Treatment Of Drug-resistant Tuberculosis Research Articles

Comorbidities and Treatment Outcomes in Patients Diagnosed with Drug-Resistant Tuberculosis in Rural Eastern Cape Province, South Africa.

Tuberculosis (TB) remains a significant global health challenge, with drug-resistant tuberculosis (DR-TB) posing a greater threat due to difficulty in treatment. This study aimed to investigate the relationship between comorbidities and treatment outcomes in patients diagnosed with DR-TB in rural Eastern Cape using logistic regression. Data on patient characteristics, comorbidities, and treatment outcomes were extracted from the medical records and analyzed using Python version 3.8. and R version 4.1.1 software. A logistic regression model was used to determine the effects of selected variables on treatment outcomes of DR-TB cases. Hearing loss and hypertension (HTN) were the most frequently observed comorbidities across various DR-TB cases, particularly rifampicin-resistant (RR), multidrug-resistant (MDR), and pre-extensively drug-resistant (pre-XDR-TB) cases. A hearing loss prevalence of 5.8% (26/445) was found among patients receiving treatment for TB, with the intensity of impairment ranging from mild to severe. Gender is significantly associated with the occurrence of HTN among these patients (p-value: 0.022). Comorbidities such as epilepsy, hearing loss, and HTN significantly impact treatment success, with higher risks of mortality and incomplete cure. Using logistic regression, obesity (OR = 3.0884; e = 1.1277; p = 0.0408) and HIV-positive status (OR = 0.4458; e = 0.8078; p = 0.0001) were highly likely and less likely associated with better treatment outcomes, respectively. The logistic regression model achieved an accuracy of 64.0%, a precision of 63.0%, and a recall of 95.0%, with an F-1 score of 76.0%. The findings underscore the importance of implementing integrated management strategies that address both DR-TB and its comorbidities, particularly in resource-limited settings where such patients are prevalent. Public health policies should incorporate strategies to provide nutritional assessments and interventions, particularly for individuals with low BMI. This could include food supplementation programs or partnerships with local food kitchens to ensure that patients have access to adequate nutrition during DR-TB treatment.

Introducing BPaL: Experiences from countries supported under the LIFT-TB project.

Previously, drug-resistant tuberculosis (DR-TB) patients were treated with long, toxic, and relatively ineffective regimens. However, in recent years, there have been major improvements made. The 2020 World Health Organization DR-TB Treatment guidelines recommended the use of a 6-months all-oral BPaL (bedaquiline, pretomanid and linezolid) regimen under operational research (OR) conditions for selected DR-TB patients. The processes, challenges, and interim results of introducing BPaL under OR conditions in 7 countries supported under the Korea International Cooperation Agency/TB Alliance-funded "Leveraging Innovation for Faster Treatment of Tuberculosis (LIFT-TB)" project are described here. The OR objectives were to explore the feasibility of introducing the BPaL regimen, and to estimate its effectiveness and safety in a select group of DR-TB patients. Between November 2020 and the end of March 2023, a total of 574 patients had been enrolled. Interim treatment success stands at an encouraging 90.9% (280/308). Although adverse events of special interest (AESI) were common, they were manageable, and only 1 patient had to discontinue the complete BPaL treatment regimen. In addition, no unexpected adverse events (AE) were seen. With careful advocacy, frequent communication with partners, and following steps to strengthen essential aspects of the delivery system, the project's experiences show that BPaL OR was feasible across different country settings. Project documents were constantly updated. The sharing of information, experiences, and interim results had a significant positive and motivating effect within and across countries. Interim OR results show excellent patient responses and are comparable to those seen under trial conditions. Although common, the observed AEs and AESIs were manageable, and no unexpected AEs were seen.

A Case of Successful Treatment of Drug Resistant Tuberculosis Using Cryorecanalization before Implantation of the Endobronchial Valve in a Patient with Multi-Stage Surgical Treatment

The article describes a clinical case of a female patients with the continuous course of tuberculosis (more than 14 years). Despite the ongoing anti-tuberculosis therapy, the use of all possible surgical methods including valvular bronchial blocking, bacterial excretion persisted, fibrous cavernous tuberculosis with pre-XDR and severe cicatricial bronchial stenosis developed. Due to comprehensive personalized approach based on implantation of an endobronchial valve in a bronchus restenotic by cryorecanalization supported by adequate chemotherapy regimen V, the patient managed to achieve sputum conversion, cavity healing and cure of tuberculosis.

