Management Of Multidrug-resistant Tuberculosis Research Articles

Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis of Second-Line Anti-Tubercular Drugs in Indian Children with Multi-Drug Resistance.

To conduct a thorough pharmacokinetic (PK)- pharmacodynamic (PD) analysis of second-line anti-tubercular therapy (ATT) in children diagnosed with multi-drug resistant tuberculosis (MDR-TB). Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software. A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population. The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.

Exploring health care providers’ engagement in prevention and management of multidrug resistant Tuberculosis and its factors in Hadiya Zone health care facilities: qualitative study

BackgroundEngagement of healthcare providers is one of the World Health Organization strategies devised for prevention and provision of patient centered care for multidrug resistant tuberculosis. The need for current research question rose because of the gaps in evidence on health professional’s engagement and its factors in multidrug resistant tuberculosis service delivery as per the protocol in the prevention and management of multidrug resistant tuberculosis.PurposeThe purpose of this study was to explore the level of health care providers’ engagement in multidrug resistant tuberculosis prevention and management and influencing factors in Hadiya Zone health facilities, Southern Ethiopia.MethodsDescriptive phenomenological qualitative study design was employed between 02 May and 09 May, 2019. We conducted a key informant interview and focus group discussions using purposely selected healthcare experts working as directly observed treatment short course providers in multidrug resistant tuberculosis treatment initiation centers, program managers, and focal persons. Verbatim transcripts were translated to English and exported to open code 4.02 for line-by-line coding and categorization of meanings into same emergent themes. Thematic analysis was conducted based on predefined themes for multidrug resistant tuberculosis prevention and management and core findings under each theme were supported by domain summaries in our final interpretation of the results. To maintain the rigors, Lincoln and Guba’s parallel quality criteria of trustworthiness was used particularly, credibility, dependability, transferability, confirmability and reflexivity.ResultsTotal of 26 service providers, program managers, and focal persons were participated through four focus group discussion and five key informant interviews. The study explored factors for engagement of health care providers in the prevention and management of multidrug resistant tuberculosis in five emergent themes such as patients’ causes, perceived susceptibility, seeking support, professional incompetence and poor linkage of the health care facilities. Our findings also suggest that service providers require additional training, particularly in programmatic management of drug-resistant tuberculosis.ConclusionThe study explored five emergent themes: patient’s underlying causes, seeking support, perceived susceptibility, professionals’ incompetence and health facilities poor linkage. Community awareness creation to avoid fear of discrimination through provision of support for those with multidrug resistant tuberculosis is expected from health care providers using social behavioral change communication strategies. Furthermore, program managers need to follow the recommendations of World Health Organization for engaging healthcare professionals in the prevention and management of multidrug resistant tuberculosis and cascade trainings in clinical programmatic management of the disease for healthcare professionals.

Cost-consequence analysis of ambulatory clinic- and home-based multidrug-resistant tuberculosis management models in Eswatini.

We compared the cost-consequence of a home-based multidrug-resistant tuberculosis (MDR-TB) model of care, based on task-shifting of directly observed therapy (DOT) and MDR-TB injection administration to lay health workers, to a routine clinic-based strategy within an established national TB programme in Eswatini. Data on costs and effects of the two ambulatory models of MDR-TB care was collected using documentary data and interviews in the Lubombo and Shiselweni regions of Eswatini. Health system, patient and caregiver costs were assessed in 2014 in US$ using standard methods. Cost-consequence was calculated as the cost per patient successfully treated. In the clinic-based and home-based models of care, respectively, a total of 96 and 106 MDR-TB patients were enrolled in 2014, with treatment success rates of 67.8% and 82.1%. Health system costs per patient treated were slightly lower in the home-based strategy (US$19 598) compared to the clinic-based model (US$20 007). The largest costs in both models were for inpatient care, administration of DOT and injectable treatment, and drugs. Costs incurred by patients and caregivers were considerably higher in the clinic-based model of care due to the higher direct travel costs to the nearest clinic to receive DOT and injections daily. In total, MDR patients in the clinic-based strategy incurred average costs of US$670 compared to US$275 for MDR-TB patients in the home-based model. MDR-TB patients in the home-based programme, where DOT and injections was provided in their homes, only incurred out-of-pocket travel expenses for monthly outpatient treatment monitoring visits averaging US$100. The cost per successfully treated patient was US$31 106 and US$24 157 in the clinic-based and home-based models of care, respectively. The analysis showed that, in addition to the health benefits, direct and indirect costs for patients and their caregivers were lower in the home-based care model. The home-based strategy used less resources and generated substantial health and economic benefits, particularly for patients and their caregivers, and decision makers can consider this approach as an alternative to expand and optimise MDR-TB control in resource-limited settings. Further research to understand the appropriate mix of treatment support components that are most important for optimal clinical and public health outcomes in the ambulatory home-based model of MDR-TB care is necessary.

