Multidrug-resistant Tuberculosis Research Articles

Study of Molecular Docking, Molecular Dynamics, Pharmacokinetics and Toxicity Prediction: Compounds from Nigella sativa Linn, Andrographis paniculata Nees, and Propolis as Inhibitors of Mycobacterium tuberculosis Growth

Background: Tuberculosis (TB) is caused by *Mycobacterium tuberculosis*, and Multiple Drug-Resistant Tuberculosis (MDR-TB) arises from resistance to first-line treatments like Rifampicin and Isoniazid. Since current TB medications have been used for over four decades, discovering new drug candidates is critical. This research focuses on herbal compounds—Black cumin (*Nigella sativa*), Sambiloto (*Andrographis paniculata*), and propolis—as potential inhibitors of *M. tuberculosis* by targeting DHFR. The objective of the study is to predict the activity of these herbal compounds prior to in vitro and in vivo testing. Methods: This study employed computational tools, including Molegro Virtual Docking (MVD) and Molecular Dynamics (MD), to assess the interactions of the herbal compounds with DHFR (PDB ID: 2CIG). Pharmacokinetic predictions were also conducted to evaluate the absorption and toxicity of the compounds. Results: Molecular docking and MD simulations indicated that Andrographolide, Thymoquinone, and Caffeic Acid Phenethyl Ester effectively inhibited the growth of *M. tuberculosis*. The analysis revealed favorable binding interactions and conformational changes in DHFR, with significant activity observed for Thymoquinone. Conclusion: This study suggests that Andrographolide, Thymoquinone, and Caffeic Acid Phenethyl Ester may serve as promising candidates for further development as anti-tuberculosis drugs. Subsequent in vitro and in vivo studies are warranted to validate their therapeutic potential.

Drug-resistance characteristics, genetic diversity, and transmission dynamics of multidrug-resistant or rifampicin-resistant Mycobacterium tuberculosis from 2019 to 2021 in Sichuan, China

BackgroundMultidrug- or rifampicin-resistant tuberculosis (TB; MDR/RR-TB) is a significant public health threat. However, the mechanisms involved in its transmission in Sichuan, China are unclear. To provide a scientific basis for MDR/RR-TB control and prevention, we investigated the drug-resistance characteristics, genetic diversity, and transmission dynamics and analyzed the demographic and clinical characteristics of patients to identify risk factors for the acquisition of MDR/RR-TB in Sichuan, Western China.MethodsWhole-genome sequencing was performed using a sample comprised of all MDR/RR-TB strains isolated from patients with pulmonary TB (≥ 15 years) at the 22 surveillance sites in Sichuan province between January 2019 and December 2021, to analyze genotypic drug resistance and genetic diversity. Moreover, we performed statistical analyses of the epidemiological characteristics and risk factors associated with the transmission dynamics of MDR/RR-TB.ResultsThe final analysis included 278 MDR/RR TB strains. Lineage 2.2, the major sub-lineage, accounted for 82.01% (228/278) of isolates, followed by lineage 4.5 (9.72%, 27/278), lineage 4.4 (6.83%, 19/278), and lineage 4.2 (1.44%, 4/278). The drug resistance rates, ranging from high to low, were as follows: isoniazid (229 [82.37%]), streptomycin (177 [63.67%]), ethambutol (144 [51.80%]), pyrazinamide (PZA, 119 [42.81%]), fluoroquinolones (FQs, 93 [33.45%]). Further, the clofazimine, bedaquiline, and delamanid resistance rates were 2.88, 2.88, and 1.04%, respectively. The gene composition cluster rate was 32.37% (90/278). In addition, 83.81% (233/278) of MDR/RR-TB cases were determined to be likely caused by transmission. Finally, patients infected with lineage two strains and strains with the KatG S315T amino acid substitution presented a higher risk of MDR/RR-TB transmission.ConclusionTransmission plays a significant role in the MDR/RR-TB burden in Sichuan province, and lineage 2 strains and strains harboring KatG S315T have a high probability of transmission. Further, high levels of FQ and PZA drug resistance suggest an urgent need for drug susceptibility testing prior to designing therapeutic regimens. New anti-TB drugs need to be used standardly and TB strains should be regularly monitored for resistance to these drugs.

