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Introduction: Ethambutol, a key anti-tuberculosis medication, is associated with optic neuropathy, which can lead to significant vision impairment. This population-based cohort study investigated the nationwide usage of ethambutol and the incidence and screening of optic neuropathy among ethambutol users. Methods: The cohort included 206,157 individuals from the Health Insurance Review and Assessment database in South Korea who initiated ethambutol therapy between 1 January 2015, and 31 December 2021. Among them, 117,309 individuals without prior ophthalmic diseases were analyzed to investigate practice patterns. The timing of the baseline examinations (an ophthalmic examination immediately preceding [within 1 month] ethambutol initiation or the first ophthalmic assessment conducted after the initiation) and subsequent monitoring and modalities used were assessed. Results: The cumulative incidences of the optic neuropathy categories, overall optic neuropathy, optic neuropathy/optic neuritis, and optic atrophy, were analyzed. The annual number of ethambutol users declined over time between 2015 and 2021. The cumulative incidences of overall optic neuropathy, optic neuropathy/optic neuritis, and optic atrophy were 2.8%, 2.0%, and 0.7%, respectively. Optical coherence tomography usage for ophthalmic examinations remarkably increased from 23.9% in 2015 to 85.5% in 2021, while visual field examinations were frequently (69.6%) employed for functional assessment at the time of diagnosis. Baseline screening within 6 months of initiating ethambutol therapy was performed in 12.0%-13.1% of ethambutol initiators annually over the study period. The percentage of ethambutol initiators receiving subsequent monitoring within 6 months following baseline screening declined over time, from 13.1% in 2015 to 7.9% in 2021. Discussion: The diminishing trend in monitoring emphasizes the need for improved pharmacovigilance to reduce the risk of optic atrophy and blindness through early detection. [ABSTRACT FROM AUTHOR]

The current treatment protocol for drug-sensitive tuberculosis involves all four first-line anti-tuberculosis drugs: rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride in a single tablet, known as fixed-dose combination tablets. However, the analytical methods are scanty to test all these drugs simultaneously in a single run without any pre-sample process or using a simple method suitable for resource-limited settings. In this method, 50 mM potassium phosphate buffer containing 0.2% triethylamine (without pH adjustment) added with acetonitrile (98:2, v/v) was served as mobile phase A, while mobile phase B was 100% acetonitrile. All four drugs were separated within 10.3 min using a gradient mobile phase program in a C18 column (150 mm × 4.6 mm; 5 μm) and detected at two ultraviolet wavelengths (238 nm for rifampicin, isoniazid and pyrazinamide, and 210 nm for ethambutol hydrochloride). The method was selective, sensitive and linear with a correlation coefficient >0.999 with the acceptable precision and accuracy (<2% relative standard deviation) for all four drugs. In conclusion, the method is simple and it does not require any pH adjustment of the buffer/mobile phase, and within 11 min, the separation of all four drugs can be achieved. Overall, the method is suitable for quality testing of fixed-dose combination tablets in limited-resource settings. [ABSTRACT FROM AUTHOR]

Background New and shorter regimens against multi-drug resistant tuberculosis (TB) remain urgently needed. To inform treatment duration in clinical trials, this study aimed to identify human pharmacokinetic equivalent doses, antimycobacterial and sterilizing activity of a novel regimen, containing bedaquiline, delamanid, moxifloxacin and sutezolid (BDMU), in the standard mouse model (BALB/c) of Mycobacterium tuberculosis (Mtb) infection. Methods Treatment of mice with B25D0.6M200U200, B25D0.6M200, B25D0.6M200(U2003) or H10R10Z150E100 (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE), started 3 weeks after Mtb infection. Bactericidal activity was assessed after 1, 2, 3 and 4 months of treatment and relapse rates were assessed 3 months after completing treatment durations of 2, 3 and 4 months. Results B25D0.6M200U200 generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B25D0.6M200U200 and the B25D0.6M200 regimen compared to the standard H10R10Z150E100 regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H10R10Z150E100 treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B25D0.6M200U200 and B25D0.6M200, respectively, compared to 40% for H10R10Z150E100 treatment showing an increased sterilizing activity of both BDM-based regimens. Conclusions BDM-based regimens, with and without sutezolid, have a higher efficacy than the HRZE regimen in the BALB/c model of TB, with some improvement by adding sutezolid. By translating these results to TB patients, this novel BDMU regimen should be able to reduce treatment duration by 25% compared to HRZE therapy. [ABSTRACT FROM AUTHOR]

