anti-TB Drug Resistance Research Articles

Diagnostic accuracy of the Xpert® MTB/XDR assay for detection of Isoniazid and second-line antituberculosis drugs resistance at central TB reference laboratory in Tanzania

IntroductionEarly diagnosis of tuberculosis (TB) and universal access to drug-susceptibility testing (DST) are critical elements of the WHO End TB Strategy. Current rapid tests (e.g., Xpert® MTB/RIF and Ultra-assays) can detect rifampicin resistance-conferring mutations, but cannot detect resistance to Isoniazid and second-line anti-TB agents. Although Line Probe Assay is capable of detecting resistance to second-line anti-TB agents, it requires sophisticated laboratory infrastructure and advanced skills which are often not readily available in settings replete with TB. A rapid test capable of detecting Isoniazid and second-line anti-TB drug resistance is highly needed.MethodsWe conducted a diagnostic accuracy study to evaluate a new automated Xpert MTB/XDR 10-colour assay for rapid detection of Isoniazid and second-line drugs, including ethionamide, fluoroquinolones, and injectable drugs (Amikacin, Kanamycin, and Capreomycin). Positive Xpert MTB/RIF respiratory specimens were prospectively collected through routine diagnosis and surveillance of drug resistance at the Central TB Reference Laboratory in Tanzania. Specimens were tested by both Xpert XDR assay and LPA against culture-based phenotypic DST as the reference standard.FindingsWe analysed specimens from 151 TB patients with a mean age (SD) of 36.2 (12.7) years. The majority (n = 109, 72.2%) were males. The sensitivity for Xpert MTB/XDR was 93.5% (95% CI, 87.4–96.7); for Isoniazid, 96.6 (95% CI, 92.1–98.6); for Fluoroquinolone, 98.7% (95% Cl 94.8–99.7); for Amikacin, 96.6%; and (95% CI 92.1–98.6) for Ethionamide. Ethionamide had the lowest specificity of 50% and the highest was 100% for Fluoroquinolone. The diagnostic performance was generally comparable to that of LPA with slight variations between the two assays. The non-determinate rate (i.e., invalid M. tuberculosis complex detection) of Xpert MTB/XDR was 2·96%.ConclusionThe Xpert MTB/XDR demonstrated high sensitivity and specificity for detecting resistance to Isoniazid, Fluoroquinolones, and injectable agents. This assay can be used in clinical settings to facilitate rapid diagnosis of mono-isoniazid and extensively drug-resistant TB.

A 10-year review of isoniazid-resistant TB management in Uzbekistan 2009-2020.

Isoniazid (INH, H) resistance is the most common drug-resistant TB pattern, with treatment success rates lower than those in drug-susceptible TB. The WHO recommends a 6-month regimen of rifampicin (RIF, R), ethambutol (EMB, E), pyrazinamide (PZA, Z), and levofloxacin (Lfx) (6REZLfx) for INH-resistant, RIF-susceptible TB (HRRS-TB). Uzbekistan has a high burden of TB (62/100,000 population) and multidrug-resistant TB (12/100,000 population). We conducted a retrospective, descriptive study of microbiologically confirmed HRRS-TB using routinely collected programmatic data from 2009 to 2020. We included 854 HRRS-TB cases. Treatment success was 80.2% overall. For REZLfx, the treatment success rate was 92.0% over a short treatment duration, with no amplifications to RIF or second-line anti-TB drug resistance. We documented 46 regimens with REZLfx plus linezolid (success 87.0%) and 539 regimens using kanamycin or capreomycin (success 76.6%). We identified 37 treatment failures (4.3%), 30 deaths (3.5%), 25 resistance amplifications (2.9%), including eight to RIF (0.9%), and 99 lost to follow-up (LTFU) cases (11.6%). Unsuccessful outcomes were more common with older age, diabetes, chest X-ray cavities, smear positivity, smear-positive persistence, and male sex. LTFU was more common with injection-containing regimens. REZLfx is a safe and effective first-line treatment for INH-resistant, RIF-susceptible TB. Treatment success was lower and LTFU was higher for injection-containing regimens.

