Spread Of Drug-resistant Tuberculosis Research Articles

Multidrug-resistant tuberculosis in children: Are the same therapy options available worldwide?

The spread of drug-resistant tuberculosis (TB) encouraged the development of new medicines and the reappraisal of old drugs rarely used in recent years. Providing access for children with drug-resistant TB to appropriate treatments is a cornerstone of strategies to reduce the burden of TB worldwide. Aim of this perspective was to describe the availability of child-friendly medicines to treat drug-resistant TB at the global level. We showed that the development of child-friendly formulations of second-line drugs should be encouraged to promote adherence to recommended treatment regimens and consequently to increase the success rate and to prevent the development of additional mycobacterial resistances. This is even more crucial, considering the long duration of antitubercular therapies. Importantly, companies and policy makers are called to more efforts in facilitating their prompt availability in every contest because drug-resistant pediatric TB is a worldwide medical problem.

Utilization of Bedaquiline among Drug Resistant-Tuberculosis patients

Background: India has one of the highest burdens of drug-resistant tuberculosis (DR-TB) globally. The persistent spread of DR-TB is one of the most daunting problems the world is witnessing. Current regimens for DR-TB are complicated, lengthy, and expensive compared to those used to treat drug-susceptible TB, leaving patients with much less effective treatment options. Bedaquiline (BDQ) is a novel drug that has strong bactericidal and sterilizing activities against Mycobacterium tuberculosis. The WHO recommends BDQ for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). The objective of the study is to evaluate the utilization of BDQ among drug-resistant tuberculosis patients in a tertiary care hospital. Materials and Methods: A hospital-based retrospective observational study was conducted at the Government General and Chest Hospital in Erragadda, Hyderabad, Telangana, where suspected Tuberculosis cases are referred. All patients who were prescribed bedaquiline regimen were included in the study. Results: 23 Patients were prescribed BDQ during the study duration. The mean age of the patients was 41± 14.24 years and most of them were in the age group of 21-40 years. 15 patients (65.21%) were Males. Diabetes mellitus was the most common co-morbid condition. Two patients (8.70%) successfully completed the treatment, 3 patients (13.04%) died during treatment and 18 patients (78.26%) were still receiving the treatment during the study period. Adverse effects were documented in 12 patients and the most common adverse events were related to gastrointestinal tract. Conclusion: Bedaquiline containing regimen was well tolerated with less number of manageable adverse effects.

Poor adult tuberculosis treatment outcome and associated factors in Gibe Woreda, Southern Ethiopia: An institution-based cross-sectional study.

Tuberculosis (TB) remains a major medical and public health problem throughout the world, especially in developing countries including Ethiopia. Its control program is currently being challenged by the spread of drug-resistant TB, which is the result of poor treatment outcomes. Hence, this study assessed poor adult TB treatment outcomes and associated factors in Gibe Woreda, Southern Ethiopia. An institution-based cross-sectional study was conducted from March 1, 2020 to March 30, 2020, using a standard checklist to review clinical charts of TB patients who enrolled on first-line TB treatment under DOTS between June 2016 and June 2019. Poor treatment outcomes constituted death during treatment, treatment failure, and loss to follow-up (LTFU). Descriptive statistics were used to describe the characteristics of study participants. A binary logistic regression model was fitted to identify factors influencing treatment outcome and adjusted odds ratios with a 95% confidence interval were reported. The statistical significance of all tests in this study was declared at P-value <5%. A total of 400 adult TB patients were participated. The mean age of study participants was 39.2±16.7 years, 55.5% were males and 79.8% were pulmonary tuberculosis cases. Regarding the treatment outcomes, 58% completed treatment, 27.5% cured, 9.3% were LTFU, 3.2% died, and 2.0% failed. The overall poor treatment outcome was 14.5% (95% CI: 11.1-17.9). Age (aOR = 1.02; 95%CI: 1.01-1.04), male gender (aOR = 1.82; 95% CI: 0.99-3.73), travel ≥ 10 kilometres to receive TB treatment (aOR = 6.55; 95% CI: 3.02-14.19), and lack of family support during the course of treatment (aOR = 3.03; 95% CI: 1.37-6.70), and bedridden baseline functional status (aOR = 4.40; 95% CI: 0.96-20.06) were factors associated with poor treatment outcome. Successful TB treatment outcome in this study area was below the national TB treatment success rate. To improve positive treatment outcomes, remote areas should be prioritized for TB interventions, and stakeholders in TB treatment and care should give special emphasis to adults over the age of 45 years, males, those who travel more than 10 kilometres to receive TB care, having bedridden baseline functional status and those who had no family support.