Mycobacterium tuberculosis evolution from monoresistance to pre-extensive drug resistance during a prolonged household outbreak

Whole genome sequencing (WGS) is sensitive tool for the analysis of tuberculosis transmission and drug-resistance. We used WGS to analyze the Mycobacterium tuberculosis evolution from isoniazid monoresistance to MDR/preXDR during a prolonged household outbreak. The outbreak started with a isoniazid resistant strain (katG S315T mutation) and evolve in two cases to pre-XDR phenotype (with mutations in katG, rpoB, embB, pncA and gyrA genes). Based on WGS data and epidemiological interview we proposed a possible chain of transmission an evolution of the strains.Similar intra-patient and inter-patient acquisition of variability was observed, making difficult to distinguish reinfection or reactivation. Analysis of WGS data together with epidemiological clinical history are discussed in order to distinguish between prolonged infections or transition from latency to reactivation. Classical interview and clinical history taking should be consider to fully understanding WGS data. With a still low incidence of TB cases, Uruguay could use universal WGS of all isolates to reduce time of diagnosis, detect outbreaks and perform public actions to reduce TB incidence.

Identifying risk factors for recurrent multidrug resistant tuberculosis based on patient’s record data from 2016 to 2021: retrospective study

Globally, the prevalence of multidrug-resistant tuberculosis (MDR-TB) has been increasing recently. This is a major public health concern, as MDR-TB is more difficult to treat and has poorer outcomes compared to drug-sensitive tuberculosis. The main objective of the study was to identify risk factors for recurrent multidrug-resistant tuberculosis, at Alert Specialized Hospital, Addis Ababa, by using different parametric shared frailty models. From January 2016 to December 2021, a retrospective study was conducted on MDR-TB patients at Alert Specialized Hospital in Addis Ababa. The data for the study were collected from the medical records of MDR-TB patients at the hospital during this time period. Gamma and inverse-Gaussian shared frailty models were used to analyze the dataset, with the exponential, Weibull, and lognormal distributions included as baseline hazard functions. The data were analyzed using R statistical software. The median recurrence time of the patients was 12 months, and 149 (34.3%) had recurrences. The clustering effect was statistically significant for multiple drug-resistant tuberculosis patients’ recurrence. According to the Weibull-Inverse-Gaussian model, factors that reduced time to MDR-TB recurrence included lower weight (ɸ = 0.944), smoking (ɸ = 0.045), alcohol use (ɸ = 0.631), hemoptysis (ɸ = 0.041), pneumonia (ɸ = 0.564), previous anti-TB treatment (ɸ = 0.106), rural residence (ɸ = 0.163), and chronic diseases like diabetes (ɸ = 0.442) were associated with faster recurrence. While, higher education (ɸ = 3.525) and age (ɸ = 1.021) extended time to recurrence. For weight increment, smokers and alcohol users, clinical complications of hemoptysis and pneumonia, patients with pulmonary disease who had a history of previous anti-TB treatment, and being rural residents are prognostic factors. There was a significant clustering effect at the Alert Specialized Hospital in Addis Ababa, Ethiopia. The Weibull-Inverse Gaussian Shared Frailty Model was chosen as the best model for predicting the time to recurrence of MDR-TB.

HIV co-infection increases the risk of post-tuberculosis mortality among persons who initiated treatment for drug-resistant tuberculosis

