pre-XDR TB Research Articles

Drug-Resistant Tuberculosis in Rural Eastern Cape, South Africa: A Study of Patients’ Characteristics in Selected Healthcare Facilities

This study investigated the characteristics and outcomes of drug-resistant tuberculosis patients in selected rural healthcare facilities in the Eastern Cape, South Africa. A retrospective review of clinical records from 456 patients, covering the period from January 2018 to December 2020, revealed a statistically significant relationship between DR-TB types and age groups (Chi-square statistic: 30.74, p-value: 0.015). Younger adults (19–35 years) and middle-aged adults (36–50 years) are more frequently affected by RR-TB and MDR-TB, which are the most prevalent forms of DR-TB. Less common types, including Pre-XDR, XDR, and INH TB, were observed in smaller numbers. The study suggests that DR-TB imposes a heavy burden on the working age population. Gender analysis shows that while the frequency of DR-TB differs between males and females, the percentage distribution of DR-TB types is relatively equal. Both genders are predominantly affected by RR-TB and MDR-TB, which together account for nearly 90% of cases. Pre-XDR, XDR, and INH-resistant TB are much less common, comprising only a small percentage of cases in both males and females. High-risk behaviors such as smoking and drinking are linked to a wider diversity of DR-TB types, while occupations like mining and prison work show higher rates of RR-TB and MDR-TB. In HIV-positive individuals, DR-TB is more common, but the distribution of DR-TB types between HIV-positive and negative groups shows no statistically significant difference. However, HIV-positive individuals have a 20% lower survival rate (65%) compared to HIV-negative patients (85%). Financial stability and comorbidities also significantly influence outcomes, with patients having stable income and fewer high-risk comorbidities experiencing better survival and treatment outcomes. The findings underscore the importance of addressing socioeconomic disparities and strengthening healthcare infrastructure to improve DR-TB treatment outcomes in rural Eastern Cape.

Primary Pre-Extensively Drug-Resistant (Pre-XDR) Tuberculosis with Meningoencephalitis in Nineteen Years Old Young Woman : A Case Report

Introduction. Mycobacterium tuberculosis (MTB) is continually evolving in order to resist treatment. This has resulted in drug-resistant tuberculosis, which has a greater rate of therapy failure and mortality, as well as the necessity for other ways of disease transmission prevention. Pre-extensively drug-resistant tuberculosis (Pre-XDR TB) is caused by MTB strains that are resistant to isoniazid, rifampicin, and any fluoroquinolone medicines. Case Report. A 19-year-old HIV-negative immunocompetent female presented to our emergency department with dyspnea and severe headache. She also complained of a cough, a low-grade temperature, and weight loss. She has no relevant medical history and has never been exposed to tuberculosis. A chest X-ray revealed infiltrates with cavities and fibrosis in both lungs, while a brain CT suggested meningoencephalitis. We performed a sputum drug sensitivity test and discovered that this patient was resistant to rifampin, isoniazid, levofloxacin, and moxifloxacin. She was later diagnosed with Pre-XDR TB and was given a tailored lengthier regimen that included Bedaquiline, Cycloserin, Linezolide, Clofazimine, and Etambutol. Her symptoms improved significantly as a result of this program. Discussion. Primary pre-XDR TB in an immunocompetent patient is uncommon, and our case is even more unusual due to meningoencephalitis involvement. The treatment of pre-XDR TB requires a personalized regimen that is tailored to the patient's clinical status and comorbidities. The possibility of transmission via a positive contact was raised in this patient, prompting us to conduct a more thorough contact inquiry to prevent future spread. Conclusion. In our region, there is a risk of'silent' drug resistant tuberculosis. Early detection and treatment of such patients are critical to preventing uncontrollable pan-resistant TB. Successful management with cautious contact investigation will minimize the mortality rate and spread rate of drug-resistant TB. Keywords. Drug-Resistant Lung Tuberculosis, Drug-Resistant Meningoencephalitis Tuberculosis

