHE发生风险的独立预测因素。结论?肝硬化患者中MHE发生率较高,特别是肝硬化失代偿期患者和肝功能基础较差的患者发生MHE风险显著增加,总胆红素水平高是发生MHE的独立危险因素。     

Genotyping and drug resistance patterns of Mycobacterium tuberculosis strains observed in a tuberculosis high-burden municipality in Northeast,Brazil

ObjectivesThis study has used a combination of clinical information, spoligotyping, and georeferencing system to elucidate the genetic diversity of the Mycobacterium tuberculosis isolates circulating in a TB-prevalent municipality of Northeast Brazil.MethodsA total of 115 M. tuberculosis strains were isolated from pulmonary tuberculosis patients from January 2007 to March 2008 in Fortaleza. Drug susceptibility and spoligotyping assays were performed and place of residence of the patients were georeferenced.ResultsOf the M. tuberculosis strains studied, 51 (44.3%) isolates were resistant to at least one drug (R-TB) and 64 (55.7%) were sensitive to all the drugs tested (S-TB). A high frequency of resistance was found in previously treated cases (84%) and among new cases (16%; p < 0.001). A total of 74 (64%) isolates were grouped into 22 spoligotyped lineages, while 41 (36%) isolates were identified as new. Among the predominant genotypes, 33% were Latim American Mediterranean (LAM), 12% Haarlem (H), and 5% U. There was no association of geographic distribution of RT-TB patients as compared to the controls and also the geographic location to the spoligotype patterns. The geospatial analysis revealed that 24 (23%) patients (hot spot zones) either shared the same residence or lived in a close neighborhood of a case. Among these concentration zones, the patients lived in the same residence and shared a common genotype pattern and resistance pattern.DiscussionIt was observed that the spoligopatterns family distribution was similar to that reported for South America, prevailing the LAM and H lineages. A high rate-case among the resistant TB group occurs as a result of transmitted and acquired resistance. A more effective surveillance program is needed in order to succeed in reducing tuberculosis in Northeast Brazil.     

Impact of extensive drug resistance on treatment outcomes in non-HIV-infected patients with multidrug-resistant tuberculosis.

BACKGROUND: Recently, serious concerns about extensively drug-resistant tuberculosis (XDR-TB), which shows resistance to second-line anti-TB drugs in addition to isoniazid and rifampicin, have been raised. The aim of this study was to elucidate the impact of extensive drug resistance on treatment outcomes in non-human immunodeficiency virus (HIV)-infected patients with multidrug-resistant tuberculosis (MDR-TB). METHODS: Patients who received the diagnosis of and treatment as having MDR-TB at Seoul National University Hospital (Seoul, Republic of Korea) between January 1996 and December 2005 were included. The definition of XDR-TB was TB caused by bacilli showing resistance to both isoniazid and rifampicin and also showing resistance to any fluoroquinolone and to at least 1 of the following 3 injectable anti-TB drugs: capreomycin, kanamycin, and amikacin. To identify the impact of extensive drug resistance on treatment outcomes, univariate comparison and multiple logistic regression were performed. RESULTS: A total of 211 non-HIV-infected patients with MDR-TB were included in the final analysis. Among them, 43 patients (20.4%) had XDR-TB. Treatment failure was observed in 19 patients (44.2%) with XDR-TB, whereas treatment of 46 patients (27.4%) with non-XDR-TB failed (P=.057). The presence of extensive drug resistance (adjusted odds ratio [OR], 4.46; 95% confidence interval [CI], 1.35-14.74) and underlying comorbidity (adjusted OR, 2.62; 95% CI, 1.00-6.87) were independent risk factors for treatment failure. However, a higher level of albumin was inversely associated with treatment failure (adjusted OR, 0.87; 95% CI, 0.77-0.97). CONCLUSION: The presence of extensive drug resistance, the presence of comorbidity, and hypoalbuminemia were independent poor prognostic factors in non-HIV-infected patients with MDR-TB.     

Molecular analysis of Mycobacterium tuberculosis causing multidrug-resistant tuberculosis meningitis.

SETTING: Tertiary referral hospitals in southern Vietnam. OBJECTIVE: Molecular characterisation of multidrug-resistant (MDR) tuberculous meningitis (TBM). DESIGN: Mycobacterium tuberculosis isolates from the cerebrospinal fluid (CSF) of 198 Vietnamese adults were compared with 237 isolates from patients with pulmonary tuberculosis (PTB) matched for age, sex and residential district. Isolates resistant to isoniazid or rifampicin (RMP) were sequenced in the rpoB and katG genes, inhA promoter and oxyR-ahpC intergenic regions. RESULTS: While drug resistance rates were lower in the CSF (2.5% MDR) than pulmonary isolates (5.9% MDR), the difference was not significant. The most commonly mutated codons were 531, 526 and 516 in rpoB and 315 in katG. Four novel triple mutants in rpoB were identified. CONCLUSION: RMP resistance is a good surrogate marker for MDR-TBM in this setting. However, probes directed against these three codons would have a maximum sensitivity of only 65%. A rapid phenotypic detection test may be more applicable for the diagnosis of MDR-TBM.     

结核分枝杆菌耐药性检测方法的研究进展

结核分枝杆菌耐药基因的检测是结核病诊断和治疗中的难题之一,近年来已有多种方法用来检测耐药基因,笔者从在我国获得注册证书的试剂盒,在国际上获得注册证书尚未进入我国的试剂盒和临床前研究的新方法3个方面概述了结核分枝杆菌耐药性检测方法的研究进展。