[Application and optimization of CRISPRi to the biology of Mycobacterium tuberculosis].

Tuberculosis, caused by infection with Mycobacterium tuberculosis (MTB), remains a global public health challenge. Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains make tuberculosis more difficult to control. New tools to study the biology of MTB can identify novel targets for drug discovery. Recently, the Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) combined with next-generation sequencing has provided many novel insights into the physiology and genetics of MTB. This review summarizes the application and optimization of CRISPRi in MTB biology.

Multidrug-resistant Mycobacterium tuberculosis transmission in Shandong, China.

Multidrug-resistant tuberculosis (MDR-TB) has imposed a significant economic and health burden worldwide, notably in China. Using whole genome sequence, we sought to understand the mutation and transmission of MDR-TB in Shandong. A retrospective study of patients diagnosed with pulmonary tuberculosis in Shandong from 2009 to 2018 was conducted. To explore transmission patterns, we performed whole genome sequencing on MDR-TB isolates, identified genomic clusters, and assessed the drug resistance of TB isolates. Our study analyzed 167 isolates of MDR-TB, finding that 100 were clustered. The predominant lineage among MDR-TB isolates was lineage 2, specifically with a notable 88.6% belonging to lineage 2.2.1. Lineage 4 constituted a smaller proportion, accounting for 4.2% of the isolates. We discovered that Shandong has a significant clustering percentage for MDR-TB, with Jining having the highest percentage among all Shandong cities. The clustering percentages of MDR-TB, pre-extensively drug-resistant tuberculosis, and extensively drug-resistant tuberculosis were 59.9%, 66.0%, and 71.4%, respectively, and the clustering percentages increased with the expansion of the anti-TB spectrum. Isolates from genomic clusters 1 and 3 belonged to lineage 2.2.1 and showed signs of cross-regional transmission. The distribution of rrs A1401G and katG S315T mutations in lineage 2.2.1 and 2.2.2 strains differed significantly (P < .05). MDR-TB isolates with rpoB I480V, embA-12C > T, and rrs A1401G mutations showed a higher likelihood of clustering (P < .05). Our findings indicate a significant problem of local transmission of MDR-TB in Shandong, China. Beijing lineage isolates and some drug-resistant mutations account for the MDR-TB transmission in Shandong.

Multidrug-resistant tuberculosis.

Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.

Transmission dynamics of drug-resistant tuberculosis in Ningbo, China: an epidemiological and genomic analysis.

Background: Tuberculosis (TB), particularly drug-resistant TB (DR-TB), remains a significant public health concern in Ningbo, China. Understanding its molecular epidemiology and spatial distribution is paramount for effective control. Methods: From December 24, 2020, to March 12, 2023, we collected clinical Mycobacterium tuberculosis (MTB) strains in Ningbo, with whole-genome sequencing performed on 130 MTB strains. We analyzed DR-related gene mutations, conducted phylogenetic and phylodynamic analyses, identified recent transmission clusters, and assessed spatial distribution. Results: Among 130 DR-TB cases, 41% were MDR-TB, 36% pre-XDR-TB, 19% RR-TB, and 3% HR-TB. The phylogenetic tree showed that 90% of strains were Lineage 2 (Beijing genotype), while remaining 10% were Lineage 4 (Euro-American genotype). The spatial analysis identified hotspots of DR-TB in Ningbo's northern region, particularly in traditional urban centers. 31 (24%) of the DR-TB cases were grouped into 7 recent transmission clusters with a large outbreak cluster containing 15 pre-XDR-TB patients. Epidemiological analyses suggested a higher risk of recent DR-TB transmission among young adult patients who frequently visited Internet cafes, game rooms, and factories. Conclusion: Our study provides comprehensive insights into the epidemiology and genetics of DR-TB in Ningbo. The presence of genomic clusters highlights recent transmission events, indicating the need for targeted interventions. These findings are vital for informing TB control strategies in Ningbo and similar settings.