Little is known regarding the relationship between common comorbidities in persons with tuberculosis (TB) (including human immunodeficiency virus [HIV], diabetes, and hepatitis C virus [HCV]) and post-TB mortality. We conducted a retrospective cohort study among persons who initiated treatment for rifampicin-resistant or multi/extensively drug-resistant (RR or M/XDR) TB reported to the country of Georgia’s TB surveillance during 2009–2017. Exposures included HIV serologic status, diabetes, and HCV status. Our outcome was all-cause post-TB mortality determined by cross-validating vital status with Georgia’s death registry through November 2019. We estimated adjusted hazard rate ratios (aHR) and 95% confidence intervals (CI) of post-TB mortality among participants with and without comorbidities using cause-specific hazard regressions. Among 1032 eligible participants, 34 (3.3%) died during treatment and 87 (8.7%) died post-TB treatment. The median time to post-TB death was 21 months (interquartile range 7–39) after TB treatment. After adjusting for confounders, the hazard rates of post-TB mortality were higher among participants with HIV co-infection (aHR = 3.74, 95%CI 1.77–7.91) compared to those without HIV co-infection. In our cohort, post-TB mortality occurred most commonly in the first 3 years post-TB treatment. Linkage to care for common TB comorbidities post-treatment may reduce post-TB mortality rates.

Comparison of Truenat Mycobacterium tuberculosis with line probe assay for the diagnosis of rifampicin resistance and mutation pattern of Mycobacterium tuberculosis

Abstract Background: There is an increasing incidence of multidrug-resistant tuberculosis (TB)/preextensively drug-resistant TB (XDR TB) and XDR TB globally. Therefore, rapid diagnostic tests with good sensitivity and specificity are need of hour. Truenat Mycobacterium tuberculosis (MTB) is one such test which gives results in 1–2 h and can withstand a variety of environmental conditions. Objective: The objective of this study was to compare Truenat MTB with line probe assay (LPA) for the diagnosis of rifampicin resistance and to study the mutation pattern of MTB. Materials and Methods: A comparative record-based study was carried out among 325 patients with multidrug-resistant TB. Sputum samples for pulmonary TB and appropriate site samples for extrapulmonary TB were obtained and tested with Truenat-MTB and LPA. A comparison between results obtained by Truenat-MTB and LPA was done. Based on first-line-LPA and second-line-LPA, gene mutation pattern was studied. Results: Males (69.2%) were more than females (30.8%). 30–49 (34.5%) years of age were most commonly affected. The sensitivity, specificity, positive predictive value, and negative predictive value of Truenat MTB compared to LPA were 82.86%, 93.45%, 60.41%, and 97.83%, respectively. The most common gene mutation observed was katG MUT1 in 59 cases. This was followed by rpoB MUT1 in three cases, rpoB MUT2A in two cases, rpoB MUT2B in four cases, and rpoB MUT3 in 12 cases. gyrA mutation was seen in nine cases among which gyrA MUT3A was seen in one case, gyrA MUT3B in one case, and gyrA MUT3C was seen in four cases. Two cases of rrs MUT1 were seen. Five cases of inhA MUT1 were seen. Conclusion: Truenat has been found to be economical, less time-consuming, giving fast results, and accurate in the diagnosis of DR-TB. The most common gene mutation observed was katG MUT1 in 59 cases.

Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches.

Tuberculosis remains a serious global health threat, exacerbated by the rise of resistant strains. This study investigates the potential of two benzofuroxan (Bfx) derivatives, 5n and 5b, as targeted treatments for MDR-TB using in silico, in vitro, and in vivo methodologies. In vitro analyses showed that Bfx compounds have significant activity against Mtb H37Rv, with Bfx 5n standing out with a MIC90 of 0.09 ± 0.04 μM. Additionally, their efficacy against MDR and pre-XDR strains was superior compared to commercial drugs. These Bfx compounds have a narrow spectrum for mycobacteria, which helps avoid dysbiosis of the gut microbiota, and they also exhibit high selectivity and low toxicity. Synergism studies indicate that Bfx derivatives could be combined with rifampicin to enhance treatment efficacy and reduce its duration. Scanning electron microscopy revealed severe damage to the morphology of Mtb following treatment with Bfx 5n, showing significant distortions in the bacillary structures. Whole-genome sequencing of the 5n-resistant isolate suggests resistance mechanisms mediated by the Rv1855c gene, supported by in silico studies. In vivo studies showed that the 5n compound reduced the pulmonary load by 3.0 log10 CFU/mL, demonstrating superiority over rifampicin, which achieved a reduction of 1.23 log10 CFU/mL. In conclusion, Bfx derivatives, especially 5n, effectively address resistant infections caused by Mtb, suggesting they could be a solid foundation for future therapeutic developments against MDR-TB.