Features of the pathogen and efficacy of drug-resistant tuberculosis treatment

According to the World Health Organization (WHO), nearly 10.6 million new cases of tuberculosis were detected in 2022, indicating an increase of 3.5 % from the reported 10.3 million in 2021. After the COVID-19 pandemic, the incidence of tuberculosis increased by 3.9 % from 2020 to 2022. According to the latest regulatory documents, multidrug-resistant pathogen is diagnosed when any bacteriologic or molecular genetic methods reveal drug resistance of M. Tuberculosis complex at least to isoniazid and rifampicin regardless of resistance to other antituberculosis drugs.With a wide range of virulence genes, the tuberculosis pathogen expresses genes in different phases of infection. Some genes are “switched on” in the early phases and are important for overcoming immune defenses and spreading the pathogen in the host, while others are important for survival in the latent phase. These characteristics of Mycobacterium tuberculosis determine the need for correct and adequate selection of therapy. The problem of diagnostics and treatment of drug-resistant tuberculosis remains extremely urgent. Despite the introduction of new tests for rapid determination of drug susceptibility spectrum of Mycobacterium tuberculosis, the problem of timely and adequate prescription of chemotherapy regimen remains. When selecting therapy, the problem of prescribing a combination of antituberculosis drugs with proven efficacy against M. tuberculosis remains. The need to assess the patient’s comorbid status, which affects the effectiveness of treatment and the occurrence of relapses, remains relevant.Despite the introduction of new tests for rapid determination of the drug susceptibility spectrum of Mycobacterium tuberculosis, the problem of timely and adequate prescription of chemotherapy remains relevant. The problem of prescribing a combination of antituberculosis drugs with proven efficacy against M. tuberculosis remains in the selection of therapy. Currently, the introduction of bedaquiline in therapy regimens is important for improving the effectiveness of tuberculosis treatment. In addition, studies are underway to shorten the duration of therapy for MDR-TB and XDR-TB, which is particularly important for maintaining patient adherence to treatment.

PECULIARITIES OF FATAL CASES IN HIV-INFECTED PATIENTS WITH CENTRAL NERVOUS SYSTEM LESIONS IN TUBERCULOSIS INPATIENT SETTINGS FOR 2014-2023

Aim of the work is to study the peculiarities of fatal cases of CNS lesions in patients with tuberculosis against the background of HIV infection.Materials and methods. A retrospective analysis of 68 medical histories of tuberculosis patients with HIV infection who died in the CNE "Zaporizhia Regional Phthisiopulmonology Clinical Treatment and Diagnostic Center" for the years 2014-2023 was carried out. An analysis of the anamnesis, clinical and radiological data, laboratory indicators, final clinical and pathological diagnoses was carried out.Results. The mortality rate among HIV-infected people in TB hospitals has a steady downward trend. In 2014-2023, 1234 patients with HIV infection were treated at the CNE "Zaporizhia Regional Phthisiopulmonology Clinical Treatment and Diagnostic Center", 214 (17.3%) died. In 2014, 33 (24.6%) out of 134 HIV-positive patients died, and in 2023, 3 (6.8%) out of 44 HIV-positive patients died. Central nervous system (CNS) lesions among the dead were noted in 68 (31.8%) patients. The study of medical records found that among those who died with CNS lesions, men prevailed - 55 (80.9%), women - 13 (19.1%), young patients - 53 (77.9%), and 15 (22.1%) patients over 45 years of age. In the structure of central nervous system lesions in patients with active tuberculosis, tuberculous meningoencephalitis prevails in fatal cases - 35 (51.5%), a significant share of cryptococcal meningoencephalitis - 18 (26.5%) and progressive multifocal leukoencephalopathy - 9 (13.2%). The main reason that leads to fatal consequences is the late diagnosis of HIV infection - in 26 (38.2%) the number of CD4<50 cl./μl, 36 (52.9%) patients did not receive antiretroviral therapy (ART), 18 (26 .5%) of patients had been taking ART for a year. Improvement of tuberculosis microbiological diagnosis due to the introduction of the Xpert MTB/RIF® (Ultra) test at all levels of the laboratory network, the introduction of a mandatory test for cryptococci, free CT, MRI examination for the diagnosis in HIV-infected patients, improvement of drug-resistant tuberculosis treatment regimens contributed to the reduction of mortality in case of HIV and tuberculosis combination, which was 24.6% in 2014, and 6.8% in 2023.Conclusions. Diagnosis and treatment of CNS diseases in patients with active tuberculosis against the background of HIV infection requires a comprehensive approach: early diagnosis of HIV infection, tuberculosis and lesions of the CNS, improvement of treatment.