Assessment of Factors Associated with Unfavorable Outcomes among Drug-Resistant TB Patients: A 6-Year Retrospective Study from Pakistan.

The spread of drug-resistant tuberculosis (DR TB) poses significant challenges to the control and successful eradication of TB globally. The current retrospective study was designed to evaluate the treatment outcomes and identify the risk factors associated with unsuccessful outcomes among DR TB patients. A total of 277/308 eligible DR TB patients were enrolled for treatment at the programmatic management unit of DR TB at the Pakistan Institute of Medical Sciences, Islamabad between January 2014 and July 2019. Treatment outcomes were defined according to the WHO recommendations. Death, treatment failure, and lost to follow-up (LTFU) were collectively grouped as unsuccessful treatment outcomes, whereas cured and treatment completed were summed up together as successful treatment outcomes. Out of the total 277 patients, 265 (95.67%) were multidrug/rifampicin-resistant TB (MDR/RR-TB) cases, 8 (2.89%) were isoniazid resistant cases, and 4 (1.44%) were extensively drug-resistant ones. In the current cohort, a total of 177 (63.9%) achieved successful treatment outcomes. Among them, 153 (55.2%) were declared cured and 24 (8.7%) completed their treatment. Of the remaining 100 (36.1%) patients with unsuccessful outcomes, 60 (21.7%) died, 32 (11.5%) were LTFU, and 8 (2.9%) had failed treatment. The proportion of male patients was relatively higher (55.2%), within the age group of 21–40 years (47.3%) and lived in rural areas (66.8%). The multivariate analysis revealed that unsuccessful outcomes had a statistically significant association with being male (adjusted odds ratio, AOR: 1.92, 95% confidence interval (CI): 1.10–3.36), being in an age group above 60 years (AOR: 3.34, 95% CI: 1.09–10.1), suffering from any comorbidity (AOR: 2.69, 95% CI: 1.35–5.38), and the history of use of second-line drugs (AOR; 3.51, 95% CI 1.35–9.12). In conclusion, treatment outcomes among DR TB patients at the study site were poor and did not achieve the treatment success target (≥75%) set by the World Health Organization.

Stigma and Discrimination in Treatment of Patients with HIV Co-Infection - Tuberculosis in the Osh Region of Kyrgyz Republic

Despite the downward trend in the incidence rate, the situation in Kyrgyzstan is complicated by the spread of drug-resistant tuberculosis and tuberculosis (TB) combined with human immunodeficiency virus (HIV) infection. Stigma and discrimination are among the strongest negative factors affecting the lives of people affected by tuberculosis, leading to many patients not seeing doctors or dropping out of treatment. This article is devoted to an important issue, the study of the manifestation of stigma and discrimination in patients with HIV - infection combined with tuberculosis, which leads to a delay in diagnosis, early initiation of treatment, an increase in the reservoir of the source of tuberculosis infection, including drug-resistant tuberculosis among population. The publication contains a thorough and detailed analysis of the complex of social and medico-biological actions necessary to prevent the spread of HIV infection and tuberculosis. Keywords: Treatment, HIV, Stigma and Discrimination, Co-Infection, Tuberculosis

Drug resistance in pulmonary tuberculosis patients in Jiamusi, Heilongjiang, 2017–2020