Azetidines Kill Multidrug-Resistant Mycobacterium tuberculosis without Detectable Resistance by Blocking Mycolate Assembly.

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 µM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.

A four-drug standardized short regimen for highly resistant TB in South-West Nigeria.

BACKGROUND: Patients with TB resistant to rifampicin (Rr-TB), and those with additional resistance to fluoroquinolones (pre-XDR-TB), should be treated with bedaquiline-pretomanid-linezolid-moxifloxacin and bedaquiline-pretomanid-linezolid, respectively. However, pretomanid is not yet widely available. METHODS: This is a pragmatic prospective single-arm study investigating the efficacy and safety of 9 mo of bedaquiline-delamanid-linezolid-clofazimine in patients with pre-XDR-TB or Rr-TB unresponsive to Rr-TB treatment in Nigeria. RESULTS: From January 2020 to June 2022, 14 of 20 patients (70%) successfully completed treatment, five died and one was lost-to-follow-up. No one experienced a treatment-emergent grade three/four event. Treatment success was higher compared with global pre-XDR-TB treatment outcomes. CONCLUSIONS: While pretomanid is unavailable, highly resistant TB can be treated with bedaquiline-delamanid-linezolid-clofazimine.

Pre-extensively drug-resistant and extensively drug-resistant tuberculosis in Latin America and the Caribbean: A systematic review and meta-analysis.

BACKGROUND: The growing threat from pre-extensively drug-resistant tuberculosis (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) poses a major public health concern in Latin America and the Caribbean (LAC). Therefore, this study aimed to summarize the available evidence on the prevalence of pre-XDR-TB and XDR-TB among patients with multidrug-resistant tuberculosis in LAC. METHODS: A systematic review was conducted in the following databases on June 3, 2023: PubMed, Scopus, Ovid Medline, Web of Science, Scielo and LILACS. We estimated pooled proportions using a random effects model (Dersimonian and Laird). The 95% confidence intervals (95% CI) were calculated using the binomial exact method (Clopper-Pearson Method). Subgroup (by time period and country) and sensitivity analyses were performed. RESULTS: Twenty-nine studies were eligible for qualitative synthesis and 27 for meta-analysis (n = 15,565). The pooled prevalence of XDR-TB in the study participants was 5% (95% CI: 3%-6%), while that of pre-XDR-TB was 10% (95% CI 7%-14%). Cuba (6%, 95% CI 0%-17%) and Peru (6%, 95% CI 5%-7%) had the highest pooled prevalence of XDR-TB. Regarding pre-XDR-TB, Brazil (16%, 95% CI 11%-22%) and Peru (13%, 95% CI: 9%-16%) showed the highest prevalence. CONCLUSIONS: The pooled prevalence of pre-XDR-TB and XDR-TB in LAC was 10% and 5%, respectively. Governments should strengthen drug-resistance surveillance and TB programs.

Pre-extensively Drug-Resistant Congenital Tuberculosis in an Extremely Premature Baby.

We describe a case of congenital tuberculosis in an extremely premature baby, with rapid molecular detection of a pre-extensively drug-resistant (XDR) pattern of drug resistance. The baby was treated successfully with a regimen including bedaquline and delamanid, drugs not previously described in the treatment of congenital tuberculosis (TB).

Treatment outcomes and risk factors for an unsuccessful outcome among patients with highly drug-resistant tuberculosis in Ukraine.

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

Defensins: A novel weapon against Mycobacterium tuberculosis?

Tuberculosis (TB) is a serious airborne communicable disease caused by organisms of the Mycobacterium tuberculosis (Mtb) complex. Although the standard treatment antimicrobials, including isoniazid, rifampicin, pyrazinamide, and ethambutol, have made great progress in the treatment of TB, problems including the rising incidence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the severe toxicity and side effects of antimicrobials, and the low immunity of TB patients have become the bottlenecks of the current TB treatments. Therefore, both safe and effective new strategies to prevent and treat TB have become a top priority. As a subfamily of cationic antimicrobial peptides, defensins are rich in cysteine and play a vital role in resisting the invasion of microorganisms and regulating the immune response. Inspired by studies on the roles of defensins in host defence, we describe their research history and then review their structural features and antimicrobial mechanisms, specifically for fighting Mtb in detail. Finally, we discuss the clinical relevance, therapeutic potential, and potential challenges of defensins in anti-TB therapy. We further debate the possible solutions of the current application of defensins to provide new insights for eliminating Mtb.

