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Miliary tuberculosis is a form of disseminated tuberculosis that can be difficult to detect when the classic pattern is absent on chest radiograph and advanced cross-sectional imaging is not readily available. While the focused assessment with sonography for HIV-associated tuberculosis (FASH) protocol for extrapulmonary tuberculosis emphasizes easy-to-teach findings, experienced sonographers may detect additional, subtler signs that can aid in diagnosis. We report a case of a 20-year-old man with miliary tuberculosis diagnosed on computed tomography of the chest. We describe subtle sonographic signs of disseminated tuberculosis including subpleural irregularities and comet-tail artifacts, a bright liver pattern, peritoneal nodules, and a nonspecific sponge spleen pattern. We then discuss important differential diagnoses for each finding. Knowledge of subtle sonographic signs outside of the FASH protocol can aid clinicians in detecting disseminated tuberculosis, including the miliary form, when advanced imaging may not be available.

TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.

BackgroundEach year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.MethodsLevofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses.ResultsData from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing 20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamils mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children

BackgroundExpanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies.Methods and findingsIn a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher's exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings.ConclusionsShort-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers.Trial registrationClinicalTrials.gov NCT03934931.

Tuberculosis (TB) remains a global health concern, necessitating the continuous search for novel therapeutic agents to combat drug-resistant strains and enhance treatment efficacy. The present study focuses on designing, synthesizing, and exploring quinoline analogues as potential anti-tubercular agents. Quinoline scaffolds like bedaquiline inhibit the ATP synthase enzyme involved in energy production. A diverse library of 19 quinoline derivatives was sys tematically synthesized through rational structural modifications. The quinoline analogues were evaluated for their anti-tubercular activity against Mycobacterium tuberculosis (M.tb). Furthermore, the study delves into the molecular interactions between the synthesized quinoline derivatives and M.tb ATP synthase, shedding light on the underlying mechanisms of their anti-tubercular activity. The initial in-vitro screening revealed that some of the designed molecules were active against M.tb, making them potential candidates for further development. A diverse library of 19 quinoline derivatives was systematically synthesized through rational structural modifications. Molecular docking studies showed to target the ATP synthase protein of Mycobacterium tuberculosis (MtB). The quinoline analogs were found to have good anti-tubercular activity again Mtb. [ABSTRACT FROM AUTHOR]

Purpose: Therapeutic drug monitoring (TDM) is a standard clinical procedure that uses the pharmacokinetic and pharmacodynamic parameters of the drug in the body to determine the optimal dose. The pharmacokinetic variability of the drug(s) is a significant contributor to poor treatment outcomes, including the development of acquired drug resistance. TDM aids in dose optimization and improves outcomes while lessening drug toxicity. TDM is used to manage patients with tuberculosis (TB) who exhibit a slow response to therapy, despite good compliance and drug-susceptible organisms. Additional indications include patients at risk of malabsorption or delayed absorption of TB drugs and patients with drug-drug interaction and drug toxicity, which confirm compliance with therapy. TDM usually requires two blood samples: the 2 h and the 6 h post-dose. This narrative review will discuss the pharmacokinetics and pharmacodynamics of TB drugs, determinants of poor response to therapy, indications of TDM, methods of performing TDM, and its interpretations. Methods: This is a narrative review. We searched PubMed, Embase, and the CINAHL from inception to April 2024. We used the following search terms: tuberculosis, therapeutic drug monitoring, anti-TB drugs, pharmacokinetics, pharmacodynamics, limited sample strategies, diabetes and TB, HIV and TB, and multidrug-resistant TB. All types of articles were selected. Results: TDM is beneficial in managing TB, especially in patients with slow responses, drug-resistance TB, recurrent TB, and comorbidities such as diabetes mellitus and human immunodeficiency virus infection. Conclusion: TDM is beneficial for improving outcomes, reducing the risk of acquired drug resistance, and avoiding side effects. [ABSTRACT FROM AUTHOR]

Purpose: Isoniazid, a first-line antitubercular drug, is associated with nervous system adverse drug reactions such as seizures, peripheral neuropathy, and psychosis. This systematic review of case reports and case series aimed to characterize the demographic, social, and clinical factors associated with isoniazid-induced psychosis in patients with active tuberculosis (TB) and those who received isoniazid for latent TB infection (LTBI). Methods: We comprehensively searched the Embase, PubMed, and Scopus databases to identify relevant studies published between the date of inception of the database and June 2024. Results: A total of 28 studies, including 21 case reports and 7 case series involved 37 patients who developed isoniazid-induced psychosis. A higher frequency of isoniazid-induced psychosis was observed during the first 2 months of treatment, with a relatively early onset observed among patients aged 18 years or less. Delusions and/or hallucinations are the common symptoms of isoniazid-induced psychosis. Psychomotor disturbances, disorganized speech or formal thought disorder, disorganized or abnormal behaviour, and neuropsychiatric symptoms (sleep disturbances, hostility or aggression, confusion, affective symptoms, anxiety symptoms, and cognitive difficulties) were the other symptoms observed in the included studies. More than 80% of cases rechallenged with isoniazid resulted in the recurrence of psychotic symptoms. Conclusion: Patients with TB and LTBI should be assessed for psychotic and neuropsychiatric symptoms during isoniazid therapy, mainly in the first 2 months. Further research is required to understand the impact of underlying risk factors, such as genetic predisposition and isoniazid pharmacokinetics, as well as the clinical utility and dosage recommendations of pyridoxine for managing isoniazid-induced psychosis. [ABSTRACT FROM AUTHOR]