P27 A challenging case of MDR TB infection following a holiday in India

Abstract Background TB is an infection caused by Mycobacterium tuberculosis. MDR TB is caused by strains of M. tuberculosis resistant to isoniazid and rifampicin.1 XDR TB refers to strains resistant to one or more second-line injectable drugs and any fluoroquinolone, whereas pre-XDR TB refers to strains resistant to either a second-line injectable drug or a fluoroquinolone.1 The implications of MDR TB include prolonged treatment requirements, increased morbidity and mortality, and risk of onward transmission to others.2 Case history A woman in her forties with poorly controlled diabetes was admitted to hospital three times in 3 months with respiratory symptoms and pulmonary consolidation. She was treated for recurrent community acquired pneumonia (CAP). On her fourth admission, sputum and stool microscopy detected acid fast bacilli (AFB) and PCR using Xpert MTB/RIF (Cepheid® GeneXpert® systems) confirmed M. tuberculosis with resistance to rifampicin. She had no known TB contacts but had had a 5 week holiday in Goa, India, 2 years prior. Management Phenotypic testing confirmed the M. tuberculosis isolate was resistant to rifampicin, isoniazid and aminoglycosides but susceptible to fluoroquinolones. Following discussion with the British Thoracic Society (BTS) MDR TB advice service she was empirically initiated on linezolid 600 mg BD, bedaquiline 200 mg OD, levofloxacin 1000 mg OD, clofazimine 200 mg OD, cycloserine 250 mg BD, pyrazinamide 2000mg OD, ethambutol 1000 mg OD and pyridoxine 10 mg OD. The isolate was later identified as of New Delhi Central Asia lineage, with additional resistance to pyrazinamide (which was then stopped). This is the first case of this lineage reported in the UK. Therapeutic drug monitoring of linezolid, levofloxacin and cycloserine was performed. Cycloserine was changed to terizidone 250 mg BD after 1 month, due to a national supply issue. She suffered from medication side effects including diarrhoea, nausea, derangement in liver functions tests, worsening of pre-existing peripheral neuropathy, myalgia, hypercalcaemia, itch, renal tubular acidosis and acute kidney injury. These were managed pharmacologically and through cessation of terizidone after 2 months and dose reduction, then cessation, of linezolid after 4 months. Outcomes Clinically she improved and repeat imaging showed gradual resolution of consolidation and C-reactive protein levels decreased. She is 10 months into an anticipated 18–24 month treatment regimen, recommended due to her extensive pulmonary disease. Medication side effects are currently well controlled. The infection prevention and control team screened all contacts from this and prior admissions, with no further cases identified. Conclusions This case highlights the importance of suspicion of TB in patients with chronic cough and radiological changes, particularly with risk factors for TB such as relevant travel history and diabetes. MDR TB infection has significant consequences and treatment remains challenging with the burden of multiple drugs, and their side effects, leading to further patient morbidity.

Effect of Bedaquiline and Delamanid Pharmacokinetics on Sputum Culture Conversion and Adverse Events in Drug-Resistant Tuberculosis.

Pharmacokinetic studies of bedaquiline and delamanid in patients with pre-extensively drug-resistant tuberculosis (pre-XDR TB) will help in the optimization of these drugs for both culture conversion and adverse events. A prospective cohort of 165 adult patients (56% male with mean [SD] age 29 [9.7] years) with pre-XDR TB was treated with bedaquiline, delamanid, clofazimine, and linezolid for 24 weeks at 5 sites in India. Bedaquiline was administered at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks, whereas delamanid was administered at 100 mg twice daily. In 23 consenting participants at 8 and 16 weeks of treatment, blood was collected at 0, 2, 4, 5, 6, 8, 12, and 24 hours postdosing for an intense pharmacokinetic study. Pharmacokinetic parameters were correlated with sputum culture conversion and adverse events. The mean (SD) age and weight of patients were 30 (10) years and 54 kg, respectively. The median minimum concentration (C min ) and time-concentration curve (AUC) for bedaquiline, respectively, were 0.6 mcg/mL and 27 mcg/mL·h at week 8 and 0.8 mcg/mL and 36 mcg/mL·h at week 16, suggesting drug accumulation over time. The median C min and AUC of delamanid, respectively, were 0.17 mcg/mL and 5.1 mcg/mL·h at week 8 and 0.20 mcg/mL and 7.5 mcg/mL·h at week 16. Delay in sputum conversion was observed in patients with drug concentrations lower than the targeted concentration. At weeks 8 and 16, 13 adverse events were observed. Adverse events were resolved through symptomatic treatment. Body mass index was found to be significantly associated with drug-exposure parameters. Bedaquiline and delamanid when co-administered exhibit plasma drug levels within the targeted concentrations, showing an exposure-response relationship.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial

BackgroundTreatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients.MethodsendTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations.DiscussionThis internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen.Trial registrationClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Sirturo- a diarylquinoline (bedaquiline): a novel approach for the treatment of MDR-TB and pre-XDR TB

Sirturo (bedaquiline fumarate) is a new antitubercular class of medicine, lately, FDA, approved and indicated for use as a part of an appropriate applicable combination regimen along with other antitubercular medicines (i. e.; 2nd line anti-TB agents) for pulmonary multidrug-resistant tuberculosis (MDR TB) in grown up with age 12 years to less than 18 years of age and weighing at least 30 kg when an alternative treatment regimen cannot be considered for the reasons of resistance or tolerability. Bedaquiline, an enantiomer chemically belongs to the diarylquinoline (DAR) compound, which is nearly related to fluoroquinolones and chloroquine with differences in their side-chain moiety. Amongst all anti-TB medicines that have been approved, bedaquiline has a unique mechanism, which targets energy metabolism i. e.; adenosine triphosphate of mycobacteria, and eventually leads to bacterial cell lysis. ATP is an essential energy-producing molecule required for metabolic actions and survival of Mycobacteria and also for many other cells. Mycobacteria generally invade into well-encapsulated lung cavities and endosomes of macrophages, which can survive even under low oxygen levels leading to resistance against standard TB drugs. Bedaquiline has a spectrum of activity against drug-susceptible TB and MDR TB. Many clinical trials and studies demonstrated that bedaquiline is a crucial component of a combination regimen for multidrug-resistant TB.

Stress resilience in patients with drug-resistant TB.

BACKGROUND: The worldwide increase in drug-resistant pulmonary TB (DR-PTB) has a significant impact on patient´s physical and mental health. The objective of this study is to assess the stress resilience of DR-PTB patients along with the factors associated with it.METHODS: A total of 385 adult DR-PTB patients with multidrug-resistant (MDR) and pre-extensive drug-resistant (pre-XDR) TB admitted to the National Institute of Diseases of the Chest Hospital (Dhaka, Bangladesh) between January 2020 and March 2021 were conveniently recruited. Resilience data were collected using a validated Stress Resilience Scale (RS 25) questionnaire.RESULTS: The mean resilience scores were significantly higher for patients with MDR-PTB than those with pre-XDR-PTB (P = 0.02). A majority of the MDR-PTB (77.0%) and pre-XDR-PTB (65.1%) patients belonged to the ≤45 years age group. Multiple linear regression revealed that sex (P < 0.001), level of education (P < 0.001), employment status (P = 0.003) and presence of asthma (P = 0.010) were significantly associated with stress resilience.CONCLUSION: We observed that stress resilience significantly differed between patients with MDR-PTB and those with pre-XDR-PTB based on sociodemographic characteristics.

Genomic Analysis of Mycobacterium tuberculosis Strains Resistant to Second-Line Anti-Tuberculosis Drugs in Lusaka, Zambia.