Objective To understand the prevalence of drug resistance in pulmonary tuberculosis (TB) patients in Jiamusi, Heilongjiang province, and provide reliable references for the prevention and control of TB. Methods Mycobacterium tuberculosis strains isolated from 575 TB cases collected by Jiamusi Tuberculosis Reference Laboratory from 2017 to 2020 were included in the study. Proportion method was used for the drug susceptibility test of the strains to isoniazid, rifampicin, ethambutol, streptomycin, ofloxacin and kanamycin. Results The overall drug resistance rate was 35.29% (198/561). The drug resistance rate of the strains from the previously untreated patients was 32.35% (143/442), and the drug resistance rate of the strains from the retreated patients was 46.22% (55/119). There was significant difference between the two groups in drug resistance rate ( χ2=7.893, P=0.005). The overall multi-drug resistance rate was 10.16% (57/561). The multi-drug resistance rate of the strains from the previously untreated patients was 7.92% (35/442), and the multi-drug resistance rate of the strains from the retreated patients was 18.49% (22/119). There was significant difference between the two groups in multi-drug resistance rate ( χ2=11.473, P=0.01).The drug resistance rates of the M. tuberculosis strains to 6 anti TB drugs were 22.82% (128/561) to streptomycin , 19.25% (108/561) to isoniazid, 15.69% (88/561) to rifampicin , 6.77% (38/561) to ofloxacin, 6.6% (37/561) to ethambutol and 2.14% (12/561) to kanamycin. Conclusion The drug resistance in pulmonary TB patients in Jiamusi was relatively serious, and the proportion of rifampicin resistant TB patients was relatively high. It is suggested that early detection and standardized treatment of TB patients with drug resistance should be strengthened to control the spread of drug resistant TB.

Identification of a predominant genotype of Mycobacterium tuberculosis in Brazilian indigenous population

After nearly a century of vaccination and six decades of drug therapy, tuberculosis (TB) kills more people annually than any other infectious disease. Substantial challenges to disease eradication remain among vulnerable and underserved populations. The Guarani-Kaiowá people are an indigenous population in Paraguay and the Brazilian state of Mato Grosso do Sul. This community, marginalized in Brazilian society, experiences severe poverty. Like other South American indigenous populations, their TB prevalence is high, but the disease has remained largely unstudied in their communities. Herein, Mycobacterium tuberculosis isolates from local clinics were whole genome sequenced, and a population genetic framework was generated. Phylogenetics show M. tuberculosis isolates in the Guarani-Kaiowá people cluster away from selected reference strains, suggesting divergence. Most cluster in a single group, further characterized as M. tuberculosis sublineage 4.3.3. Closer analysis of SNPs showed numerous variants across the genome, including in drug resistance-associated genes, and with many unique changes fixed in each group. We report that local M. tuberculosis strains have acquired unique polymorphisms in the Guarani-Kaiowá people, and drug resistance characterization is urgently needed to inform public health to ensure proper care and avoid further evolution and spread of drug-resistant TB.

Use of the Invertebrate &lt;em&gt;Galleria mellonella&lt;/em&gt; as an Infection Model to Study the &lt;em&gt;Mycobacterium tuberculosis&lt;/em&gt; Complex

Tuberculosis is the leading global cause of infectious disease mortality and roughly a quarter of the world's population is believed to be infected with Mycobacterium tuberculosis. Despite decades of research, many of the mechanisms behind the success of M. tuberculosis as a pathogenic organism remain to be investigated, and the development of safer, more effective antimycobacterial drugs are urgently needed to tackle the rise and spread of drug resistant tuberculosis. However, the progression of tuberculosis research is bottlenecked by traditional mammalian infection models that are expensive, time consuming, and ethically challenging. Previously we established the larvae of the insect Galleria mellonella (greater wax moth) as a novel, reproducible, low cost, high-throughput and ethically acceptable infection model for members of the M. tuberculosis complex. Here we describe the maintenance, preparation, and infection of G. mellonella with bioluminescent Mycobacterium bovis BCG lux. Using this infection model, mycobacterial dose dependent virulence can be observed, and a rapid readout of in vivo mycobacterial burden using bioluminescence measurements is easily achievable and reproducible. Although limitations exist, such as the lack of a fully annotated genome for transcriptomic analysis, ontological analysis against genetically similar insects can be carried out. As a low cost, rapid, and ethically acceptable model for tuberculosis, G. mellonella can be used as a pre-screen to determine drug efficacy and toxicity, and to determine comparative mycobacterial virulence prior to the use of conventional mammalian models. The use of the G. mellonella-mycobacteria model will lead to a reduction in the substantial number of animals currently used in tuberculosis research.