Nano vs Resistant Tuberculosis: Taking the Lung Route.

Tuberculosis (TB) is among the top 10 infectious diseases worldwide. It is categorized among the leading killer diseases that are the reason for the death of millions of people globally. Although a standardized treatment regimen is available, non-adherence to treatment has increased multi-drug resistance (MDR) and extensive drug-resistant (XDR) TB development. Another challenge is targeting the death of TB reservoirs in the alveoli via conventional treatment. TB Drug resistance may emerge as a futuristic restraint of TB with the scarcity of effective Anti-tubercular drugs. The paradigm change towards nano-targeted drug delivery systems is mostly due to the absence of effective therapy and increased TB infection recurrent episodes with MDR. The emerging field of nanotechnology gave an admirable opportunity to combat MDR and XDR via accurate diagnosis with effective treatment. The new strategies targeting the lung via the pulmonary route may overcome the new incidence of MDR and enhance patient compliance. Therefore, this review highlights the importance and recent research on pulmonary drug delivery with nanotechnology along with prevalence, the need for the development of nanotechnology, beneficial aspects of nanomedicine, safety concerns of nanocarriers, and clinical studies.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

A critical review of risk factors influencing the prevalence of extensive drug-resistant tuberculosis in India.

Globally, extensive drug-resistant tuberculosis (XDR-TB) is a major element to cause morbidity and death among tuberculosis patients. The present study identifies the vital risk variables contributing to XDR-TB prevalence in India. Scopus, PubMed/Medline, Science Direct, and Google Scholar databases were searched thoroughly for the articles, using medical subject heading as a key term published between the years 2012 and 2022. According to the inclusion criteria, 11 publications were selected. Socioeconomic characteristics include employment, educational attainment, undernourishment, and the rest, and demographic factors such as gender, age, and more. Were examined in the review, whereas alcoholics, smoking, and diabetes mellitus were investigated under comorbidities and behavioral risk factors. We observed that noncompliance, poor knowledge, and insufficient health-care facilities could significantly accelerate the spread of XDR-TB, and the present review imparts a remarkable and detailed evaluation of XDR-TB. The study analysis is markedly useful for policymakers as well as researchers to discover and implement effective solutions for tuberculosis-infected patients.

[Study on the resistance of rifampicin-resistant Mycobacterium tuberculosis to anti-tuberculosis drugs in group A].