The emergence of pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is a threat to TB control programs in developing countries such as Zambia. Studies in Zambia have applied molecular techniques to understand drug-resistance-associated mutations, circulating lineages and transmission patterns of multi-drug-resistant (MDR) Mycobacterium tuberculosis. However, none has reported genotypes and mutations associated with pre-XDR TB. This study characterized 63 drug-resistant M. tuberculosis strains from the University Teaching Hospital between 2018 and 2019 using targeted gene sequencing and conveniently selected 50 strains for whole genome sequencing. Sixty strains had resistance mutations associated to MDR, one polyresistant, and two rifampicin resistant. Among MDR strains, seven percent (4/60) had mutations associated with pre-XDR-TB. While four, one and nine strains had mutations associated with ethionamide, para-amino-salicylic acid and streptomycin resistances, respectively. All 50 strains belonged to lineage 4 with the predominant sub-lineage 4.3.4.2.1 (38%). Three of four pre-XDR strains belonged to sub-lineage 4.3.4.2.1. Sub-lineage 4.3.4.2.1 strains were less clustered when compared to sub-lineages L4.9.1 and L4.3.4.1 based on single nucleotide polymorphism differences. The finding that resistances to second-line drugs have emerged among MDR-TB is a threat to TB control. Hence, the study recommends a strengthened routine drug susceptibility testing for second-line TB drugs to stop the progression of pre-XDR to XDR-TB and improve patient treatment outcomes.

Prevalence of pre-extensively drug-resistant tuberculosis (Pre XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) among extra pulmonary (EP) multidrug resistant tuberculosis (MDR-TB) at a tertiary care center in Mumbai in pre Bedaquiline (BDQ) era.

Drug-resistant tuberculosis (DR-TB) is the most exigent and calamitous challenge encountered in treatment of TB. Extra pulmonary (EP) DR-TB poses a complex diagnostic and therapeutic challenge owing to myriad of presentations and paucibacillary nature. Data available on this subset is limited. We studied the prevalence of EPDR-TB cases among the total DR-TB cases visiting our Programmatic management of Drug-Resistant TB (PMDT) site. We also studied the demographic and microbiological profile of these cases and analyzed the prevalence of pre-extensively drug-resistant TB (pre XDR-TB) and extensively drug-resistant TB (XDR-TB) among patients of EPDR-TB in pre Bdq era. Of the 1086 DR-TB patients, 64 (5.89%) were cases of EPDR-TB. Seven out of 64 (10.93%) were primary EPDR-TB. The site wise distribution of cases was 34 (53.125%) lymph node DR-TB, 18 (28.125%) pleural DR-TB, 9 (14.0625%) spinal DR-TB/paraspinal abscess/psoas abscess, 1 case (1.5625%) each of abdominal DR-TB, sternal and gluteal abscess. On the basis of the second-line drug susceptibility testing (DST), patients were grouped into: (1) multidrug-resistant TB (MDR-TB), (2) MDR-TB with fluoroquinolone (FQ) resistance {pre XDR XDR-TB (FQ)}, (3) MDR-TB with second-line injectable (SLI) resistance {pre XDR XDR-TB (SLI)}, (4) XDR-TB. Of the 64 patients, 43 (67.185%) had MDR-TB, 19 (29.687%) had preXDR-TB (FQ), none had preXDR-TB (SLI) and 2 (3.125%) had XDR-TB. Gastro esophageal reflux disease (GERD) was the most common comorbidity seen in 26 (40.6%) patients, followed by anemia in 5 (7.8%), psychiatry problems 5 (7.8%), hypertension in 3 (4.6%), renal disorders in 2 (3.1%) while thyroid disorder, HIV and thalassemia in 1 each (1.5%). EPDR-TB forms a small but significant proportion of total DR-TB. Lymph node DR-TB is its most common subclass. Our study emphasises the momentousness and essentiality of baseline DST to FQ and SLI in patients of DR-TB. This enables an appropriate modification of therapy at baseline itself to better the treatment outcomes. We observed a strikingly high proportion of preXDR-TB (FQ) in our study group.

Genotypic and phenotypic characteristics of &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; 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 &lt; 0.05) and nonBeijing (5/12) (Chi-square with Yates correction = 6.741; p &lt; 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.

