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Background Rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) is featured by challenges in the treatment, low cure rate, and high infectivity. Fluoroquinolones (FQs), as the core drugs for the treatment of RR/MDR-TB, have a severe trend of resistance. Analyzing influencing factors for FQs can help to increase the cure rate of RR/MDR-TB and to control the occurrence of the pre-extensive drug resistance (pre-XDR) and extensive drug resistance. Objective To analyze the drug resistance of FQs in hospitalized patients with pulmonary tuberculosis and the influencing factors, and to construct and validate a Nomogram prediction model for the risk factors of drug resistance of FQs. Methods A total of 583 patients with pulmonary tuberculosis who were hospitalized in Guiyang Public Health Clinical Center from January 2021 to February 2022 and tested for drug sensitivity were retrospectively selected as study subjects. They were divided into the initial treatment group (296 patients) and the retreatment group (287 patients) according to the history of previous treatment. Moreover, they were divided into the FQs-resistant group (63 patients) and FQs-sensitive group (520 patients) according to their FQs-resistance status. The distribution of total resistance to 13 antituberculosis drugs in 583 patients was analyzed, and the baseline characteristics of patients in the FQs-resistant group and FQs-sensitive group were compared. After screening the characteristic variables using least absolute shrinkage and selection operator (LASSO) regression model, multivariate Logistic regression was performed to analyze the independent risk factors for the resistance of FQs. A Nomogram prediction model was constructed, and its performance was validated by calculating the area under the curve (AUC) of receiver operating characteristic (ROC), and plotting the calibration curve. Results Among 583 patients, 520 cases were sensitive to FQs and 63 cases were resistant (resistance rate of 10.81%). The resistance rate of FQs was secondary to the total resistance rate of first-line antituberculosis drugs, including the isoniazid (36.36%), rifampicin (32.76%), streptomycin (21.61%), and ethambutol (12.86%). The resistance rates of rifampicin, isoniazid, ethambutol, streptomycin, levofloxacin, moxifloxacin and rifampicin resistance (RR), multidrug resistance (MDR), and pre-XDR were significantly higher in patients of the retreatment group than those of the initial treatment group (P

BACKGROUND: Treatment 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. METHODS: endTB-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. DISCUSSION: This 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 REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, has been a persistent global health challenge for thousands of years, known historically by various names and often romanticized in 19th-century literature. Despite advancements in medical science, TB remains a significant issue, particularly in economically disadvantaged regions like Romania, which has one of the highest TB mortality rates in the European Union. The disease's ability to remain latent and become active when the immune system is weakened contributes to its persistence and danger. Adherence to TB treatment is crucial for controlling the disease and preventing the development of drug resistance. Factors affecting adherence include socio-economic status, education, access to healthcare, and social support. Financial incentives have been shown to improve treatment adherence among vulnerable populations, suggesting that addressing economic barriers is essential for effective TB control. This study explores the socio-historical context of TB and evaluates the effectiveness of financial incentives in improving treatment adherence, especially for multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Moreover, a quantitative analysis was performed on MDR-TB and XDR-TB patients in order to achieve a comprehensive grasp on the interaction between financial incentives and adherence to treatment. This article highlights the importance of a patient-centered approach in TB treatment, incorporating psychological and social support to enhance adherence. More precisely, the combination of socio-historical and quantitative analyses pinpoints the fact that improving living conditions and providing financial aid are vital components in the battle against TB. [ABSTRACT FROM AUTHOR]

While the goal of universal drug susceptibility testing has been a key component of the WHO End TB Strategy, in practice, this remains inaccessible to many. Rapid molecular tests for tuberculosis (TB) and antituberculosis drug resistance could significantly improve access to testing. In this study, we evaluated the accuracy of the Akonni Biosystems XDR-TB (extensively drug-resistant TB) TruArray and lateral-flow-cell (XDR-LFC) assay (Akonni Biosystems, Inc., Frederick, MD, USA), a novel assay that detects mutations in seven genes associated with resistance to antituberculosis drugs: katG, the inhA promoter, and the ahpC promoter for isoniazid; rpoB for rifampin; gyrA for fluoroquinolones; rrs and the eis promoter for kanamycin; and rrs for capreomycin and amikacin. We evaluated assay performance using direct sputum samples from 566 participants recruited in a prospective cohort in Moldova over 2 years. The sensitivity and specificity against the phenotypic reference were both 100% for isoniazid, 99.2% and 97.9% for rifampin, 84.8% and 99.1% for fluoroquinolones, 87.0% and 84.1% for kanamycin, 54.3% and 100% for capreomycin, and 79.2% and 100% for amikacin, respectively. Whole-genome sequencing data for a subsample of 272 isolates showed 95 to 99% concordance with the XDR-LFC-reported suspected mutations. The XDR-LFC assay demonstrated a high level of accuracy for multiple drugs and met the WHO's minimum target product profile criteria for isoniazid and rifampin, while the sensitivity for fluoroquinolones and amikacin fell below target thresholds, likely due to the absence of a gyrB target in the assay. With optimization, the XDR-LFC shows promise as a novel near-patient technology to rapidly diagnose drug-resistant tuberculosis.

To describe demographics, clinical features, and treatment outcomes of patients with highly drug-resistant tuberculosis (TB) in Ukraine, and to evaluate risk factors for an unsuccessful outcome. Data from patients with multi-, pre-extensively, or extensively drug-resistant TB were collected prospectively from TB dispensaries in 15 out of 24 Ukrainian oblasts (regions) from 2020 to 2021. Treatment outcomes were evaluated using WHO definitions. Risk factors for an unsuccessful outcome were identified using a multivariable logistic regression model. Among 1748 patients, the overall proportion of successful outcomes was 58% (95% confidence interval [95% CI] 56–60) (n = 1015/1748), ranging from 65% (95% CI: 62–69) (n = 531/814) for multidrug-resistant TB to 54% (95% CI: 49–58) (n = 301/563) for pre-extensively drug-resistant TB and 49% (95% CI: 44–55) (n = 183/371) for extensively drug-resistant TB. Results were similar across oblasts, with few exceptions. The strongest risk factors for an unsuccessful outcome were extensively drug-resistant TB (adjusted OR [aOR] 3.23; 95% CI: 1.88–5.53), total serum protein below 62 g/L in adults and below 57 g/L for children and adolescents (aOR 2.79; 95% CI: 1.93–4.04), psychiatric illness (aOR 2.79; 95% CI: 1.46–5.33), age at TB diagnosis >65 years (aOR 2.50; 95% CI: 1.42–4.42), and alcohol misuse (aOR 2.48; 95% CI: 1.89–3.26). The overall proportion of successful outcomes among Ukrainians treated for highly drug-resistant TB was 58%, notably better compared with previous years, but still low for extensively drug-resistant TB. Risk factors for unsuccessful outcomes highlight that addressing socioeconomic factors in TB management is crucial. Efforts in maintaining TB dispensaries during and following the ongoing war are highly warranted. [ABSTRACT FROM AUTHOR]