Study of Culture Conversion in Drug-Resistant Pulmonary Tuberculosis on All-Oral Longer Regimen at IGIMS, Patna

ABSTRACT Background: Multidrug-resistant tuberculosis (MDR-TB) refers to tuberculosis that resists at least two primary drugs, namely isoniazid and rifampicin. To assess the management of MDR-TB, sputum culture conversion is performed. This study aimed to determine the culture conversion status of MDR-TB patients undergoing an all-oral longer regimen. Methods: This research constitutes an observational and prospective study conducted within a hospital setting. The study was done at the Department of Microbiology, IGIMS, Patna, from October 2020 to March 2022. Culture conversion in multidrug resistance pulmonary tuberculosis on all-oral longer regimens took one spot and one morning sample of sputum as per standard protocol after completing two months of all-oral longer regimens and culturing it in liquid broth using Mycobacterium Growth Indicator Tube (MGIT) 960 System at two, four then six months till we got a negative result. Results: Maximum number of the cases, 77 (74.8%), belonged to 19–35 years of age group. Males were 68 (66.1%) and females were 35 (33.9%), respectively, with male to female ratio of 1.9:1. After 2 months of oral longer regimen treatment, out of 103 cases, we found 98 (95.1%) patients had sputum for culture positive and only five (4.2%) patients had sputum for culture negative. After 6 months of oral longer regimen treatment, out of 101 cases, we found 16 (15.8%) patients had sputum for culture positive and 85 (85.2%) patients had sputum for culture negative. Conclusion: In patients with multidrug-resistant pulmonary tuberculosis (MDR-TB) who received an all-oral longer regimen, the introduction of bedaquiline led to positive outcomes as evidenced by a greater number of negative sputum cultures, a decrease in culture reversions, and a reduced risk of developing a more resistant form of MDR-TB.

Apo Lipoproteins A1 and B in Multidrug-Resistant Tuberculosis (MDR-TB)

Aims: The medical management of multidrug-resistant tuberculosis (MDR-TB) has become a major public health issue. Apolipoproteins play a key role in lipoprotein metabolism such as the recognition of receptors involved in lipoprotein metabolism. Thus, the study of the inter- relationships between apolipoproteins (A1 and B) and MDR-TB could represent an important approach to the biological management of MDR-TB patients. Methodology: This is an experimental study carried out on eighty-two (82) patients including thirty-eight (38) MDR-TB patients which age ranged from 18 to 60 years old recruited from three tuberculosis centers (CAT) in the city of Abidjan and forty-four (44) non-tuberculosis patients used as control aged 18 to 60 years old recruited at the National Blood Transfusion Center (CNTS) in Treichville (Abidjan, Côte d’Ivoire). Total cholesterol, HDL-cholesterol and triglycerides were measured by the colorimetric-enzymatic method. Apolipoproteins A1 and B were measured using the immunoturbidimetric method. Results and Conclusion: Showed a dyslipidemia concerning cholesterol and its HDL fraction, triglycerides and apolipoproteins A1 and B suggest an atherogenic profile in multidrug-resistant TB patients.

Contact investigation in multidrug-resistant tuberculosis:ethical challenges.

Contact investigation is an evidence-based intervention of multidrug-resistant tuberculosis (MDR-TB) to protect public health by interrupting the chain of transmission. In pursuit of contact investigation, patients' MDR-TB status has to be disclosed to third parties (to the minimum necessary) for tracing the contacts. Nevertheless, disclosure to third parties often unintentionally leads the MDR-TB patients suffered from social discrimination and stigma. For this reason, patients are less inclined to reveal their MDR-TB status and becomes a significant issue in contact investigation. This issue certainly turns into a negative impact on the public interest. Tension between keeping MDR-TB status confidential and safeguarding public health arises in relation to this issue. Regarding MDR-TB management, patient compliance with treatment and contact investigation are equally important. Patients might fail to comply with anti-TB therapy and be reluctant to seek healthcare due to disclosure concerns. In order to have treatment adherence, MDRTB patients should not live through social discrimination and stigma arising from disclosure and TB team has a duty to support them as a mean of reciprocity. However, implementation of contact investigation as a public health policy can still be challenging even with promising reciprocal support to the patients because MDR-TB patients are living in different contexts and situations. There can be no straight forward settlement but an appropriate justification for each distinct context is needed to strike a balance between individual confidentiality and public interest.