Introduction: Intestinal obstruction is a common complication in patients with advanced malignancies, often attributed to the disease itself or as a side effect of opioid analgesics used for pain management. However, the occurrence of intestinal obstruction following antituberculosis therapy is rare. Case presentation: We report a unique case of a 58-year-old Asian male diagnosed with stage IV pancreatic carcinoma and pulmonary tuberculosis. The patient was initiated on a regimen of ethambutol hydrochloride, pyrazinamide, rifampicin, and isoniazid tablets (II) for tuberculosis, alongside morphine for the management of severe cancer-related pain. Subsequently, he developed symptoms indicative of intestinal obstruction. Despite discontinuation of morphine, the patient's symptoms persisted until he autonomously ceased all medications, leading to a rapid improvement in his condition. This unexpected resolution highlighted the antituberculosis drugs as the probable cause of his intestinal obstruction. Conclusions: This case underscores the importance of considering antituberculosis drugs as a potential cause of intestinal obstruction, especially in patients who do not respond to conventional management strategies for drug-induced gastrointestinal side effects. It also emphasizes the need for heightened vigilance and monitoring when prescribing these medications to patients with advanced malignancies, to promptly identify and address rare but significant side effects. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a global health concern caused by the bacterium Mycobacterium tuberculosis. This infectious disease primarily affects the lungs but can also impact other organs. Effective TB control involves early diagnosis, appropriate treatment with a combination of antibiotics, and public health measures to prevent transmission. However, ongoing challenges include drug-resistant strains and socioeconomic factors influencing its prevalence. Drugs such as isoniazid, pyrazinamide, ethambutol, ethionamide, linezolid, and levofloxacin are approved for the treatment of drug-susceptible tuberculosis. The properties and other activities of the drug, can be analyzed by modelling its chemical structure in terms of a molecular graph , by considering the atoms as the vertex set and the bonds between the two atoms as the edge set . A molecular descriptor or topological index of represents the corresponding chemical molecule as a numerical value. Domination is one of the key concepts in the molecular structure used to analyze the properties of atoms. In this article, the domination distance-based topological indices of the drugs isoniazid, pyrazinamide, ethambutol, ethionamide, linezolid, and levofloxacin are computed to conduct QSPR (Quantitative Structure–Property Relationship) analysis, exploring their physicochemical and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties. Quadratic regression is then used in the QSPR analysis to examine the physicochemical and ADMET properties of these drugs. The results of this analysis indicate that the domination Schultz index and domination SM index are the indices most strongly correlated with the majority of the physicochemical and ADMET properties. The QSPR analysis can also be extended to analogs of these drugs and to other treatment drugs, such as rifampin and rifapentine, to further explore their properties. [ABSTRACT FROM AUTHOR]

Owing to the emergence of multi‐drug resistant tuberculosis, there is a need for the exploration of new antitubercular agents. In this context, new coumarin‐based 1,2,3‐triazole hybrids were developed and evaluated for their antimicrobial activity against ESKAPE pathogens and the Mtb H37Rv strain. Among them, compounds 9 c and 12 showed MICs of 1 and 2 μg/mL, respectively, against the Mtb strain. The lead compounds exhibited a good selectivity index against Vero cells and were equally effective against ETB‐resistant and RIF‐resistant Mtb strains. Time‐kill kinetic studies revealed the bacteriostatic properties of the lead compounds, while combination studies using FDA‐approved antibiotics showed no drug interactions. Based on the structural similarity, it was envisaged that they might inhibit the DNA gyrase, which was further proved by the DNA supercoiling inhibition assay. Additionally, in silico docking studies, binding energy calculations, and ADME/T studies for the synthesized conjugates showed favourable pharmacokinetic and physicochemical characteristics. Hence, these molecules could further pave the way for discovering new potent antitubercular agents to combat AMR. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The emergence of drug‐resistant tuberculosis has necessitated novel treatments like the pretomanid, bedaquiline and linezolid (BPaL) regimen. This study investigated the association of drug‐induced liver injury (DILI) with the BPaL regimen compared to first‐line antituberculosis drugs (isoniazid, rifampin, pyrazinamide and ethambutol [HRZE]).A retrospective pharmacovigilance analysis was conducted using data from the US Food and Drug Administration Adverse Event Reporting System database from July 2019 to June 2023. Disproportionality analysis was employed to calculate the reporting odds ratio (ROR) of DILI for each component of the BPaL regimen. Onset time and mortality rates of DILI across different regimens were also compared.We identified 1242 cases of BPaL‐related DILI. Most cases occurred in individuals under 65 years of age (63.8%), with more male patients affected than females (51.4% vs 39.5%). The association between antituberculosis drugs and DILI was stronger for the HRZE regimen (ROR = 7.99, 95% confidence interval [CI] 7.74‐8.25) than the BPaL regimen (ROR = 4.75, 95% CI 4.55‐4.97). The median onset time for DILI was significantly shorter with the BPaL regimen (8 days, interquartile range [IQR] 3‐28) compared to the HRZE regimen (20 days, IQR 6‐48) (P < .001). Additionally, the BPaL regimen was associated with a higher risk of death due to DILI compared to the HRZE regimen (14.1% vs 10.4%, P = .003).Although the BPaL regimen had a lower overall risk of DILI compared to the HRZE regimen, it was significantly associated with DILI, indicating a need for careful monitoring during treatment. [ABSTRACT FROM AUTHOR]

Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs. [Display omitted] • Flexible synthesis of callyaerin-type natural product analogs is developed • Callyaerins inhibit axenic and intracellular growth of Mycobacterium tuberculosis • Callyaerins target the non-essential membrane protein Rv2113 • Binding of callyaerins to Rv2113 causes a broad dysregulation of the proteome Podlesainski et al. develop natural and non-natural callyaerin derivatives that potently inhibit axenic and intracellular growth of Mycobacterium tuberculosis through establishing flexible synthesis of these derivatives. Chemoproteomics and mode-of-action studies identify the non-essential membrane protein Rv2113 as the target of callyaerins, which cause a broad dysregulation of the proteome. [ABSTRACT FROM AUTHOR]

In this prospective cohort of 2006 individuals with drug-susceptible tuberculosis in India, 18% had unfavorable treatment outcomes (4.7% treatment failure, 2.5% recurrent infection, 4.1% death, 6.8% loss to follow-up) over a median 12-month follow-up period. Age, male sex, low education, nutritional status, and alcohol use were predictors of unfavorable outcomes. [ABSTRACT FROM AUTHOR]

Background In 2019, the World Health Organization called for operational research on all-oral shortened regimens for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We report safety and effectiveness of three 9-month all-oral regimens containing bedaquiline (Bdq), linezolid (Lzd), and levofloxacin (Lfx) and reinforced with cycloserine (Cs) and clofazimine (Cfz), delamanid (Dlm) and pyrazinamide (Z), or Dlm and Cfz. Methods We conducted a prospective cohort study of patients initiating treatment for pulmonary MDR/RR-TB under operational research conditions at public health facilities in Kazakhstan. Participants were screened monthly for adverse events. Participants with baseline resistance were excluded from the study and treated with a longer regimen. We analyzed clinically relevant adverse events of special interest in all participants and sputum culture conversion and end-of-treatment outcomes among individuals who were not excluded. Results Of 510 participants, 41% were women, the median age was 37 years (25th–75th percentile: 28–49), 18% had a body mass index <18.5 kg/m2, and 51% had cavitary disease. A total of 399 (78%) initiated Bdq-Lzd-Lfx-Cs-Cfz, 83 (16%) started Bdq-Lzd-Lfx-Dlm-Z, and 28 (5%) initiated Bdq-Lzd-Lfx-Dlm-Cfz. Fifty-eight individuals (11%) were excluded from the study, most commonly due to identification of baseline drug resistance (n = 52; 90%). Among the remaining 452 participants, treatment success frequencies were 92% (95% CI: 89–95%), 89% (95% CI: 80–94%), and 100% (95% CI: 86–100%) for regimens with Cs/Cfz, Dlm/Z, and Dlm/Cfz, respectively. Clinically relevant adverse events of special interest were uncommon. Conclusions All regimens demonstrated excellent safety and effectiveness, expanding the potential treatment options for patients, providers, and programs. [ABSTRACT FROM AUTHOR]

Background One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for tuberculosis prevention in people with human immunodeficiency virus (HIV). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. AIDS Clinical Trials Group A5372 evaluated the effect of 1HP on the pharmacokinetics of twice-daily dolutegravir. Methods A5372 was a multicenter, pharmacokinetic study in people with HIV (≥18 years) already on dolutegravir-containing antiretroviral therapy with HIV RNA <50 copies/mL. Participants received daily rifapentine/isoniazid (600 mg/300 mg) for 28 days as part of 1HP. Dolutegravir was increased to 50 mg twice daily during 1HP, and intensive pharmacokinetic sampling was performed on day 0 (before 1HP) and on the final day of 1HP treatment. Results Thirty-two participants (41% female; 66% Black/African; median [Q1, Q3] age, 42 [34, 49] years) were included in the pharmacokinetic analysis; 31 had HIV RNA <50 copies/mL at the end of 1HP dosing. One participant had an HIV RNA of 160 copies/mL at day 28, with HIV RNA <50 copies/mL upon repeat testing on day 42. The median (Q1, Q3) dolutegravir trough concentration was 1751 ng/mL (1195, 2542) on day 0 versus 1987 ng/mL (1331, 2278) on day 28 (day 28:day 0 geometric mean ratio, 1.05 [90% confidence interval,.93–1.2]; P =.43). No serious adverse events were reported. Conclusions Dolutegravir trough concentrations with 50 mg twice-daily dosing during 1HP treatment were greater than those with standard-dose dolutegravir once daily without 1HP. These pharmacokinetic, virologic, and safety data provide support for twice-daily dolutegravir use in combination with 1HP for tuberculosis prevention. Clinical Trials Registration NCT04272242. [ABSTRACT FROM AUTHOR]

The rapid emergence of various forms of drug‐resistant tuberculosis (TB) has massively impacted people's health globally. According to the WHO, TB care and facilities have been downgraded by 21% since the COVID‐19 pandemic, which has further slowed down the progress toward the "End TB Strategy." Multiple studies have shown drug‐resistant tuberculosis to be resilient to front‐line antituberculosis drugs, including isoniazid (INH), thus constantly prompting researchers worldwide to probe new potent chemical entities to replace/supplement the current artillery of anti‐TB therapeutics. The molecular hybridization (MH) technique has recently been adopted by many synthetic and medicinal chemists to combine different pharmacophoric units into a single molecular architecture which in most cases has been reported to exhibit a better pharmacological profile as compared to its precursors. The present review provides a concise account of the MH hybridization strategies directed at the structural manipulations of isoniazid to develop new anti‐TB agents and their structure‐activity relationships. Furthermore, their toxicity profiles and docking studies with relevant receptors are also briefly discussed. [ABSTRACT FROM AUTHOR]

