Correlations between Gene Resistant Markers and Second-Line Anti-TB Drug Resistance in Pre-XDR and XDR-TB Patients

Background: Extensively drug resistant tuberculosis (XDR-TB) is a serious problem in public health and XDR-TB patients usually develop from multi-drug resistance tuberculosis (MDR-TB) and pre-XDR-TB. The rapid molecular test for drug susceptibility testing (DST) can be used for early detection to prevent XDR-TB. Methods: We examined 34 clinical Mycobacterium tuberculosis (M. tuberculosis) isolates from MDR/XDR-TB patients in the upper north of Thailand that were identified with drug susceptibility profiles by indirect agar proportion method from 2005-2012. Our study investigated the genetic mutations in gyrA for ofloxacin resistance and rrs for kanamycin resistance. The genetic mutations and drug susceptibility test results were analyzed using the exact test. Results: The majority of the ofloxacin resistance was detected in gyrA 21, gyrA 70, gyrA 87, gyrA 102, gyrA 162, and gyrA 187 were at 0%, 12.5%, 37.5%, 0%, 50.0% and 25.0% sensitivity, respectively, and at 96.2, 96.2%, 20.1%, 96.2%, 57.7% and 61.5% specificity, respectively. Kanamycin resistance was found in rrs 512, rrs 241, rrs 223, rrs 414 and rrs 408 at 16.7%, 0%, 0%, 16.7% and 16.7% sensitivity, respectively, and at 96.4%, 92.9%, 82.1%, 82.1% and 71.4% specificity, respectively. This study found no significant correlation between gyrA mutations and ofloxacin resistance and also no correlation between the rrs gene and kanamycin resistance. Conclusion: These primer sequences and PCR products in our study such as gyrA and rrs might be unsuitable to detect ofloxacin and kanamycin resistance in the upper north of Thailand.

Pre-Extensively Drug Resistant Tuberculosis (Pre-XDR-TB) among Pulmonary Multidrug Resistant Tuberculosis (MDR-TB) Patients in Bangladesh

Background & Objectives: Emergence of drug resistant Tuberculosis (TB) is a major obstacle in the TB control programme of Bangladesh. This study was carried out to detect pre-extensively drug resistant TB (pre-XDR-TB) cases among the multidrug resistant TB (MDR-TB) patients in Bangladesh, as the early detection of pre-XDR-TB can guide clinicians in the appropriate modification of MDR-TB treatment regimen with effective drugs to prevent treatment failure. Methodology: A total of 68 MDR-TB cases were enrolled in this study. Multiplex Real-time PCR was done to detect pre-XDR-TB cases directly from sputum samples of MDR-TB patients. Results: Out of 68 MDR-TB cases 11 (16.18%) cases were detected as pre-XDR-TB. The resistant profile of the 11 pre-XDR-TB revealed 9 (81.82%) cases of fluoroquinolone (FLQ) resistant pre-XDR-TB and 2 (18.18%) cases of injectable second line (ISL) agent resistant pre-XDR-TB. Out of 11 pre-XDR-TB cases 7 (63.64%) cases had history of taking treatment for MDR-TB regularly, 1 (9.09%) case had history of taking treatment for MDR-TB irregularly and 3 (27.27%) cases had no history of taking treatment for MDR-TB. Conclusion: This study encountered a high rate of pre-XDR-TB cases along with a significant number of primarily resistant bacilli which is of concern in the management of MDR-TB. It is evident that Bangladesh is in urgent need to device strategies for rapid and early detection of pre-XDR-TB in order to prevent treatment failure of MDR-TB cases and also to halt the progression of MDR-TB cases to extensively drug resistant TB (XDR-TB), which is not only difficult but also very expensive to treat.

Combination of the MODS Assay with the Sensititre^TMMYCOTB Plate for Rapid Detection of MDR- and XDR-TB

We combined the new SensititreTM MYCOTB test with the MODS assay for detection of MDR- and XDR-TB. Categorical agreement of the MODS assay with the critical concentrations at 3 days of incubation was highest for INH (91.4%) and RIF (100%) and at 5 days 86.7% and 94.6% for the fluoroquinolones and aminoglycosides, respectively. By combining these two methods, it is possible to identify MDR-TB in as little as 3 days and XDR- or pre-XDR-TB within 5 days.