Empowering care: Unleashing pharmaceutical care to confront MDR-TB transmission risks-A prospective interventional study

IntroductionAccording to recent NTEP report it was estimated that in India the MDR-TB cases were 9.1/lakh population. Patients undergoing the pulmonary TB are known to cause MDR-TB due to multi drug resistance. Early identification of risk elements in Multidrug resistant-TB patients is crucial to managing and preventing the disease. ObjectiveTo evaluate risk variables that contribute to cause Multidrug resistant tuberculosis and to providing patient counselling to TB patients regarding risk factors. Methodology: A Prospective interventional study to assess the various Risk factors involved in cause of Multi drug resistance tuberculosis. This study was conducted for period of 09 months. The study is conducted with standard validated questionnaires which are prepared to assess the risk factors among Multidrug resistant-TB patients. Study site includes the tertiary care hospitals in Belagavi. ResultOverall, 120 Multidrug resistant tuberculosis patients were recruited from the district tuberculosis centre, Belagavi District, Karnataka. India. Most patients (47.50%) were aged 25–44 years. Of the 120 MDR-TB patients, 67.50% are male and 32.5% are female. Of 120 MDR-TB patients, 7.50% are HIV positive. As part of the study, smoking (26.67%), chewing tobacco (50%), and alcohol consumption (33.33%) were found to be other major risk factors. 24.17% of patients had a family history of tuberculosis, of which 5% had contact with an infected person as a source of infection. ConclusionThis study documented various risk variables involved in the emergence of Multidrug resistant TB. This research also highlighted the significance of pharmaceutical care in the effective management of multidrug-resistant tuberculosis (MDR-TB). This study identified risk variables that contribute to MDR-TB and helped educate tuberculosis patients about these risk factors.

Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis.

Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07-1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06-1.16), treatment success (aRR, 1.07; 95% CI, 1.03-1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14-1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC0-24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens.

MHealth application for improving treatment outcomes for patients with multidrug-resistant tuberculosis in Vietnam: an economic evaluation protocol for the V-SMART trial

IntroductionThe Strengthen the Management of Multidrug-Resistant Tuberculosis in Vietnam (V-SMART) trial is a randomised controlled trial of using mobile health (mHealth) technologies to improve adherence to medications and management of...

Cost of digital technologies and family-observed DOT for a shorter MDR-TB regimen: a modelling study in Ethiopia, India and Uganda

BackgroundIn 2017, the WHO recommended the use of digital technologies, such as medication monitors and video observed treatment (VOT), for directly observed treatment (DOT) of drug-susceptible TB. The WHO’s 2020 guidelines extended these recommendations to multidrug-resistant tuberculosis (MDR-TB), based on low evidence. The impact of COVID on health systems and patients underscored the need to use digital technologies in the management of MDR-TB.MethodsA decision-tree model was developed to explore the costs of several potential DOT alternatives: VOT, 99DOTS (Directly-observed Treatment, Short-course) and family-observed DOT. Assuming a 9-month, all-oral regimen (as evaluated within the STREAM trial), we constructed base-case cost models for the standard-of-care DOTs in Ethiopia, India, and Uganda, as well as for the three alternative DOT approaches. The models were populated with STREAM Stage 2 clinical trial outcome and cost data, supplemented with market prices data for the digital DOT strategies. Sensitivity analyses were conducted on key parameters.ResultsModelling suggested that the standard-of-care DOT approach is the most expensive DOT strategy from a societal perspective in all three countries evaluated (Ethiopia, India, Uganda), with considerable direct- and indirect-costs incurred by patients. The second most expensive DOT approach is VOT, with high health-system costs, largely caused by up-front technology expenditure.Each of VOT, 99DOTS and family-observed DOT would reduce by more than 90% patients’ direct and indirect costs compared to standard of care DOT.Results were robust to the sensitivity analyses.ConclusionsWhile data on the costs and efficacy of alternative DOT approaches in the context of shorter MDR-TB treatment is limited, our modelling suggests alternative DOT approaches can significantly reduce patient costs in all three countries. Health system costs are higher for VOT and lower for 99DOTS and family-observed therapy when compared to standard of care DOT, as low smartphone penetration and internet availability requires the VOT health system to fund the cost of making them available to patients.