Purpose: The purpose was to study the effect of ethambutol (EMB) and cause for optic neuropathy in the hope that better understanding of the condition will help us to reduce the burden of visual loss. MATERIALS AND METHODS: A retrospective analysis of patients with EMB-induced optic neuropathy was done, which included 30 patients attending our outpatient department from January 2022 to March 2022. Results: The mean age was 53.73 with male (70%) preponderance. Visual fields showed bitemporal hemianopia in 43% (13), temporal field defects in 26% (8), centrocecal scotoma in 17% (5), and low reliability in 10% (3). Visual evoked potential amplitude was reduced in 87% (26). Magnetic resonance imaging showed enhancement of optic chiasma in 40% (12). After discontinuing and replacing EMB, with Vitamin B complex and zinc supplements, 53% (16) had visual improvement on 1-month follow-up. Conclusion: India has launched the Pradhan Mantri TB Mukt Bharat Abhiyan “Ni-kshay 2.0” portal to eradicate tuberculosis by 2025. Hence, aggressive treatment protocols are underway. The increased duration of EMB in new directly observed therapy short-course regimen has caused increased incidence of EMB optic neuropathy. Regular screening is needed to diagnose and prevent further visual deterioration in these patients. Timely replacement of the drug with another drug is a key in visual recovery of these patients. Further studies are needed to assess if the genetic predisposition is responsible for optic nerve damage.

Background: Tuberculosis (TB), one of the deadliest infectious diseases globally, is increasingly exacerbated in China by the emergence of resistant Mycobacterium tuberculosis (MTB) strains. Drug-resistant TB, including mono-drug-resistant TB, multidrug-resistant TB (MDR-TB), and extensively drug-resistant TB (XDR-TB), presents significant public health challenges. Methods: We conducted a systematic literature review from January 2010 to February 2024 using databases such as PubMed, Embase, Web of Science, and Google Scholar. Our focus was on empirical data related to drug resistance patterns in newly diagnosed TB cases. Non-empirical studies were excluded through meticulous filtering. For the meta-analysis, we used Review Manager (RevMan) 5.2 and assessed evidence quality using the Newcastle-Ottawa Scale (NOS). Results: Our search strategy identified 40 studies that met the inclusion criteria, encompassing a total sample size of 87,667 participants. Among new TB cases, the estimated prevalence of MDR-TB in China was 6.9% (95% CI: 5.6–8.1%). Prevalence rates for mono-drug resistance to first-line anti-TB medications were as follows: isoniazid at 18.2% (95% CI: 16.4–20.6%), rifampicin at 10.5% (95% CI: 8.6–12.8%), and ethambutol at 5.7% (95% CI: 4.1–7.3%). The prevalence of streptomycin resistance, a former first-line anti-TB drug, was 17.1% (95% CI: 14.6–19.1%). The prevalence of other types of mono-drug resistance was 15.2% (95% CI: 13.9–17.3%), and for XDR-TB, it was 0.9% (95% CI: 0.6–1.4%). Conclusions: The high prevalence of drug-resistant TB in China poses a significant public health challenge. There is an urgent need for targeted interventions and continued surveillance to combat the spread of drug-resistant TB.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Xiao-tian Nan,1,&ast; Ma-chao Li,1,&ast; Tong-yang Xiao,2,&ast; Hai-can Liu,1,&ast; Shi-qiang Lin,3 Wei Wang,1 Cheng Qian,4 Hao Hang,1 Gui-lian Li,1 Xiu-qin Zhao,1 Kang-Lin Wan,1 Li-li Zhao1 1National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, People’s Republic of China; 2Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 3College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China; 4Beijing Center for Disease Control and Prevention, Beijing, 100013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-li Zhao, Email zhaolili@icdc.cnObjective: To explore the association between the variant mutations within embB and ubiA, and the degree of ethambutol (EMB) resistance of Mycobacterium tuberculosis (M. tuberculosis) isolates.Methods: A total of 146 M. tuberculosis isolates were used to determine the minimum inhibitory concentrations (MICs) of EMB with a 96-well microplate-based assay. The mutations within embB and ubiA among these isolates were identified with DNA sequencing. Moreover, a multivariate regression model and a computer model were established to assess the effects of mutations on EMB resistance.Results: Our data showed that overall 100 isolates exhibited 28 mutated patterns within the sequenced embB and ubiA. Statistical analysis indicated that embB mutations Met306Val, Met306Ile, Gly406Ala, and Gln497Arg, were strongly associated with EMB resistance. Of these mutations, Met306Val and Gln497Arg were significantly associated with high-level EMB resistance. Almost all multiple mutations occurred in high-level EMB-resistant isolates. Although the mutation within ubiA accompanied with embB mutation presented exclusively in EMB-resistant isolates, four single ubiA mutations (Ala39Glu, Ser173Ala, Trp175Cys, and Val283Leu) leading to protein instability were observed in EMB-susceptible isolates.Conclusion: This study highlighted the complexity of EMB resistance. Some individual mutations and multiple mutations within embB and ubiA contributed to the different levels of EMB resistance.Keywords: ethambutol, multidrug-resistant tuberculosis, embB, ubiA, mutations, minimum inhibitory concentration