Rapid resistance detection is reliable for prompt adaptation of isoniazid resistant tuberculosis management

ObjectivesAppropriate tuberculosis (TB) management requires anti-TB drugs resistance detection. We assessed the performance of rapid resistance detection assays and their impact on treatment adaptation, focusing on isoniazid resistant (Hr) TB. MethodsFrom 2016 to 2022, all TB cases enrolled in 3 hospitals were reviewed for phenotypic drug susceptibility testing (p-DST) and genotypic DST (g-DST) performed by rapid molecular testing, and next generation sequencing (NGS). Clinical characteristics, treatment and outcome were collected for Hr-TB patients. The concordance between g-DST and p-DST results, and delay between treatment initiation and results of g-DST and p-DST were respectively recorded to assess the contribution of DST results on Hr-TB management. ResultsAmong 654 TB cases enrolled, 29 were Hr-TB. Concordance between g-DST by rapid molecular methods and p-DST was 76.9 %, whilst concordance between NGS-based g-DST and p-DST was 98.7 %. Rapid resistance detection significantly fastened Hr-TB treatment adaptation (median delay between g-DST results and treatment modification was 6 days). It consisted in fluoroquinolone implementation for 17/23 patients; outcome was favourable except for 2 patients who died before DST reporting. ConclusionRapid resistance detection fastened treatment adaptation. Also, NGS-based g-DST showed almost perfect concordance with p-DST, thus providing rapid and safe culture-free DST alternative.

Study protocol for safety and efficacy of all-oral shortened regimens for multidrug-resistant tuberculosis: a multicenter randomized withdrawal trial and a single-arm trial [SEAL-MDR

IntroductionThe urgent need for new treatments for multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is evident. However, the classic randomized controlled trial (RCT) approach faces ethical and practical constraints, making alternative research designs and treatment strategies necessary, such as single-arm trials and host-directed therapies (HDTs).MethodsOur study adopts a randomized withdrawal trial design for MDR-TB to maximize resource allocation and better mimic real-world conditions. Patients’ treatment regimens are initially based on drug resistance profiles and patient’s preference, and later, treatment-responsive cases are randomized to different treatment durations. Alongside, a single-arm trial is being conducted to evaluate the potential of sulfasalazine (SASP) as an HDT for pre-XDR-TB, as well as another short-course regimen without HDT for pre-XDR-TB. Both approaches account for the limitations in second-line anti-TB drug resistance testing in various regions.DiscussionAlthough our study designs may lack the internal validity commonly associated with RCTs, they offer advantages in external validity, feasibility, and ethical appropriateness. These designs align with real-world clinical settings and also open doors for exploring alternative treatments like SASP for tackling drug-resistant TB forms. Ultimately, our research aims to strike a balance between scientific rigor and practical utility, offering valuable insights into treating MDR-TB and pre-XDR-TB in a challenging global health landscape. In summary, our study employs innovative trial designs and treatment strategies to address the complexities of treating drug-resistant TB, fulfilling a critical gap between ideal clinical trials and the reality of constrained resources and ethical considerations.Trail registrationChictr.org.cn, ChiCTR2100045930. Registered on April 29, 2021.

Social and biological factors associated with unsuccessful TB treatment outcome in Ireland 2011-2021

Abstract Background Tuberculosis (TB) treatment success rates are crucial for TB control programme evaluations. The World Health Organisation sets targets of > 90% but Ireland remains below 70%. We analysed notifications from the Irish National TB Surveillance System from 2011-2021 to explore factors associated with successful treatment outcome in Ireland. Methods We selected potential predictor variables based on clinical relevance and literature review. We examined each predictor's unadjusted association with treatment success using univariable logistic regression. We used backwards elimination to remove predictors that failed to remain significant in multivariable logistic regression. Treatment success was defined as treatment completed or cured, while unsuccessful treatment was defined as treatment failed, treatment interrupted, transferred out and died from any cause. We used Stata for analysis. Results Between 2011-2021, 52% of cases were successfully treated, 10.7% were unsuccessfully treated and treatment outcome was not reported for 37%. Treatment outcome completeness declined significantly between 2019-2021. Univariable analysis showed successfully treated cases had higher odds of being a migrant (OR:1.9; 1.5-2.5), being linked to outbreaks (OR:1.9; 1.2-3.0), being a contact of a case (OR: 1.0-2.5;), having a normal X-ray (OR:1.7;1.1-2.6) and being an outpatient (OR:3.0;2.2-4.2). Significant predictors of unsuccessful treatment in the final model were age >70 years, unemployment, immunesuppression and any anti-TB drug resistance. Conclusions Surveillance data shows that Ireland fails to meet the WHO target of > 90% treatment success with high levels of missing data. Data quality improvement initiatives are needed to reverse the decline in completeness associated with the Covid-19 pandemic period so control programmes can robustly evaluate performance. Additional supports should be considered for patients who are older, unemployed, immunesuppressed or with drug resistant TB. Key messages • Additional patient supports should be considered for patients who are unemployed, age 70 years and older, immunesuppressed or with drug resistant forms of TB. • Ireland fails to meet the WHO TB treatment success target with high levels of missing data. Treatment outcome completeness needs to be improved so control programmes can robustly evaluate performance.