The efficacy of the tuberculosis treatment is restricted by innate drug resistance of Mycobacterial tuberculosis and its ability to acquire resistance to all antituberculosis drugs in clinical use. A profound understanding of bacterial ploys that decrease the effectiveness of drugs would identify new mechanisms for drug resistance, which would subsequently lead to the development of more potent TB therapies. In the current study, we identified a virulence-associated small RNA (sRNA) MTS1338-driven drug efflux mechanism in M. tuberculosis. The treatment of a frontline antitubercular drug rifampicin upregulated MTS1338 by >4-fold. Higher intrabacterial abundance of MTS1338 increased the growth rate of cells in rifampicin-treated conditions. This fact was attributed by the upregulation of an efflux protein CydC by MTS1338. Gel-shift assay identified a stable interaction of MTS1338 with the coding region of cydC mRNA thereby potentially stabilizing it at the posttranscriptional level. The drug efflux measurement assays revealed that cells with higher MTS1338 abundance accumulate less drug in the cells. This study identified a new regulatory mechanism of drug efflux controlled by an infection-induced sRNA in M. tuberculosis. [ABSTRACT FROM AUTHOR]

Importance: Pericarditis accounts for up to 5% of emergency department visits for nonischemic chest pain in North America and Western Europe. With appropriate treatment, 70% to 85% of these patients have a benign course. In acute pericarditis, the development of constrictive pericarditis (<0.5%) and pericardial tamponade (<3%) can be life-threatening. Observations: Acute pericarditis is diagnosed with presence of 2 or more of the following: sharp, pleuritic chest pain that worsens when supine (≈90%); new widespread electrocardiographic ST-segment elevation and PR depression (≈25%-50%); a new or increased pericardial effusion that is most often small (≈60%); or a pericardial friction rub (<30%). In North America and Western Europe, the most common causes of acute pericarditis are idiopathic or viral, followed by pericarditis after cardiac procedures or operations. Tuberculosis is the most common cause in endemic areas and is treated with antituberculosis therapy, with corticosteroids considered for associated constrictive pericarditis. Treatment of acute idiopathic and pericarditis after cardiac procedures or operations involves use of high-dose nonsteroidal anti-inflammatory drugs (NSAIDs), with doses tapered once chest pain has resolved and C-reactive protein level has normalized, typically over several weeks. These patients should receive a 3-month course of colchicine to relieve symptoms and reduce the risk of recurrence (37.5% vs 16.7%; absolute risk reduction, 20.8%). With a first recurrence of pericarditis, colchicine should be continued for at least 6 months. Corticosteroids are often used if pericarditis does not improve with NSAIDs and colchicine. In certain patients with multiple recurrences, which can occur for several years, interleukin 1 (IL-1) blockers have demonstrated efficacy and may be preferred to corticosteroids. Conclusions: Acute pericarditis is a common cause of nonischemic chest pain. Tuberculosis is the leading cause of pericarditis in endemic areas and is treated with antitubercular therapy. In North America and Western Europe, pericarditis is typically idiopathic, develops after a viral infection, or develops following cardiac procedures or surgery. Treatment with NSAIDs and colchicine leads to a favorable prognosis in most patients, although 15% to 30% of patients develop recurrence. Patients with multiple recurrent pericarditis can have a disease duration of several years or more, are often treated with corticosteroids, and IL-1 blockers may be used for selected patients as steroid-sparing therapy. This review summarizes current evidence on recommended treatments for acute pericarditis, its prognosis, and the diagnostic evaluation of individuals with suspected initial or recurrent pericarditis. [ABSTRACT FROM AUTHOR]

Tuberculosis is a common occurrence in developing countries. Drug resistance, co-morbidities, and limited availability of new rapid tests such as the GeneXpert/MTB Rif assay make diagnosis and treatment of extrapulmonary tuberculosis burdensome. A cross-sectional study was carried out at Employees' State Insurance Corporation Medical College and Hospital, Faridabad, Haryana of patients treated for tubercular cervical lymphadenopathy from December 2021 to March 2023 in the department of ENT. This study included 58 patients. The clinicopathological profile of patients and the outcome of treatment with antitubercular therapy were noted. The majority of patients had level V (39.6%) involvement. Incidental diagnosis of diabetes mellitus was seen in 2 cases (3.4%). Fever was the commonest constitutional symptom observed in 27.5% of cases. FNAC was suggestive of tubercular abscess in 48.2% and the GeneXpert MTB/RIF assay detected Mycobacterial tuberculosis in all the cases with rifampicin resistance in only one case. 56 cases (96.5%) had complete resolution after completion of antitubercular therapy including patients with rifampicin resistance and patients with diabetes mellitus. In the remaining two cases, treatment was prolonged for a few months before the resolution of the disease was observed. Timely diagnosis, patient compliance to antitubercular therapy, and adequate management of comorbidities lead to successful treatment outcomes in tubercular cervical lymphadenitis. Delayed response to treatment in a few cases needs further research into factors like immune status, nutrition, living conditions, and quality of drugs available to the public. [ABSTRACT FROM AUTHOR]

We here present a case providing valuable insights for clinicians who deliver care to patients identifying as transgender or nonbinary. A 30‐year‐old trans woman presented to sexual health services requesting a routine sexual health screen and was subsequently diagnosed with HIV and syphilis. She started antiretrovirals for HIV (bictegravir/tenoforvir alafenamide/emtricitabine) 12 days later and was treated with benzathine penicillin G. The patient also had a positive tuberculosis (TB) ELIspot blood test result and further investigations proved the presence of active TB in the chest with mediastinal involvement. She commenced treatment for TB with quadruple therapy, including rifampicin. Due to the clinically significant interaction between rifampicin and bictegravir, the patient's antiretroviral treatment was switched to dolutegravir 50 mg twice daily in combination with tenofovir disoproxil fumarate and emtricitabine. As the patient had transitioned from male to female and was self‐medicating with oestrogen‐containing feminizing hormone therapy, her hormonal treatment was optimized and blood levels of oestradiol were closely monitored and titrated to manage the drug–drug interaction between rifampicin and oestrogen to ensure the latter would be maintained within the expected therapeutic range. Our case report demonstrates the importance of combining treatment of multiple conditions under 1 team ideally integrated with gender services to prevent multiple attendances and mismanagement of feminizing hormone therapies. [ABSTRACT FROM AUTHOR]