Objective: To summarize the resistance of rifampicin-resistant Mycobacterium tuberculosis to anti-tuberculosis drugs in group A. Methods: In the retrospective study, a total of 1 226 clinical isolates from suspected multidrug-resistant pulmonary tuberculosis patients in Beijing TB control system from 2016 to 2021 were identified as Mycobacterium tuberculosis (MTB) strains by MPB64 antigen detection test. Rifampicin-resistant tuberculosis (RR-TB) strains were screened by the phenotypic drug susceptibility using the proportion method. The drug susceptibilities of Levofloxacin(LFX), Moxifloxacin(MFX), Bedaquiline(BDQ) and Linezolid(LZD)were detected by the phenotypic drug susceptibility with microplate method. The drug resistance rate, drug resistance level and minimum inhibitory concentration (MIC) distribution of four anti-tuberculosis drugs in group A were analyzed. We calculated the demographic distribution of RR-TB, multidrug-resistant tuberculosis(MDR-TB), pre-extensively drug resistant tuberculosis (pre-XDR-TB), extensively drug resistant tuberculosis (XDR-TB) patients and the cross resistance of LFX and MFX, then summarized the drug-resistance spectrum of BDQ-resistant and LZD-resistant strains and the treatment outcome of RR-TB patients. Measurement data were expressed as rate or composition ratio,χ2 test was used between and within groups, and P<0.05 was considered statistically significant. Results: Among the 1 226 suspected multidrug-resistant pulmonary tuberculosis patients, the detection rates of RR/MDR/pre-XDR/XDR-TB patients were 20.8%(255/1 226), 15.2%(186/1 226), 5.7%(70/1 226), 0.5%(6/1 226), respectively. There were statistically significant differences in the distribution of patients with the four types of drug resistance in terms of age and treatment history (χ2=14.95, P=0.020;χ2=15.91, P=0.001). The drug resistance rates of LFX, MFX, BDQ and LZD in RR-TB patients were 27.5% (70/255), 27.5% (70/255), 0.4% (1/255) and 2.4% (6/255), respectively. The MICs of LFX, MFX and LZD-susceptible MTB were mainly at 0.25 mg/L, and the MIC of BDQ-susceptible MTB was mainly concentrated at 0.03 mg/L. 25.1% (64/255) of the RR MTB were resistant to both LFX and MFX, and 6 strains were resistant to LFX or MFX, showing incomplete two-way cross resistance. One BDQ-resistant strain and six LZD-resistant strains were detected. The treatment success rate of RR-TB patients was 74.4% (151/203), and there were statistically significant differences in treatment outcomes between resistant and sensitive patients on the LFX-containing treatment regimen (Fisher's exact test, P=0.012). Conclusions: The prevalence of fluoroquinolones (LFX and MFX) resistance in rifampicin-resistant MTB is very serious. LFX and MFX show incomplete bidirectional cross-resistance. BDQ and LZD have the most promising future in the treatment of MDR-TB. Improve drug-resistance testing will help to further improve the success rate of treatment.

Study protocol for safety and efficacy of all-oral shortened regimens for multidrug-resistant tuberculosis: a multicenter randomized withdrawal trial and a single-arm trial [SEAL-MDR].

INTRODUCTION: The urgent need for new treatments for multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is evident. However, the classic randomized controlled trial (RCT) approach faces ethical and practical constraints, making alternative research designs and treatment strategies necessary, such as single-arm trials and host-directed therapies (HDTs). METHODS: Our study adopts a randomized withdrawal trial design for MDR-TB to maximize resource allocation and better mimic real-world conditions. Patients' treatment regimens are initially based on drug resistance profiles and patient's preference, and later, treatment-responsive cases are randomized to different treatment durations. Alongside, a single-arm trial is being conducted to evaluate the potential of sulfasalazine (SASP) as an HDT for pre-XDR-TB, as well as another short-course regimen without HDT for pre-XDR-TB. Both approaches account for the limitations in second-line anti-TB drug resistance testing in various regions. DISCUSSION: Although our study designs may lack the internal validity commonly associated with RCTs, they offer advantages in external validity, feasibility, and ethical appropriateness. These designs align with real-world clinical settings and also open doors for exploring alternative treatments like SASP for tackling drug-resistant TB forms. Ultimately, our research aims to strike a balance between scientific rigor and practical utility, offering valuable insights into treating MDR-TB and pre-XDR-TB in a challenging global health landscape. In summary, our study employs innovative trial designs and treatment strategies to address the complexities of treating drug-resistant TB, fulfilling a critical gap between ideal clinical trials and the reality of constrained resources and ethical considerations. TRAIL REGISTRATION: Chictr.org.cn, ChiCTR2100045930. Registered on April 29, 2021.

Call for special attention to the caregiver burden of patients with drug-resistant tuberculosis in low- and middle-income countries.

The tuberculosis (TB)-related caregiver burden (CB), and particularly the multidrug and extensively drug-resistant tuberculosis (M/XDR-TB)-related CB, is not rare in caregivers caring for TB patients, especially when a family member is the caregiver. However, the existing studies on this topic are insufficient. This study briefly summarized the risk factors for the imposition of a TB-related CB and reasons why caregivers for patients with M/XDR-TB are more susceptible to a CB. We propose that special measures should be implemented to alleviate the TB-related CB based on our clinical experience and insights from China. This may improve the situation of caregivers for TB patients and ultimately improve the quality of life of TB patients.