Magnitude and Impacts of Adverse Events of Injectable Containing Shorter Regimen in Programmatic Management of Multi-Drug Resistant Tuberculosis in Ethiopia: A Retrospective Cohort Study.

Since its launch as a standardized treatment for multidrug-resistant tuberculosis (MDR-TB) in Ethiopia in April 2018, the safety profile of the shorter injectable regimen under a programmatic setting has not been well studied. Thus, this study aimed to assess the status of adverse events in patients treated with a shorter injectable regimen in Ethiopia. This is a retrospective cohort study. Data were collected using a structured data abstraction form and analyzed using SPSS, version 25, both descriptively and analytically. Logistic regression was conducted to assess predictors, and Kaplan-Meier analysis was used to examine the time to AEs and survival experiences. Of 256 patients, 245 (95.7%) were eligible for the study. Of 245, 107 (43.7%) patients experienced at least one AE. In total, 276 AE cases were observed out of which the most common were nausea/vomiting (20.3%), dyspepsia (18.1%), and ototoxicity (11.6%). Of 276 AEs, approximately 49 (17.8%) were serious. AEs led to drug discontinuation, dose modification, and regimen change in 29 (27%), 15 (14%) and 10 (9.3%) patients, respectively. Only 19.2% of 276 the overall AEs and 22.6% of 62 AE of special interest (AESI) were reported to the National Pharmacovigilance Center. Although the observed extent of AEs associated with the shorter regimen (SR) seemed to be moderate, it significantly influenced the treatment schemes and patient conditions. Reporting of AEs was low, irrespective of their severity and AESI. Therefore, strengthening the implementation of active drug safety monitoring and management is required.

Development of Bedaquiline-Loaded SNEDDS Using Quality by Design (QbD) Approach to Improve Biopharmaceutical Attributes for the Management of Multidrug-Resistant Tuberculosis (MDR-TB).

Background: The ever-growing emergence of antibiotic resistance associated with tuberculosis (TB) has become a global challenge. In 2012, the USFDA gave expedited approval to bedaquiline (BDQ) as a new treatment for drug-resistant TB in adults when no other viable options are available. BDQ is a diarylquinoline derivative and exhibits targeted action on mycobacterium tuberculosis, but due to poor solubility, the desired therapeutic action is not achieved. Objective: To develop a QbD-based self-nanoemulsifying drug delivery system of bedaquiline using various oils, surfactants, and co-surfactants. Methods: The quality target product profile (QTPP) and critical quality attributes (CQAs) were identified with a patient-centric approach, which facilitated the selection of critical material attributes (CMAs) during pre-formulation studies and initial risk assessment. Caprylic acid as a lipid, propylene glycol as a surfactant, and Transcutol-P as a co-surfactant were selected as CMAs for the formulation of bedaquiline fumarate SNEDDS. Pseudo-ternary phase diagrams were constructed to determine the optimal ratio of oil and Smix. To optimize the formulation, a Box-Benkhen design (BBD) was used. The optimized formulation (BDQ-F-SNEDSS) was further evaluated for parameters such as droplet size, polydispersity index (PDI), percentage transmittance, dilution studies, stability studies, and cell toxicity through the A549 cell. Results: Optimized BDQ-F-SNEDDS showed well-formed droplets of 98.88 ± 2.1 nm with a zeta potential of 21.16 mV. In vitro studies showed enhanced drug release with a high degree of stability at 25 ± 2 °C, 60 ± 5% and 40 ± 2 °C, 75 ± 5%. Furthermore, BDQ-F-SNEDDS showed promising cell viability in A549 cells, indicating BDQ-F-SNEDDS as a safer formulation for oral delivery. Conclusion: Finally, it was concluded that the utilization of a QbD approach in the development of BDQ-F-loaded SNEDDS offers a promising strategy to improve the biopharmaceutical properties of the drug, resulting in potential cost and time savings.