Comparison of Sputum Evaluation Conversion of Pulmonary TB patients with DM and non-DM in High Burden Setting

ABSTRACT
 Background
 Tuberculosis (TB) remains a global health problem and is one of the leading causes of death worldwide. By 2022, an estimated 10 million people will suffer from TB worldwide. Based on data from the Global Tuberculosis Report in 2022, Indonesia ranks second as a high-burden country in the world after India. An estimated 1.5 million people die from tuberculosis, becoming the 13th leading cause of death worldwide and the second most deadly infectious disease after COVID-19.
 Currently, many new cases of TB are influenced by several risk factors, one of which is Diabetes Mellitus (DM). Pulmonary TB is a potential opportunistic infection for people with Diabetes Mellitus. TB patients with DM are at risk of sputum conversion failure after TB treatment, 1.69 times higher risk of treatment failure, 1.24 times higher risk of anti-TB drug resistance, 3.89 times higher risk of relapse, and 4.95 times higher risk of death during treatment compared to TB patients.
 Aim of Study
 To evaluate the sputum smear conversion results at the end of the second month of treatment of patients with Tuberculosis with Diabetes Mellitus (TB-DM) and Tuberculosis Non-Diabetes Mellitus (TB-NDM).
 Methods
 This research was analytical with a retrospective cohort design by taking secondary data from the Tuberculosis Information System (SITB). The data were recorded in SITB and registered as TB patients undergoing Anti-Tuberculosis Drug treatment and screening for Diabetes Mellitus in all districts in West Nusa Tenggara Province in 2022.
 Results
 Among 200 patients with TB in this study, male patients dominated 62% of TB patients. TB patients are mostly found in the age group 46-55 years with 28,5%. Generally, TB patients come from Mataram, with an 18% percentage. Most TB patients were diagnosed using GeneXpert (80,5%). The sputum conversion rate at the end intensive phase in TB-DM patients reached 95%, while in TB-NDM patients, only 85%. The comparative test showed a significant difference between the AFB Sputum Evaluation conversion results between TB patients and those without DM (p-value: 0.018, p<0.05).
 Conclusion 
 There is a significant difference between the AFB Sputum Evaluation conversion results between TB patients and those without DM.
 
 Keywords : Diabetes, diabetes mellitus, sputum conversion, tuberculosis, TB, DM

Whole-Genome Sequencing to Predict Mycobacterium tuberculosis Drug Resistance: A Retrospective Observational Study in Eastern China.

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB). Whole-genome sequencing (WGS) holds great promise as an advanced technology for accurately predicting anti-TB drug resistance. The development of a reliable method for detecting drug resistance is crucial in order to standardize anti-TB treatments, enhance patient prognosis, and effectively reduce the risk of transmission. In this study, our primary objective was to explore and determine the potential of WGS for assessing drug resistance based on genetic variants recommended by the World Health Organization (WHO). A total of 1105 MTB strains were selected from samples collected from 2014-2018 in Zhejiang Province, China. Phenotypic drug sensitivity tests (DST) of the anti-TB drugs were conducted for isoniazid (INH), rifampicin (RFP), streptomycin, ethambutol, fluoroquinolones (levofloxacin and moxifloxacin), amikacin, kanamycin, and capreomycin, and the drug-resistance rates were calculated. The clean WGS data of the 1105 strains were acquired and analyzed. The predictive performance of WGS was evaluated by the comparison between genotypic and phenotypic DST results. For all anti-TB drugs, WGS achieved good specificity values (>90%). The sensitivity values for INH and RFP were 91.78% and 82.26%, respectively; however, they were ≤60% for other drugs. The positive predictive values for anti-TB drugs were >80%, except for ethambutol and moxifloxacin, and the negative predictive values were >90% for all drugs. In light of the findings from our study, we draw the conclusion that WGS is a valuable tool for identifying genome-wide variants. Leveraging the genetic variants recommended by the WHO, WGS proves to be effective in detecting resistance to RFP and INH, enabling the identification of multi-drug resistant TB patients. However, it is evident that the genetic variants recommended for predicting resistance to other anti-TB drugs require further optimization and improvement.