A series of novel 3,4,7- or 3,4,8-trisubstituted-3a,4-dihydro[1,2,3]triazolo[1,5-a] quinazolin-5(3H)-one analogues was synthesized and characterized by using HRMS, 1H NMR and 13C NMR spectral data. All the compounds were tested for their in vitro antitubercular activity by using the Microplate Alamar Blue Assay technique, the minimum inhibitory concentration values of the most effective inhibitors were determined for Mycobacterium tuberculosis H37Rv and H37Ra strains by using rifampicin, isoniazid and ethambutol as reference standards. Among all synthesized compounds 7-chloro-3-(3-chloropyridin-4-yl)-4-methyl[1,2,3]triazolo[1,5-a]quinazolin-5(4H)-one, 7-bromo-8-chloro-4-(4-fluorophenyl)-3-(3-methylpyridin-4-yl)[1,2,3]triazolo[1,5-a]quinazolin-5(4H)-one and 7-bromo-4-(4-methoxyphenyl)-3-(3-methylpyridin-4-yl)-[1,2,3]triazolo[1,5-a]quinazolin-5(4H)-one exhibit excellent in vitro antitubercular activity when compared to the reference standards. Further 7-bromo-8-chloro-4-(4-fluorophenyl)-3-(3-methylpyridin-4-yl)[1,2,3]triazolo[1,5-a]quinazolin-5(4H)-one was evaluated for in vivo antitubercular activity after post treatment in female BALB/c mice by determination of log10 colony formation unit in lungs and spleen. Therefore, this compound could serve as the lead molecule for further development as antitubercular agent. [ABSTRACT FROM AUTHOR]