The rise of drug-resistant tuberculosis (TB) has become a significant public health concern, representing a threat to global TB control programs. Extensively drug-resistant TB (XDR-TB) accounts for approximately 9% of all drug-resistant cases, and its incidence has been increasing. In this study, we aimed to investigate the burden of TB during 1990-2019 in six regions of the World Health Organization according to sex. Geographical distribution and trend of incidence, prevalence, years of life lost (YLL) from mortality, and years lived with disability (YLD) of XDR-TB were evaluated according to sex using geographic maps and trend plots. In both sex groups, the rate of the four indicators were the highest in Europe and the lowest in America (values in the first quartile). In Africa, the incidence, prevalence, YLD values fell in the first quartile. The trend of incidence, prevalence, and YLD generally increased in all the regions. However, a decreasing trend has been observed in recent years in the Western Pacific region and Europe. Additionally, in general, YLL exhibited a stable or decreasing trend in the last few years in all the regions. The strategies that have achieved a decrease in trend in some years should be further analyzed by policymakers to identify appropriate solutions to control XDR-TB. Furthermore, Europe, South-East Asia, and the Eastern Mediterranean region require special attention. Additionally, implementation of effective strategies can greatly improve TB control in the world.

In 2021, the World Health Organization recommended new extensively drug-resistant (XDR) and pre-XDR tuberculosis (TB) definitions. In a recent cohort of TB patients in Eastern Europe, we show that XDR TB as currently defined is associated with exceptionally poor treatment outcomes, considerably worse than for the former definition (31% vs. 54% treatment success).

Purpose: To describe katG and inhA mutations, clinical characteristics, treatment outcomes and clustering of drug-resistant tuberculosis (TB) in the State of São Paulo, southeast Brazil. Methods: Mycobacterium tuberculosis isolates from patients diagnosed with drug-resistant TB were screened for mutations in katG and inhA genes by line probe assay and Sanger sequencing, and typed by IS6110-restriction fragment-length polymorphism for clustering assessment. Clinical, epidemiological and demographic data were obtained from surveillance information systems for TB. Results: Among the 298 isolates studied, 127 (42.6%) were isoniazid-monoresistant, 36 (12.1%) polydrug-resistant, 93 (31.2%) MDR, 16 (5.4%) pre-extensively drug-resistant (pre-XDR), 9 (3%) extensively drug-resistant (XDR) and 17 (5.7%) susceptible after isoniazid retesting. The frequency of katG 315 mutations alone was higher in MDR isolates, while inhA promoter mutations alone were more common in isoniazid-monoresistant isolates. Twenty-six isolates phenotypically resistant to isoniazid had no mutations either in katG or inhA genes. The isolates with inhA mutations were found more frequently in clusters (75%) when compared to the isolates with katG 315 mutations (59.8%, p = 0.04). In our population, being 35–64 years old, presenting MDR-, pre-XDR- or XDR-TB and being a retreatment case were associated with unfavourable TB treatment outcomes. Conclusion: We found that katG and inhA mutations were not equally distributed between isoniazid-monoresistant and MDR isolates. In our population, clustering was higher for isolates with inhA mutations. Finally, unfavourable TB outcomes were associated with specific factors. [ABSTRACT FROM AUTHOR]

A wide range of comorbidities, especially in multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) patients, markedly complicates selecting effective treatment of tuberculosis (TB) and preventing the development of adverse events. At present, it is impossible to assess the severity of comorbid pathologies and develop indications for the administration of accompanying therapy in TB patients. The aim of this study was to identify the difference in the range of comorbidities between patients with MDR-TB and XDR-TB and assess the impact of comorbidities on TB treatment. Materials and Methods: A retrospective, prospective study was conducted where 307 patients with MDR-TB and XDR-TB pulmonary tuberculosis aged 18 to 75 years who received eTB treatment from 2016 to 2021 in St. Petersburg hospitals were analyzed. The analysis showed that the comorbidity level in MDR-TB and XDR-TB patients with TB treatment success and treatment failure was comparable with the use of the Charlson Comorbidity Index (CCI). The CCI demonstrated declining data in terms of TB treatment outcome period in both groups. A slight predominance of CCI score (3 to 4 points) in XDR-TB (22.7%) vs. MDR-TB (15.4%) patients was found. In the case of an TB treatment failure, the CCI level in MDR-TB vs. XDR-TB patients was characterized by a significantly higher rate of low magnitude (ranging from 1 to 2 points) in 21.1% vs. 4.5% (p < 0.05), which was higher in XDR-TB patients (ranging from 4 to 5 points, in 10.0% vs. 0, χ2 = 33.7 (p < 0.01)). Chronic viral hepatitis B and C infection, cardiovascular pathology, chronic obstructive pulmonary disease, and chronic alcoholism were found to be significant comorbidity factors that influenced the TB treatment success. Conclusions: It is evident that XDR-TB patients comprise a cohort with the most severe disease course due to comorbidities impacting TB treatment efficacy. The obtained data pointed to the need to determine comorbidity severity in patients with drug-resistant Mbt prior to administering TB treatment schemes. [ABSTRACT FROM AUTHOR]

Objective: To assess the patterns of drug resistance (DR) among patients previously treated for pulmonary tuberculosis (TB). Study Design: Cross-sectional study. Place and Duration of Study: Department of Medicine, Pak-Emirates Military Hospital, Rawalpindi Pakistan, from Jul 2020 to Mar 2021. Methodology: Patients with previously treated pulmonary TB were included, based on their clinical history and characteristic chest X-ray findings. Patients were evaluated through an examination of sputum and/or bronchoalveolar washings for acidfast bacilli (AFB), Mycobacterium TB-GeneXpert/RIF (Rifampicin) assay, and mycobacterial culture with drug susceptibility testing (DST). Patients with resistance to any anti-TB drug were classified as cases of DR-TB, and a pattern of drug resistance was documented. Results: One hundred twenty patients were identified as having been previously treated for TB. DST demonstrated DR-TB among 38(31.7%) cases, while isoniazid (INH) resistance was the most commonly reported problem in 29(24.2%) cases. Up to 26(21.6%) relapsing cases were resistant to Rifampicin (RFM). Moreover, 15(12.5%) instances of resistance against second-line anti-TB drugs (fluoroquinolones and aminoglycosides) were documented. Multidrug-resistant TB (MDR-TB) was the most prevalent resistance pattern in 20(16.7%) cases, followed by mono-drug-resistant TB in 7(5.8%) and extensively resistant TB (XDR-TB) in 2(1.6%) cases. No definitive resistance pattern was evident among 9(7.5%) cases. Conclusion: MDR-TB constitutes a major barrier in the line of TB eradication in Pakistan. Strict compliance with anti-TB protocols, along with a universal application of DST, can minimize the overall prevalence of relapsing cases of TB

BackgroundWe evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. .MethodsA pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥ grade 3 adverse events according to the NIAID Division of Microbiology and Infectious Disease Adult Toxicity table.ResultsPredicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [CI], 17%-22% vs 5%, 4%-7%) and severe anemia (15%, 12%-17% vs 1%, 0%-2%) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median, 10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the dose from 1200 to 600 mg triggered by this marker may prevent 60% (90% CI, 45%-72%) of severe anemia.ConclusionsSimple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm the benefit-to-risk ratio.