Actor Sensemaking and its Role in Implementation of the Decentralized Drug-Resistant TB Policy in South Africa.

South Africa has a high burden of drug-resistant tuberculosis (DR-TB). A policy to decentralize DR-TB treatment from specialized central hospitals to more accessible district facilities was introduced in 2011, but to date implementation has been suboptimal, with variable pace, coverage and models of care emerging. This study explored multilevel policy implementation of DR-TB decentralization in two provinces of South Africa, Western Cape and KwaZulu-Natal. Applying interpretive policy analysis, this paper describes how actors across health system levels and geographies made sense of the DR-TB policy and how this shaped implementation. In an embedded qualitative case study, districts of the two provinces were compared, through data collected in 94 in-depth interviews, and analysed using Vickers' framework of reality, value and action judgements. Five district cases characterise variation in the pace of implementation and models of DR-TB care that emerged. Individual and collective attitudes for and against the policy were underpinned by different systems of meaning for interpreting policy problems and making decisions. These meaning systems were reflected in actor stances on whether DR-TB care needed to be specialized or generalized, nurse- or doctor-led, and institutionalized or ambulatory. Actors' stances influenced their actions and implementation strategies adopted. Resistance to decentralized DR-TB care related to perceived threats of budget cuts to and loss of authority of central facilities, and was often justified in fears of increased transmission, poor quality of care and inadequate resources at lower levels. New advances in diagnosis and treatment to address the growing burden of DR-TB in South Africa will have little impact unless implementation dynamics are better understood, and attention paid to the mindsets, interests and interpretations of policy by actors tasked with implementation. Deliberative policy implementation processes will enhance the quality of discourse, communication and cross-learning between policy actors, critical for reaching synthesis of meaning systems.

Dynamic modelling of improved diagnostic testing for drug-resistant tuberculosis in high burden settings.

Limited diagnostic testing for drug-resistant TB (DR-TB) may lead to high rates of misdiagnosis and undertreatment. Current diagnostic tests focus only on detection of rifampicin-resistant TB (RR-TB). This study aims to determine the impact of improved diagnostic testing for a wider range of drug resistance on DR-TB outcomes in high-burden TB settings, using the Philippines and Thailand as case studies. A dynamic compartmental model was designed to simulate population level TB transmission, accounting for acquired drug resistance from treatment failure of drug susceptible TB. Three scenarios were analyzed: (1) Use of GeneXpert MTB/RIF on all presumptive TB cases (Status Quo); (2) GeneXpert MTB/RIF + GeneXpert XDR, (3) GeneXpert MTB/RIF + targeted Next Generation Sequencing (tNGS). Scenarios were modelled over a 10-year period, from 2025 to 2034. Compared to the status quo, Scenario 2 results in a fourfold increase in annual DR-TB cases diagnosed in the Philippines and a fivefold increase in Thailand. DR-TB treatment failure decreases by 20% in the Philippines and 23% in Thailand. Scenario 3 further increases DR-TB case detection, reducing DR-TB treatment failure by 26% in the Philippines and 29% in Thailand. Reductions in DR-TB incidence and mortality ranged from 3 to 6%. The use of GeneXpert XDR or tNGS as an additional diagnostic test for DR-TB significantly improves DR-TB case detection and reduces treatment failure, supporting their consideration for use in high burden settings. These findings highlight the importance of detecting a wider range of TB resistance in addition to RR-TB, the potential impact these improved diagnostic tests can have on DR-TB outcomes, and the need for additional research on cost-effectiveness of these interventions.

Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis

Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5′-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and AMDE profiles.

Safety, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both in adults with pulmonary tuberculosis: a randomised, active-controlled, open-label trial