There remains a clinical need for better approaches to rapid drug susceptibility testing in view of the increasing burden of multidrug resistant tuberculosis. Binary susceptibility phenotypes only capture changes in minimum inhibitory concentration when these cross the critical concentration, even though other changes may be clinically relevant. We developed a machine learning system to predict minimum inhibitory concentration from unassembled whole-genome sequencing data for 13 anti-tuberculosis drugs. We trained, validated and tested the system on 10,859 isolates from the CRyPTIC dataset. Essential agreement rates (predicted MIC within one doubling dilution of observed MIC) were above 92% for first-line drugs, 91% for fluoroquinolones and aminoglycosides, and 90% for new and repurposed drugs, albeit with a significant drop in performance for the very few phenotypically resistant isolates in the latter group. To further validate the model in the absence of external MIC datasets, we predicted MIC and converted values to binary for an external set of 15,239 isolates with binary phenotypes, and compare their performance against a previously validated mutation catalogue, the expected performance of existing molecular assays, and World Health Organization Target Product Profiles. The sensitivity of the model on the external dataset was greater than 90% for all drugs except ethionamide, clofazimine and linezolid. Specificity was greater than 95% for all drugs except ethambutol, ethionamide, bedaquiline, delamanid and clofazimine. The proposed system can provide quantitative susceptibility phenotyping to help guide antimicrobial therapy, although further data collection and validation are required before machine learning can be used clinically for all drugs. Author summary: Tuberculosis is a leading cause of morbidity and mortality globally, killing over 1.5 million people each year. Tuberculosis drug susceptibility testing is used to determine which antibiotics should be used to manage the disease, particularly in view of the rise in multidrug resistant tuberculosis. The current standard for testing, binary phenotypes, only capture changes in minimum inhibitory concentration when these cross a critical concentration, even though other changes may be clinically relevant. We developed a machine learning system to predict minimum inhibitory concentration directly from sequencing data for 13 antibiotics. We find that the model has an accuracy of 92% for first-line drugs, 91% for fluoroquinolones and aminoglycosides, and 90% for new and repurposed drugs, with a significant drop in performance for resistant isolates in the latter group. We validated the model on an external dataset with binary phenotypes. The sensitivity of the model on the external dataset was greater than 90% for all drugs except ethionamide, clofazimine and linezolid. Specificity was greater than 95% for all drugs except ethambutol, ethionamide, bedaquiline, delamanid and clofazimine. The proposed system could help guide antimicrobial therapy. However, further data and validation are required before machine learning can be used clinically for all drugs. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the characteristics of non-immediate type hypersensitivity reactions with first-line antituberculosis drugs and determine the causative drugs by patch tests and drug provocation tests. Materials and Methods: Baseline data including patients' demographics, disease characteristics, and drug hypersensitivity reaction characteristics were recorded. Patch testing was performed with all the drugs used during hypersensitivity reaction at 1/10 and 1/1 concentrations. Drug provocation tests were performed at 3-day intervals with drugs that had negative patch test results. Results: A total of 32 patients were included in the study. The clinical phenotype was maculopapular eruption in 11(34.4%), dermatitis in 10 (31.3%), drug reaction with eosinophilia and systemic symptoms in 1 (3.1%), and Stevens-Johnson syndrome/Toxic epidermal necrolysis in 10 (31.3%) patients. Combination therapy during the index reaction consisted of isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) in 28 (87.5%) patients, Patch tests were performed with 95 drugs consisting of 25 H, 25 R, 21 Z, and 24 E in 25 patients. Results were positive in 8 patients with 10 drugs: 8 (32%) H, 1 (4%) R, and 1 (4.2%) E positivity were detected. Drug provocation tests were performed with 78 drugs (18 H, 23 R, 15 Z, 22 E) in 25 patients and resulted positive with H, R, Z, and E in 16.7% (3 of 18), 21.7% (5 of 23), 46.7% (7 of 15), and 54.5% (12 of 22) of the patients respectively. Negative predictive values of patch tests with H, R, Z, and E were calculated as 87.5% (14/16), 81.8% (18/22), 50% (7/14), and 45% (9/20) respectively. According to the results of the patch tests and provocation tests, the most common culprit of hypersensitivity reactions was found to be E (n=12), followed by H (n=10). Multiple drug hypersensitivity was detected in 9 of 23 (39.1%) patients. Conclusion: Patch testing is useful in the management of non-immediate type hypersensitivity with first-line antituberculosis drugs. However, further studies are needed to determine its predictive value [ABSTRACT FROM AUTHOR]

Introduction: Tuberculosis (TB) in children under 15 years often results in airway compression, with bronchus intermedius (BI) being the most common site. Endoscopic enucleations can be used to remove lymph nodes and establish an airway in severe cases. Both rigid and flexible bronchoscopy are suitable, with alligator forceps being preferred for its ability to extract tissue. Recent studies have also explored cryoprobe enucleation. Case Presentation: An HIV-positive boy with persistent symptoms after 9 months of TB treatment was diagnosed based on his mother's and sister's Xpert MTB/RIF positive status. He was started on 4-drug TB treatment, but the child remained clinically symptomatic with abnormal chest X-ray and unconfirmed TB. Bronchoscopy was performed, revealing complete obstruction of BI due to caseating granulomas causing collapse of the right middle and lower lobes. Cryotherapy was used to recanalize the airway, and follow-up bronchoscopy confirmed patent BI. Conclusion: While cryotherapy was effective in the restoration of airway patency in this case, there is a lack of knowledge about its use in children. [ABSTRACT FROM AUTHOR]