Objectives: To estimate the pooled proportion of extensively drug-resistant tuberculosis (XDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) in patients with multidrug-resistant TB (MDR-TB). Methods: We systematically searched articles from electronic databases: MEDLINE (PubMed), ScienceDirect, and Google Scholar. We also searched gray literature from the different literature sources main outcome of the review was either XDR-TB or pre-XDR-TB in patients with MDR-TB. We used the random-effects model, considering the substantial heterogeneity among studies. Heterogeneity was assessed by subgroup analyses. STATA version 14 was used for analysis. Results: A total of 64 studies that reported on 12,711 patients with MDR-TB from 22 countries were retrieved. The pooled proportion of pre-XDR-TB was 26% (95% confidence interval [CI]: 22-31%), whereas XDR-TB in MDR-TB cases was 9% (95% CI: 7-11%) in patients treated for MDR-TB. The pooled proportion of resistance to fluoroquinolones was 27% (95% CI: 22-33%) and second-line injectable drugs was 11% (95% CI: 9-13%). Whereas the pooled resistance proportions to bedaquiline, clofazimine, delamanid, and linezolid were 5% (95% CI: 1-8%), 4% (95% CI: 0-10%), 5% (95% CI; 2-8%), and 4% (95% CI: 2-10%), respectively. Conclusion: The burden of pre-XDR-TB and XDR-TB in MDR-TB were considerable. The high burdens of pre-XDR-TB and XDR-TB in patients treated for MDR-TB suggests the need to strengthen TB programs and drug resistance surveillance.

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the second leading cause of death from a single infectious disease globally and poses a significant economic and clinical burden in the world in 2022. Of particular concern is the emergence of drug-resistant TB, accounting for 15%–20% of TB deaths. It is imperative to delve into the global trends of incidence and death rate for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), drawing upon the comprehensive Global Burden of Disease (GBD) 2021 drug-resistant tuberculosis dataset. Methods: From the GBD 2021, data on incidence, prevalence, disability-adjusted life years (DALYs), and death of MDR-TB and XDR-TB from 1990 to 2021 were collected. We calculated the estimated annual percentage changes in age standardized incidence rate (ASIR) and age-standardized death rate (ASDR), segmented by age, sex, and Socio-demographic Index (SDI). The impacts of various risk factors on MDR-TB and XDR-TB were also analyzed. Results: In 2021, there were an estimated 443,680 (95% uncertainty interval [UI]: 259,196–766,545) incident cases of MDR-TB, and an estimated 106,818 (95% UI: 41,612–211,854) death cases of MDR-TB, while there were an estimated 24,036 (95% UI: 17,144–34,587) incident cases of XDR-TB and 7,946 (95% UI: 3,326–14,859) death cases of XDR-TB. The incidence and death cases of MDR-TB were lowest in high SDI regions, whereas the incidence rates of XDR-TB in high-middle SDI regions were higher than those in middle SDI and high SDI regions. Conclusion: This study reported the disease burden of drug-resistant TB from 1990 to 2021. Until 2021, drug-resistant TB is still a serious problem in low SDI countries, especially for high-risk age populations with high-risk factors. Controlling drug-resistant TB requires effective control strategies and healthcare systems.

Abstract Objectives: to identify the scientific evidence on excessively resistant and multidrug resistant tuberculosis in pediatric patients. Methods: this is a scope review of the literature, with a guiding question: “What is the scientific evidence on multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis in pediatric patients?”. The research used the descriptors: “extensively drug-resistant tuberculosis” OR “multidrug-resistant tuberculosis” AND “pediatrics”. The research was carried out in a double-blind manner in the following databases of the Medical Literature Analysis and Retrieval System Online, Regional Office for the Western Pacific’s Institutional Repository for Information Sharing, Embase/Elsevier and International Clinical Trials Registry Platform, with a temporal cut-off from 2011 to 2021, sending a final synthesized sample of 18 articles, which evaluated the methodological content through the level of evidence. Results: the results show the lack of research with a high level of evidence related to MDR-TB in children, the lack of adequate dosage of second-line drugs for the pediatric population and the importance of drug sensitivity testing for the cases of treatment Conclusions: it was identified that the obstacles to MDR-TB treatment were concentrated in the lack of detailed protocols, safe drug dosages with a low side effect, and mainly in the social health determinants and disease process involving MDR-TB.

ABSTRACT Objective: To assess the impact of COVID-19 on the morbidity and mortality associated with drug-resistant tuberculosis (DR-TB). Methods: A comprehensive review of articles published in international databases since December 2019 was conducted. The findings are presented in a narrative format, supplemented with tables, diagrams, and a map created using ArcGIS software. Results: Thirty-five studies were selected, highlighting the significant consequences of COVID-19 on TB and DR-TB treatment progress. Four main thematic areas were identified: Clinical and epidemiological aspects of the interaction between COVID-19 and DR-TB; Management of physical resources and the team; Challenges and circumstances; Perspectives and possibilities. Conclusions: This study revealed that the COVID-19 pandemic significantly negatively impacted the control of long-standing diseases like TB, particularly in the context of morbidity and mortality related to DR-TB.

Mycobacterium tuberculosis , the causative agent of tuberculosis, is acquiring drug resistance at a faster rate than the discovery of new antibiotics. Therefore, alternate therapies that can limit the drug resistance and disease recurrence are urgently needed. Emerging evidence indicates that combined treatment with antibiotics and an immunomodulator provides superior treatment efficacy. Clofazimine (CFZ) enhances the generation of T central memory (TCM) cells by blocking the Kv1.3+ potassium channels. Rapamycin (RAPA) facilitates M. tuberculosis clearance by inducing autophagy. In this study, we observed that cotreatment with CFZ and RAPA potently eliminates both multiple and extensively drug-resistant (MDR and XDR) clinical isolates of M. tuberculosis in a mouse model by inducing robust T-cell memory and polyfunctional TCM responses. Furthermore, cotreatment reduces the expression of latency-associated genes of M. tuberculosis in human macrophages. Therefore, CFZ and RAPA cotherapy holds promise for treating patients infected with MDR and XDR strains of M. tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Proline-glutamate (PE)/proline-PE (PPE) proteins play an important role in the development of mycobacterial pathogenicity by modulating the host immune system. In the present investigation, the structural changes in PE-polymorphic GC-rich sequences (PGRS) family protein Wag22 (Rv1759c), PE_PGRS31 (Rv1768), PE_PGRS32 (Rv1803), and PE_PGRS33 gene (Rv1818c) were compared and analyzed in exponential state and under in vitro model of latency in same clinical isolates of Mycobacterium tuberculosis (MTB). Methods: MTB strains were isolated from clinically and laboratory-confirmed cases of tuberculosis (TB). The TB isolates were subjected to the Xpert MTB/rifampin test and then, further susceptibility testing using proportional methods was performed on them. The isolates were characterized using both 16S–23S RNA and hsp65 genes spacer polymerase chain reaction-restriction fragment length polymorphism. Selected isolates studied at two experimental set–up at exponential phase OD 600 = 0.05 (5 cfu/mL × 106 cfu/mL) and under zero oxygen and nutrition for 26 months to selected isolates studied at two experimental setup in exponential phase OD600 = 0.05 (5 cfu/mL × 106 cfu/mL) and under zero oxygen and nutrition after 26 months. Whole-genome sequencing was performed on studied isolates and the protein structures were analyzed using a bioinformatics web server. Results: No deletion, insertion, or substation occurred in susceptible, mono-drug and multidrug resistant-TB isolates were observed at PE-PGRS family protein Wag22 (Rv1759c) and PE_PGRS31 (Rv1768) at exponential phase. Although, a large deletion (at Rv1759c; Rv1768) was observed in extensively drug-resistant (XDR) and totally drug-resistant (TDR) TB isolates at the exponential phase. All studied TDR-TB isolates had a common deletion position from amino acid 1 (methionine) to amino acid 83 (glycine) and from amino acid 725 (proline) to amino acid 914 (threonine) at PE-PGRS family protein Wag22 (Rv1759c). At PE_PGRS32 (Rv1803), deletion occurred from amino acid 1 (methionine) to amino acid 212 (glycine) in latent TDR-TB bacilli. No changes in Rv1803 were observed in other studied isolates. In contrast, 66.6% of studied isolates had either insertion, deletion, substitution, or combination of changes at PE_PGRS33 (Rv1818c). However, the majority of changes at Rv1818c occurred in drug-resistant isolates. We also documented the region of deletion and insertion at PE_PGRS33 (Rv1818c) is different in active and latent TDR-TB isolates. Conclusions: Changes in these PE-PGRS family protein was associated with drug susceptibility patterns of individual isolates. Our result showed a total frameshift mutation of protein that had a different length in comparison to the original protein. These changes might disturb the interactions between XDR and TDR-TB isolates and immune responses, which needs further investigation. [ABSTRACT FROM AUTHOR]

Historically, extensively drug-resistant tuberculosis has been notoriously difficult to treat with devasting outcomes. As we are coming to the end of an era where the 2006 extensively drug-resistant tuberculosis definitions and old treatment regimens are being replaced, we aimed to estimate the proportion of extensively drug-resistant tuberculosis patients globally who achieved successful treatment outcomes. We conducted a systematic review of PubMed/MEDLINE, Scopus, Web of Science, and Embase from January 1, 2005, through April 3, 2023. Included studies reported WHO treatment outcomes, or adaptions hereof, for pre-extensively and/or extensively drug-resistant tuberculosis patients according to the 2006 WHO definition. Eligible studies included cohorts of at least 10 adults (aged>18 years) that were not pregnant. Using a random-effects model, we calculated pooled proportions of treatment outcomes and performed sensitivity and subgroup analyses. PROSPERO registration number: CRD42022340961. Among 5056 studies reviewed, we identified 94 studies from 26 countries, involving 10,223 extensively drug-resistant tuberculosis patients. The pooled proportion of successful treatment outcomes was 44.2% (95%CI: 38.3–50.3). Sensitivity analyses consistently produced similar estimates. A slight improvement in treatment outcomes was observed after 2013. Furthermore, 25 studies reported outcomes for 3564 individuals with pre-extensively drug-resistant tuberculosis, of which 63.3% achieved successful treatment (95%CI: 43.1–72.5). Globally, the success rate of extensively drug-resistant tuberculosis treatment is 44.2%, far below the WHO's target rate of 75%. These results may serve as a reference for future studies assessing extensively drug-resistant tuberculosis treatment outcomes under the 2021 definition treated with better treatment regimens available. Comprehensive surveillance data of extensively drug-resistant tuberculosis outcomes from the whole world are desirable to monitor treatment progress. [ABSTRACT FROM AUTHOR]

BACKGROUND: Delays in seeking and accessing treatment for rifampicin-resistant tuberculosis (RR-TB) and multi-drug resistant (MDR-TB) are major impediments to TB control in high-burden, resource-limited settings. METHOD: We prospectively determined health-seeking behavioural patterns and associations with treatment outcomes and costs among 68 RR-TB patients attending conveniently selected facilities in a decentralised system in Harare, Zimbabwe. RESULTS: From initial symptoms to initiation of effective treatment, patients made a median number of three health care visits (IQR 2-4 visits) at a median cost of 13% (IQR 6-31%) of their total annual household income (mean cost, US$410). Cumulatively, RR-TB patients most frequently first visited private facilities, i.e., private pharmacies (30%) and other private health care providers (24%) combined. Median patient delay was 26 days (IQR 14-42 days); median health system delay was 97 days (IQR 30-215 days) and median total delay from symptom onset to initiation of effective treatment was 132 days (IQR 51-287 days). The majority of patients (88%) attributed initial delay in seeking care to not feeling sick enough. Total delay, total cost and number of health care visits were not associated with treatment or clinical outcomes, though our study was not adequately powered for these determinations. CONCLUSIONS: Despite the public availability of rapid molecular TB tests, patients experienced significant delays and high costs in accessing RR-TB treatment. Active case finding, integration of private health care providers and enhanced service delivery may reduce treatment delay and TB associated costs.

• Patients with multidrug-resistant tuberculosis (MDR-TB) have high pre-extensively drug-resistant and extensively drug-resistant levels, with 9% and 26%, respectively. • Fluoroquinolones and second-line injectable drugs were 27% and 11%, respectively, among patients with MDR-TB. • Patients with MDR-TB are resistant to new TB drugs in 4-5% of cases. To estimate the pooled proportion of extensively drug-resistant tuberculosis (XDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) in patients with multidrug-resistant TB (MDR-TB). We systematically searched articles from electronic databases: MEDLINE (PubMed), ScienceDirect, and Google Scholar. We also searched gray literature from the different literature sources main outcome of the review was either XDR-TB or pre-XDR-TB in patients with MDR-TB. We used the random-effects model, considering the substantial heterogeneity among studies. Heterogeneity was assessed by subgroup analyses. STATA version 14 was used for analysis. A total of 64 studies that reported on 12,711 patients with MDR-TB from 22 countries were retrieved. The pooled proportion of pre-XDR-TB was 26% (95% confidence interval [CI]: 22-31%), whereas XDR-TB in MDR-TB cases was 9% (95% CI: 7-11%) in patients treated for MDR-TB. The pooled proportion of resistance to fluoroquinolones was 27% (95% CI: 22-33%) and second-line injectable drugs was 11% (95% CI: 9-13%). Whereas the pooled resistance proportions to bedaquiline, clofazimine, delamanid, and linezolid were 5% (95% CI: 1-8%), 4% (95% CI: 0-10%), 5% (95% CI; 2-8%), and 4% (95% CI: 2-10%), respectively. The burden of pre-XDR-TB and XDR-TB in MDR-TB were considerable. The high burdens of pre-XDR-TB and XDR-TB in patients treated for MDR-TB suggests the need to strengthen TB programs and drug resistance surveillance. [ABSTRACT FROM AUTHOR]

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Background: Making a preliminary diagnosis using X-ray methods for the study of resistant and resistant tuberculosis (TB) will help to make a preliminary diagnosis and determine further tactics for the treatment of TB, even with limited resources for microbiological diagnosis of drug resistance of TB. The present study was aimed at identifying chest X-ray differences between susceptible and resistant TB. Methods: A prospective cohort study of data from all consecutive patients with culture-confirmed pulmonary TB admitted during the year to the Kharkiv TB Dispensary No. 1 in Kharkiv, Ukraine. Results: One hundred and sixty-eight patients with lung TB were examined. Patients were divided into two groups: 1st patients with pulmonary TB with resistance of Mycobacterium tuberculosis (MTB) to at least isoniazid and rifampicin (resistant TB) and 2nd pulmonary TB with preserved susceptibility of MTB to anti-TB drugs (susceptible-TB). Patients of 1st group often had lesions in two lobes of the lungs 31.1% and one lung 43.3% versus 15.4% and 2.6% of patients with susceptible TB (P < 0.001). In addition, more than 3 cavities in the lungs 45.5% were significantly more often observed in patients with resistant TB versus 7.9%-the 2nd group (P < 0.001). Smaller cavities were observed in patients with susceptible TB up to 1.99 cm 74% versus 35.2% in 1st group (P < 0.001). We did not observe any significant radiological features depending on the right or left lung, as well as the lobar localization of the TB process. Conclusions: For resistant forms of TB, radiologically, a more widespread TB process in the lungs with the presence of a larger number of cavities and their larger size against a background of a more pronounced clinical picture and mycobacterium excretion than with susceptible TB is characteristic. [ABSTRACT FROM AUTHOR]

Background: Proline-glutamate (PE)/proline-PE (PPE) proteins play an important role in the development of mycobacterial pathogenicity by modulating the host immune system. In the present investigation, the structural changes in PE-polymorphic GC-rich sequences (PGRS) family protein Wag22 (Rv1759c), PE_PGRS31 (Rv1768), PE_PGRS32 (Rv1803), and PE_PGRS33 gene (Rv1818c) were compared and analyzed in exponential state and under in vitro model of latency in same clinical isolates of Mycobacterium tuberculosis (MTB). Methods: MTB strains were isolated from clinically and laboratory-confirmed cases of tuberculosis (TB). The TB isolates were subjected to the Xpert MTB/rifampin test and then, further susceptibility testing using proportional methods was performed on them. The isolates were characterized using both 16S–23S RNA and hsp65 genes spacer polymerase chain reaction-restriction fragment length polymorphism. Selected isolates studied at two experimental set–up at exponential phase OD 600 = 0.05 (5 cfu/mL × 106 cfu/mL) and under zero oxygen and nutrition for 26 months to selected isolates studied at two experimental setup in exponential phase OD600 = 0.05 (5 cfu/mL × 106 cfu/mL) and under zero oxygen and nutrition after 26 months. Whole-genome sequencing was performed on studied isolates and the protein structures were analyzed using a bioinformatics web server. Results: No deletion, insertion, or substation occurred in susceptible, mono-drug and multidrug resistant-TB isolates were observed at PE-PGRS family protein Wag22 (Rv1759c) and PE_PGRS31 (Rv1768) at exponential phase. Although, a large deletion (at Rv1759c; Rv1768) was observed in extensively drug-resistant (XDR) and totally drug-resistant (TDR) TB isolates at the exponential phase. All studied TDR-TB isolates had a common deletion position from amino acid 1 (methionine) to amino acid 83 (glycine) and from amino acid 725 (proline) to amino acid 914 (threonine) at PE-PGRS family protein Wag22 (Rv1759c). At PE_PGRS32 (Rv1803), deletion occurred from amino acid 1 (methionine) to amino acid 212 (glycine) in latent TDR-TB bacilli. No changes in Rv1803 were observed in other studied isolates. In contrast, 66.6% of studied isolates had either insertion, deletion, substitution, or combination of changes at PE_PGRS33 (Rv1818c). However, the majority of changes at Rv1818c occurred in drug-resistant isolates. We also documented the region of deletion and insertion at PE_PGRS33 (Rv1818c) is different in active and latent TDR-TB isolates. Conclusions: Changes in these PE-PGRS family protein was associated with drug susceptibility patterns of individual isolates. Our result showed a total frameshift mutation of protein that had a different length in comparison to the original protein. These changes might disturb the interactions between XDR and TDR-TB isolates and immune responses, which needs further investigation.

Background: Making a preliminary diagnosis using X-ray methods for the study of resistant and resistant tuberculosis (TB) will help to make a preliminary diagnosis and determine further tactics for the treatment of TB, even with limited resources for microbiological diagnosis of drug resistance of TB. The present study was aimed at identifying chest X-ray differences between susceptible and resistant TB. Methods: A prospective cohort study of data from all consecutive patients with culture-confirmed pulmonary TB admitted during the year to the Kharkiv TB Dispensary No. 1 in Kharkiv, Ukraine. Results: One hundred and sixty-eight patients with lung TB were examined. Patients were divided into two groups: 1st patients with pulmonary TB with resistance of Mycobacterium tuberculosis (MTB) to at least isoniazid and rifampicin (resistant TB) and 2nd pulmonary TB with preserved susceptibility of MTB to anti-TB drugs (susceptible-TB). Patients of 1st group often had lesions in two lobes of the lungs 31.1% and one lung 43.3% versus 15.4% and 2.6% of patients with susceptible TB (P < 0.001). In addition, more than 3 cavities in the lungs 45.5% were significantly more often observed in patients with resistant TB versus 7.9%-the 2nd group (P < 0.001). Smaller cavities were observed in patients with susceptible TB up to 1.99 cm 74% versus 35.2% in 1st group (P < 0.001). We did not observe any significant radiological features depending on the right or left lung, as well as the lobar localization of the TB process. Conclusions: For resistant forms of TB, radiologically, a more widespread TB process in the lungs with the presence of a larger number of cavities and their larger size against a background of a more pronounced clinical picture and mycobacterium excretion than with susceptible TB is characteristic.

Tuberculosis is a leading cause of death in our country. Multidrug-resistant tuberculosis increases the morbidity and mortality due to severe manifestations and difficult and prolonged medications. Newer antitubercular drugs like delamanid have been approved by WHO in management of these cases, but the real-world experience of this drug is lacking in our country. We present our early experience of use of delamanid in extensively drug-resistant pulmonary tuberculosis.

Presentation: In this article we present our critical appraisal of a randomized clinical trial published in the New England Journal of Medicine in 2022. Study conclusions: The study compares four linezolid regimens (in addition to bedaquiline and pretomanid) for the management of drug-resistant tuberculosis. Finally, it shows that the regimen of 600 mg of linezolid for 26 weeks had less frequency of therapeutic failure and adverse events (compared to giving it for fewer weeks or at higher doses). Critical comment: The article is relevant because the appropriate dose of linezolid and duration of treatment with this agent to minimize adverse effects and maintain efficacy against highly resistant tuberculosis is still unclear. Despite some limitations such as low number of participants, high loss to follow-up, and no statistical comparisons between groups, the results are relatively reliable for decision making. [ABSTRACT FROM AUTHOR]

Objectives: To describe the clinical characteristics and outcomes of cycloserine (CS)-induced psychosis in adults diagnosed with drug-resistant tuberculosis (DR-TB). Materials and methods: A systematic review of case reports was carried out according to PRISMA guidelines. Subsequently, information was extracted concerning sociodemographic variables, clinical characteristics of psychosis, treatment, and clinical outcomes, as well as the quality of the articles using a standardized tool (Joanna Briggs Institute—JBI—Case Reports Tool). Results: Of 3416 articles, 20 reports from seven countries were included, encompassing 22 patients (68.18% male participants, mean age: 31.45 ± 10.88 years). Delusions (68.2%, primarily persecutory) were the most frequent psychotic symptom. The median duration of the psychotic episode was 13 days (interquartile range: 35). Other frequently appearing symptoms in CS-induced psychosis were aggressiveness (68.2%), insomnia (59.1%), hallucinations (54.5%), incoherent/disorganized speech (45.5%), and irritability (45.5%). After antipsychotic treatment (81.81% of the reported cases were treated with at least one antipsychotic), 95.5% presented improvement, while 4.54% died by suicide. Finally, after the quality assessment of studies using the JBI tool, 85% of the articles showed a low risk of bias. Conclusions: CS-induced psychosis is a rare presentation, generally of short duration, that includes delusions (mostly persecutory) as its main psychotic symptom and shows mostly a symptom improvement after medical treatment. Trial registration PROSPERO registration number: CRD42022359551 (Date of registration: 22/09/2022) [ABSTRACT FROM AUTHOR]

BackgroundGrowth-based drug susceptibility testing (DST) is the reference standard for diagnosing drug-resistant tuberculosis (TB), but standard time to result (TTR) is typically ≥ 3 weeks. Rapid tests can reduce that TTR to days or hours, but accuracy may be lowered. In addition to the TTR and test accuracy, the cost of a diagnostic test may affect whether it is adopted in clinical settings. We examine the cost-effectiveness of rapid diagnostics for extremely drug-resistant TB (XDR-TB) in three different high-prevalence settings.Methods1128 patients with confirmed TB were enrolled at clinics in Mumbai, India; Chisinau, Moldova; and Port Elizabeth, South Africa. Patient sputum samples underwent DST for first and second line TB drugs using 2 growth-based (MGIT, MODS) and 2 molecular (Pyrosequencing [PSQ], line-probe assays [LPA]) assays. TTR was the primary measure of effectiveness. Sensitivity and specificity were also evaluated. The cost to perform each test at each site was recorded and included test-specific materials, personnel, and equipment costs. Incremental cost-effectiveness ratios were calculated in terms of $/day saved. Sensitivity analyses examine the impact of batch size, equipment, and personnel costs.ResultsOur prior results indicated that the LPA and PSQ returned results in a little over 1 day. Mean cost per sample without equipment or overhead was $23, $28, $33, and $41 for the MODS, MGIT, PSQ, and LPA, respectively. For diagnosing XDR-TB, MODS was the most accurate, followed by PSQ, and LPA. MODS was quicker and less costly than MGIT. PSQ and LPA were considerably faster but cost more than MODS. Batch size and personnel costs were the main drivers of cost variation.ConclusionsMultiple factors must be weighed when selecting a test for diagnosis of XDR-TB. Rapid tests can greatly improve the time required to diagnose drug-resistant TB, potentially improving treatment success, and preventing the spread of XDR-TB. Faster time to result must be weighed against the potential for reduced accuracy, and increased costs.Trial registrationClinicalTrials.gov Identifier: NCT02170441 .

Summary: Background: Physical sequelae related to multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are emerging and under-recognised global challenges. This systematic review and meta-analysis aimed to quantify the prevalence and the types of long-term physical sequelae associated with patients treated for MDR- and XDR-TB. Methods: We systematically searched CINAHL (EBSCO), MEDLINE (via Ovid), Embase, Scopus, and Web of Science from inception through to July 1, 2022, and the last search was updated to January 23, 2023. We included studies reporting physical sequelae associated with all forms of drug-resistant TB, including rifampicin-resistant TB (RR-TB), MDR-TB, Pre-XDR-TB, and XDR-TB. The primary outcome of interest was long-term physical sequelae. Meta-analysis was conducted using a random-effect model to estimate the pooled proportion of physical sequelae. The sources of heterogeneity were explored through meta-regression using study characteristics as covariates. The research protocol was registered in PROSPERO (CRD42021250909). Findings: From 3047 unique publications identified, 66 studies consisting of 37,380 patients conducted in 30 different countries were included in the meta-analysis. The overall pooled estimate was 44.4% (95% Confidence Interval (CI): 36.7–52.1) for respiratory sequelae, 26.7% (95% CI: 23.85–29.7) for hearing sequelae, 10.1% (95% CI: 7.0–13.2) for musculoskeletal sequelae, 8.4% (95% CI: 6.5–10.3) for neurological sequelae, 8.1% (95% CI: 6.3–10.0) for renal sequelae, 7.3% (95% CI: 5.1–9.4) for hepatic sequelae, and 4.5% (95% CI: 2.7–6.3) for visual sequelae. There was substantial heterogeneity in the estimates. The stratified analysis showed that the pooled prevalence of hearing sequelae was 26.6% (95% CI: 12.3–40.9), neurological sequelae was 31.5% (95% CI: 5.5–57.5), and musculoskeletal sequelae were 21.5% (95% CI: 9.9–33.1) for patients with XDR-TB, which were higher than the pooled prevalence of sequelae among patients with MDR-TB. Respiratory sequelae were the highest in low-income countries (59.3%) and after completion of MDR-TB treatment (57.7%). Interpretation: This systematic review found that long-term physical sequelae such as respiratory, hearing, musculoskeletal, neurological, renal, hepatic, and visual sequelae were common among survivors of MDR- and XDR-TB. There was a significant difference in the prevalence of sequelae between patients with MDR- and XDR-TB. Post-MDR- and XDR-TB treatment surveillance for adverse outcomes needs to be incorporated into the current programmatic management of MDR-TB to enable early detection and prevention of post-treatment sequelae. Funding: Australian National Health and Medical Research Council, through an Emerging Leadership Investigator grant, and the Curtin University Higher Degree Research scholarship.

Tuberculosis is a leading cause of death in our country. Multidrug-resistant tuberculosis increases the morbidity and mortality due to severe manifestations and difficult and prolonged medications. Newer antitubercular drugs like delamanid have been approved by WHO in management of these cases, but the real-world experience of this drug is lacking in our country. We present our early experience of use of delamanid in extensively drug-resistant pulmonary tuberculosis. [ABSTRACT FROM AUTHOR]

Drug-resistant tuberculosis (TB) is a major global health challenge in part because there are fewer effective treatments and these treatments have been prolonged and more toxic. The evidence base for more effective, shorter, standardized treatments is evolving rapidly. Herein, we report the first case of pre-extensively drug-resistant pulmonary TB treated with a novel six-month all oral bedaquiline, pretomanid and linezolid (BPaL) regimen in Canada. Recent clinical trial data supporting BPaL therapy is presented in the context of current and evolving clinical guidelines. In this article, we highlight significant implementation challenges and make recommendations for what needs to be addressed to ensure safe programmatic use of BPaL in Canada. Key recommendations include the development of infrastructure for timely access to novel TB drug susceptibility testing, streamlining access to novel TB drugs, and cautious use of such drugs in collaboration with care teams with expertise in drug-resistant TB management. [ABSTRACT FROM AUTHOR]

A wide range of comorbidities, especially in multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) patients, markedly complicates selecting effective treatment of tuberculosis (TB) and preventing the development of adverse events. At present, it is impossible to assess the severity of comorbid pathologies and develop indications for the administration of accompanying therapy in TB patients. The aim of this study was to identify the difference in the range of comorbidities between patients with MDR-TB and XDR-TB and assess the impact of comorbidities on TB treatment. Materials and Methods: A retrospective, prospective study was conducted where 307 patients with MDR-TB and XDR-TB pulmonary tuberculosis aged 18 to 75 years who received eTB treatment from 2016 to 2021 in St. Petersburg hospitals were analyzed. The analysis showed that the comorbidity level in MDR-TB and XDR-TB patients with TB treatment success and treatment failure was comparable with the use of the Charlson Comorbidity Index (CCI). The CCI demonstrated declining data in terms of TB treatment outcome period in both groups. A slight predominance of CCI score (3 to 4 points) in XDR-TB (22.7%) vs. MDR-TB (15.4%) patients was found. In the case of an TB treatment failure, the CCI level in MDR-TB vs. XDR-TB patients was characterized by a significantly higher rate of low magnitude (ranging from 1 to 2 points) in 21.1% vs. 4.5% (p < 0.05), which was higher in XDR-TB patients (ranging from 4 to 5 points, in 10.0% vs. 0, χ2 = 33.7 (p < 0.01)). Chronic viral hepatitis B and C infection, cardiovascular pathology, chronic obstructive pulmonary disease, and chronic alcoholism were found to be significant comorbidity factors that influenced the TB treatment success. Conclusions: It is evident that XDR-TB patients comprise a cohort with the most severe disease course due to comorbidities impacting TB treatment efficacy. The obtained data pointed to the need to determine comorbidity severity in patients with drug-resistant Mbt prior to administering TB treatment schemes.

Rationale: Tuberculosis (TB) and diabetes mellitus (DM) are converging epidemics, each worsening the morbidity of the other. Chronic hyperglycemia is associated with dysfunctional immunity to Mycobacterium in patients with DM and, therefore, is likely to decrease the efficiency of anti-mycobacterial treatment. Early aggressive management of TB and timely initiation of insulin therapy helps in controlling the glycemic excursions that are otherwise not controlled by multiple oral antidiabetic agents. Patient Concerns: A 42-year-old female with type 2 diabetes for six years presented with complaints of persistent cough, pain in the chest, weight loss, and loss of appetite for two months in November 2018. Diagnosis: The patient was diagnosed with multidrug-resistant TB (MDR-TB), which further progressed to extensively drug-resistant TB (XDR-TB) in February 2019. Her hemoglobin A1c (HbA1c), which was 8.3% prior to TB diagnosis, increased to 13.8%. Interventions: The patient was initiated on anti-TB medications as per the Revised National TB Control Programme (RNTCP) guidelines. The antidiabetic regimen consisted of glimepiride 2 mg b.i.d, metformin 500 mg b.i.d, and voglibose 0.2 mg b.i.d. On confirmation of XDR-TB and persistently high HbA1c, insulin glargine was initiated in July 2019. Due to continued uncontrolled blood glucose levels, insulin IDegAsp (30% Aspart and 70% Degludec) was initiated in February 2020. Results: After the initiation of IdegAsp, HbA1c levels reduced significantly and there was improvement in the measures of daily blood glucose level indices such as time in target range (TIR), time below target range (TBR), and time above target range (TAR). Optimal blood glucose was achieved in a significant amount of time in a day. Sputum was negative for XDR-TB in February 2021, and the patient recovered from TB. Her HbA1c was reported to be 7.5% in February 2021. Conclusion: In patients with type 2 diabetes and TB, maintaining optimal blood glucose level for a longer duration of time can have a positive impact on host immunity and also enhance the effect of ATT and better outcomes of TB infection. This case study highlights the importance of good glycemic control in patients with type 2 diabetes who acquire TB infection.