High incidence of multidrug-resistant tuberculosis in Bhutan: A cohort study based on national TB surveillance data

ObjectivesThe emergence of multidrug-resistant tuberculosis (MDR-TB) has made the elimination of TB difficult. Currently, there are limited data on MDR-TB and other drug-resistant TB in Bhutan. We aimed to estimate the incidence and explore the potential risk factors associated with MDR/pre-extensively drug-resistant (pre-XDR)-TB using comprehensive national TB data. MethodsWe used the data from the Tuberculosis Information Surveillance System of the National Tuberculosis Reference Laboratory to analyze the resistance pattern and epidemiologic data for all TB cases tested for resistance for the year 2018-2021. Multiple logistic regression was performed to identify risk factors associated with MDR/pre-XDR-TB. ResultsOf the 2,290 samples tested for drug resistance, 10.6% (n = 243) was MDR-TB, 3.5% (n = 81) was isoniazid-resistant TB, and 0.61% (n = 14) was pre-XDR-TB. A high incidence of MDR/RR-TB/pre-XDR-TB was documented among patients in Thimphu, Samtse, and Sarpang districts. MDR/pre-XDR-TB was more likely documented among patients aged 18-39 years (adjusted odds ratio [aOR] 2.79; 95% confidence interval [CI] 1.46-6.07), female sex (aOR 1.37; 95% CI 1.01-1.86), and patients previously treated for TB (aOR 2.98; 95% CI 1.99-4.42). ConclusionsGiven the high burden of MDR-TB in some districts, decentralization of diagnostic facilities for more rapid characterization could improve early recognition of drug-resistant cases and assist in management. Comprehensive follow-up and monitoring of high-risk groups should be performed.

Experience of Using Delamanid in the Treatment of Multiple Drug Resistant Tuberculosis

The objective: to evaluate treatment results in MDR TB patients when delamanid is added to the treatment regimen.Subjects and Methods. 91 patients with multiple drug resistant pulmonary tuberculosis were included in the study, of which 36 people (39.6%) were HIV positive. Patients were divided into four comparison groups depending on HIV status and inclusion of delamanid in the treatment regimen. Groups receiving delamanid included only patients in whom bedaquiline or linezolid had been discontinued due to adverse reactions.Results. The results of treatment of MDR TB when delamanid is added to the chemotherapy regimen during the intensive phase, indicate its high effectiveness and safety including HIV positive patients.

Detection of Rifampicin Resistance rpoB Gene Using GeneXpert MTB/RIF Assay in Pulmonary Tuberculosis Cases at Debre Tabor Comprehensive Specialized Hospital, Northwest Ethiopia.

Tuberculosis (TB) is a preventable and treatable disease leading to the second death globally. The evolution of drug resistance in Mycobacterium tuberculosis (MTB), particularly rifampicin resistance (RR), has hampered TB control efforts. Thus, this study aimed to provide information regarding the magnitude of MTB and rifampicin resistance among patients tested using the GeneXpert method. A retrospective analysis was carried out at DTCSH. The study included TB registration logbook data from all patients who visited the hospital and were tested for MTB with the Xpert MTB/RIF assay from 2017 to 2024. The laboratory-based data were entered, cleaned, and analyzed using SPSS version 26 software. Multilogistic regression analysis was employed, and a p value ≤ 0.05 was considered statistically significant. A total of 12,981 patient results were included, of which 8.9% (1160/12,981) were MTB-positive and 7.1% (82/1160) were RR. Individuals aged 15-29 years (AOR = 2.13; 95% CI = 1.55-2.93, p < 0.001), living in rural areas (AOR = 1.23; 95% CI = 1.08-1.41, p = 0.003), and HIV+ (AOR = 1.79; 95% CI = 1.48-2.33, p < 0.001) had a higher risk of developing tuberculosis. While RR was identified in 63.4% (52/82) of new, 24.4% (20/82) of re-treated, and 12.2% (10/82) of failed presumptive TB patients. In this study, MTB and RR trends were high. Productive age groups, rural populations, and HIV patients were at risk. To lessen the burden of this contagious and fatal disease, it is recommended to increase early diagnosis of drug-resistant TB and enhance infection control.