Identification of potential compounds for the management of multidrug-resistant tuberculosis using computational methods

Background: Tuberculosis is caused by Mycobacterium tuberculosis and is spread through the air. Multidrug-resistant tuberculosis (MDR TB) has become a global health concern. This study focuses on developing alternative compounds to Levofloxacin, Moxifloxacin, Bedaquiline, Kanamycin, Amikacin, Cycloserine, Ethambutol, Pyrazinamide, Linezolid and Streptomycin that can be used to treat patients with multidrug resistance TB. The virtual screening will aid in discovering other possible compounds for use in the management of MDR TB, thereby providing a superior alternative to currently existing medications and aid in eradicating TB. The objective of this study was to identify potential compounds that can be used in managing MDR TB in chronic tuberculosis patients using computational methods. Methods: The Swiss Similarity tool was used to identify similar compounds to the tuberculosis drugs in a ZINC database. Compounds more similar to the tuberculosis drugs were selected and used to test the molecular docking with their respective targets. The pharmacokinetics and toxicity profiles of the selected compounds were analyzed using Swiss ADME and Pro Tox Server, respectively. Results: Overall, 90 compounds had higher binding energies than the medications, 88 had lower binding energies, and 14 had binding energies that were equivalent to those of the drugs. Only 14 of the 200 compounds lacked CYP inhibition, were p-glycoprotein substrates, had superior docking scores to the compounds, and fell into toxicity classes V and VI. Conclusions: The 14 potential compounds should undergo further in vivo and in vitro studies to develop new compounds for managing multidrug-resistant tuberculosis.

Prevalence of long-term physical sequelae among patients treated with multi-drug and extensively drug-resistant tuberculosis: a systematic review and meta-analysis.

Physical sequelae related to multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are emerging and under-recognised global challenges. This systematic review and meta-analysis aimed to quantify the prevalence and the types of long-term physical sequelae associated with patients treated for MDR- and XDR-TB. We systematically searched CINAHL (EBSCO), MEDLINE (via Ovid), Embase, Scopus, and Web of Science from inception through to July 1, 2022, and the last search was updated to January 23, 2023. We included studies reporting physical sequelae associated with all forms of drug-resistant TB, including rifampicin-resistant TB (RR-TB), MDR-TB, Pre-XDR-TB, and XDR-TB. The primary outcome of interest was long-term physical sequelae. Meta-analysis was conducted using a random-effect model to estimate the pooled proportion of physical sequelae. The sources of heterogeneity were explored through meta-regression using study characteristics as covariates. The research protocol was registered in PROSPERO (CRD42021250909). From 3047 unique publications identified, 66 studies consisting of 37,380 patients conducted in 30 different countries were included in the meta-analysis. The overall pooled estimate was 44.4% (95% Confidence Interval (CI): 36.7-52.1) for respiratory sequelae, 26.7% (95% CI: 23.85-29.7) for hearing sequelae, 10.1% (95% CI: 7.0-13.2) for musculoskeletal sequelae, 8.4% (95% CI: 6.5-10.3) for neurological sequelae, 8.1% (95% CI: 6.3-10.0) for renal sequelae, 7.3% (95% CI: 5.1-9.4) for hepatic sequelae, and 4.5% (95% CI: 2.7-6.3) for visual sequelae. There was substantial heterogeneity in the estimates. The stratified analysis showed that the pooled prevalence of hearing sequelae was 26.6% (95% CI: 12.3-40.9), neurological sequelae was 31.5% (95% CI: 5.5-57.5), and musculoskeletal sequelae were 21.5% (95% CI: 9.9-33.1) for patients with XDR-TB, which were higher than the pooled prevalence of sequelae among patients with MDR-TB. Respiratory sequelae were the highest in low-income countries (59.3%) and after completion of MDR-TB treatment (57.7%). This systematic review found that long-term physical sequelae such as respiratory, hearing, musculoskeletal, neurological, renal, hepatic, and visual sequelae were common among survivors of MDR- and XDR-TB. There was a significant difference in the prevalence of sequelae between patients with MDR- and XDR-TB. Post-MDR- and XDR-TB treatment surveillance for adverse outcomes needs to be incorporated into the current programmatic management of MDR-TB to enable early detection and prevention of post-treatment sequelae. Australian National Health and Medical Research Council, through an Emerging Leadership Investigator grant, and the Curtin University Higher Degree Research scholarship.