DRUG-RESISTANCE AND COMPENSATORY MUTATIONS IN MYCOBACTERIUM TUBERCULOSIS

Gram-positive bacteria of Mycobacterium tuberculosis complex (MTBC) are causative agents of tuberculosis disease. According to the report of the World Health Organization, tuberculosis is one of the leading causes of mortality worldwide. Moreover, epidemiological data shows that due to the COVID-19 pandemic tuberculosis mortality has risen in comparison with previous years. Drug resistance is another threatening issue when the resistance to antitubercular (anti-TB) drugs makes therapy less effective. Furthermore, drug resistance is often burdened with compensatory mechanisms that overcome fitness defects related to drug-resistant mutations. This review discusses the drug resistance and compensatory mutations in Mycobacterium tuberculosis and the current situation with anti-TB drug resistance in the Republic of Kazakhstan.

Expert Review on Contemporary Management of Common Benign Pleural Effusions.

Heart failure (HF) and cirrhosis are frequently associated with pleural effusions (PEs). Despite their apparently benign nature, both HF-related effusions and hepatic hydrothorax (HH) have poor prognosis because they represent an advanced stage of the disease. Optimization of medical therapy in these two entities involve not only the use of diuretics, but also other pharmacological therapies. For instance, all HF patients with reduced or mildly reduced left ventricular ejection fraction can benefit from angiotensin receptor-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors. Conversely, it is better for HH patients to avoid nonselective beta blockers. Refractory cardiac- and cirrhosis-related PEs are commonly managed by iterative therapeutic thoracentesis. When repeated aspirations are needed, thereby diminishing quality of life, the insertion of an indwelling pleural catheter (IPC) may be warranted. However, in selected HH patients who are diuretic-resistant or diuretic-intractable, placement of transjugular intrahepatic portosystemic shunts should be considered as a bridge to liver transplantation, whereas in transplant candidates the role of IPC is debatable. Another benign condition, pleural tuberculosis (TB) is a serious health problem in developing countries. Diagnostic certainty is still a concern due to the paucibacillary nature of the infection, although the use of more sensitive nucleic acid amplification tests is becoming more widespread. Its treatment is the same as that of pulmonary TB, but the potential drug interactions between antiretroviral and anti-TB drugs in HIV-coinfected patients as well as the current recommended guidelines for the different types of anti-TB drugs resistance should be followed.

DETECTION AND CHARACTERIZATION OF MUTATIONS IN GENES RELATED TO SECOND-LINE ANTI-TUBERCULOSIS DRUGS RESISTANCE IN MDR TB

Introduction: Drug-resistant tuberculosis is a major global health issue. Multidrug-resistant TB (MDRTB) and extensively drug-resistant TB (XDR-TB) are particularly concerning. Conventional phenotypic methods being cumbersome and time consuming, molecular assays for the detection of mutations that are associated with resistance to anti-TB drugs have emerged as an important tool for rapid diagnosis. Aims and Objectives: To determine and characterize mutations associated with resistance to second line anti-TB drugs in MDR TB. Methods: First line LPA Conrmed MDR TB and/ or mono rifampicin or mono isoniazid resistant cases were subjected to second line LPA (MTBDRsl ver 2.0 kit)) and banding patterns of resistant cases were obtained. These were then subjected to extended phenotypic DST (Gold Standard) using MGIT 960 for Moxioxacin – 1.0µg/ml, Kanamycin -2.5µg/ml, Capreomycin -2.5µg/ml. Results: The study analysed 1580 samples subjected to SL LPA and found that 37.65% were sensitive to both FQ and SLID. FQ resistance accounted for 60.56% and SLID resistance for 17.02%. Resistance to both seen in 15.15% samples. The most common mutation associated with FQ resistance was gyr A gene at codon D94G, for SLID resistance it was in rrs gene (A1401G) and eis gene (C-12T,G-10A). Conclusion: It was observed that there is a high prevalence (62.34%) of second-line anti-TB drug resistance and mutations in gyrA, gyrB (for FQ), rrs ( for SLID) and eis promoter regions (for low level kanamycin) were signicantly associated with secondline anti-TB drug resistance.