Clinical research for saliva-based therapeutic drug monitoring of linezolid.

Linezolid is primarily used to treat of methicillin-resistant Staphylococcus aureus and multidrug-resistant tuberculosis infections. Thrombocytopenia due to linezolid usage is a concern, and therapeutic drug monitoring has been reported to be effective in its prevention. Plasma concentrations provide valuable information for treatment decisions; however, collecting plasma samples can be burdensome for both patients and healthcare providers. Therefore, there is interest in saliva as an alternative for monitoring, considering its potential to replace plasma samples. Patients hospitalized at Hokkaido University Hospital and Hokkaido Spinal Cord Injury Center between April 2022 and July 2024, who received oral or intravenous linezolid treatment, were enrolled. The concentrations of linezolid were simultaneously measured in plasma and saliva samples. We determined the concentration profiles of linezolid in the saliva and examined the correlation between saliva and plasma linezolid concentrations. Eighteen patients receiving linezolid were enrolled. The average of saliva/plasma (S/P) concentration ratios of linezolid were 1.018. A strong correlation was found between the salivary and plasma concentrations of linezolid (R= .833, P< .001). Notably, in patients receiving intravenous administration of linezolid, the correlation was even more pronounced (R= .885, P< .001). Additionally, when focusing on the S/P ratio of the trough concentrations in the morning and at night, the S/P ratios at night were much closer to 1.0. The concentrations of linezolid in plasma and saliva were similar, indicating their potential applicability in clinical settings. The monitoring of linezolid concentrations in saliva has been shown to be particularly suitable for patients receiving intravenous administration.

Extracorporeal membrane oxygenation for tuberculosis-related acute respiratory distress syndrome: An international multicentre retrospective cohort study

ObjectiveTo report the outcomes of patients with severe tuberculosis (TB)-related acute respiratory distress syndrome (ARDS) on extracorporeal membrane oxygenation (ECMO), including predictors of 90-day mortality and associated complications.MethodsAn international multicenter retrospective study was conducted in 20 ECMO centers across 13 countries between 2002 and 2022.ResultsWe collected demographic data, clinical details, ECMO-related complications, and 90-day survival status for 79 patients (median APACHE II score of 20 [25th to 75th percentile, 16 to 28], median age 39 [28 to 48] years, PaO2/FiO2 ratio of 69 [55 to 82] mmHg before ECMO) who met the inclusion criteria. Thoracic computed tomography showed that 61 patients (77%) had cavitary TB, while 18 patients (23%) had miliary TB. ECMO-related complications included major bleeding (23%), ventilator-associated pneumonia (41%), and bloodstream infections (32%). The overall 90-day survival rate was 51%, with a median ECMO duration of 20 days [10 to 34] and a median ICU stay of 42 days [24 to 65]. Among patients on VV ECMO, those with miliary TB had a higher 90-day survival rate than those with cavitary TB (90-day survival rates of 81% vs. 46%, respectively; log-rank P = 0.02). Multivariable analyses identified older age, drug-resistant TB, and pre-ECMO SOFA scores as independent predictors of 90-day mortality.ConclusionThe use of ECMO for TB-related ARDS appears to be justifiable. Patients with miliary TB have a much better prognosis compared to those with cavitary TB on VV ECMO.