The Prediction Factors of Pre-XDR and XDR-TB among MDR-TB Patients in Northern Thailand

Background: Molecular diagnosis based on the detection of mutations conferring genetic drug resistance is useful for early diagnosis and treatment of Pre-XDR and XDR-TB patients. However, the study of mutation as a marker to predict Pre-XDR and XDR-TB is rare. Methods: Thirty-four Mycobacterium tuberculosis (MTB) isolates from MDR, Pre-XDR and XDR-TB patients in the upper north of Thailand, who had been identified for drug susceptibility using the indirect agar proportion method from 2005-2012, were examined for genetic site mutations of katG, inhA, and ahpC for isoniazid (INH) drug resistance, rpoB for rifampicin (RIF) drug resistance, gyrA for ofloxacin (OFX), and rrs for kanamycin (KAN). Associations between resistant genes and Pre-XDR and XDR-TB in the MDR patients were performed using exact probability tests. Univariable logistic regression was used to quantify the strength of association between the gene mutation with Mycobacterium tuberculosis and the prevalence of Pre-XDR and XDR-TB in the MDR patients. Results: The mutations in the region of the rpoB gene at codon 445 (C445T) in the Pre-XDR or XDR-TB patients were significantly 20.6 times more prevalent among the MDR-TB patients. The inhA gene mutation at codon 114 (T114G) was also significantly 8.1 times more prevalent. Conclusion: The findings can be used to predict the odds of Pre-XDR and XDR-TB in MDR-TB patients, as a guide for prevention and treatments.

常见问题——广泛耐药结核(XDR-TB)之二

12.什么是广泛耐药结核与艾滋病毒/艾滋病之间的联系?为什么在一些地方广泛耐药结核如此高地与艾滋病毒有联系或关联?

应用BACTEC MGIT 960分析临床结核菌株耐药性分析

目的研究我院结核病患者的抗结核药物耐药特点。方法我院就医的结核病患者抗结核药物的敏感性试验结果,分析临床抗结核药物的耐药现状。结果 2008～2010年,耐药菌株为4825株(耐药率为66.68%,4825/7236,MDR为1142株,XDR为105株)。XDR-TB比例2008、2009、2010年分别为1.73%(30/1732)、1.33%(34/2548)、1.39%(41/2956)。结论结核病患者的抗结核药物的耐药形势依然严峻,加强抗结核药物的耐药性监测,合理使用药物非常必要。

利奈唑胺治疗重症耐多药肺结核临床观察及不良反应分析

目的探讨利奈唑胺在治疗重症耐多药结核病,特别是广泛耐药结核病前期(pre-XDR-TB)和广泛耐药结核病(XDR-TB)中的作用。方法收集2015年7月1日至2017年6月30日深圳市慢性病防治中心结核病门诊确诊为pre-XDR-TB患者9例,XDR-TB患者3例,总结人口学特征及疾病特征,经科室专家会诊后制定含利奈唑胺的个体化治疗方案,治疗过程中根据药敏结果及不良反应调整治疗方案,观察临床疗效及药物不良反应。结果12例患者中10例治愈,2例失败,治疗成功率83.3%(10/12)。12例患者中8例出现需处理的不良反应,其中视神经损伤3例,停用利奈唑胺经眼科处理后视力恢复。1例出现轻度贫血,3例出现白细胞减少,经对症治疗后恢复正常。7例出现肝功损害,其中5例需短时间停药并修订治疗方案,之后顺利完成治疗。结论利奈唑胺是治疗重症耐多药结核病的重要组成药物,疗效理想,副作用可控,值得推广。

Human mpox co-infection with advanced HIV-1 and XDR-TB in a MSM patient previously vaccinated against smallpox:A case report

Mpox is a zoonotic infectious disease caused by the mpox virus(MPXV).Historically,the majority of mpox cases have been documented in Central Africa.However,since May 2022,there has been a notable rise in reported cases from regions beyond Africa.Currently,over 110 countries spanning Europe,North America,South America,Asia,and other territories have reported mpox infections.This report details a case involving a patient who identifies as a man who has sex with men(MSM)and is concurrently infected with MPXV,human immunodeficiency virus type 1(HIV-1),Pneumocystis jiroveci,as well as extensively drug-resistant tuberculosis(XDR-TB).This patient had also received a vaccination for smallpox in the past.Additionally,we provide photographic documentation charting the progression of dermatological manifestations associated with mpox.This case highlights the significance of sexual intercourse as a crucial mode of transmission for mpox.The rapid and widespread dissemination of the MPXV across various regions,especially among MSM communities,underscores the importance of enhancing preventive education efforts targeted at high-risk populations.