[Progress on the safety and efficacy of bedaquiline for the treatment of drug-resistant tuberculosis in special populations].

Antimicrobial resistance in Mycobacterium tuberculosis is a serious threat to global tuberculosis(TB) control. WHO listed bedaquiline as one of the first-choice drugs for the treatment of MDR/RR-TB in 2018. Bedaquiline is marketed for adult patients with MDR-TB and XDR-TB. However, there are few studies of bedaquiline in adolescents, pregnant women, the elderly, and other special populations with drug-resistant TB. This paper aimed to review the effectiveness and safety of bedaquiline in the treatment of special populations of drug-resistant TB for the clinical use.

Polypharmacological repurposing approach identifies approved drugs as potential inhibitors of Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tb), the causative pathogen of tuberculosis (TB) remains the leading cause of death from single infectious agent. Furthermore, its evolution to multi-drug resistant (MDR) and extremely drug-resistant (XDR) strains necessitate de novo identification of drug-targets/candidates or to repurpose existing drugs against known targets through drug repurposing. Repurposing of drugs has gained traction recently where orphan drugs are exploited for new indications. In the current study, we have combined drug repurposing with polypharmacological targeting approach to modulate structure-function of multiple proteins in M. tb. Based on previously established essentiality of genes in M. tb, four proteins implicated in acceleration of protein folding (PpiB), chaperone assisted protein folding (MoxR1), microbial replication (RipA) and host immune modulation (S-adenosyl dependent methyltransferase, sMTase) were selected. Genetic diversity analyses in target proteins showed accumulation of mutations outside respective substrate/drug binding sites. Using a composite receptor-template based screening method followed by molecular dynamics simulations, we have identified potential candidates from FDA approved drugs database; Anidulafungin (anti-fungal), Azilsartan (anti-hypertensive) and Degarelix (anti-cancer). Isothermal titration calorimetric analyses showed that the drugs can bind with high affinity to target proteins and interfere with known protein-protein interaction of MoxR1 and RipA. Cell based inhibitory assays of these drugs against M. tb (H37Ra) culture indicates their potential to interfere with pathogen growth and replication. Topographic assessment of drug-treated bacteria showed induction of morphological aberrations in M. tb. The approved candidates may also serve as scaffolds for optimization to future anti-mycobacterial agents which can target MDR strains of M. tb.

Global treatment outcomes of extensively drug-resistant tuberculosis in adults: A systematic review and meta-analysis.

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

Stress resilience in patients with drug-resistant TB.

BACKGROUND: The worldwide increase in drug-resistant pulmonary TB (DR-PTB) has a significant impact on patient´s physical and mental health. The objective of this study is to assess the stress resilience of DR-PTB patients along with the factors associated with it.METHODS: A total of 385 adult DR-PTB patients with multidrug-resistant (MDR) and pre-extensive drug-resistant (pre-XDR) TB admitted to the National Institute of Diseases of the Chest Hospital (Dhaka, Bangladesh) between January 2020 and March 2021 were conveniently recruited. Resilience data were collected using a validated Stress Resilience Scale (RS 25) questionnaire.RESULTS: The mean resilience scores were significantly higher for patients with MDR-PTB than those with pre-XDR-PTB (P = 0.02). A majority of the MDR-PTB (77.0%) and pre-XDR-PTB (65.1%) patients belonged to the ≤45 years age group. Multiple linear regression revealed that sex (P < 0.001), level of education (P < 0.001), employment status (P = 0.003) and presence of asthma (P = 0.010) were significantly associated with stress resilience.CONCLUSION: We observed that stress resilience significantly differed between patients with MDR-PTB and those with pre-XDR-PTB based on sociodemographic characteristics.