Prevalence of Multidrug-Resistant Tuberculosis (MDR-TB) in India: A Mini Systematic Review and Meta-Analysis (2016–2022)

ABSTRACT India carries the highest global burden of tuberculosis and multidrug-resistant tuberculosis (MDR-TB) (26%). There remains an uncertainty around the population-based estimates of MDR-TB in India. Applying a systematic review approach, we searched PubMed and Scopus to identify studies reporting the prevalence of MDR-TB among new and/or previously treated patients (cases) at any site in India and published during 2016–2022. Of 341 retrieved articles, we could select only 10 and excluded many as they were either unrelated or had limitations. From the meta-analysis of available studies, we found the pooled prevalence of MDR-TB among new cases as 3.9% (95% (CI 2.2–6.1) and as 13.4% (95% CI 8.8–18.7) among previously treated cases. Overall, it was 6.7% (95% CI 4.2–9.6). Albeit with a wider confidence intervals, the prevalence figures calculated from the present study are comparable to those reported by the National Anti-TB Drug Resistance Survey. Among selected studies, the majority were from North India and the recent data on prevalence are lacking for other Indian regions. This mini-review highlights the need for the Indian National TB Elimination Program to make provisions for regional periodic prevalence surveys for careful designing of MDR-TB control strategies.

Spread of Mycobacterium tuberculosis in Southern Brazilian persons deprived of liberty: a molecular epidemiology study

To evaluate the genetic diversity and clustering rates of M. tuberculosis strains to better understand transmission among persons deprived of liberty (PDL) in Rio Grande do Sul (RS), southern Brazil. This is a cross-sectional study, including strains of M. tuberculosis isolated from PDL, stored at the Central Laboratory of RS, in the period from 2013 to 2018. The molecular characterization was performed using the MIRU-VNTR 15 loci method. A total of 598M. tuberculosis strains were genotyped, and 37.5% were grouped into 53 clusters. Cluster sizes ranged from 2 to 34 strains. The largest cluster of the study had strains from 34 PDL, and 58.8% of the PDL of this cluster were in P01. Among the clusters formed, in 60.3%, there was at least one strain from P01. The most common strains in RS were LAM (53.2%) and Haarlem (31.1%). The LAM strain was the most likely to form clusters, and Haarlem was associated with anti-TB drug resistance. This was translational research, and the results can collaborate with the TB control programs, leading to improved strategies that allow the reduction of the TB burden in prisons.

Genotypic and phenotypic characteristics of <i>Mycobacterium tuberculosis</i> drug resistance in TB children

Background. Russian Federation is included in the list of 30 countries with the highest burden of tuberculosis, including MDR tuberculosis. The most important part of this problem is the primary MDR/XDR TB in children.The aim: a comparative analysis of the phenotypic and genotypic profile of drug resistance to anti-tuberculosis drugs (ATP) according to whole genome sequencing of M. tuberculosis strains from children.Materials and methods. Whole genome sequencing (WGS) results of 61 M. tuberculosis isolates from children with tuberculosis in 2006–2020 in the Russian Federation were analyzed for anti-TB drug resistance mutations, according to the WHO catalog and were compared with the results of phenotypic drug sensitivity.Results. The M. tuberculosis belonged to two genetic groups: Beijing genotype – 82 % (50/61) dominant Central Asian Russian (31/50) and B0/W148 (16/50) subtypes, and non-Beijing (Ural, S, LAM) – 18 % (11/61). Three isolates belonged to Asian Ancestral subtype (3/50). Of the 61 isolates, only 14.7 % (9/61) were sensitive to antiTB drugs, 49.2 % (30/61) were MDR and 14.7 % (9/61) were pre-XDR. Comparison of the resistance profile (MDR/pre-XDR) with genotype revealed an upward shift for Beijing isolates, in particular Beijing B0/W148 (15/16) subline compared to other Beijing (19/34) (Chi-square with Yates correction = 5.535; p < 0.05) and nonBeijing (5/12) (Chi-square with Yates correction = 6.741; p < 0.05) subtypes. Discrepancies between genotypic and phenotypic drug resistance profiles were found in 11.5 % (7/61) of cases.Conclusions. Based on the analysis of WGS data, the genotypic characteristics of M. tuberculosis and the most complete set of drug resistance mutations were obtained, indicating a significant prevalence in MDR and pre-XDR TB of cases caused by epidemic subtypes of Beijing (B0/W148 and Central Asian Russian). The molecular mechanisms of adaptation of M. tuberculosis to the treatment of anti-TB drugs are not unique for the child population but reflect the general processes of the spread of MDR/XDR in Russia.