Prevalence of Tuberculosis Among High Altitude Residents of Nepal

Introduction: Tuberculosis is a global health concern, and its prevalence can vary widely from one region to another. Factors such as altitude, climate, population density, and healthcare infrastructure can all influence the dynamics of Tuberculosis in a particular area. This study aimed to provide insights into whether altitude played a role in the occurrence of tuberculosis and its different forms in the specific region of Jumla the western rural district of Nepal. &#x0D; Methods: Jumla is a high-altitude mountainous region ranging from 915m- 4679 m with a population of 119,337 (2021) having 8 municipalities. Data were collected from all the municipalities over a period starting from July 15th2021-July 14th2022 and were compared with prior years in number and diagnosis with national data of Nepal. &#x0D; Results: A total of 84 cases were recorded of which 52.4% (n=44) were females. The group affected most was between the ages 16-30 years (34.5%) and 61-75yr (22.6%). The cases detected by the sputum Xpert MTB/RIF testing were 54.7%, with positive sputum Acid-fast bacilli being 27.4%. Most of the patients were diagnosed to have pulmonary bacteriologically confirmed (PBC) tuberculosis 52.4%, PCD (Pulmonary clinically diagnosed) 16.7%, Extra-pulmonary 28.6% with one case of each multi-drug resistant tuberculosis (MDR-TB), and Pre-XDR (Extensive drug resistant) TB. Among them, 12% of people had a history of TB undergone ATT (anti-tuberculosis drugs) in the past with 6% having a close contact history. &#x0D; Conclusions: Tuberculosis infection, disease, and mortality seem to be less common at high than low altitudes. As in Karnali Province, Humla with the second being Jumla has the lowest number of TB patients than other parts of Nepal, affecting younger people.

Revised Definitions of Tuberculosis Resistance and Treatment Outcomes, France, 2006-2019.

Definitions of resistance in multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) have been updated. Pre–XDR TB, defined as MDR TB with additional resistance to fluoroquinolones, and XDR TB, with additional resistance to bedaquiline or linezolid, are frequently associated with treatment failure and toxicity. We retrospectively determined the effects of pre-XDR/XDR TB resistance on outcomes and safety of MDR TB treatment in France. The study included 298 patients treated for MDR TB at 3 reference centers during 2006–2019. Of those, 205 (68.8%) cases were fluoroquinolone-susceptible MDR TB and 93 (31.2%) were pre-XDR/XDR TB. Compared with fluoroquinolone-susceptible MDR TB, pre-XDR/XDR TB was associated with more cavitary lung lesions and bilateral disease and required longer treatment. Overall, 202 patients (67.8%) had favorable treatment outcomes, with no significant difference between pre-XDR/XDR TB (67.7%) and fluoroquinolone-susceptible MDR TB (67.8%; p = 0.99). Pre-XDR/XDR TB was not associated with higher risk for serious adverse events.

Rapid Diagnosis of XDR and Pre-XDR TB: A Systematic Review of Available Tools

IntroductionNo previous systematic reviews have comprehensively investigated the features of Xpert MTB/XDR and other rapid tests to diagnose pre-XDR/XDR-TB. The aim of this systematic review is to assess existing rapid diagnostics for pre-XDR/XDR-TB from a point-of-care perspective and describe their technical characteristics (i.e., sensitivity, specificity, positive and negative predictive values). MethodsEmbase, PubMed, Scopus, and Web of Science were searched to detect the articles focused on the accuracy of commercially available rapid molecular diagnostic tests for XDR-TB according to PRISMA guidelines. The analysis compared the diagnostic techniques and approaches in terms of sensitivity, specificity, laboratory complexity, time to confirmed diagnosis. ResultsOf 1298 records identified, after valuating article titles and abstracts, 97 (7.5%) records underwent full-text evaluation and 38 records met the inclusion criteria.Two rapid World Health Organization (WHO)-endorsed tests are available: Xpert MTB/XDR and GenoType MTBDRsl (VER1.0 and VER 2.0). Both tests had similar performance, slightly favouring Xpert, although only 2 studies were available (sensitivity 91.4–94; specificity 98.5–99; accuracy 97.2–97.7; PPV 88.9–99.1; NPV 95.8–98.9). ConclusionsXpert MTB/XDR could be suggested at near-point-of-care settings to be used primarily as a follow-on test for laboratory-confirmed TB, complementing existing rapid tests detecting at least rifampicin-resistance.Both Xpert MTB/XDR and GenoType MTBDRsl are presently diagnosing what WHO defined, in 2021, as pre-XDR-TB.