南京地区2013—2014年结核分枝杆菌耐药流行情况调查

目的了解南京地区胸科医院2013-2014年结核杆菌对药物的耐药情况。方法使用绝对浓度法对本院2013、2014年获得的2510株抗酸分枝杆菌株进行耐药监测及对比研究;此外统计耐多药患者临床资料,了解耐多药肺结核与糖尿病的合并情况。结果 2013-2014年南京胸科医院RR-TB、Pre-XDRTB耐二线药物发病率呈增长趋势。Pre-XDR-TB在MDR-TB构成比可达51%,且在Pre-XDR-TB中耐左氧氟沙星明显多于耐二线注射用药。结核菌对丁胺卡那霉素、卡那霉素、卷曲霉素三种药物的敏感、耐药性高度一致,其交叉耐药明显。耐药肺结核患者中糖尿病比例呈增长趋势。结论南京地区胸科医院结核杆菌耐药率高,应加强抗结核药物耐药性监测、门诊随访、合并症分析,根据药敏试验结果选择科学有效的化疗方案。

利奈唑胺治疗广泛耐药结核病的临床疗效评价

目的评价利奈唑胺治疗广泛耐药结核病的临床疗效。方法我院收治的24例广泛耐药结核病患者,随机分为两组,对照组12人采用常规化疗,试验组12人加用利奈唑胺,比较不良反应和疗效。结果试验组试验组症状改善、病灶吸收、空洞闭合、抗酸染色涂片阴性、痰结核分枝杆菌阴性、痰定量PCR阴性例数均明显高于对照组,试验组不良反应发生率高于对照组,差异均有统计学意义(P<0.05),经对症治疗后均痊愈。结论利奈唑胺治疗广泛耐药结核病疗效显著。

四川泸州地区耐多药及广泛耐药结核病的临床特点

目的分析泸州地区耐多药结核(MDR-TB)及广泛耐药结核病(XDR-TB)的临床特点,为早期发现及防治提供临床经验。方法采集泸州地区2013年1月至2016年10月1 218例痰涂片阳性肺结核患者临床资料,并对痰标本进行传统罗氏培养,培养菌株再进行线性探针杂交试验。对杂交试验提示为MDR-TB的菌株进行传统药物敏感试验,探讨传统药敏试验MDR-TB及XDR-TB的结核患者,并对其进行电话问卷调查,分析临床特点。结果涂片阳性标本总计1 218例,最终获得结核分枝杆菌1 055例,非结核分枝杆菌41例。结核分枝杆菌耐药标本188例,总耐药率17.82%(188/1 055),耐多药率9.67%(102/1 055)。MDR-TB患者102例,主要为男性(77.45%)、中老年(79.41%)、农民(80.39%)及复治(75.49%)患者。结论泸州地区MDR-TB情况严重。MDR-TB患者的依从性普遍较差;应特别重视复治及农民工的MDR-TB及XDR-TB问题。

Natural Remedies against Multi-Drug Resistant <i>Mycobacterium tuberculosis</i>

Tuberculosis (TB), caused by Mycobacterium tuberculosis is an infectious deadly disease and the treatment of which is one of the most severe challenges at the global level. Currently more than 20 chemical medications are described for the treatment of TB. Regardless of availability of several drugs to treat TB, the causative agent, M. tuberculosis is nowadays getting resistant toward the conventional drugs and leading to conditions known as Multidrug-resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB). This situation has terrified the global health community and raised a demand for new anti-tuberculosis drugs. Medicinal plants have been used to cure different common as well as lethal diseases by ancient civilizations due to its virtue of variety of chemical compounds which may have some important remedial properties. The aim of the present review is to focus the anti-tubercular medicinal plants native to India as well as the plants effective against MDR or XDR-TB across the globe. In the present review, we have addressed 25 medicinal plants for TB and 16 plants effective against MDR-TB testified from India and 23 herbal plants described for MDR-TB across the world during 2011-2015. These herbal plants can serve as promising candidates for developing novel medications to combat multidrug resistant M. tuberculosis.