Detection of resistance to anti-tuberculosis drugs in the clinical isolates of Mycobacterium tuberculosis from Slovakia through comparison between phenotypic and genetic methods and evaluation of resistance levels with clinical parameter.

The incidence of tuberculosis (TB) in some countries increases continuously, especially caused by mycobacterial strains resistant to various anti-tuberculotic drugs (AT). The emergence and spread of drug-resistant tuberculosis (multidrug-resistant - MDR-TB, and extensively drug-resistant - XDR-TB) suggest the crucial role of pharmacotherapy protocol tailored to the respective patient with MDR-TB or XDR-TB (a personalized approach) and requirements for fast and precise diagnostics of the degree of resistance. The aim of this study was to characterize a molecular basis of resistance to AT, and to identify the presence of the resistance using conventional susceptibility testing and molecular genetic methods using PCR tests in Slovakia during years 2009 - 2017. Furthermore, we focused on evaluation of the relationship between the level of resistance, the clinical status, and some laboratory markers of patients with drug-resistant TB. Totally 1157 strains isolated from patients in 2009 - 2017 were tested for resistance using classical methods and in resistant strains, the molecular-genetic tests were performed. Increased incidence of recurrence, prolonged time required to culture conversion, increased mortality during treatment, plasma C-reactive protein concentrations and sedimentation rate, broader spectrum of AT used, as well as higher incidence of adverse effects (sufficiently controlled with symptomatic treatment) were observed with higher degree of resistance. Contrary, the number of patients who achieved remission decreased. Rapid and precise identification of MDR-TB or XDR-TB strains using both classical and molecular-genetic testing is an essential tool for personalized drug treatment and prevention of resistance spread and worsening. Both tests should be used for correct diagnosis of resistant TB. Higher level of resistance required more aggressive therapeutic approach, associated with adverse effects and prolongation of the culture conversion time, as well as increased risk of relapse. Effective pharmacotherapy led to significant decrease of CRP levels in all groups of patients. The most frequent adverse effects of ATs - impairment of liver and kidney functions - were effectively managed by symptomatic treatment.

Management of multidrug-resistant tuberculosis in the 21st century.

The spread of drug-resistant tuberculosis (TB) continues to be a global health crisis with increasing cases of multidrug-resistant TB (MDR-TB) being diagnosed worldwide. The identification and clinical management of MDR-TB is associated with additional problems related to resistance, diagnosis and treatment as compared to drug-susceptible TB. Treatment of MDR-TB usually involves therapy with long regimens of second-line drugs up to 24 months resulting in higher risks of serious adverse effects, lack of compliance and heightened economic burden on the patients. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and lengthy, toxic treatments need to be overcome by innovative approaches such as quick diagnostic tools and shorter drug regimens as already recommended by the World Health Organization (WHO) in its 2018 Global Tuberculosis Report. This review highlights the challenges being faced by clinicians worldwide in the diagnosis and treatment of MDR-TB.

MULTIDRUG RESISTANT MYCOBACTERIUM TUBERCULOSIS IN ADAMAWA STATE, NIGERIA.

Background:There is a need to have regular updates from regions where high burden of tuberculosis (TB) have been reported in order to assist the local and global bodies in their objective to curtail the spread of drug resistant TB (DRTB). This study presents a situation report of DRTB in Adamawa State which has been identified as one of the States with high burden of TB in Nigeria.Materials and Methods:Sputum culture in Lowenstein-Jensen Media, drug sensitivity tests and the GeneXpert MTB/Rif analysis were used in the identification and drug susceptibility studies of M. tuberculosis isolates obtained from forty TB patients who were enrolled from three selected hospitals with DOTS facilities in the State.Results:The age of TB patients range from 17 to 70 years (median = 30 years). Twenty (50 %) M. tuberculosis isolates were detected by the GeneXpertMTB/Rif analysis while the media culture detected 31 (77.5%). The two methods however detected rifampicin resistance in 4 (10%) of the total isolates. All rifampicin resistant isolates were multidrug resistant TB (MDRTB) and three of them were from male patients aged 30, 38 and 45. There was only one case of resistance to streptomycin, 3 to ethambutol and 6 to isoniazid. Monoresistance were only observed for ethambutol and isoniazid and it was found in two isolates for each.Conclusion:There is a need to provide interventions to control MDRTB in the state and to make such interventions available and closer to the patients.