After the pandemic COVID-19, global health agencies remind us that tuberculosis is the deadliest infectious disease worldwide. As per WHO reports, approximately ten million people are infected with tuberculosis every year. Only a small portion of global cases receive imperative life-saving medicines. Even in the face of enduring efforts in the discovery of effective management of tuberculosis, the disease remains to affect millions of patients worldwide, with a high rate of morbidity and mortality. Considering the low treatment success, high drug treatment failure, and resistance to existing antituberculosis drugs, there is an urgency for the development of new chemical entities as antituberculosis agents. The development of resistance in tuberculosis (TB) patients to the medications used to treat and prevent the disease presents a significant challenge worldwide. Extensive research confines the molecules to counteract this disease has led to identifying many inhibitory pharmacophores. A wide range of compounds has been screened to find a novel ideal drug candidate for curing tuberculosis. Chalcone and its derivatives are considered precursors of flavonoids and isoflavonoids and display a diverse array of reported pharmacological activities including anti-inflammatory and antituberculosis activities. As this field continues to evolve, these molecules present further opportunities for understanding the mechanism of antituberculosis action and the treatment of MDR. Here, we summarize the impact of chalcone derivatives in tuberculosis treatment. The current statuses of various synthetic chalcone-based approaches for tuberculosis treatment are systematically reviewed here. [ABSTRACT FROM AUTHOR]

Paradoxical reactions (PR) to tuberculosis (TB) treatment are common during treatment, but have also been described after treatment. A presentation with recurrent signs or symptoms of TB after cure or completion of prior treatment needs to be differentiated between microbiological relapse and a paradoxical reaction. We searched all published literature on post-treatment PR, and present a synthesis of 30 studies, focusing on the epidemiology, diagnosis and management of this phenomenon. We report an additional case vignette. The majority of studies were of lymph node TB (LN-TB), followed by central nervous system TB (CNS-TB). A total of 112 confirmed and 42 possible post-treatment PR cases were reported. The incidence ranged between 3 and 14% in LN-TB and was more frequent than relapses, and between 0 and 2% in all TB. We found four reports of pulmonary or pleural TB post-treatment PR cases. The incidence did not differ by length of treatment, but was associated with younger age at initial diagnosis, and having had a PR (later) during treatment. Post-treatment PR developed mainly within the first 6 months after the end of TB treatment but has been reported many years later (longest report 10 years). The mainstays of diagnosis and management are negative mycobacterial cultures and anti-inflammatory treatment, respectively. Due to the favourable prognosis in LN-TB recurrent symptoms, a short period of observation is warranted to assess for spontaneous regression. In CNS-TB with recurrent symptoms, immediate investigation and anti-inflammatory treatment with the possibility of TB retreatment should be undertaken. [ABSTRACT FROM AUTHOR]

Background: Galatella is a genus in the family Asteraceae, represented by 35-45 species. Considering the high effectiveness of the ethyl acetate (EtOAc) fraction of G. grimmii against Mycobacterium tuberculosis (MIC = 0.5 µg/mL), a bioassay-directed fractionation of this extract was carried out. Methods: The methanolic extract of the aerial parts of G. grimmii was obtained using maceration, then it was suspended in water and partitioned with petroleum ether, dichloromethane (CH2Cl2), EtOAc, and n-butanol (n-BuOH), successively. The most potent fraction (EtOAc), was selected for further isolation by Sephadex LH–20 and semi-preparative HPLC to obtain active compounds. Results: Fractionation of the EtOAc solvent fraction resulted in the characterization of five compounds, among them, compounds 1 and 2 showed the highest anti-mycobacterial effects with MICs of 0.062 and 1.00 µg/mL against H37Rv M. tuberculosis, respectively, which were higher than those of rifampin (MIC of 1.25 µg/mL) and isoniazid (MIC of 0.31 µg/mL), as positive controls. Also, compound 1 ​​inhibited all tested strains of drug-resistant Mycobacterium (MDR and XDR). Notably, the isolated compounds have been reported for the first time from G. grimmii. Conclusion: Due to the potent anti-mycobacterial effect of isolated compounds from G. grimmii, this study could pave the way for developing a novel class of natural anti-tuberculosis compounds. [ABSTRACT FROM AUTHOR]

Introduction: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases. Methods: This study evaluated the suitability of a high-throughput infection system composed of the host amoeba Dictyostelium discoideum (Dd) and Mycobacterium marinum (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes. Results: The study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of trans-δ-viniferins and in particular of two compounds 17 and 19 with an IC50 of 18.1 μM, 9 μM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense. Discussion: The study highlights the potential of biotransformation and NPinspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds. [ABSTRACT FROM AUTHOR]