Drug resistance patterns and dynamics of tuberculosis in Zhejiang Province, China: Results from five periodic longitudinal surveys.

As one of the high multi-drug resistance tuberculosis countries, it is critical for China to understand patterns of drug resistance to better formulate effective treatment regimens. The anti-TB Drug resistance surveillance has been conducted in Zheijang Province in years 1999, 2004, 2008, 2013, and 2018 respectively. We compared the prevalence of DR-TB from the latest survey with that of the previous four surveys in terms of all four first-line anti-TB drugs. We also examined the prevalence of rifampin-resistant TB (RR-TB) between the last two surveys and routine surveillance data. Among 996 patients surveyed in 2018, the prevalence of RR-TB in new and previously treated TB cases was 2.5 and 4.3%, respectively. The prevalence of RR-TB among previously treated cases was much higher than for new cases in the four surveys from 1999 to 2013, while there was no significant difference between these groups in the 2018 survey. The percentage of TB cases resistant to fluoroquinolones in new patients was 3.8%. The prevalence of non-tuberculous mycobacteria increased over time; the prevalence of RR-TB among new cases slowly decreased. The prevalence of RR-TB in both new and previously treated TB cases from the latest two surveys was consistent with routine surveillance data. This consistency between routine surveillance and periodic surveys for TB cases implies that with universal testing in Zhejiang Province, data from routine surveillance could be used instead of periodic surveys to improve access to timely and appropriate treatment for DR-TB. Levels of resistance were lower than whole-country and global estimates, further indicating the value of universal drug susceptibility testing.

Mycobacterium tuberculosis Drug Resistance in Ethiopia: An Updated Systematic Review and Meta-Analysis.

Background: Tuberculosis (TB) remains a significant global public health issue, despite advances in diagnostic technologies, substantial global efforts, and the availability of effective chemotherapies. Mycobacterium tuberculosis, a species of pathogenic bacteria resistant to currently available anti-TB drugs, is on the rise, threatening national and international TB-control efforts. This systematic review and meta-analysis aims to estimate the pooled prevalence of drug-resistant TB (DR-TB) in Ethiopia. Materials and Methods: A systematic literature search was undertaken using PubMed/MEDLINE, HINARI, the Web of Science, ScienceDirect electronic databases, and Google Scholar (1 January 2011 to 30 November 2020). After cleaning and sorting the records, the data were analyzed using STATA 11. The study outcomes revealed the weighted pooled prevalence of any anti-tuberculosis drug resistance, any isoniazid (INH) and rifampicin (RIF) resistance, monoresistance to INH and RIF, and multidrug-resistant TB (MDR-TB) in newly diagnosed and previously treated patients with TB. Results: A total of 24 studies with 18,908 patients with TB were included in the final analysis. The weighted pooled prevalence of any anti-TB drug resistance was 14.25% (95% confidence interval (CI): 7.05–21.44%)), whereas the pooled prevalence of any INH and RIF resistance was found in 15.62% (95%CI: 6.77–24.47%) and 9.75% (95%CI: 4.69–14.82%) of patients with TB, respectively. The pooled prevalence for INH and RIF-monoresistance was 6.23% (95%CI: 4.44–8.02%) and 2.33% (95%CI: 1.00–3.66%), respectively. MDR-TB was detected in 2.64% (95%CI: 1.46–3.82%) of newly diagnosed cases and 11.54% (95%CI: 2.12–20.96%) of retreated patients with TB, while the overall pooled prevalence of MDR-TB was 10.78% (95%CI: 4.74–16.83%). Conclusions: In Ethiopia, anti-tuberculosis drug resistance is widespread. The estimated pooled prevalence of INH and RIF-monoresistance rates were significantly higher in this review than in previous reports. Moreover, MDR-TB in newly diagnosed cases remained strong. Thus, early detection of TB cases, drug-resistance testing, proper and timely treatment, and diligent follow-up of TB patients all contribute to the improvement of DR-TB management and prevention. Besides this, we urge that a robust, routine laboratory-based drug-resistance surveillance system be implemented in the country.

The second national anti-tuberculosis drug resistance survey in Tanzania, 2017-2018.