Tuberculosis in the Russian Federation: Situation, Challenges and Perspectives

Tuberculosis (TB) is a significant problem of public health both in Russia and abroad. About one third of the world’s population is infected with Mycobacterium tuberculosis. Every year more than 10 million new TB cases are registered in the world, and about 1.7 million people die from TB. In the Russian Federation, due to the measures taken by the Government and health authorities the epidemic TB situation has been noticeably improved since the sharp deterioration in the 90s of the last century. At the same time, the spread of drug-resistant TB and its low treatment effectiveness, the spread of combined HIV and TB infection reduces the effectiveness of anti-tuberculosis interventions. The research conducted by CTRI, the WHO Collaborating Center for TB in the Russian Federation, is aimed at solving such urgent problems as studying latent infection mechanisms, developing new test systems for accelerated diagnostics of drug resistance, clinical approbation and introduction of short effective regimens of chemotherapy, developing new antituberculosis agents. The achieved successes in the study of tuberculosis in the 21st century creates preconditions for eliminating its epidemic both in Russia and the world, though suggesting imminent breakthrough for tuberculosis is a hasty conclusion.

Expanding Benzoxazole-Based Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure-Activity As Potential Antituberculosis Agents.

New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis ( Mtb) inosine 5'-monophosphate dehydrogenase 2 ( MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure-activity relationship (SAR) for the benzoxazole series of MtbIMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ≤1 μM can be achieved. The antibacterial activity of the most promising compound, 17b (Q151), is derived from the inhibition of MtbIMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of 17b, alleviating the concern that guanine salvage can protect Mtb in vivo. These findings suggest that MtbIMPDH2 is a vulnerable target for tuberculosis.

Significance of Coexisting Mutations on Determination of the Degree of Isoniazid Resistance inMycobacterium tuberculosisStrains

The emergence and spread of drug-resistant tuberculosis (TB) pose a threat to TB control in Sri Lanka. Isoniazid (INH) is a key element of the first-line anti-TB treatment regimen. Resistance to INH is mainly associated with point mutations in katG, inhA, and ahpC genes. The objective of this study was to determine mutations of these three genes in INH-resistant Mycobacterium tuberculosis (MTb) strains in Sri Lanka. Complete nucleotide sequence of the three genes was amplified by polymerase chain reaction and subjected to DNA sequencing. Point mutations in the katG gene were identified in 93% isolates, of which the majority (78.6%) were at codon 315. Mutations at codons 212 and 293 of the katG gene have not been reported previously. Novel mutations were recognized in the promoter region of the inhA gene (C deletion at -34), fabG1 gene (codon 27), and ahpC gene (codon 39). Single S315T mutation in the katG gene led to a high level of resistance, while a low level of resistance with high frequency (41%) was observed when katG codon 315 coexisted with the mutation at codon 463. Since most of the observed mutations of all three genes coexisted with the katG315 mutation, screening of katG315 mutations will be a useful marker for molecular detection of INH resistance of MTb in Sri Lanka.

The occurrence and frequency of genomic mutations that mediate Isoniazid and Rifampicin resistance in Mycobacterium tuberculosis isolates from untreated pulmonary Tuberculosis cases in urban Blantyre, Malawi.