Effectiveness of new antituberculosis drugs in the treatment of children and adolescents with chemoresistant tuberculosis

BACKGROUND. There is a significant decrease the effectiveness of antituberculous (anti-TB) treatment on the background of multidrug and extensive drug resistance (MDR/XDR) of Mycobacterium tuberculosis. Therefore, in order to increase the effectiveness of treatment MDR-/XDR-TB a new antimycobacterial drugs such as bedaquiline (Bdq), delamanid (Dlm) and pretomanid have been introduced both for adults, children and adolescents in recent years. MATERIALS AND METHODS. On the basis of a retrospective cohort analysis of the data of patients' medical records the evaluation of the clinical effectiveness of chemotherapy with Bdq and Dlm was carried out. The main group: 40 children and adolescents with MDR-/XDR-TB of lungs, who received complex antimycobacterial therapy (AMBT) with Bdq and Dlm. The control group consisted of 27 patients who received complex AMBT without Bdq and Dlm. Age range – from 3 to 18 years. RESULTS AND DISCUSSION. On the background of AMBT during the first 3 months of treatment was established stopping bacterial secretion among all patients of main and control groups. However, in control group compare to main one stopping bacterial secretion was significant slowly (p&lt;0.05). At the stage of completion of the intensive phase of AMBT, the normalization of immunological indicators occurred in 29.6±2.8 % of control group and in 43.4±4.5 % of main one. A significant difference between the groups among the immunoregulatory index CD3+CD4+/CD3+CD8+, IgM and circulating immune complexes was obtained. Among children and adolescents of the main group positive dynamic of immunological changes were observed 1.5 times more often. Among all patients of main group the resolution of the infiltration, consolidation of the focus and the absence of decay cavities were ascertained at the end of the anti-TB course. Anti-TB treatment with the formation of small residual changes into lung tissue ended in 77.5 % patients of main group. In 12.5 % cases of control group destructions persisted and bacterial excretion resumed. A large residual changes such as multiple dense foci, fibrosis and residual decay cavities in control group were observed 2.3 times more often (51.9 % vs 22.5 %), p&lt;0.05, than in main one. Using Bdq and Dlm among children and adolescents with MDR-/XDR-TB significantly increased efficiency of complex treatment. Among main group (72.5 %) compare to control (33.3 %) one the results of treatment to be considered “cured” were 2.2 times more likely and 1.5 times less often – “completed” (27.5 % vs 51.8 % respectively). The success rate of treatment among children and adolescents who received Bdq and Dlm was 100.0 % and among patients without these new drugs – 85.2 %. CONCLUSIONS. The criteria used show that AMBT combined with Bdq and Dlm is 1.5-2.2 times more effective (according to a separate criterion) than AMBT without these drugs.

Mechanism research of Tollip negative feedback regulation in TLR4 signaling pathways based on spinal tuberculosis: Detection of Tollip and NF-κB expression levels

The emergence of drug-resistant mycobacterium tuberculosis (MTB, or TB) strains has led to an increasing incidence of TB. Spinal tuberculosis is the most common extrapulmonary tuberculosis. In the present study, tollip, a negative feedback regulatory factor in TLR4 signaling pathway was chosen based on previous studies on osteoarticular tuberculosis. U937 cells were transfected with recombinant lentivirus containing shRNA (RNA interference, RNAi) or overexpression vector containing Tollip gene and tested in vitro. The expression levels of Tollip and TLR4 were detected by Real-time PCR and immunofluorescence techniques, and the cell morphology and infection effect were observed by DAPI staining. The results suggested that Tollip gene could negatively inhibit the expression of related factors in TLR4 signaling pathway, and thus is a potential biomarker for early diagnosis.

Advancing against drug-resistant tuberculosis: an extensive review, novel strategies and patent landscape.

Drug-resistant tuberculosis (DR-TB) represents a pressing global health issue, leading to heightened morbidity and mortality. Despite extensive research efforts, the escalation of DR-TB cases underscores the urgent need for enhanced prevention, diagnosis, and treatment strategies. This review delves deep into the molecular and genetic origins of different types of DR-TB, highlighting recent breakthroughs in detection and diagnosis, including Rapid Diagnostic Tests like Xpert Ultra, Whole Genome Sequencing, and AI-based tools along with latest viewpoints on diagnosis and treatment of DR-TB utilizing newer and repurposed drug molecules. Special emphasis is given to the pivotal role of novel drugs and discusses updated treatment regimens endorsed by governing bodies, alongside innovative personalized drug-delivery systems such as nano-carriers, along with an analysis of relevant patents in this area. All the compiled information highlights the inherent challenges of current DR-TB treatments, discussing their complexity, potential side effects, and the socioeconomic strain they impose, particularly in under-resourced regions, emphasizing the cost-effective and accessible solutions. By offering insights, this review aims to serve as a compass for researchers, healthcare practitioners, and policymakers, emphasizing the critical need for ongoing R&D to improve treatments and broaden access to crucial TB interventions.

QT Prolongation Associated with Administration of Bedaquiline, a Novel Anti-Tuberculosis Drug.

Bedaquiline is a diarylquinoline compound that has recently been introduced and approved for use in the treatment of multidrug-resistant tuberculosis (MDR-TB). Its mechanism of action is inhibition of adenosine triphosphate-synthase. In combination with other antibiotics, bedaquiline-containing regimens administered for 6 months achieve cure rates of roughly 90%, in contrast to the previously used, 24-month-long WHO-recommended regimens for the treatment of MDR-TB. However, since its introduction, concerns have been raised about its effects on QT prolongation and its safety in routine clinical use. We reviewed the published experience regarding bedaquiline use, QT prolongation, and adverse cardiac events when the drug was used alone or in combination. Overall, data are reassuring that bedaquiline use in clinical practice is not associated with an excess of cardiac deaths or other clinically meaningful cardiac events. This review provides reassurance and support for the continued use of bedaquiline in the treatment of MDR-TB.

A modified BPaL regimen for tuberculosis treatment replaces linezolid with inhaled spectinamides.

The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug-resistant or extensively drug-resistant TB participants were cured but many patients also developed severe adverse events (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 is also a protein synthesis inhibitor of Mycobacterium tuberculosis with an excellent safety profile, but it lacks oral bioavailability. Here, we propose to replace L in the BPaL regimen with spectinamide (S) administered via inhalation and we demonstrate that inhaled spectinamide 1599, combined with BPa --BPaS regimen--has similar efficacy to that of the BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the BALB/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effects in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested the development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL and BPa, but not the BPaS treatment, also decreased myeloid to erythroid ratio suggesting the S in the BPaS regimen was able to recover this effect. Moreover, the BPaL also increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen without L-associated AEs.

Bedaquiline versus injectable containing regimens for rifampicin-resistant and multidrug-resistant tuberculosis in a reference center in Brazil – a real-world evidence study using a retrospective design

BackgroundDrug resistance (DR) is one of the several challenges to global tuberculosis (TB) control. The implementation of bedaquiline (BED) for DR-TB after more than 40 years was expected to improve treatment outcomes as well as microbiologic conversion and adverse events (AE) occurrence.MethodsRetrospective cohort study based on secondary data of patients with rifampicin-resistant (RR) or multidrug-resistant (MDR) TB reported to the Outpatient Clinic of Mycobacterial Diseases of the Thorax Diseases Institute – Federal University of Rio de Janeiro - Brazil, between 2016 and 2023. We aimed to evaluate microbiologic conversion, AE and TB treatment outcomes and compare them according to the treatment regimen used for RR/MDR-TB patients under routine conditions [Injectable Containing Regimens (ICR) versus BED Containing Regimens (BCR)]. Logistic regression and survival analysis using Cox regression and Kaplan Meier curve were used for statistical analysis.ResultsOf the 463 DR-TB patients notified during the study period, 297 (64.1%) were included for analysis (ICR = 197 and BCR = 100). Overall AEs were more frequent (83.7 vs. 16.3%, p < 0.001) and occurred earlier in the ICR group (15 days vs. 65 days, p = 0.003). There were no cases of cardiotoxicity requiring interruption of BED treatment. None of the regimens of treatment tested were associated with smear or culture conversion on Cox regression analysis (p = 0.60 and 0.88, respectively). BED-containing regimens were also associated with favorable outcomes in multivariable logistic regression [adjusted odds ratio (aOR) = 2.63, 95% confidence interval (CI)1.36–5.07, p = 0.004], as higher years of schooling, primary drug resistance, and no previous TB treatment. In the survival analysis, BCR was inversely associated with the occurrence of AE during treatment follow-up (aHR 0.24, 95% CI 0.14–0.41, p < 0.001). In addition, TB treatment regimens with BED were also associated with favorable outcomes (aHR 2.41, 95% CI 1.62–3.57, p < 0.001), along with no illicit drug use and primary drug resistance.ConclusionsThe implementation of a fully oral treatment for RR/MDR-TB in a reference center in Brazil was safe and associated with favorable outcomes under routine conditions, despite social, demographic, and behavioral factors that may influence TB treatment completion.

Eco-friendly Biosynthesis of Silver Nanoparticles Using Elephantorrhiza elephantina: Characterization and Antimicrobial Activity against Mycobacterium tuberculosis Surrogate Models

The emergence of multidrug-resistant (MDR) and extensively-drug resistant (XDR) Mycobacterium tuberculosis (MTB) strains have scampered efforts to arrest the tuberculosis (TB) pandemic due to treatment failures based on current drugs. The need for novel therapeutics has never been more urgent. Research is leaning towards alternative composite antimicrobials such as silver nanoparticles (AgNPs). Elephantorrhiza elephantina (E. elephantina) is an indigenous Southern African rhizomatous plant which has been used for eons in African traditional medicine for the management of TB. The purpose of this study was to biosynthesize and characterize AgNps using E. elephantina, and to evaluate their antimicrobial effectiveness against surrogate MTB species. The study also sought to screen for the participating secondary metabolites in E. elephantina acting as bio reducing, capping and stabilising agents; and to determine the toxicity of the lyophilised root extract in vivo. Qualitative phytochemical screening techniques confirmed the presence of bioactive secondary metabolites with functional groups capable of mediating in the biosynthesis of AgNPs. UV-Vis spectrometry established the identity of the nanostructures as AgNPs. Transmission electron microscopy and dynamic light scattering confirmed the AgNPs to have an average size of 44 nm, with spherical and cubic morphologies. The biosynthesised AgNPs were potent inhibitors of the model MTB species with an MIC of 19.53 µg/mL, and inhibition zones of 20mm and 18mm against Mycolicibacterium aurum and Mycolicibacterium smegmatis respectively at their MICs. Oral toxicity evaluations based on OECD guideline 425 determined the LD50 of the lyophilised E. elephantina root extract to be safe above 4000mg/kg body weight. The study concluded that biosynthesized AgNPs from E. elephantina root extract, using a one-pot green-synthesis technique, were both safe and effective, offering a promising alternative therapeutic strategy for combating multidrug-resistant TB.

Identification of common spatial and temporal trends in the epidemiology of cattle bovine tuberculosis and human extrapulmonary and drug-resistant tuberculosis in Malawi

BackgroundIdentification of common spatial disease trends between cattle bovine tuberculosis (BTB) and human extrapulmonary tuberculosis (EPTB) and drug-resistant tuberculosis (DRTB) can support integrated disease control and monitoring programmes. We employed the recently developed multivariate disease mapping methods to examine whether the diseases exhibited any spatial correlation. MethodsA retrospective study of cattle BTB and human EPTB and DRTB cases from 2018 to 2022 was conducted. Bivariate shared spatiotemporal components models were fitted to a) cattle BTB and human EPTB and b) cattle BTB and human DRTB at the district level in Malawi, with cattle density, human density and climatic variables as independent variables. ResultsDisease specific spatial effects were higher in the southern half of the country, while the shared spatial effects were more dominant in both the south and western parts of the country. The shared temporal effects showed constant trends, while disease specific temporal effects showed an increasing pattern for cattle BTB and a constant pattern for human EPTB and DRTB. The predicted disease incidence pattern for all forms of TB in the period without data showed a constant pattern over the years. Cattle density was positively associated with cattle BTB (β: 0.022; 95% Credible Interval (CI): 0.004, 0.042). Human density was positively associated with human EPTB (β: 0.005; 95% CI: 0.001, 0.009). ConclusionCattle BTB and human EPTB and DRTB have a common spatial pattern in the west and southern parts of Malawi. Integrated interventions targeting high-density areas for cattle and human may have positive impacts on cattle BTB and human EPTB and DRTB.