如皋市耐多药肺结核患者发现、治疗转归情况分析

目的了解如皋市确诊耐多药肺结核患者来源及治疗转归情况。方法收集2010年7月-2013年6月如皋市中国全球基金结核病项目(-期)基础资料、病案信息、督导汇总表、服药卡和督导表等,分析不同分类肺结核的耐多药肺结核患者检出和治疗转归情况。结果 3年间确诊耐多药肺结核患者36例,检出率为11.92%。初治涂阳肺结核耐多药检出率为3.70%,MDR-TB高危人群为18.56%,差异有统计学意义(χ2=12.59,P<0.05)。纳入治疗耐多药肺结核患者34例,治愈率为39.29%,死亡率为14.71%,失败率为14.71%,治疗成功率为55.88%。结论如皋市耐多药肺结核疫情低于全国平均水平,DOTS-PLUS策略是MDR-TB防治最重要的策略。

莫西沙星治疗广泛耐多药肺结核的可行性研究

目的探讨莫西沙星(moxifloxacin,MXFX)治疗广泛耐多药肺结核(extensively drug Resistance-tuberculosis,XDR-TB)的可行性。方法选取98例XDR-TB患者,随机分为莫西沙星(MXFX)组和左氧氟沙星(levofloxacin,LVFX)组,各49例。2组均采用常规抗结核药物,MXFX组加用莫西沙星,LVFX组加用左氧氟沙星,观察2组治疗效果。结果 MXFX组在治疗后4个月、12个月、18个月的痰菌转阴率均高于同期的LVFX组(79.59%vs 59.18%,P<0.05;89.79%vs 73.47%,P<0.05;95.92%vs 81.63%,P<0.05);病灶吸收率(93.88%)高于LVFX组(79.51%)(P<0.05);2组不良反应率对比差异无统计学意义(14.29%vs 16.32%,P>0.05)。结论采用MXFX治疗XDR-TB,病灶吸收率高,生物利用度高,疗效显著。

Isoniazid and Rifampicin as Therapeutic Regimen in the Current Era: A Review

Tuberculosis represents one of the biggest challenges in the medical field. According to World Health Organization (WHO) Global Tuberculosis Report, 2012, there were estimated 8.7 million new TB cases worldwide while 1.4 million people died of TB. Additionally, 90% of the cases of TB are reported in developing countries, with India having the largest number of incident cases. The current treatment method includes the administration of a cocktail of drugs which includes Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) and Pyrazinamide (PZA) which are referred to as the first line of drugs. Isoniazid and Rifampicin are currently the two most powerful anti-TB medications. The occurrences of multi-drug and extensive-drug resistant strains (MDR-TB and XDR-TB, respectively) have become a global concern and pose a serious challenge for public health management. Treatment of these resistant cases involves the usage of the second line of anti-tuberculosis drugs which are less effective than the first line and are known to cause adverse reactions or toxic side-effects. Tuberculosis research should not only focus on treatment methods but also on management of the current cases of resistance and measures to prevent an outbreak of resistant TB infection. This review outlines the mechanism of action of isoniazid and rifampicin and how resistance to these drugs emerges. We also provide a brief insight into the prevalence of HIV in TB patients and the challenges associated with treatment regimens in this co-infection.