Systematic evaluation of line probe assays for the diagnosis of tuberculosis and drug-resistant tuberculosis

BackgroundLine probe assays (LPAs) are PCR-based assays used for the rapid diagnosis of Mycobacterium tuberculosis (MTB) and drug-resistant tuberculosis (DR-TB). But studies on its performance are insufficient. Thus, in this study, we conducted a systematic review and meta-analysis to evaluate the effect of LPAs in the detection of MTB and drug-resistant TB in comparison with the traditional culture and DST methods. MethodsA systemic literature search was conducted on the Web of Science, Embase, PubMed, the Cochrane Library, Scopus, and OVID databases. All the included studies were classified according to different detecting objects. Sensitivity, specificity, Positive Likely Ratio (PLR), Negative Likely Ratio (NLR), Diagnostic Odds Ratio (DOR), corresponding 95% confidence interval, Area Under Curve (AUC), Deeks’ funnel plot, and Bivariate Boxplot was used to do the evaluation. Results147 studies included 491 datasets, with 182,448 samples, were incorporated into our analysis. The sensitivity (95% CI), specificity (95% CI), PLR, NLR, DOR and AUC for MTB were 0.89 (0.86 to 0.92), 0.94 (0.90 to 0.97), 15.70, 0.11, 139 and 0.96, respectively; for rifampicin-resistant TB were 0.96 (0.95 to 0.97), 0.99 (0.98 to 0.99), 82.9, 0.04, 1994 and 1.00, respectively; for isoniazid-resistant TB were 0.91 (0.89 to 0.93), 0.99 (0.98 to 0.99), 83.4, 0.09, (0.99 to 1.00), 195.7, 0.07, 2783 and 1.00, respectively; for Multi-drug resistant TB (MDR-TB) were 0.93 (0.90 to 0.95), 1.00 (0.99 to 1.00), 195.7, 0.07, 2783 and 1.00, respectively; for extensively drug-resistant TB (XDR-TB) were 0.60 (0.33 to 0.82), 1.00 (0.95 to 1.00), 291.3, 0.4, 726 and 0.95, respectively; for (second-line drug-resistant TB) SLID-TB were 0.83 (0.78 to 0.87), 0.98 (0.97 to 0.99), 44.6, 0.17, 262 and 0.98, respectively. Sensitivity in pre-extensively drug-resistant TB (Pre-XDR-TB) was 0.67, specificity was 0.91. No publication bias existed according to Deeks’ funnel plot. ConclusionHigh diagnosis performance was confirmed in LPAs for the diagnosis of MTB and drug-resistant TB. LPAs might be a good alternative to culture and DST in detecting MTB, RR-TB, INH-TB, XDR-TB, SLID-TB, and MDR-TB. While more studies were still needed to explore the diagnosis performance of LPAs for Pre-XDR TB.

Effectiveness of chemotherapy of multidrug-resistant tuberculosis using bedaquiline

The aim of the study was to evaluate the effectiveness of MDR/XDR TB treatment with bedaquiline. Methods. The author analyzed the treatment results of 56 patients in Staint Petersburg in 2017 with MDR/XDR TB whose treatment regimen included bedaquiline. All patients were smear/ culture-positive: 43 (67.8%) cases with XDR MBT; 7 (12.5%) with pre-XDR MBT and only 6 (10.7 %) cases with MDR TB. Results. 35 (62.5%) patients received full bedaquiline course, 16 received the treatment for a few days to 4 months and did not complete the course, 5 patients with XDR tuberculosis who underwent surgery were treated for more than 6 months. The average duration of bedaquiline course was 4.7 ± 0.3 months. Among the 27 (48.2%) patients who completed the treatment effectively, 22 had XDR TB, 3 – pre-XDR TB, and 2 – MDR TB. The median sputum conversion period was 4.00 ± 0.42 months (CI: 3.14 – 4.86). 13 (23.2%) patients interrupted the treatment, but 9 of them had negative cultures for MBT at this time. These patients received bedaquiline for 1 to 14 months. Treatment failure was recorded in 12 (21.4%) patients, and 4 (7.14%) patients died during the intensive treatment phase. In general, 27 patients with a successful outcome had negative cultures at the end of the intensive phase and 9 patients who effectively completed the intensive phase but interrupted the treatment continuation phase. In total, 36 patients (64.3%) had a successful treatment outcome. Conclusion. The analysis showed that routine administration of the drug without consideration for treatment compliance increases the effectiveness of the intensive phase (64.3%) and does not significantly affect general effectiveness of the treatment (48.2%). The high frequency of treatment interruption remains a serious obstacle to improving the treatment effectiveness.