Detection of katG and inhA Genes Mutation in Rifampicin-Resistant Mycobacterium Tuberculosis Using Line Probe Assay (LPA) In Kebbi, Nigeria

Elimination of tuberculosis remains a public health menace, due to multidrug resistant strains of Mycobacterium tuberculosis, that are resistant to the first-line anti-tubercular drugs. Consequently, detection of resistant strains depends on early diagnosis. Intervention of molecular techniques is essential to reduce mortality and morbidity rates. This study aimed to detect katG and inhA gene mutations among rifampicin resistant strain of Mycobacterium tuberculosis in Kebbi State. A cross-sectional study was conducted which covered all the five major health zones in Kebbi State. Two hundred and forty (240) acid fast bacilli confirmed sputum samples were recruited and subjected to Gene Xpert testing. Positive sputum samples were later subjected to Line Probe Assay technique. 14 sputum samples were resistant to rifampicin out of the 240 confirmed acid fast bacilli sputum samples while 226 were sensitive to rifampicin. Mutations were found at the frequency of 100% for katG gene (katG/S315T) in all the 14 rifampicin resistant samples (rpoB/S531L) at the different health zones in kebbi state using the line probe assay. The research has also detected inhA gene mutation at a frequency of 100% in all rifampicin resistant samples showing that mutation is associated with multi resistance to isoniazid and rifampicin. This study confirms that resistance due to katG and inhA mutation is a better surrogate of multidrug-resistant tuberculosis among TB patients in Kebbi State compared to the single-marker analysis. Hence, early molecular detection of rifampicin resistant strains will suffice in determining the management of multidrug resistant tuberculosis in Kebbi State.

Patients' perceived quality of care and their satisfaction with care given for MDR-TB at referral hospitals in Ethiopia.

There is presently dearth of evidence in Ethiopia on patients' perception on quality of care given for multi-drug resistant tuberculosis (MDR-TB) and their satisfaction with the care and services they receive for the disease. Moreover, there is no evidence on the experiences and practices of caregivers for MDR-TB regarding the functionality of the programmatic management of MDR-TB at referral hospitals in Ethiopia. Thus, this study was conducted to address these gaps. Evidence in these areas would help to institute interventions that could enhance patient satisfaction and their adherence to the treatment given for MDR-TB. This study employed an inductive phenomenological approach to investigate patients' perception of the quality of care given for MDR-TB, level of their satisfaction with the care they received for MDR-TB and the experiences and practices of caregivers for MDR-TB on the functionality of the programmatic management of MDR-TB at referral hospitals in Ethiopia. The data were analysed manually, and that helped to get more control over the data. The majority of the patients were satisfied with the compassionate communication and clinical care they received at hospitals. However, as no doctor was dedicated exclusively for the MDR-TB centre of the hospitals, patients could not get timely medical attention during emergent medical conditions. Patients were dissatisfied with the poor communication and uncaring practice of caregivers found at treatment follow-up centres (TFCs). Patients perceived that socio-economic difficulties are both the cause of MDR-TB and it has also challenged their ability to cope-up with the disease and its treatment. Patients were dissatisfied with the poor quality and inadequate quantity of the socio-economic support they got from the programme. Despite the high MDR-TB and HIV/AIDS co-infection, services for both diseases were not available under one roof. Socio-economic challenges, inadequate socio-economic support, absence of integrated care for MDR-TB and HIV/AIDS, and the uncaring practice of caregivers at treatment follow-up centres are found to negatively affect patients' perceived quality of care and their satisfaction with the care given for MDR-TB. Addressing these challenges is recommended to assist patients' coping ability with MDR-TB and its treatment.

Discovery of small molecule inhibitors of Mycobacterium tuberculosis ClpC1: SAR studies and antimycobacterial evaluation

The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, is a primary reason for treatment failure. Currently, only limited options are available for the management of multi-drug resistant TB, warranting the design of novel anti-TB drugs by exploiting newer targets. One of the caseinolytic protease (Clp) machinery components, an unfoldase known as ClpC1, has emerged as a distinct anti-TB drug target owing to its essential role in the pathogen's survival. The naturally occurring cyclic peptides targeting the Mtb ClpC1, exhibit potent antimycobacterial activity. However, the large, complex, and poor synthetic tractability of these peptides limit their clinical application. Identification of small molecule inhibitors of Mtb ClpC1 will be useful for future drug development. Here, we report the discovery of a bisquinoline chemotype from the screening of a small molecule chemical library against Mtb ClpC1. The hit molecule binds with ClpC1 and exhibits dose-dependent inhibition of its enzymatic activity by direct binding. The in vitro growth of Mtb is inhibited by the hit molecule at a minimum inhibitory concentration of 12.5 µM. Investigation of the structure–activity relationship by chemical synthesis underlines the requirement of the two quinoline rings, 9/10 carbon linker, and the importance of basic ring nitrogen for its inhibitory activity. To our knowledge, this is the first report on the systematic analysis of small molecule inhibitors of Mtb ClpC1.