To determine the levels and patterns of resistance to first- and second-line anti-tuberculosis (TB) drugs among new and previously treated sputum smear positive pulmonary TB (PTB) patients. We conducted a nationally representative cross-sectional facility-based survey in June 2017-July 2018 involving 45 clusters selected based on probability proportional to size. The survey aimed to determine the prevalence of anti-TB drug resistance and associated risk factors among smear positive PTB patients in Tanzania. Sputum samples were examined using smear microscopy, Xpert MTB/RIF, culture and drug susceptibility testing (DST). Logistic regression was used to account for missing data and sampling design effects on the estimates and their standard errors. We enrolled 1557 TB patients, including 1408 (90.4%) newly diagnosed and 149 (9.6%) previously treated patients. The prevalence of multidrug-resistant TB (MDR-TB) was 0.85% [95% confidence interval (CI): 0.4-1.3] among new cases and 4.6% (95% CI: 1.1-8.2) among previously treated cases. The prevalence of Mycobacterium tuberculosis strains resistant to any of the four first-line anti-TB drugs (isoniazid, rifampicin, streptomycin and ethambutol) was 1.7% among new TB patients and 6.5% among those previously treated. Drug resistance to all first-line drugs was similar (0.1%) in new and previously treated patients. None of the isolates displayed poly-resistance or extensively drug-resistant TB (XDR-TB). The only risk factor for MDR-TB was history of previous TB treatment (odds ratio=5.7, 95% CI: 1.9-17.2). The burden of MDR-TB in the country was relatively low with no evidence of XDR-TB. Given the overall small number of MDR-TB cases in this survey, it will be beneficial focusing efforts on intensified case detection including universal DST.

Pre-extensively drug-resistant tuberculosis among multidrug-resistant tuberculosis patients in Ethiopia: a laboratory-based surveillance study

BackgroundThe rise of drug-resistant tuberculosis (DR-TB) has presented a substantial challenge to the national tuberculosis (TB) control program. Understanding the epidemiology of pre-extensively drug-resistant tuberculosis (pre-XDR-TB) could help clinicians to adapt MDR-TB treatment regimens at an earlier stage. This study aimed to assess second-line anti-TB drug resistance among MDR-TB patients in Ethiopia using routine laboratory-based data. MethodsLaboratory-based cross-sectional data were collected from the national TB reference laboratory and seven regional tuberculosis culture laboratories in Ethiopia from July 2019 to March 2022. The required data, such as drug-susceptibility testing (DST) results and sociodemographics, were collected on a structured checklist from laboratory registration books and electronic databases. Data were entered into a Microsoft Excel spreadsheet and analyzed using SPSS version 23. Descriptive statistics were performed to show the distribution and magnitude of drug resistance. ResultsSecond-line drugs (SLDs) susceptibility testing was performed for 644 MDR isolates, of which 19 (3%) were found to be pre-XDR-TB cases. Of the total MDR-TB isolates, 19 (3%) were resistant to at least one fluoroquinolone drug, while 11 (1.7%) were resistant to at least one injectable second-line drug. Of the 644 MDR-TB isolates, 1.9% (5/261) pre-XDR were from new MDR-TB cases, while 3.7% (14/383) were from previously treated MDR-TB patients. The most frequently identified mutations, based on MTBDRsl results, were in codon A90V of the gyrA gene (77.3%) and A1401G of the rrs gene (45.5%). ConclusionThe overall prevalence of pre-XDR-TB in Ethiopia is considerable. The majority of SLD resistance mutations were in the gyrA gene at position A90V. Modern, rapid DST is necessary to enable identification of pre-XDR-TB and XDR-TB in supporting proper regimen administration for patients.

Proportion of Extrapulmonary MDR-TB Confirmed by GeneXpert® in Dr. Hasan Sadikin General Hospital, West Java, Indonesia Year 2012–2021