阿米卡星与卷曲霉素治疗耐多药和广泛耐药结核病的药物不良反应比较

目的比较阿米卡星与卷曲霉素治疗耐多药和广泛耐药肺结核的药物不良反应发生情况。方法选择2014年1月至2017年8月于首都医科大学附属北京胸科医院就诊并采用阿米卡星或卷曲霉素作为治疗药物的耐药结核病患者264例,其中阿米卡星组142例,卷曲霉素组122例。所有患者均进行病史采集、查体、听力、尿常规、肝肾功能和电解质检查,每2周进行耳毒性和肾毒性药物不良反应的评价。结果阿米卡星组56例(39.4%)患者治愈,卷曲霉素组49例(40.2%)患者治愈,差异无显著性(P>0.05)。阿米卡星组平均用药时长为92 d,卷曲霉素组为101 d,差异有显著性(P<0.05)。两组均有患者发生耳毒性药物不良反应,包括耳鸣、听力下降或眩晕症状,阿米卡星组耳毒性发生率(23.9%)高于卷曲霉素组(10.7%),差异有显著性(P<0.05)。两组均有患者发生肾毒性,包括合并尿蛋白阳性或肾功能异常,阿米卡星组肾毒性发生率(7.0%)与卷曲微素组(11.5%)比较差异无显著性(P>0.05)。阿米卡星组无低钾血症发生,卷曲霉素组21.3%发生低钾血症,差异有显著性(P<0.05)。结论相较与阿米卡星,使用卷曲霉素治疗耐多药和广泛耐药肺结核可延长强化期疗程,且耳毒性药物不良反应发生率更低。

The Introduction of Bedaquiline Regimen for Drug-Resistant Tuberculosis in the Philippines: An Operational Study

Objectives: Bedaquiline (BDQ) is the first new anti-tuberculosis (TB) drug introduced to the market after 45 years. Recent studies have shown the potential benefits of adding bedaquiline to regimens for drug-resistant TB (DR-TB). In search of more effective regimens for DR-TB, bedaquiline was introduced in the TB program in the Philippines under operational research to assess its effectiveness, safety, and tolerability when given with background regimens among patients with multi-or extensively DR-TB (MDR/XDR-TB). Design: A prospective cohort study of patients with MDR/XDR-TB was given with a bedaquiline-containing regimen from June 2016 to May 2017. Demographic data, presence of comorbidities, and microbiologic profile on entry were recorded. Bedaquiline was administered at the recommended dose of 400 mg once daily for 14 days, then 200 mg three times a week for 22 weeks together with World Health Organization (WHO)-compliant background regimen. The time to culture conversion, interim outcomes at the 6th month of treatment, end-of-treatment outcomes, and post-treatment follow-up outcomes after one year was determined. The frequency and severity of adverse events (SAE) were recorded as part of pharmacovigilance. Results: Seventy-five patients were given with bedaquiline-containing regimen during the study period. Forty-two (56.0%) had second-line injectable resistance, 23 (30.7%) had fluoroquinolone-resistance, 6 (8.0%) had MDR-TB, and 4 (5.3%) had XDR-TB. In the 6th month of post-enrolment, 79% were culture-negative. The treatment success rate was 65.3% (37 were cured and 12 completed treatment), 7 (9.3%) died, 17 (22.7%) lost to follow-up, and 2 (2.7%) were withdrawn from treatment. Adverse events included vomiting (80%), dizziness (69%), nausea (52%), cough (44%), and headache (36%). The post-treatment follow-up of 49 patients in the 12th month showed 92% were culture-negative while 8% of TBC were not done. Conclusion: Bedaquiline-containing regimens for patients with MDR/XDR-TB were highly effective with an acceptable safety profile and favorable treatment outcomes, but the proportion of patients who lost to follow-up remains substantial.

耐多药肺结核标准化治疗效果评价及生存分析

评价世界卫生组织（WHO）推荐的标准化治疗方案（STR）在大连市耐多药治疗疗效,分析耐多药（MDR）结核死亡病例高危因素。收集大连市结核病医院2012年12月-2015年12月117名MDR肺结核患者的临床资料,进行疗效评价及死亡高危因素分析。92例MDR患者中,38例（41.30%）治愈,4例（4.35%）完成治疗,14例（15.22%）治疗失败,16例（17.39%）死亡。25例广泛耐多药（XDR）患者中,6例（24.00%）治愈,5例（20.00%）治疗失败,5例（20.00%）患者死亡。方案不完整,贫血及低蛋白血症为MDR/XDR患者死亡的高危因素。因此,STR可行、有效,但仍有诸多问题尚待解决,新药研用及新的方案需要进一步研究。