Bedaquiline (BDQ) is an orally administered diarylquinoline class anti-tuberculosis drug used in the combination therapy of MDR-TB. Currently, it is marketed as bedaquiline fumarate (BDQ--FA). However, due to its poor water solubility, BDQ--FA must be taken with food to enhance bioavailability. Concurrent administration reduces patient compliance and may increase the risk of inconsistent serum levels due to differences in dietary habits. This study designed and synthesized the saccharin salt of bedaquiline (BDQ--SA). Compared to the marketed fumarate salt, BDQ--SA exhibits better solubility and absorption. The food effect of commercially available BDQ--FA in beagle dogs was 7.2 times, while that of BDQ--SA was 3.2 times. This study provides a good example of using a new salt form to improve drug solubility and mitigate the food effect of the drug. [ABSTRACT FROM AUTHOR]

In an attempt to identify a new pharmacological lead which should be more potent than the established drug pyrazinamide, a molecular hybridization technique was applied to fuse two pharmacophore moieties: pyrazine‐2‐carbohydrazide (1) and diphenyl ether/piperazinyl derivative (2), to isolate a new series of hybrid molecules. The synthesized compounds were tested in vitro for their antibacterial and antimycobacterial properties against E. coli and S. aureus and Mycobacterium TB H37Rv strains. In comparison to the reference medication (pyrazinamide) these compounds exhibited moderate antitubercular and antibacterial action, with a MIC value of 15.625–125 µg/mL. All the synthesized molecules were characterized through IR, NMR and mass spectrometry. Docking studies were carried out in order to have better understanding related to protein and ligand receptor interactions. [ABSTRACT FROM AUTHOR]

Background: Worldwide, there is an increase in the frequency of reports of psoas abscesses due to advances in imaging technology, which has led to early diagnosis and treatment. A bilateral psoas abscess is rare and, when it occurs, is usually secondary and in immunocompromised patients. We present a case of a bilateral tuberculosis psoas abscess in a human immunodeficiency virus-positive patient. Case presentation: A 21-year-old Ugandan female undergraduate who contracted human immunodeficiency virus through vertical transmission and has been on highly active antiretroviral drugs presented with bilateral lower abdominal pain with associated fever and headache. Clinical examination revealed abdominal tenderness in both iliac fossae with palpable masses. Ultrasonography revealed fluid collection in both psoas muscles confirming bilateral abscesses. The aspirate was acid-fast bacilli positive. A diagnosis of bilateral tuberculosis psoas abscess was made. Open drainage was performed and antituberculosis drugs were commenced. Conclusions: Bilateral tuberculosis psoas abscesses occurring in human immunodeficiency virus-positive patients, although uncommon, is not unexpected. It is a form of secondary psoas abscess in immunocompromised patients. Here, the outcome was successful with a combination of early surgical drainage and appropriate medical therapy. [ABSTRACT FROM AUTHOR]

Tuberculous meningitis (TBM) is a serious form of TB disease that can result in high morbidity and mortality, particularly if there are delays in diagnosis and treatment. In this case report, a 9‐month‐old girl was admitted with persistent vomiting and focal seizures. On examination, she was found to have a right‐side hemiparesis. Brain imaging showed intense nodular leptomeningeal enhancement, hydrocephalus, a hypolucent lesion in the left basal ganglia, arterial stenosis and vasculitis, and an old ischemic insult. The patient was initially diagnosed with an acute ischemic stroke and was treated with aspirin and antiepileptic drugs. The patient's condition failed to improve despite initial treatment, leading to further diagnostic procedures. The results uncovered a diagnosis of TBM. The case highlights the importance of considering TBM as a possible cause of neurological symptoms, especially during the coronavirus disease 2019 (COVID‐19) pandemic where similar symptoms can be present in cases of neurological complications of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and multisystem inflammatory syndrome in children (MIS‐C). [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions. Methods This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes. Findings We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P <.001) and TPT prescriptions (45% vs 30%, P =.13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51–68; P <.001) more participants with TBI results and 12% (95% confidence interval, −6 to 31; P =.18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively). Interpretation In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm. Clinical Trials Registration NCT02119130. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium tuberculosis (Mtb) carbonic anhydrases (CAs) are critical enzymes that regulate pH by converting CO2 to HCO3-, essential for Mtb's survival in acidic environments. Inhibiting γ-CAs presents a potential target for novel antituberculosis drugs with unique mechanisms of action. Objective: This study aimed to explore the biological connections underlying Mtb pathogenesis and investigate the mechanistic actions of antituberculosis compounds targeting the Cas9 protein. Methods: We employed homology modeling and virtual screening to identify compounds with high binding affinities for Cas9 protein. This study used the homology modeling approach employing high-quality AlphaFold DB models for γ-CA. Furthermore, the systems biology approach was used for analyzing the integrated modelling of compounds, integrating data on genes, pathways, phenotypes, and molecular descriptors. Single-cell RNA sequencing was also conducted to profile gene expression. Results: Three compounds, F10921405, F08060425, and F14437079, potentially binding to Cas9 protein, have been identified. F10921405 and F08060425 showed significant overlap in their effects on pathways related to the immune response, while F14437079 displayed distinct mechanistic pathways. Expression profiling revealed high levels of genes such as PDE4D, ROCK2, ITK, MAPK10, and SYK in response to F1092-1405 and F0806-0425, and MMP2 and CALCRL in response to F1443-7079. These genes, which play a role in immune modulation and lung tissue integrity, are essential to fight against Mtb. Conclusion: The molecular relationship and pathways linked to the mentioned compounds give the study a holistic perspective of targeting Mtb, which is essential in designing specific therapeutic approaches. Subsequent research will involve experimental validation to demonstrate the efficacy of the promising candidates in Mtb infections. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The aim of this study was to explore the clinical characteristics and risk factors for hypersensitivity reactions induced by antituberculosis drugs.A retrospective analysis was conducted on the medical records of patients with active tuberculosis (TB) treated in the TB ward at West China Hospital, Sichuan University, from November 2010 to April 2020.Out of 7106 patients with active tuberculosis, 205 experienced hypersensitivity reactions to antituberculosis drugs; the incidence of hypersensitivity was 2.9%. The predominant clinical manifestation was a rash, observed in 57.1% (117/205) of these cases. Additionally, 19.0% (39/205) of patients presented with concurrent liver injury. The laboratory parameters white blood cell count, total lymphocyte count, monocyte count, eosinophil count, basophil count, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were significantly elevated in patients with hypersensitivity compared to those without. In 38 patients who tested positive for oral antituberculosis drug provocation, 14 (36.8%) were allergic to more than two antituberculosis drugs. Significant risk factors included being female (odds ratio [OR] = 1.387, 95% confidence intervals [CI]: 1.016–1.894), under 65 years of age (OR = 1.826, 95% CI: 1.145–2.913), existing liver disease (OR = 2.464, 95% CI: 1.822–3.333) and a history of allergic diseases (OR = 6.633, 95% CI: 2.681–16.406) and were significantly correlated with hypersensitivity to antituberculosis drugs.Hypersensitivity reactions to antituberculosis drugs primarily affect the skin, with significant associations observed with liver injury. Females, individuals younger than 65 years, those with pre‐existing liver disease and patients with a history of allergic diseases are at elevated risk for hypersensitivity. [ABSTRACT FROM AUTHOR]