Background In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics. Objectives To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB. Methods We prospectively enrolled participants ≥15 years old, without HIV, and initiating drug-susceptible TB treatment in Worcester, South Africa. Alcohol use was measured via self-report and blood biomarkers. Other illicit substances were captured through a urine drug test. Plasma samples were drawn 1 month into treatment pre-dose, and 1.5, 3, 5 and 8 h post-dose. Non-linear mixed-effects modelling was used to describe the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol. Alcohol and drug use were tested as covariates. Results The study included 104 participants, of whom 70% were male, with a median age of 37 years (IQR 27–48). Alcohol use was high, with 42% and 28% of participants having moderate and high alcohol use, respectively. Rifampicin and isoniazid had slightly lower pharmacokinetics compared with previous reports, whereas pyrazinamide and ethambutol were consistent. No significant alcohol use effect was detected, other than 13% higher ethambutol clearance in participants with high alcohol use. Methaqualone use reduced rifampicin bioavailability by 19%. Conclusion No clinically relevant effect of alcohol use was observed on the pharmacokinetics of first-line TB drugs, suggesting that poor treatment outcome is unlikely due to pharmacokinetic alterations. That methaqualone reduced rifampicin means dose adjustment may be beneficial. [ABSTRACT FROM AUTHOR]

Introduction: Granulomatosis due to immune reconstitution inflammatory syndrome (IRIS) and disseminated Mycobacterium avium-intracellulare (M. avium) infection may trigger hypercalcemia. Here, we report a rare case of hypercalcemia and acute kidney damage related to IRIS in a person living with Human Immunodeficiency Virus (HIV). Case presentation: A 39-year-old male person living with HIV presented with muscle weakness and unwanted weight loss of 8 kg within the last 2 weeks. Laboratory findings included serum hypercalcemia of 3.27 mmol/mL associated with elevated calcitriol and acute kidney damage. Since the first diagnosis of HIV and concomitant disseminated M. avium infection, the patient received antiretroviral therapy (ART), rifabutin, clarithromycin, and ethambutol. 18Fluoro-D-glucose positron emission computed tomography (18FDG-PET/CT) showed progressive multilocular lymphadenopathy. Biopsy specimen from the duodenum as well as retroperitoneal and mediastinal lymph nodes revealed granulomatous inflammation consistent with IRIS. Treatment with forced diuresis, bisphosphonates, and calcitonin normalized serum calcium and kidney function recovered. Conclusion: Hypercalcemia due to IRIS is a rare differential diagnosis in persons living with HIV and may lead to acute kidney damage, despite sufficient ART and antimycobacterial treatment. [ABSTRACT FROM AUTHOR]

(1) Background: To investigate the risk factors associated with optic neuropathy (ON) and validate the hypothesis that concomitant isoniazid use and other causes of toxic ON affect the development of ON in ethambutol users. (2) Methods: This cohort study identified ethambutol users who initiated ethambutol therapy between January 2015 and December 2021 and had no ON prior to ethambutol therapy. ON incidence up to 31 December 2022 was evaluated. The users were grouped on the basis of the presence of ON. Demographic and clinical characteristics were investigated for risk factor analyses of ON. Odds ratios (ORs) were calculated using multivariate logistic regression analyses. (3) Results: Among 204,598 ethambutol users, 5277 (2.6%) patients developed ON over the study period. Patients with ON included a higher percentage of women and had a higher mean age than patients without ON. In the multivariate analyses, the risk factors for ON and visual impairment included sex, age, cumulative dose, extrapulmonary indications for ethambutol use, and systemic conditions such as diabetes, hypertension, hyperlipidemia, diabetes, kidney disease, and liver disease. Malnutrition or nutritional disorders significantly increased the risk of ON (OR = 1.27, 95% confidence interval [CI] = 1.19–1.34), whereas concomitant isoniazid use decreased the risk (OR = 0.78, 95% CI = 0.72–0.86). (4) Conclusion: An increased risk of ON in patients with systemic diseases and nutritional deficiency was identified, whereas concomitant isoniazid use was associated with a decreased risk of ON. Patients with these risk factors should be carefully monitored to minimize the vision-threatening ON. [ABSTRACT FROM AUTHOR]