As the third-highest country with tuberculosis (TB) incidence worldwide in 2020, Indonesia has increasing TB cases resistant to various anti-TB therapy or multidrug-resistant (MDR)-TB, and ranked fifth for its high incidence reported in Global Tuberculosis Report 2020. Moreover, extrapulmonary TB (EPTB) is rising, and data studies on EPTB with MDR-TB in Indonesia are scarce. This study aimed to explore the proportion of extrapulmonary MDR-TB among TB cases in Dr. Hasan Sadikin General Hospital Bandung, West Java, Indonesia. A descriptive retrospective and cross-sectional study design were conducted, retrieving medical records from all suspect MDR-TB adult patients examined by GeneXpert®, at Dr. Hasan Sadikin General Hospital Bandung, West Java period 2012–2021. Those with EPTB were further analyzed, and the demographic data was collected as well as clinical history, behavioral history, sites of extrapulmonary MDR-TB, and drug resistance. Of a total 7,013 TB cases, 1,900 (27.1%) were MDR-TB cases, of whom 0.08% (n6) were extrapulmonary MDR-TB cases and 0.16% (n11) were combined with PTB. The main characteristics of cases with extrapulmonary MDR-TB were median age 27-year-old (range 25–34), male gender (64.7%), underweight BMI (84.6%), and predominantly were primary cases (35.3%). The anti-TB drug resistance in MDR-TB were pre-XDR-TB (11.7%), XDR-TB (5.6%), MDR-TB (42%), and RR-TB (40.7%). Although the proportion of extrapulmonary MDR-TB among all TB cases is small (0.2%), this disease can’t be ignored and has a great potential to be explored. Most of them are rifampicin-resistant. Further studies need to include a larger population to have more overview of MDR-TB with EPTB.

Spoligotype-based population structure and isoniazid-resistance gene mutation of Mycobacterium tuberculosis isolates from Thailand

The present study aims to investigate the population structure of Thai Mycobacterium tuberculosis (MTB) isolates and anti-tuberculosis (TB) drug resistance and to determine the most frequent genetic mutations conferring isoniazid (INH) resistance. Genomic DNA from 287 MTB clinical isolates were extracted and used for spoligotyping, amplification and sequencing analysis of the region of different (RD) 105, and of the INH resistance (IR) associated genes, inhA, katG and oxyR-ahpC genes. Eighty-one clinical isolates were resistant to at least one first-line drug; 53 of these were resistant to INH. All strains were classified into three lineages based on their spoligotypes: East Asia (EA)/Beijing, Indo-Oceanic (IO), and Euro-American (EuA). EA and IO lineages revealed a strong association with anti-TB drug resistance (P=0.005 and 0.013, respectively). A total of 33 mutations were found among IR isolates, which for 28 (84.8%), 3 (9.1%), and 2 (6.1%) occurred in katG, inhA, and oxyR-ahpC genes, respectively. Moreover, the most common mutations found were 54.7% of IR presented Ser315Thr at katG (54.7%) and C-15T at inhA (15.1%) presented. This result suggests the involvement of other genetic markers or other mechanisms of resistance. This study provides information about strains diversity, drug resistance profiles, and their possible association. EA and IO lineages were predominant in Thailand, and they were highly associated with anti-TB drug resistance. Testing two mutations including katGSer315Thr and inhA-15C→T could detect 68% of the IR strains.

Time of Liver Function Abnormal Identification on Prediction of the Risk of Anti-tuberculosis-induced Liver Injury.

Anti-tuberculosis (anti-TB) drug-induced liver injury (AT-DILI) is the most common side effect in patients who received anti-TB therapy. AT-DILI management includes monitoring liver function until symptoms arise in patients without high-risk factors for liver damage. The present study aimed to investigate the effect of liver function test (LFT) abnormal identification on the risk of DILI, including liver failure and anti-TB drug resistance in patients without high-risk factors. A total of 399 patients without high-risk factors for liver damage at baseline and who experienced LFT abnormal during the 6 months of first-line anti-TB treatment were enrolled. The Roussel Uclaf Causal Relationship Assessment Method (RUCAM, 2016) was applied in suspected DILI. The correlations between the time of LFT abnormal identification and DILI, liver failure, and anti-TB drug resistance were analyzed by smooth curve fitting and multivariable logistic regression models. Among all study patients, 131 met the criteria for DILI with a mean RUCAM causality score of 8.86±0.63. 26/131 and 105/131 were in the probable grading and highly probable grading, respectively. The time of abnormal LFT identification was an independent predictor of DILI, liver failure, and anti-TB drug resistance in the crude model and after adjusting for other risk patient factors. The time of abnormal LFT identification was positively correlated with DILI, liver failure, and anti-TB drug resistance. The late identification group (>8 weeks) had the highest risk of DILI, followed by liver failure compared with the other two groups. The time to identification of LFT was positively correlated with DILI, liver failure, and anti-TB drug resistance. The risk of DILI and liver failure was significantly increased in the late identification group with abnormal LFT identified after 8 weeks compared with 4 and 8 weeks. Early monitoring of LFT is recommended for patients without the high-risk factor of DILI after anti-TB treatment is initiated.