Quabodepistat (formerly OPC-167832) showed potent activity in preclinical studies and in the first stage of an early bactericidal activity study in adults with smear-positive, drug-susceptible pulmonary tuberculosis. Stage 2 of this study was designed to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both versus rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy for 14 days. Stage 2 of this open-label, active-controlled, randomised, parallel-group study was conducted at two research sites in South Africa in adults (aged 18-64 years) with drug-susceptible pulmonary tuberculosis. Eligible participants had a BMI of 16-32 kg/m2 and the ability to produce an adequate volume of sputum (≥10 mL overnight) and were excluded if they had drug-resistant tuberculosis or previous treatment for Mycobacterium tuberculosis within the past 3 years. Participants were centrally randomly assigned via interactive web response technology system, with no stratification, into four treatment groups in a ratio of 14:14:14:4 (quabodepistat 30 mg plus delamanid 300 mg, quabodepistat 30 mg plus bedaquiline 400 mg, or quabodepistat 30 mg plus delamanid 300 mg plus bedaquiline 400 mg orally once daily for 14 days, or rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy [control] according to local standard of care for 20 days). The primary outcomes were safety and tolerability during and after 14 days of treatment in all participants who received any study medication and pharmacokinetics at day 1 and day 14 in participants in the quabodepistat groups with adequate data for deriving pharmacokinetics parameters. The main secondary outcome was bactericidal activity from baseline to day 14 in all eligible participants who were quantitatively culture-positive at baseline. The study was not powered for formal statistical hypothesis testing; therefore, data were summarised by treatment group with descriptive statistics. This study is registered with ClinicalTrials.gov (NCT03678688) and is closed to new participants. 98 participants were screened for entry into stage 2 of the trial between Feb 1, 2021, and Jan 27, 2022, of whom 46 were randomly assigned (14 to each quabodepistat group, 4 to the control group) and 44 received at least one dose of study medication (one patient excluded from the quabodepistat plus delamanid and quabodepistat plus bedaquiline groups). 32 (73%) of 44 participants had at least one treatment-emergent adverse event. Most events (30/32 [94%]) were mild or moderate; the most common treatment-emergent adverse events (≥2 participants; not related to study drugs) were headache (4/44 [9%]), dizziness (3/44 [7%]), abdominal pain (2/44 [5%]), pruritus (2/44 [5%]), and nausea (2/44 [5%]). Two serious adverse events were reported in two participants in the quabodepistat and bedaquiline cohort (anal abscess [n=1], pneumothorax [n=1]); both were deemed not related to study drug. Quabodepistat exposure was minimally affected by coadministration of delamanid or bedaquiline, with lower exposure in the quabodepistat and bedaquiline cohorts (maximum plasma concentration for quabodepistat plus delamanid 208 ng/mL [SD 61; n=11]; quabodepistat plus bedaquiline 175 ng/mL [31; n=10]; quabodepistat plus delamanid plus bedaquiline 183 ng/mL [52; n=11]). Maximum quabodepistat concentrations were achieved approximately 3 h after administration in all combinations. Mean elimination half-life was shorter in combinations with bedaquiline than without bedaquiline (12·3-14·5 h vs 15·2 h). Mean changes from baseline to day 14 of sputum log10 colony-forming units per mL were -2·73 (SD 1·51) for quabodepistat plus delamanid plus bedaquiline (n=12) and -2·71 (SD 0·92) for control (n=19); mean change was -2·17 (SD 1·83) in the quabodepistat plus delamanid cohort (n=11) and -1·97 (SD 1·29) in the quabodepistat plus bedaquiline cohort (n=11). In this 14-day trial, quabodepistat plus delamanid plus bedaquiline, a novel three-drug combination, appeared to be safe, well tolerated, and provided robust early bactericidal activity in adults with drug-susceptible pulmonary tuberculosis. Further evaluation is warranted. Otsuka Pharmaceutical Development & Commercialization and the Bill & Melinda Gates Foundation.

A Rare Case of Tremor Induces by Cycloserine in Drug-Resistant Tuberculosis Patient

Background: Tuberculosis is a contagious disease that generated by Mycobacterium tuberculosis. Drug-Resistant tuberculosis (DR-TB) is inculpated the use of the second-line anti-tubercular treatment which is associated with many drug side effects or so called, Adverse Drug Reactions (ADR). Cycloserine (Cs) is an important drug against drug resistant tuberculosis (DR-TB). Cycloserine has been used in tuberculosis therapy since the late 1950s. Identical with most drug, Cycloserine can cause many Adverse Drug Reactions (ADR). Case Illustration: A 23-year-old woman diagnosed with drug-resistant tuberculosis is undergoing long-term treatment. The patient received treatment for DR-TB with the Bdq-Lfx-Cfz-Cs-E regimen. After the patient underwent the 10th month of advanced phase treatment, the patient complained of shaking in both hands (tremors). The tremor is felt to be more severe in the right hand and the patient cannot grip objects tightly. Discussion: Cycloserine (Cs) play an important role in second-line drug management of DR-TB. Cs-Induced psychosis and other neurological side-effects can be detrimental towards patients yet they are rarely reports in DR-TB cases. Cs is correlated with severe psychiatric cases and Central Nervous System related ADRs. Cs-associated ADR is most likely because of production of gamma-aminobutyric acid as a result of inhibition of glutamic decarboxylase. Study Shown that among 132 patients who reported side effects in the cycloserine group, 2 (1.4%) experienced major side effects, namely tremors. Side effects possibly or probably related to Cs appeared after a median of 71 days (range 10–331 days) of Cs treatment. Conclusion: the drug side effects such as tremors are very rare in drug-resistant tuberculosis patients. In this case, the patient's complaint of tremors could be caused by cycloserine as an anti-tuberculosis drug.

Predicting Treatment Outcomes in Patients with Drug-Resistant Tuberculosis and Human Immunodeficiency Virus Coinfection, Using Supervised Machine Learning Algorithm.

Drug-resistant tuberculosis (DR-TB) and HIV coinfection present a conundrum to public health globally and the achievement of the global END TB strategy in 2035. A descriptive, retrospective review of medical records of patients, who were diagnosed with DR-TB and received treatment, was conducted. Student's t-test was performed to assess differences between two means and ANOVA between groups. The Chi-square test with or without trend or Fischer's exact test was used to test the degree of association of categorical variables. Logistic regression was used to determine predictors of DR-TB treatment outcomes. A decision tree classifier, which is a supervised machine learning algorithm, was also used. Python version 3.8. and R version 4.1.1 software were used for data analysis. A p-value of 0.05 with a 95% confidence interval (CI) was used to determine statistical significance. A total of 456 DR-TB patients were included in the study, with more male patients (n = 256, 56.1%) than female patients (n = 200, 43.9%). The overall treatment success rate was 61.4%. There was a significant decrease in the % of patients cured during the COVID-19 pandemic compared to the pre-pandemic period. Our findings showed that machine learning can be used to predict TB patients' treatment outcomes.

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

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. 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). 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.

A non-randomized pragmatic historically controlled trial evaluating the effectiveness and safety of a bedaquiline or a linezolid-based short regimen for rifampicin-resistant tuberculosis

Short all-oral regimens for Rifampicin-resistant tuberculosis (ShORRT) have been a turning point in the treatment of drug-resistant tuberculosis. Despite this, access to drugs, stockouts, or adverse effects may limit the use of the recommended regimens. Pragmatic non-randomized trial evaluating the efficacy and safety of a ShORRT strategy for the treatment of rifampicin-resistant Tuberculosis (RR-TB) at the Hospital Nossa Senhora da Paz (Angola). The strategy assigned participants to receive a bedaquiline (BDQ) or a linezolid-based (LZF) regimen supplemented with levofloxacin, clofazimine, and cycloserine for up to 9 months. One hundred and twenty-one participants with pulmonary RR-TB were treated with the ShORRT strategy; 69 received the bedaquiline- and 52 the linezolid-based regimen. Overall, 98 (81%) participants had successful treatment outcomes, which was significantly higher compared to a 20-month historical injectable-based regimen (successful outcome rate including cure and treatment completed: 53.7%) (p<0.001). No significant differences between treatment success rates (85.5% vs. 75.0%), treatment failure (0.0% vs. 1.9%), death (5.8% vs. 13.5%), or lost to follow-up (LTFU) (8.7% vs. 9.6%) were seen between the BDQ and the LZF-based regimen. Globally, 72 adverse events (AE) occurred in 36 (29.7%) participants. Eighteen (14.9%) of these were grade ≥3 and were more frequently observed in those receiving the LZD-based regimen (p=0.02). The ShORRT strategy with a nine-month BDQ- or LZD-based regimen supports the efficacy of shorter all-oral regimens for the treatment of RR-TB and presents real-world data from schemes without bedaquiline, nitroimidazole, or injectables.

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.

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.

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.

Sputum culture conversion and its predictors among drug-resistant pulmonary tuberculosis patients in eastern Ethiopia.