Risk Factors of Prolonged QTc Interval in Patients with Drugs-Resistant Tuberculosis

Background: Drug-Resistant Tuberculosis (DRTB) is still one of the biggest health problems worldwide. In 2016, WHO published new guidelines for DRTB management using 7 second-line drugs that only required 9-11 months of treatment with a higher success rate. Unfortunately, one of the side effects was the possibility of a prolonged QT-c interval on electrocardiography. However, to date there have been no known factors which increased the risk of QTc prolongation in DRTB patients.Methods: This was a retrospective cohort study that analyzed the medical records of 50 DRTB patients who underwent treatment from August 2017 to August 2020 at the DRTB Clinic of Adam Malik Hospital Medan. Statistical analysis was performed using logistic regression to determine the factors which increased the risk of QTc prolongation in DRTB patients.Results: Of the 50 study samples consisting of 40 MDR TB patients, 9 pre-XDR TB patients and 1 XDR TB patient, 14 (28%) subjects were found to have QTc prolongation. There were no correlation between the regimen type (P = 0.51), age (P = 0.40), sex (P = 0.74), nutritional status (P = 0.35) and comorbid diseases (P = 0.31) on the prolongation of QTc interval. Patients receiving clofazimine had a greater percentage (78.6% vs 21.4%) to experience prolonged QTc interval, although not statistically significant (P = 0.41). Conclusion: Treatment regimen, age, sex, nutritional status and comorbid disease were not associated with prolonged QTc interval in DRTB.

Frequency of Pre-Extensively Drug Resistant Tuberculosis and Extensively Drug Resistant Tuberculosis

Aim: To determine the frequency of pre-extensively drug resistant tuberculosis, extensively drug resistant tuberculosis in patients with multi-drug resistant tuberculosis. Study design: Retrospective/observational Place and duration of study: Department of Medicine, Bolan Medical College Quetta from 1st July 2019 to 31st December 2020. Methodology: One hundred and eighty patients of both genders presented with multi drug resistant tuberculosis were enrolled in this study. Patient’s detailed information including age between 20-70 years, sex, body mass index were recorded. Sputum samples were taken from all the patients and then drug sensitivity testing (DST) for 1st and 2ndline drugs. Frequency of pre-XDR TB and XDR tuberculosis were recorded. Results: There were 100 (55.56%) males and 80 (44.44%) patients were females and mean age was 37.38±10.75 years. Mean body mass index was 24.18±2.41 kg/m2. Among all the multi-drug resistant tuberculosis patients, pre extensively drug resistant tuberculosis was found in 62(34.44%) patients and extensively drug resistant tuberculosis was found in 8(4.44%) patients. All 62(100%) patients of pre-XDR tuberculosis were resistant to fluoroquinolone while among XDR tuberculosis patients 4 were resisted to amikacin, 2 were resisted to kanamycin and fluoroquinolone, 1 patient was resisted to amikacin and kanamycin. Conclusion: Frequency of pre-extensively tuberculosis among multi drug resistant tuberculosis was high while only 4% patients had extensively drug resistant tuberculosis. Keywords: Tuberculosis, Multi-drug resistant, Pre-extensively drug resistant, Extensively drug resistant

Multidrug-resistant tuberculosis imported into low-incidence countries-a GeoSentinel analysis, 2008-2020.