The emergence and spread of drug-resistant Tuberculosis (TB) is a major public health threat. TB resistance originates in the course of treatment due to genomic mutations in Mycobacterium tuberculosis (MTB). An increase in new cases with drug-resistant TB could be an indicator of high levels of circulating resistant strains. This study was conducted to determine the occurrence and frequency of genomic mutations that mediate Isoniazid (INH) and Rifampicin (RIF) resistance among isolates from untreated TB cases in urban Blantyre, Malawi. A cross-sectional retrospective study was conducted on a panel of 141(n=141) MTB clinical isolates recovered between June 2010 and January 2012 from >2+ Ziehl-Neelsen smear positive new pulmonary-TB patients with no history of treatment. Frozen isolates were revived using the BACTEC MGIT detection system. DNA was extracted using GenoLyse DNA extraction kit and detection of genomic mutations was carried out using the GenoType MTBDRplus Ver 2.0 assay. Out of the 141 isolates studied, 3 (2.1%) were found carrying mutations in the katG gene that confer resistance to Isoniazid (INH). No mutations were detected in the inhA promoter region gene that confer weak INH resistance or in the rpoB gene that confer Rifampicin resistance. All katG mutant genes had a S315T1 single point mutation, a genomic alteration that mediates high INH resistance. The katG mutant gene conferring resistance to INH was the only genomic mutation observed among the isolates studied and the frequency of occurrence was low. Our findings suggest low levels of circulating drug-resistant MTB strains in urban Blantyre, Malawi.

The war on tuberculosis must continue

“Practices for the management of individual patients in settings with a high tuberculosis burden are not sufficient to prevent the emergence, amplification, and spread of drug-resistant tuberculosis” is one of the key messages from our latest Commission published in this issue, led by Keertan Dheda from the University of Cape Town. The Commission focuses on multidrug-resistant, extensively drug-resistant, and incurable tuberculosis, and highlights the growing burden of disease, its implications for patient management, as well as social and legal aspects. The authors also provide practical solutions for tackling emerging resistant cases—an exponentially increasing concern in high-burden countries. When going to press with this Commission, its timeliness was highlighted by the WHO announcement on Feb 27, 2017, of its list of bacteria for which new antibiotics are urgently needed; a list that tuberculosis did not make. This has prompted José Luis Castro, Executive Director of The Union, to send a letter of protest to Margaret Chan at WHO saying that the exclusion of tuberculosis is “completely unjustified” and suggests a deprioritisation of tuberculosis research. We hope that the Commission will remind key stakeholders to keep this devastating disease at the forefront of research and development. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosisGlobal tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). Full-Text PDF

Frequency of mutations in rifampicin and isoniazid resistant isolates of M. tuberculosis: an analysis from Central India.

The spread of drug-resistant tuberculosis has challenged tuberculosis control strategies globally. The present study aims to analyze the frequency of mutations in rpoB, katG and inhA genes in strains of M. tuberculosis complex (MTBC) circulating in Central India. It is anticipated that the findings may provide a starting point to understand the evolutionary success of drug-resistant strains of MTBC in this region. Line probe assay was carried out on 720 consecutive sputum samples of MDR suspects from June 2012 to May 2013. Mutation frequencies in the rpoB, katG and inhA genes were analyzed. Mutations were identified in 269 (37.6%) samples, as follows: 55 (7.6%) samples had mutations conferring resistance to only isoniazid, 84 (11.6%) had mutations conferring resistance to only rifampicin and 130 (18%) isolates had mutations conferring resistance to both isoniazid and rifampicin. The most frequent mutation in the rpoB gene was at codon S531L, seen in 141 (19.5%) isolates. The most frequent mutation in the katG gene was at codon S315T1, seen in 151 (20.9%) isolates; and in the inhA gene at codon C15T, seen in 21 (2.9%) isolates. Some unidentified mutations were also observed. The patterns and the frequency of the mutations identified in this study indicate the most frequent mutations at S531L codon in the rpoB gene, S315T1 codon in the katG gene and C15T codon in the promoter region of the inhA gene. Controlling the emergence and spread of MDR TB requires an understanding of the evolution of these mutations.

First-Line Anti-Tubercular Drug Resistance of Mycobacterium tuberculosis in IRAN: A Systematic Review.