四川地区346例耐药肺结核患者临床特征分析

目的了解四川地区346例耐多药(MDR-TB)和泛耐药(XDR-TB)肺结核患者的临床特征以及可能与耐药发生有关的因素。方法回顾分析成都市公共卫生临床医疗中心2016年1月~2017年6月收治的346例耐药肺结核患者以及2370例药物敏感肺结核患者的临床资料,通过比较分析二组的差异,探讨耐药肺结核患者的患病特点以及可能影响耐药发生的因素。结果耐药肺结核发病人群以男性为主,占70.52%(244/346),且各年龄组男性均多于女性;青壮年居多,占81.79%(283/346),老年和18岁以下患者占比分别为13.58%(47/346)和4.62%(16/346)。性别和年龄分布情况与药物敏感肺结核无明显差异。耐药患者中少数民族患者占比接近五分之一;初、复治病例分别占23.70%(82/346)和76.30%(264/346)。在86例使用过喹诺酮类药物的耐药患者中73.26%(63/86)的病例对此类药物耐药。主要临床症状与药物敏感肺结核患者无明显差异。耐药患者中并发肺组织外结核者占65.32%(226/346),与药物敏感肺结核组(72.57%,1720/2370)相比无明显差异。耐药患者胸部影像改变中,空洞、支气管扩张和肺叶毁损分别占75.72%(262/346),23.12%(80/346)和19.08%(66/346),均高于药物敏感肺结核组;病变累及范围分布与药物敏感肺结核组无差别。主要合并症中,合并HIV感染者18例,糖尿病53例,慢性肺部疾患者17例,与药物敏感组相比无明显差异。耐药结核分枝杆菌检出标本最常见者为痰液(82.08%,284/346)和支气管肺泡灌洗液(28.90%,100/346),其他多种组织均有检出。通过Xpert MTB/RIF检测方法,检出利福平突变阳性者82.56%(142/172);北京博奥晶芯分枝杆菌+耐药检测方法检出利福平耐药者90.65%(97/107)。结论耐药结核病在各年龄段人群均可发生,男性高于女性。主要表现与药物敏感肺结核患者无明显差异。复治患者是耐药结核病发病的高危人群,但初始耐药不少见。喹诺酮类药物的不规范使用可能与继发耐药有关。耐药患者肺外结核发生率与药物敏感肺结核患者无明显差异。其肺部影像改变较之药物敏感肺结核患者有更多的空洞、支气管扩张和肺叶毁损。快速分子生物学方法阳性率高,快捷有效。

A Comparative Study of Drug Susceptibility Testing Techniques for Identification of Drug Resistant TB in a Tertiary Care Centre, South India

India tops the global list for Drug resistant Tuberculosis, but inadequate and expensive laboratory culture techniques have led to delay in the diagnosis and treatment. We studied the potential of an alternative method which could be cost-effective by combining the drugs in the same tube for identification of drug resistance. Drug Susceptibility Test (DST) results of 1000 sputum samples are got from suspected TB patients against INH (isoniazid) and Rifampicin by two techniques: a) a modified technique with both drugs in the same MGIT tube and b) a standard technique with the antibiotics in separate MGIT tubes for the diagnosis of MDR-TB (Multidrug Resistant). 39 samples were contaminated and were excluded from final analysis. 198 were smear positives by the concentrated Ziehl-Neelsen’s staining method. 219 were found to be culture positive out of which 195 were identified as M. tuberculosis complex. 40 (20.5%) strains were identified as MDR-TB by the conventional method and 39 were picked up by the modified DST. INH and Rifampicin mono-resistance accounted for 32 (16.4%) and 4 (2%) respectively. 99% concordance was observed between the two tests in categorizing MDR-TB. Similarly modified technique with combination of the second line Antibiotics-Ofloxacin, Kanamycin and Capreomycin was applied on the identified MDR strains in a stepwise manner. 6 (15%) were identified as Pre-XDR strains and 2 (5%) were found to be XDR-TB strains. This study implies that combining drugs in the same tube may be an equivalent and possibly a cost-effective alternative which needs to be explored further.