Early detection of imported multidrug-resistant tuberculosis (MDR-TB) is crucial, but knowledge gaps remain about migration- and travel-associated MDR-TB epidemiology. The aim was to describe epidemiologic characteristics among international travellers and migrants with MDR-TB. Clinician-determined and microbiologically confirmed MDR-TB diagnoses deemed to be related to travel or migration were extracted from GeoSentinel, a global surveillance network of travel and tropical medicine clinics, from January 2008 through December 2020. MDR-TB was defined as resistance to both isoniazid and rifampicin. Additional resistance to either a fluoroquinolone or a second-line injectable drug was categorized as pre-extensively drug-resistant (pre-XDR) TB, and as extensively drug-resistant (XDR) TB when resistance was detected for both. Sub-analyses were performed based on degree of resistance and country of origin. Of 201 patients, 136 had MDR-TB (67.7%), 25 had XDR-TB (12.4%), 23 had pre-XDR TB (11.4%) and 17 had unspecified MDR- or XDR-TB (8.5%); 196 (97.5%) were immigrants, of which 92 (45.8%) originated from the former Soviet Union. The median interval from arrival to presentation was 154days (interquartile range [IQR]: 10-751days); 34.3% of patients presented within 1month after immigration, 30.9% between 1 and 12months and 34.9% after ≥1year. Pre-XDR- and XDR-TB patients from the former Soviet Union other than Georgia presented earlier than those with MDR-TB (26days [IQR: 8-522] vs. 369days [IQR: 84-827]), while patients from Georgia presented very early, irrespective of the level of resistance (8days [IQR: 2-18] vs. 2days [IQR: 1-17]). MDR-TB is uncommon in traditional travellers. Purposeful medical migration may partly explain differences in time to presentation among different groups. Public health resources are needed to better understand factors contributing to cross-border MDR-TB spread and to develop strategies to optimize care of TB-infected patients in their home countries before migration.

Cross-Resistance in Anti-Tubercular Drugs - A Conundrum in the Management of Drug-Resistant Tuberculosis

The problem of DR-TB especially MDR-TB/RR-TB, Pre-XDR TB, and XDR TB is menacing the world in a fearsome manner. The treatment of patients with such complicated forms of TB is fraught with difficulties owing to the toxicity of second-line drugs and decreased efficacy, not to mention poor compliance by patients keeping in view the adverse effects and long duration of treatment. To add to all these strictures in the successful outcome of DR-TB outcomes, the phenomenon of Cross-Resistance amongst anti-tubercular drugs has also to be reckoned with. In this review, we have tried to address this particular aspect which plays one of the key roles in the final treatment outcome of patients with such complicated forms of TB.

Cross-Contamination versus Outbreak: Pre-XDR Mycobacterial Strains Confirmed by Whole-Genome Sequencing.

Whole-genome sequencing (WGS) is promising for the quality control of laboratory facilities for Mycobacterium tuberculosis (MTB) strains. We describe the clinical and laboratory characteristics of false positive versus true positive MTB cultures based on WGS, which were experienced in a real clinical setting. Strain harvest and DNA extraction from seven isolates from pre-extensive drug-resistant (pre-XDR) TB patients transferred to the Korea University Ansan Hospital were performed, and epidemiologic links and clinical information, including the phenotypic drug susceptibility test (pDST), were investigated. WGS was performed using Ion GeneStudio with an ION530tm chip (average sequencing depth, ~100-fold). In the phylogenetic tree, identical and different strains were distributed separately. Five of the seven isolates were identical; the remaining two isolates differed from the others. The images of the referred pre-XDR-TB patients with false positive MTB that were analyzed were of regions close to old TB scars. Further, the results of WGS gene mutation analysis for ethambutol, streptomycin, and fluoroquinolone resistance in all six patients were not concordant with the pDST results. WGS and clinical information were useful in differentiating laboratory cross-contamination from true positive TB, thereby avoiding the unnecessary treatment of false positive patients and delay in treating true positive TB patients, with reliable genotypic drug resistance results.