Evidence of time to culture conversion is used to predict the time of cure from the disease and the overall drug-resistant tuberculosis (TB) treatment duration. Even though evidence about sputum culture conversion is enormous in TB treatment, no study has yet been done in our areas, where cases are common. The study aimed to assess the time to sputum conversion and its predictors among drug-resistant TB patients from October 2013 to September 2021 in eastern Ethiopia. A retrospective cohort study was conducted in eastern Ethiopia among 273 drug-resistant TB patients who were treated from October 2013 to September 2021 at Dire Dawa City and Harari regional treatment centres. The Kaplan-Meier method was used to estimate the median time of sputum culture conversion. Cox proportional hazards regression was employed to detect the predictors of sputum culture conversion. An adjusted hazard ratio (aHR) with 95% confidence interval (CI) was used to determine the strength and significance of the association. Of the 273 drug-resistant TB patients, the sputum culture of 216 (79.12%) patients became negative in a median time of 3months (interquartile range 2-7). The time to sputum culture conversion was negatively associated with underweight (aHR 0.65 [95% CI 0.49 to 0.90]) and poor adherence (aHR 0.41 [95% CI 0.24 to 0.69]). The time to sputum culture conversion was also positively associated with patients resistant to two or more drugs (aHR 1.58 [95% CI 1.07 to 2.32]) and patients receiving a short treatment regimen (aHR 2.24 [95% CI 1.10 to 2.55]). A shorter culture conversion rate was observed compared with the median time recommended by the World Health Organization. Being underweight, poor adherence to treatment, resistance to two or more drugs and receiving a short treatment regimen were found to be predictors of time to sputum culture conversion. Implementing nutrition assessment, counselling and support of drug adherence may improve sputum culture conversion.

Evaluating the Effects of Decentralized District-Based Treatment of Drug-Resistant Tuberculosis in Pakistan: An Alternative Model of Care

Background: Pakistan faces a high burden of drug-resistant tuberculosis (DR-TB), with traditional centralized care resulting in delays and poor treatment outcomes. Decentralizing care to district-level hospitals offers a potentially more effective alternative.Objective: This study aimed to evaluate the impact of decentralized DR-TB care on treatment initiation time, patient follow-up, and treatment outcomes.Methods: A descriptive post-intervention study was conducted at a decentralized DR-TB clinic in Sheikhupura, Punjab, between June 2021 and December 2022. Data from 100 patients were retrospectively collected from hospital records and diagnostic labs, including demographic information, treatment compliance, smear and culture conversion rates, and adverse drug reactions. SPSS 25 was used for statistical analysis, including descriptive statistics.Results: The average time from diagnosis to treatment initiation was 14.9 days. Smear conversion by the sixth month was 99%, while culture conversion was 98%. The treatment success rate was 70%, with a 7% loss to follow-up, 2% treatment failure, and 15% mortality.Conclusion: Decentralized DR-TB care significantly reduced delays in treatment initiation and improved patient outcomes. This model is feasible for national implementation with potential to enhance DR-TB management in Pakistan.

Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India.

Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1-18 years (median: 12 years; IQR: 9-14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

Age and gender in drug resistance tuberculosis: A cross-sectional case study at a national tuberculosis reference hospital in Nigeria

ObjectivesDrug resistance in tuberculosis (TB) is a very important public health threat that should not be ignored. Understanding the gender, age, and characteristics of individuals affected by TB (without HIV, diabetes, or hepatitis B complications), particularly in terms of drug resistance or susceptibility, is crucial for effective prevention and management strategies, as most studies focus on TB/HIV co-infection. MethodsA cross-sectional case study of age and gender was carried out in 140 individuals grouped into drug-resistant tuberculosis (DR-TB), drug-susceptible tuberculosis (DS-TB), and apparently healthy controls (AHCs). Data collection was through medical records and a structured questionnaire. Statistical analyses compared age, gender, and selected risk factors across the groups. ResultsThe mean age of the DR-TB group was 32 years (SD ≈ 2). A total of 80.0% were ≤40 years of age and four times more likely to have DR-TB; 55% were male, with 1.22 times more likelihood of DR-TB in males. The mean age of the DS-TB group was 34 years (SD ≈ 12); 66.7% were ≤40 years old. The odds ratio of DS-TB in males was 2.16. Only 10% of DR-TB enrolees had BCG scars compared with 65% AHCs. A high percentage of the DR-TB group reported handling raw meat (75%) and drinking unpasteurised milk (70%) compared with the DS-TB group. ConclusionsThe observed gender disparities and age-related factors, particularly among the DR-TB group, highlight the importance of considering age and gender factors in DR-TB prevention, diagnosis, and treatment. Our findings also highlight the need to bridge gaps in awareness as well as for the prevention of zoonotic TB and issues around effective BCG vaccination and coverage.