Introduction: With the rising use of medications, Adverse Drug Reactions (ADRs) have emerged as a significant public health issue. Therefore, establishing a robust pharmacovigilance system across the nation has become imperative. The present study focussed to analyse the trends and frequency of ADRs to enhance the safety of drug prescriptions and ensure public health protection. Aim: To assess the pattern of adverse effects, drugs implicated, causality, severity, and outcomes of ADRs reported to the ADR monitoring centre in the Department of Pharmacology, Government TD Medical College, Alappuzha, Kerala, India. Materials and Methods: This was a cross-sectional study in which 262 ADRs reported to the Department of Pharmacology, Government TD Medical College, Alappuzha, Kerala, India from May 2022 to April 2023 were analysed for patient demographics, drug and ADR characteristics, and the outcomes of the ADR. Causality and severity assessments of these ADRs were performed using the World Health Organisation (WHO)-Uppsala Monitoring Centre (UMC) scale and the modified Hartwig and Siegel's scale, respectively. Data were tabulated using Microsoft Excel and expressed as mean, standard deviation, frequency, and percentage as appropriate, with the help of descriptive statistics using Epi Info 7 software. Results: A total of 262 ADRs were analysed. The mean age of the patients was 47.4±20.1 years. The majority were females 160 (61.1%). The intravenous route was the most common route involved in ADRs 158 (59.8%), followed by the oral route 91 (34.5%). Skin reactions accounted for more than half of the ADRs 151 (53.2%), followed by blood dyscrasias 48 (16.9%). Antibiotics were the most common group of implicated drugs 124 (44.9%), followed by anticancer drugs 43 (15.6%) and antitubercular drugs 34 (12.3%). Among antibiotics, cephalosporins (36.3%) were the most frequently encountered, followed by penicillins (30.6%). A total of 148 patients (56.5%) had recovered by the day of reporting, 146 (55.7%) ADRs were found to be 'possible' using the WHO-UMC causality scale, and 144 (54.9%) ADRs were classified as moderate severity. Conclusion: The study identified a widespread occurrence of ADRs, some of which increased healthcare costs due to prolonged hospital stays. The high incidence of ADRs from antimicrobials is concerning, as it contributes to antimicrobial resistance. This underscores the urgent need for prudent antimicrobial usage. The present study emphasises the importance of ADR reporting among healthcare workers and the necessity for hospitals to establish ADR reporting strategies for optimal patient care. [ABSTRACT FROM AUTHOR]

Introduction: The Coronavirus Disease-2019 (COVID-19) pandemic has halted the progress of India made towards the ambition of achieving Tuberculosis (TB)-free status by 2025. Steps taken to control the disease have affected many national health programs, including those for TB. Aim: To understand the delays in diagnosing and initiating therapy among TB patients receiving Antitubercular Therapy (ATT) during the early COVID-19 pandemic period. Materials and Methods: This was a cross-sectional study conducted in the Sonepat District of Haryana state, India. The study was conducted among 20% of the total Nikshay Portal-notified TB patients who received treatment from the public sector in the second and third quarters of 2020. Data was collected using a pretested semistructured schedule consisting of variables related to demography, past medical history, symptoms leading to TB diagnosis, place of diagnosis, time between symptom onset and diagnosis, duration taken for initiating therapy, and reasons for delays. The Chi-square test and Fisher's exact test were used to test the significance of the differences. A p-value <0.05 was considered significant. Results: 'Diagnostic Time delay' was observed among 86 (35.1%) of the participants, with a 30-day median delay. 'ATT initiation delays' were observed in 51 (20.8%) with a four-day median delay, and 23 (8.6%) of patients reported at least one episode of treatment interruption. 'Being diagnosed for other diseases' 70 (28.6%) and 'ignoring symptoms' 28 (11.4%) constituted the major reasons for 'Diagnostic time delay'. The non availability of drugs 11 (47.8%) and discomfort with drugs 07 (30.4%) were the major reasons for treatment interruption. Conclusion: Ignorance of symptoms and suspicion of other diseases constituted diagnostic delays, and therapy initiations were prolonged more during the pandemic period. [ABSTRACT FROM AUTHOR]