In Mycobacterium tuberculosis, molecular predictions of ethambutol resistance rely primarily on the detection of mutations within embB. However, discordance between embB406 mutations and gold standard phenotypic drug sensitivity testing (DST) questions the significance of embB406 mutations used in molecular DST. This study tabulates embB mutations found in Canadian M. tuberculosis isolates and evaluates the impact of specific mutations on ethambutol resistance. The National Reference Centre for Mycobacteriology culture collection (n = 2796) was screened for isolates with embB mutations. Phenotypic DST was performed on the BACTEC™ MGIT™ 960 at ethambutol concentrations of 2–5 μg/mL. Whole genome sequencing was used for drug resistance predictions, phylogenomics and single nucleotide polymorphism analysis. Detection of resistance-associated embB mutations corresponded to a positive predictive value of 64.3%, negative predictive value of 99.2%, 98.7% specificity, and 73.3% sensitivity compared to phenotypic DST. Two embB406 mutation subtypes (Gly406Asp, Gly406Ala) were found among 16 isolates, of which 12 were sensitive at 5 µg/mL ethambutol with variable resistance between 2–4 µg/mL. A novel frameshift mutation in regulator embR (Gln258fs) was found in nine isolates. Mutations in embB406 were associated with low-level ethambutol resistance undetectable at the recommended critical concentration (5 μg/mL). These novel mutations may exacerbate variability in ethambutol resistance. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculosis (TB) is one of the most prevalent infectious diseases globally, often presenting with nonspecific symptoms that can obscure diagnosis, especially when it manifests in uncommon sites such as osteoarticular tuberculosis (OA-TB). Case presentation: We report a rare case of a 9-year-old male diagnosed with right knee tuberculosis after enduring severe symptoms for several months. Despite multiple negative biopsies and aspirates during initial debridement surgeries, a biopsy taken 6 months later confirmed the presence of Mycobacterium tuberculosis (MTB). The patient was subsequently treated with debridement and anti-tubercular therapy. Conclusion: This case underscores the critical need to consider tuberculosis in patients presenting with chronic bone pain to avoid misdiagnosis, particularly in the developing world. The atypical presentation of osteoarticular tuberculosis in this young patient emphasizes the need for healthcare professionals to recognize subtle symptoms. Advanced imaging studies like MRI and microbiological evaluations, including site biopsies, are essential for accurate diagnosis. Increased awareness and collaborative research are crucial to improving the understanding and management of pediatric osteoarticular tuberculosis and extrapulmonary tuberculosis. [ABSTRACT FROM AUTHOR]

Objectives Participation in an external (interlaboratory) quality control (QC) programme is an essential part of quality assurance as it provides laboratories with valuable insights into their analytical performance. We describe the 10 year results of an international QC programme for the measurement of anti-tuberculosis (TB) drugs. Methods Each year, two rounds were organized in which serum (or plasma) samples, spiked with known concentrations of anti-TB drugs, were provided to participating laboratories for analysis. Reported measurements within 80%–120% of weighed-in concentrations were considered accurate. Mixed model linear regression was performed to assess the effect of the measured drug, concentration level, analytical technique and performing laboratory on the absolute inaccuracy. Results By 2022, 31 laboratories had participated in the QC programme and 13 anti-TB drugs and metabolites were included. In total 1407 measurements were reported. First-line TB drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) represented 58% of all measurements. Overall, 83.2% of 1407 measurements were accurate, and the median absolute inaccuracy was 7.3% (IQR, 3.3%–15.1%). The absolute inaccuracy was related to the measured anti-TB drug and to the performing laboratory, but not to the concentration level or to the analytical technique used. The median absolute inaccuracies of rifampicin and isoniazid were relatively high (10.2% and 10.9%, respectively). Conclusions The 10 year results of this external QC programme illustrate the need for continuous external QC for the measurement of anti-TB drugs for research and patient care purposes, because one in six measurements was inaccurate. Participation in the programme alerts laboratories to previously undetected analytical problems. [ABSTRACT FROM AUTHOR]

Background: Non-tuberculous mycobacteria (NTM) are generally free-living organism, widely distributed in the environment, with sporadic potential to infect. In recent years, there has been a significant increase in the global incidence of NTM-related disease, spanning across all continents and an increased mortality after the diagnosis has been reported. The decisions on whether to treat or not and which drugs to use are complex and require a multidisciplinary approach as well as patients' involvement in the decision process. Methods and Results: This review aims at describing the drugs used for treating NTM-associated diseases emphasizing the efficacy, tolerability, optimization strategies as well as possible drugs that might be used in case of intolerance or resistance. We also reviewed data on newer compounds highlighting the lack of randomised clinical trials for many drugs but also encouraging preliminary data for others. We also focused on non-pharmacological interventions that need to be adopted during care of individuals with NTM-associated diseases Conclusions: Despite insufficient efficacy and poor tolerability this review emphasizes the improvement in patients' care and the needs for future studies in the field of anti-NTM treatments. [ABSTRACT FROM AUTHOR]

BackgroundOptimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures.MethodsTitles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged