A Narrative Review of Bedaquiline and Delamanid: New Arsenals Against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis.

BACKGROUND: The treatment of multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) is a formidable challenge. Treatment of MDR- and XDR-TB using bedaquiline (BDQ) and delamanid (DLM), two newly introduced medications, is steadily increasing. This narrative review aimed to present a concise overview of the existing information regarding BDQ and DLM, and elucidate their antimicrobial characteristics, resistance mechanisms, synergism with other drugs, and side effects. METHODS: To collect the required information about the antimicrobial properties, a search for scientific evidence from the Scopus, PubMed, and Embase databases was performed, and all recently published articles up to May 2024 were considered. RESULTS: BDQ had potent antimicrobial effects on various types of nontuberculous mycobacteria (NTM), including rapid-growing and slow-growing species, and MDR/XDR Mycobacterium tuberculosis. The mechanisms of BDQ resistance in M. tuberculosis primarily involve mutations in three genes: atpE, mmpR (Rv0678) and pepQ. BDQ may have synergistic effects when combined with DLM, pyrazinamide, and pretomanid/linezolid. BDQ has a low incidence of side effects. The use of BDQ may prolong the QTc interval. Similarly, DLM showed potent antimicrobial effects on NTM and MDR/XDR M. tuberculosis. The main resistance mechanisms to DLM are induced by mutations in fbiA, fbiB, fbiC, fgd1, and ddn genes. The DLM had synergistic effects with BDQ and moxifloxacin. The DLM also has few side effects in some patients including QTc prolongation. CONCLUSION: BDQ and DLM are suitable antibiotics with few side effects for the treatment of MDR/XDR-TB. These antibiotics have synergistic effects when combined with other antituberculosis drugs.

Patient and provider costs of the new BPaL regimen for drug-resistant tuberculosis treatment in South Africa: A cost-effectiveness analysis.

BACKGROUND: Drug-resistant (DR) tuberculosis (TB) is typically characterized by resistance to a single or combination of first- and/or second-line anti-TB agents and commonly includes rifampicin-resistant (RR)-TB, multidrug-resistant (MDR)-TB, pre-extensively drug-resistant (pre-XDR)-TB and XDR-TB. Historically, all variations of DR-TB required treatment with second-line drugs which are less effective and more toxic than first-line options, have a longer treatment duration and are more expensive to both patients and providers. The World Health Organization (WHO) now recommends a new second-line 3-drug 6-month all-oral regimen consisting of bedaquiline, pretomanid, and linezolid referred to as BPaL. We estimate patient and provider costs of DR-TB treatment with BPaL compared to the current standard of care in South Africa. METHODS AND FINDINGS: In coordination with South Africa's BPaL clinical access programme (CAP) we conducted an economic evaluation of A) patient costs through a cross-sectional patient cost survey and B) provider costs through a bottom-up costing analysis consisting of a retrospective medical record review (patient resource-use) and top-down financial record review (fixed/shared costs such as overhead). Across both costing perspectives, we compare costs of 1) BPaL, to current standard of care options including the 2) 9-11-month standard short oral regimen (SSOR) and 3) 18-21-month standard long oral regimen (SLOR). Eligible patients included those ≥14 years old with confirmed sputum pulmonary RR/MDR-TB, pre-XDR or XDR-TB. All costs are reported in 2022 United States Dollar (US$). A total of 72 patients were enrolled and completed the patient cost survey (41.7% on BPaL, 16.7% on the SSOR and 41.7% on the SLOR). Mean on-treatment patient costs were lowest among those on BPaL ($56.6) and increased four-fold among those on the SSOR ($228.1) and SLOR ($224.7). Direct medical patient costs were negligible across all treatment regimens, while direct non-medical patient and guardian costs for travel, food and nutritional supplementation accounted for the largest proportion of total costs ($54.6, $227.8 and $224.3 for BPaL, the SSOR and SLOR respectively). In assessing provider costs, a total of 112 medical records were reviewed (37.5%, 41.1% and 21.4% on BPaL, the SSOR and SLOR respectively). Total provider costs for producing a favorable treatment outcome (cured/completed treatment) were similar among those on BPaL ($4,948.7 per patient) and the SSOR ($4,905.6 per patient) with costs increasing substantially among those on the SLOR ($8,919.9 per patient). Based on incremental cost-effectiveness ratios (ICERs), at even the lowest willingness to pay (WTP) threshold, treatment with the new BPaL regimen was more cost-effective than current standard of care treatment options (ICER: $311.4 < WTP: $3,341). CONCLUSIONS: When using the newly recommended BPaL regimen, cost to patients decreased by 75% compared to current standard of care treatment options in South Africa. Due in part to higher resource-use within the BPaL CAP offsetting the shorter treatment duration, cost of treatment provision through BPaL and the 9-11-month SSOR were similar. However, when considering cost and treatment outcomes, BPaL was more cost-effective than other standard of care regimens currently available for DR-TB in South Africa.

Identification of drug resistance-related virulence gene mutations in 667 clinical Mycobacterium tuberculosis isolates.

INTRODUCTION: Drug-resistant tuberculosis is a severe global public health threat. Virulence factors and antibiotic resistance are generally considered to play a significant role in bacterial pathogenesis. However, the interaction between resistance and virulence in Mycobacterium tuberculosis (MTB) remains unclear. METHODOLOGY: Here, we used whole genome sequences from 667 MTB isolates from 14 countries to complete an in silico evaluation of the correlations between virulence gene mutations, drug resistance, and lineage classification. The chi-square (χ2) test was used to determine whether specific virulence gene mutations and drug resistance were related. RESULTS: Our results showed that Mce1R_G171R and Pks15_V333A, were positively correlated with streptomycin and ethambutol resistance, respectively, and Pks15_T46I was correlated with isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin resistance. We also identified an additional 24 and 40 single nucleotide polymorphisms as well as 6 and 2 insertions or deletions in various virulence genes that are likely to be associated with changes in drug susceptibility in L2 and L4, respectively. CONCLUSIONS: Taken together our data suggest that there may be some degree of co-selection between virulence and resistance factors, which may help MTB more easily adapt to new environments.

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.

Prevalence and epidemic pattern of ecdemic multidrug-resistant tuberculosis during 2012-2022 in Hangzhou, China: implication for public health strategies.

BACKGROUND: To assess the prevalence and epidemic pattern of multidrug-resistant tuberculosis in Hangzhou City, Zhejiang Province, China during 2012-2022. METHODS: All the tuberculosis cases undergoing drug susceptibility testing during 2012-2022 were included in this study. De-identified information was extracted from the electronic database Tuberculosis Information Management System for analysis of drug resistance prevalence in Hangzhou and ecdemic multidrug-resistant tuberculosis which originated from other regions. Chi-square tests were used to compare drug resistance rates between different groups, while Chi-square tests for trend were used to evaluate the change of drug resistance rates over the years of 2012-2022. The sources and destinations of ecdemic multidrug-resistant tuberculosis were illustrated using a Sankey diagram. RESULTS: Of 21,127 cases included in this study, 1119 (5.3%) were multidrug-resistant tuberculosis. A significant decline in multidrug-resistant tuberculosis rates was observed during 2012-2022. There was a significant difference in multidrug-resistant tuberculosis rates among immigrant population and local residents in Hangzhou City. Of 1119 multidrug-resistant tuberculosis cases, 515(46%) were ecdemic multidrug-resistant tuberculosis cases, of which 277(53.8%) were from other parts of Zhejiang Province and 238(46.2%) were from other provinces in China. Anhui, Jiangxi and Sichuan were among top three provinces which were the source of ecdemic multidrug-resistant tuberculosis cases. Three districts including Xiaoshan, Shangcheng and Linping districts had the most cases in Hangzhou. The proportion of ecdemic multidrug-resistant tuberculosis cases in Binjiang, Xiaoshan, Qiantang and Linping districtalso exceeded 30% of total cases. CONCLUSIONS: Multidrug-resistant tuberculosis prevalence has been declining in Hangzhou. Migrant population contributed to a significant potion of cases in Hangzhou. Interventions should be tailed to local and migrant residents.

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.

Predictors of early and interim culture un-conversion in multidrug-resistant/rifampicin-resistant tuberculosis: a retrospective multi-center cohort study in China.

BACKGROUND: We aimed to evaluate the predictors for early and interim culture conversion within 2 months and 6 months of treatment in multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) patients in China. METHODS: This study included adult MDR/RR-TB patients with a positive baseline sputum culture from 8 institutions located in different cities in China from May 2018 to January 2022. We mainly used logistic regression model to derive possible predictors of early and interim culture conversion. RESULTS: A total of 813 patients were enrolled and 28.5% of them received multidrug-resistant treatment regimens containing bedaquiline. Of these, 362 (44.5%) patients experienced culture conversion within 2 months of treatment, and 649 (79.8%) within 6 months. The results of the multivariable logistic regression analysis revealed that acid-fast bacilli smear positive (adjusted odds ratio [aOR] = 1.637, 95% confidence interval [CI] = 1.197-2.238), cavities (aOR = 1.539, 95% CI = 1.132-2.092), bilateral disease (aOR = 1.638, 95% CI = 1.183-2.269), and viral hepatitis (aOR = 2.585, 95% CI = 1.189-5.622) were identified as risk factors for early culture un-conversion within 2 months of treatment. Additionally, smoking history (aOR = 2.197, 95% CI = 1.475-3.273), previous treatment for tuberculosis (aOR = 1.909, 95% CI = 1.282-2.844), bilateral disease (aOR = 2.201, 95% CI = 1.369-3.537), viral hepatitis (aOR = 2.329, 95% CI = 1.094-4.962) were identified as risk factors for interim culture un-conversion within 6 months of treatment, while patients with regimen containing bedaquiline (aOR = 0.310, 95% CI = 0.191-0.502) was a protective factor. CONCLUSIONS: A history of smoking, a baseline sputum AFB smear positive, lung cavities, bilateral disease, previous anti-tuberculosis treatment, or a comorbidity of viral hepatitis can be used as the predictors for early and interim culture un-conversion in MDR/RR-TB patients, while bedaquiline was a protective factor .

A novel dual probe-based method for mutation detection using isothermal amplification.

Cost efficient and rapid detection tools to detect mutations especially those linked to drug-resistance are important to address concerns of the rising multi-drug resistance infections. Here we integrated dual probes, namely a calibrator probe and an indicator probe, into isothermal amplification detection system. These two probes are designed to bind distinct regions on the same amplicon to determine the presence or absence of mutation. The calibrator probe signal is used as an internal signal calibrator for indicator probe which detects the presence or absence of the mutation. As an illustrative example, we evaluated the applicability of this dual probe method for detecting mutations associated with rifampicin (RIF) drug resistance at codons 516, 526 and 531 of the rpoB gene in Mycobacterium tuberculosis. In this assessment, we examined 127 artificial samples comprising wild types and mutants with single or multiple mutations. Our results demonstrated 100% accuracy for both wild types and mutants for mutations at codons 526 and 531. As regards to mutations at codon 516, the wild type was identified with 100% accuracy, while the mutants were identified with 95% accuracy. Moreover, when we extended our evaluation to include clinical MTB strains and the Zeptometrix MTB Verification panel, our method achieved 100% accuracy (5 out of 5) in identifying wild-type strains. Additionally, we successfully detected a RIF-resistant strain with mutations at codon 531 of the rpoB gene in Zeptometrix verification panel. Our isothermal mutation detection system, relying on dual probes exhibits a versatile approach. With the capability to identify mutations without prior knowledge of their specific mutation direction, our dual-probe method shows significant promise for applications in drug resistance nucleic acid testing, particularly in resource-limited settings.

Multidrug-resistant tuberculosis treatment outcomes and associated factors at Yirgalem General Hospital, Sidama Region, South Ethiopia: a retrospective cohort study.

BACKGROUND: The spread of multidrug-resistant tuberculosis (MDR-TB) poses a significant challenge to TB control efforts. This study evaluated the treatment outcomes and associated factors among patients receiving treatment for MDR-TB in southern Ethiopia. METHODS: A retrospective follow-up study covering ten years, from 2014 to 2023, analyzed the records of confirmed cases of pulmonary TB admitted to Yirgalem General Hospital, an MDR-TB treatment initiation center in the Sidama Region. To compare the successful treatment outcomes across the years, a chi-square test of independence was conducted. Bivariate and multivariable logistic regression models were used to identify factors associated with treatment outcomes for MDR-TB. RESULTS: Out of 276 confirmed MDR-TB cases, 4(1.4%) were diagnosed with resistance to second-line drugs (SLDs). Overall, 138 patients achieved favourable treatment outcomes, resulting in a treatment success rate of 50.0% [95% CI 44.1-55.9%]. Among these 138 patients, 105(76.1%, 95 CI 68.7-83.5%) were cured, while 33(23.9%, 95 CI 16.5-31.3%) completed their treatment. The successful treatment outcomes varied significantly across the years, ranging from 3.6% in 2020 to 90% in 2021. The analysis indicated a statistically significant difference in treatment outcomes when considering data from 2014 to 2023 (χ2 = 44.539, p = 0.001). The proportion of patients with deaths, lost-to-follow-up (LTFU), treatment failures and not evaluated were 7.9% [95% CI 4.8-11.2%], 10.9% [95% CI 7.2-14.6%), 2.2% [95% CI 1.1-3.3%), and 28.9% [95% CI 23.7-34.2%] respectively. Individuals with a positive HIV status had significantly lower odds of a favorable treatment outcome [AOR = 0.628, 95% CI (0.479-0.824), p = 0.018]. Similarly, patients with a BMI of less than 18 are more likely to have unfavorable treatment outcomes compared to those with a BMI of 18 or higher [AOR = 2.353, 95% CI 1.404-3.942, p < 0.001]. CONCLUSION: The study revealed a concerning 1.4% prevalence of additional resistance to SLDs. The 50% rate of unfavorable treatment among MDR-TB cases exceeds the target set by the WHO. A significant number of patients (10.9%) were LTFU, and the 28.9% categorized as 'not evaluated' is also concerning. Enhanced strategic interventions are needed to reduce such cases, and factors associated with poor treatment outcomes should receive greater attention. Future prospective studies can further explore the factors influencing improved treatment success.

Prevalence of rifampicin and isoniazid mono-resistance among cases of pulmonary tuberculosis from Western Uttar Pradesh, North India.

BACKGROUND: Mono-resistance to rifampicin/isoniazid increases poor treatment outcomes and the risk of multi-drug resistance (MDR) in tuberculosis (TB) patients. Limited information exists about mono-resistance status of TB patients in Uttar Pradesh, North India. This study aimed to estimate the burden of rifampicin and isoniazid mono-resistance in Western Uttar Pradesh. METHODS AND RESULTS: 153 sputum samples of suspected pulmonary tuberculosis patients were processed to isolate Mycobacterium tuberculosis using the Lowenstein-Jensen (L-J) culture medium. The isolates were identified using an immuno-chromatographic test and IS6110 PCR. The confirmed Mycobacterium tuberculosis isolates were tested for drug susceptibility testing against rifampicin and isoniazid anti-tuberculosis drugs. The results of the drug susceptibility testing were compared with demographic information and analyzed statistically. Out of 153 sputum samples, 83 (54.24%) samples were positive for growth on L-J medium, including 82 (98.79%) Mycobacterium tuberculosis isolates. Of the 82 Mycobacterium tuberculosis isolates, 16 (19.51%), 7 (8.54%), and 5 (6.10%) isolates were MDR, mono-resistant to rifampicin and isoniazid, respectively. The occurrence of RIF/INH mono-resistant-TB was higher in patients of male gender, age above 45 years, living in rural conditions, history of weight loss, and previous anti-TB treatment, but the effect was not statistically significant. CONCLUSIONS: The study reported the status of rifampicin and isoniazid mono-resistance among TB patients and highlighted the need for continuous monitoring and improved intervention for the initial detection of mono-drug-resistant cases. This will improve clinical treatment outcomes and decrease the rate of drug-resistant TB in Uttar Pradesh, North India.

Silicosis predicts drug resistance and retreatment among tuberculosis patients in India: a secondary data analysis from Khambhat, Gujarat (2006-2022).

BACKGROUND: India, with the highest global burden of tuberculosis (TB) and drug-resistant TB, aims to eliminate TB by 2025. Yet, limited evidence exists on drug resistance patterns and retreatment among patients with silico-tuberculosis. This study explores these patterns and assesses the impact of silicosis on TB retreatment in India. METHODS: This secondary data analysis stems from a larger retrospective cohort study conducted in Khambhat, Gujarat, between January 2006 and February 2022. It included 138 patients with silico-tuberculosis and 2,610 TB patients without silicosis. Data from the Nikshay TB information portal were linked with silicosis diagnosis reports from the Pneumoconiosis Board using the unique Nikshay ID as the linking variable. Drug-resistant TB was defined as resistance to any anti-TB drug recorded in Nikshay. Retreatment refers to TB patients who have previously undergone anti-TB treatment for one month or more and need further treatment. Recurrent TB denotes patients who were previously declared cured or had completed treatment but later tested positive for microbiologically confirmed TB. Multivariable logistic regression was used to determine the impact of co-prevalent silicosis on drug resistance and retreatment. RESULTS: Patients with silico-tuberculosis showed a higher proportion of retreatment compared to those without silicosis (55% vs. 23%, p < 0.001). Notably, 28% of patients with silico-tuberculosis were recurrent TB cases, compared to 11% among those without silicosis. Regarding drug resistance, the silico-tuberculosis group exhibited a higher rate (6% vs. 3%), largely due to rifampicin resistance (5% vs. 2%, p = 0.022). Co-prevalent silicosis was associated with a 2.5 times greater risk of drug-resistant TB (adjusted OR 2.5, 95% CI, 1.1-5.3; p = 0.021). Additionally, patients with silico-tuberculosis had a fourfold increased risk of retreatment for TB (adjusted OR 4, 95% CI, 3-6; p < 0.001). CONCLUSIONS: Co-prevalent silicosis significantly elevates the risk of drug resistance, recurrence, and retreatment among TB patients in India. This study indicates a need for improved treatment protocols and suggests that future research should focus on randomized controlled trials to evaluate appropriate anti-TB regimen and duration of therapy for this high-risk group. Given India's goal to eliminate TB by 2025, addressing the challenges posed by silico-tuberculosis is critical.

Efficacy and safety of shorter multidrug-resistant or rifampicin-resistant tuberculosis regimens: a network meta-analysis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) remains a threat to public health. Shorter regimens have been proposed as potentially valuable treatments for multidrug or rifampicin resistant tuberculosis (MDR/RR-TB). We undertook a systematic review and network meta-analysis to evaluate the efficacy and safety of shorter MDR/RR-TB regimens. METHODS: We searched PubMed/MEDLINE, Cochrane Center for Clinical Trials (CENTRAL), Scopus, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, US Food and Drug Administration, and Chinese Clinical Trial Registry for primary articles published from 2013 to July 2023. Favorable (cured and treatment completed) and unfavorable (treatment failure, death, loss to follow-up, and culture conversion) outcomes were assessed as the main efficacy outcomes, while adverse events were assessed as the safety outcomes. The network meta-analysis was performed using R Studio version 4.3.1 and the Netmeta package. The study protocol adhered to the PRISMA-NMA guidelines and was registered in PROSPERO (CRD42023434050). RESULT: We included 11 eligible studies (4 randomized control trials and 7 cohorts) that enrolled 3,548 patients with MDR/RR-TB. Treatment with a 6-month combination of BdqLzdLfxZTrd/Eto/H had two times more favorable outcomes [RR 2.2 (95% CI 1.22, 4.13), P = 0.0094], followed by a 9-11 month combination of km/CmMfx/LfxPtoCfzZEHh [RR1.67 (95% CI 1.45, 1.92), P < 0.001] and a 6-month BdqPaLzdMfx [RR 1.64 (95% CI 1.24, 2.16), P < 0.0005] compared to the standard longer regimens. Treatment with 6 months of BdqPaLzdMfx [RR 0.33 (95% CI 0.2, 0.55), P < 0.0001] had a low risk of severe adverse events, followed by 6 months of BdqPaLzd [RR 0.36 (95% CI 0.22, 0.59), P ≤ 0.001] and BdqPaLzdCfz [RR 0.54 (95% CI 0.37, 0.80), P < 0.0001] than standard of care. CONCLUSION: Treatment of patients with RR/MDR-TB using shorter regimens of 6 months BdqLzdLfxZTrd/Eto/H, 9-11 months km/CmMfx/LfxPtoCfzZEHh, and 6 months BdqPaLzdMfx provides significantly higher cure and treatment completion rates compared to the standard longer MDR/RR-TB. However, 6BdqPaLzdMfx, 6BdqPaLzd, and 6BdqPaLzdCfz short regimens are significantly associated with decreased severity of adverse events. The findings are in support of the current WHO-recommended 6-month shorter regimens.

Exploring gene mutations and multidrug resistance in Mycobacterium tuberculosis: a study from the Lung Hospital in Vietnam.

BACKGROUND: Drug-resistant tuberculosis not only diminishes treatment efficacy but also heightens the risk of transmission and mortality. Investigating Mycobacterium tuberculosis resistance to first-line antituberculosis drugs is essential to tackle a major global health challenge. METHODS AND RESULTS: Using Sanger sequencing, this study investigates gene mutations associated with multidrug resistance in drug-resistant M. tuberculosis strains. Among 30 samples, mutations were found in genes linked to first-line anti-tuberculosis drug resistance. Rifampicin resistance was observed in 46.67% of the samples, with the most frequent mutation in the rpoB gene at codon 450 (S450L) occurring in 23.33% of cases. Similarly, isoniazid resistance was found in 86.67% of samples, with 33.33% of cases indicating the katG gene mutation at codon 315 (S315T). Additionally, streptomycin resistance was present in 76.67% of samples, and 30% of these cases were mainly linked to the rpsL gene mutation at codon 43 (K43R). CONCLUSION: These findings illuminate the genetic mechanisms behind drug resistance in M. tuberculosis. By identifying specific genetic markers, this research enhances our ability to diagnose and treat drug-resistant Tuberculosis more accurately and efficiently.

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

BACKGROUND: Multidrug- 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. METHODS: Whole-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. RESULTS: The 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. CONCLUSION: Transmission 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.

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.

BACKGROUND: Drug 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. METHODS: Retrospective 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. RESULTS: Of 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. CONCLUSIONS: The 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.

Impact of isoniazid monoresistance on overall and vulnerable patient populations in Taiwan.

Isoniazid is an early bactericidal anti-tuberculosis (TB) agent and isoniazid mono-resistance TB is the most prevalent drug-resistant TB worldwide. Concerns exist regarding whether resistance to isoniazid would lead to delayed culture conversion and worst outcomes. From January 2008 to November 2017, adult culture-positive pulmonary TB patients receiving isoniazid, rifampicin, pyrazinamide, and ethambutol were identified through Taiwan Center for Disease Control database and were followed until the end of 2017. Primary outcomes included time to sputum culture conversion (SCC) within two months. Secondary outcomes included death and unfavourable outcomes at the end of 2nd month. A total of 37,193 drug-susceptible and 2,832 isoniazid monoresistant pulmonary TB patients were identified. Compared with no resistance, isoniazid monoresistance was not associated with a delayed SCC (HR: 0.99, 95% CI: 0.94─1.05, p = 0.8145), a higher risk of 2-month mortality (HR: 1.19, 95% CI: 0.92─1.53, p = 0.1884), and unfavourable outcomes at 2nd month (OR: 1.05, 95% CI: 0.97─1.14, p = 0.2427). Isoniazid monoresistance was associated with delayed SCC (HR: 0.90, 95% CI: 0.83─0.98, p = 0.0099) and a higher risk of unfavourable outcomes (OR:1.18, 95% CI: 1.05─1.32, p = 0.0053) in patients aged between 20 and 65, and delayed SCC in patients without underlying comorbidities (HR: 0.90, 95% CI: 0.81─0.98, p = 0.0237). Isoniazid mono-resistant TB had a comparable outcome with drug-susceptible TB at the end of the intensive phase. Healthy, and non-elderly patients were more likely to had culture persistence, raising concerns about disease transmission in these subgroups and warranting early molecular testing for isoniazid resistance.