Introduction: Multidrug-resistant tuberculosis is a significant public health problem for which drugs are used with many adverse effects. Among the devastating consequences of these diseases, there is a wide variation in the incidence of ototoxicity and hearing loss in patients with multidrugresistant and extremely resistant tuberculosis. Cochlear implants may be indicated in patients with unilateral/severe bilateral hearing loss with no benefit from conventional hearing aids, but their use in patients with tuberculosis is rare. Case report: We present the first case of a right unilateral cochlear implant performed on a 34-year-old Peruvian patient who presented profound sensorineural hearing loss of cochlear origin. Conclusion: Cochlear implant surgery is an essential milestone in the treatment of patients with auditory sequelae of tuberculosis treatment. Close monitoring of possible complications of tuberculosis treatment should be strengthened in countries with a high incidence of multidrug-resistant and extremely resistant tuberculosis. [ABSTRACT FROM AUTHOR]

BackgroundRapid molecular diagnostics, with their ability to quickly identify genetic mutations associated with drug resistance in Mycobacterium tuberculosis clinical specimens, have great potential as tools to control multi- and extensively drug-resistant tuberculosis (M/XDR-TB). The Qiagen PyroMark Q96 ID system is a commercially available pyrosequencing (PSQ) platform that has been validated for rapid M/XDR-TB diagnosis. However, the details of the assay's diagnostic and technical performance have yet to be thoroughly investigated in diverse clinical environments.MethodsThis study evaluates the diagnostic performance of the PSQ assay for 1128 clinical specimens from patients from three areas of high TB burden. We report on the diagnostic performance of the PSQ assay between the three sites and identify variables associated with poor PSQ technical performance.ResultsIn India, the sensitivity of the PSQ assay ranged from 89 to 98 % for the detection of phenotypic resistance to isoniazid, rifampicin, fluoroquinolones, and the injectables. In Moldova, assay sensitivity ranged from 7 to 94 %, and in South Africa, assay sensitivity ranged from 71 to 92 %. Specificity was high (94-100 %) across all sites. The addition of eis promoter sequencing information greatly improved the sensitivity of kanamycin resistance detection in Moldova (7 % to 79 %). Nearly all (89.4 %) sequencing reactions conducted on smear-positive, culture-positive specimens and most (70.8 %) reactions conducted on smear-negative, culture-positive specimens yielded valid PSQ reads. An investigation into the variables influencing sequencing failures indicated smear negativity, culture negativity, site (Moldova), and sequencing of the rpoB, gyrA, and rrs genes were highly associated with poor PSQ technical performance (adj. OR > 2.0).ConclusionsThis study has important implications for the global implementation of PSQ as a molecular TB diagnostic, as it demonstrates how regional factors may impact PSQ diagnostic performance, while underscoring potential gene targets for optimization to improve overall PSQ assay technical performance.Trial registrationClinicalTrials.gov ( #NCT02170441 ). Registered 12 June 2014.

Sokleaph Cheng,1– 3 Mallorie Hide,3– 5 Sok Heng Pheng,6 Alexandra Kerléguer,2 Gauthier Delvallez,2 Sophan Sam,7 Tan Eang Mao,6 Thi Van Anh Nguyen,3,8 Anne-Laure Bañuls3– 5 1Institut Pasteur du Cambodge and Ministry of Health, Phnom Penh, Cambodia; 2Medical Biology Laboratory, Institut Pasteur du Cambodge, Phnom Penh, Cambodia; 3LMI Drug Resistance in South East Asia, Institut Pasteur du Cambodge, Phnom Penh, Cambodia; 4MIVEGEC, University of Montpellier, Institute of Research for Development, Centre National de la Recherche Scientifique, Montpellier, France; 5CREES (Centre de Recherche En Écologie Et Évolution de la Santé), Montpellier, France; 6National Center for Tuberculosis and Leprosy Control, Phnom Penh, Cambodia; 7Cambodian Health Committee, Phnom Penh, Cambodia; 8Department of Bacteriology, National Institute of Hygiene and Epidemiology, Hanoi, Martinique, VietnamCorrespondence: Sokleaph ChengInstitut Pasteur du Cambodge, No. 5, Monivong Boulevard, Phnom Penh 120210, CambodiaTel +855 12 222 684Email csokleaph@pasteur-kh.orgBackground: Due to the emergence of Mycobacterium tuberculosis (M.tb) clinical isolates resistant to most potent first-line drugs (FLD), second-line drugs (SLD) are being prescribed more frequently. We explore the genetic characteristics and molecular mechanisms of M.tb isolates phenotypically resistant to SLD, including pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) isolates.Methods: Drug-resistant (DR) M.tb isolates collected from 2012 to 2017 were tested using sequencing and phenotypic drug susceptibility testing. Genotypes were determined to explore their links with SLD resistance patterns.Results: Of the 272 DR M.tb isolates, 6 non-multidrug resistant (non-MDR) isolates were fluoroquinolones (FQ)-resistant, 3 were XDR and 16 were pre-XDR (14 resistant to FQ and 2 to second-line injectable drugs). The most frequent mutations in FQ-resistant and second-line injectable drugs resistant isolates were gyrA D94G (15/23) and rrs a1401g (3/5), respectively. Seventy-five percent of pre-XDR isolates and 100% of XDR isolates harbored mutations conferring resistance to pyrazinamide. All XDR isolates belonged to the Beijing genotype, of which one, named XDR+, was resistant to all drugs tested. One cluster including pre-XDR and XDR isolates was observed.Conclusion: This is the first description of SLD resistance in Cambodia. The data suggest that the proportion of XDR and pre-XDR isolates remains low but is on the rise compared to previous reports. The characterization of the XDR+ isolate in a patient who refused treatment underlines the risk of transmission in the population. In addition, genotypic results show, as expected, that the Beijing family is the main involved in pre-XDR and XDR isolates and that the spread of the Beijing pre-XDR strain is capable of evolving into XDR strain. This study strongly indicates the need for rapid interventions in terms of diagnostic and treatment to prevent the spread of the pre-XDR and XDR strains and the emergence of more resistant ones.Keywords: Mycobacterium tuberculosis, extensively drug-resistant tuberculosis, pre-extensively drug-resistant tuberculosis, fluoroquinolone, second-line injectable drugs