Despite the large number of works on the synthesis of polylactide-co-glycolide (PLGA) nanoparticles (NP) loaded with antituberculosis drugs, the data on the influence of various factors on the final characteristics of the complexes are quite contradictory. In the present study, a comprehensive analysis of the effect of multiple factors, including the molecular weight of PLGA, on the size and stability of nanoparticles, as well as the loading efficiency and release of the antituberculosis drug rifampicin (RIF), was carried out. Emulsification was carried out using different surfactants (polyvinyl alcohol, Tween 80 and Pluronic F127), different aqueous-to-organic phase ratios, and different solvents (dichloromethane, dimethyl sulfoxide, ethyl acetate). In this research, the PLGA nanoemulsion formation process was accompanied by ultrasonic dispersion, at different frequencies and durations of homogenization. The use of the central composite design method made it possible to select optimal conditions for the preparation of PLGA-RIF NPs (particle size 223 ± 2 nm, loading efficiency 67 ± 1%, nanoparticles yield 47 ± 2%). The release of rifampicin from PLGA NPs was studied for the first time using the flow cell method and vertical diffusion method on Franz cells at different pH levels, simulating the gastrointestinal tract. For the purpose of the possible inhalation administration of rifampicin immobilized in PLGA NPs, their mucoadhesion to mucin was studied, and a high degree of adhesion of polymeric nanoparticles to the mucosa was shown (more than 40% within 4 h). In the example of strain H37Rv in vitro, the sensitivity of Mycobacterium tuberculosis to PLGA-RIF NPs was proven by the complete inhibition of their growth. [ABSTRACT FROM AUTHOR]

Background The dispersible fixed-dose combination drug has been recommended as the mainstay of treatment for TB in children. However, more needs to be known about its effect on treatment. This study aimed to assess the effectiveness of the formulation on treatment adherence among children with TB. Methods A historical cohort design was used to assess and compare adherences of old loose non-dispersible and new dispersible fixed-dose anti-TB drugs, using a convergent parallel mixed-method approach for data collection. Determinants of treatment adherence were assessed using binary logistic regression. Results The proportion of children with good treatment adherence was higher in the new dispersible formulation group (82 [64.6%]) relative to the proportion among the loose non-dispersible formulation group (29 [23.4%]). Reports of forgetfulness, travelling and pill burden were significantly higher among those with poor adherence in the loose non-dispersible formulation group. Significant predictors of treatment adherence were acceptability (adjusted OR [AOR]=4.1, p=0.013, 95% CI 1.342 to 12.756), travelling from treatment areas (AOR=8.9, p=0.002, 95% CI 2.211 to 35.771) and forgetfulness (AOR=74.0, p<0.001, 95% CI 23.319 to 234.725). Conclusions The determinants of treatment adherence are multifactorial. In addition to ensuring universal access to the drug, flexible referral in case of travelling and ensuring treatment partners' participation to minimise forgetfulness to take pills, are essential. [ABSTRACT FROM AUTHOR]

There is currently a lack of guidelines with regard to tubercular uveitis (TBU) management in Taiwan. We therefore propose an evidence-based consensus on the management for TBU. The Taiwan Ocular Inflammation Society conducted a meeting that included nine ophthalmologist and one infection disease expert that focused on three broad areas of (1) nomenclature for TBU, (2) assessment and diagnosis for TBU, and (3) treatment of TBU. Brief literature review on TBU diagnosis and management was conducted that informed this panel meeting in order to make decisions on each consensus statements. In terms of our results, a consensus statements and recommendations for the diagnosis and management of TBU were developed. This consensus statement provides an algorithmic approach toward diagnosing and managing TBU. These statements are meant to enhance but not replace individual clinician–patient interactions and to facilitate real-world clinical practice improvement in terms of TBU patients care. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic's first wave and subsequent lockdowns disrupted global healthcare systems, significantly impacting essential services including tuberculosis (TB) care. Non-adherence to anti-TB drugs is a critical concern, leading to treatment failure, drug resistance, and increased morbidity and mortality. This study assessed the rate and determinants of non-adherence to TB treatment among patients at TB centers during the first wave of the pandemic. Material and Methods: A cross-sectional study was conducted from June 15 to July 30, 2020, involving 255 TB patients at three centers in Mogadishu. Data were gathered using the Morisky Medication Adherence Scale-8 (MMAS-8) through structured interviews and analyzed using descriptive statistics and binary logistic regression. Results: The study found a 34.5% non-adherence rate during the pandemic. Key reasons for non-adherence included forgetting to take medication (33%), feeling well (29%), experiencing side effects (18%), and fear of contracting COVID-19 (16%). Significant factors associated with non-adherence were age groups 25– 34 years (OR = 2.96, p = 0.024) and 35– 44 years (OR = 4.55, p = 0.005), unemployment (OR = 2.57, p = 0.037), smoking (OR = 3.49, p = 0.029), tobacco use (OR = 4.15, p = 0.034), proximity to a health facility (OR = 0.44, p = 0.033), perception of healthcare providers as very friendly (OR = 0.24, p = 0.031) or friendly (OR = 0.45, p = 0.023), being in the continuous treatment phase (OR = 3.2, p < 0.001), and experiencing adverse treatment effects (OR = 2.42, p = 0.003). Conclusion: Non-adherence to anti-tuberculosis treatment was notably high in Mogadishu during the first wave of the pandemic, necessitating targeted interventions to improve adherence. [ABSTRACT FROM AUTHOR]

Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets.Trial registration: ClinicalTrials.gov identifier: NCT05117788..

In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.