Adverse drug reactions and associated factors in multidrug-resistant tuberculosis: A retrospective review of patient medical records at Mbarara Regional Referral Hospital, Uganda.

The World Health Organization pragmatic guidelines recommend shorter duration drug regimens with newer, more efficacious agents for treatment of multidrug-resistant tuberculosis. However, adverse drug reactions associated with the use of newer, second-line agents may pose a major barrier to adequate management of multidrug-resistant tuberculosis. We therefore sought to investigate the prevalence and factors associated with adverse drug reactions among patients with multidrug-resistant tuberculosis. We retrospectively reviewed patient medical records at the tuberculosis treatment unit of Mbarara Regional Referral Hospital, between January 2013 and December 2020. Medical records were included in the study, if the patients were aged ⩾18 years, tested sputum positive for multidrug-resistant tuberculosis, with adequate pharmacovigilance data documented. We assessed all documented health-related patient complaints, deranged laboratory values, and clinician suspected adverse drug reactions for scientific/clinical plausibility. Adverse drug reactions were confirmed using published and manufacturer drug references materials. A multidisciplinary clinician team was involved to decide whether to exclude or include a suspected adverse drug reaction. About 6 in 10 (67.4%; 120/178) patients experienced at least one adverse drug reactions during treatment, of which 18.3%, 14.6%, and 11.4% of adverse drug reactions affected the endocrine/metabolic, otic, and musculoskeletal body systems, respectively. Majority of the adverse drug reactions were probable and had a moderate severity. There was an upward trend in adverse drug reaction incidence between 2015 and 2019. Adverse drug reaction occurrence was associated with previous adverse drug reaction history (adjusted odds ratio = 2.85 (1.08, 7.53 at 95% confidence interval)); however, patients who were underweight (adjusted odds ratio = 0.34 (0.16, 0.69 at 95% confidence interval)) and those treated with bedaquiline-based drug regimens (adjusted odds ratio = 0.2 (0.07, 0.59 at 95% confidence interval)) were less likely to experience an adverse drug reaction. Majority of patients with multidrug-resistant tuberculosis experience at least adverse drug reaction during the course of treatment. The newer standard shorter duration drug regimens (9-12 months) may be associated with intolerable adverse drug reactions that hamper effective management of multidrug-resistant tuberculosis. There is need for more studies to assess the clinical adverse drug reaction burden associated with the implementation of shorter duration regimens.

Management of Multidrug-resistant Tuberculosis in a Ukrainian Refugee with HIV/HCV Coinfection: A Case Report

Management of Multidrug-resistant Tuberculosis in a Ukrainian Refugee with HIV/HCV Coinfection: A Case Report

Prevention and management of hearing loss in patients receiving ototoxic medications.

Following the efforts of patient advocates, the World Health Organization published updated guidelines for management of multidrug-resistant tuberculosis in 2018 that advised against the routine use of ototoxic second-line injectable drugs (amikacin, capreomycin and kanamycin). Although hearing loss is no longer considered an unavoidable harm for patients with multidrug-resistant tuberculosis, ototoxic medications continue to be used for several infectious and oncological disorders around the world. These drugs contribute to more than a half a million cases of hearing loss worldwide annually. Currently, there are no international standards for preventing and managing hearing loss associated with ototoxic medications. We present recent data on the prevention and management of hearing loss related to these drugs and highlight the variability in care across settings. More importantly, we aim to provide an evidence-based framework for evaluating, screening and preventing ototoxicity. Finally, we identify avenues for future research so that patients no longer have to choose between hearing loss and a disease cure. There remain significant gaps in our understanding about optimal screening and treatment of ototoxic hearing loss. Here we aim to inspire future international guidelines to address gaps in ototoxicity care and establish research agendas for eliminating ototoxic medications.