Background: The spread of drug-resistant tuberculosis (TB) is one of the major public health problems through the world. Surveillance of anti-TB drug resistance is essential for monitoring of TB control strategies. The occurrence of drug resistance, particularly multi-drug resistance Mycobacterium tuberculosis (MDR), defined as resistance to at least rifampicin (RIF) and isoniazid (INH), has become a significant public health dilemma. The status of drug-resistance TB in Iran, one of the eastern Mediterranean countries locating between Azerbaijan and Armenia and high-TB burden countries (such as Afghanistan and Pakistan) has been reported inconsistently. Therefore, the aim of this study was to summarize reports of first-line anti-tubercular drug resistance in M. tuberculosis in Iran.Material and Methods: We systematically reviewed published studies on drug-resistant M. tuberculosis in Iran. The search terms were “Mycobacterium tuberculosis susceptibility” or “Mycobacterium tuberculosis resistant” and Iran.Results: Fifty-two eligible articles, published during 1998–2014, were included in this review. Most of the studies were conducted in Tehran. The most common used laboratory method for detecting M. tuberculosis drug resistant was Agar proportion. The highest resistance to first-line drugs was seen in Tehran, the capital city of Iran. The average prevalence of isoniazid (INH), rifampin (RIF), streptomycin (SM), and ethambotol (EMB) resistance via Agar proportion method in Tehran was 26, 23, 22.5, and 16%, respectively. In general, resistance to INH was more common than RIF, SM, and EMB in TehranConclusions: In conclusion, this systematic review summarized the prevalence and distribution of first-line anti-tubercular drug resistance of M. tuberculosis in Iran. Our results suggested that effective strategies to minimize the acquired drug resistance, to control the transmission of resistance and improve the diagnosis measures for TB control in Iran.

Epidemiological Trends of Drug-Resistant Tuberculosis in China From 2007 to 2014: A Retrospective Study.

The emergence and spread of drug-resistant tuberculosis (DR-TB) has become the major concern in global TB control nowadays due to its limited therapy options and high mortality. A comprehensive evaluation for the epidemiological trends of DR-TB in mainland China, of which TB incidences remain high, is essential but lacking. This study aimed to describe the trends of DR-TB overtime, especially multidrug-resistant TB (MDR-TB); and to identify unique characteristics of MDR-TB cases compared with drug-susceptible TB cases in Mainland China.We retrospectively analyzed surveillance data collected from 36 TB prevention and control institutions in Shandong Province, China over an 8-year period. Unique characteristics of MDR-TB were identified; Chi-square test for trends and linear regression were used to assess the changes in proportions of different resistance patterns overtime.The overall MDR rate was 6.2% in our sample population. There were no statistically significant changes in the percentage of drug-susceptible, isoniazid (INH) resistance, ethambutol (EMB) resistance, streptomycin (SM) resistance, and MDR TB during our study period except that the overall rifampin (RFP) resistance and rifampin monoresistance (RMR) increased at a yearly rate of 0.2% and 0.1%, respectively. Among those with known treatment histories, a higher MDR rate of 8.7% was observed, in which 53.9% were primary MDR-TB patients, and this rate was increasing at a yearly rate of 4.1% over our study period. MDR-TB patients were more likely to be female (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.05–1.34), aged 25 to 44 years (OR, 1.67; 95%CI, 1.45–1.93), retreated (OR, 11.95; 95%CI, 9.68–14.76), having prior TB contact (OR, 1.89; 95%CI, 1.19–2.78) and having cavity (OR, 1.57; 95%CI 1.36–1.81), or bilateral disease (OR, 1.45; 95%CI 1.19–1.76) on chest radiology.Persistent high levels of MDR-TB, increasing rates of primary MDR-TB and RMR characterize DR-TB cases in mainland China; community-acquired drug resistance may be one of the most modifiable factors in future TB control strategies.

Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance.

BackgroundCombating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance.MethodsTo investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods.ResultsThe analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites.ConclusionsUsing the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance mutations to improve the design of tuberculosis control measures, such as diagnostics, and inform patient management.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0575-9) contains supplementary material, which is available to authorized users.