Haematological parameter among drug resistant tuberculosis patients in Ibadan.

Background: Haematological abnormalities are common among tuberculosis patients but there is dearth of information on their value as prognostic markers in Multidrug resistant tuberculosis patients. This study examined the association between complete blood count variables and drug resistant tuberculosis. Materials and methods: Nighty (90) consenting adults comprising 30 Drug Resistant Tuberculosis patients (DR-TB), 30 Drug susceptible tuberculosis patients (DS-TB) and 30 healthy participants were recruited in this study. Ethical approval was obtained from Oyo State Ministry of Health Institutional Review Board while patients' demographic data were collected using structured questionnaire. Five milliliters (5mL) of blood samples were collected in EDTA bottle. Haematological parameters were analysed using impedance technique and Mindary-BG5380 5-part automated system. Result: The mean hemoglobin levels were significantly lower in DR-TB patients (11.70 ± 2.73 g/dL) than in DS-TB patients (8.33 ± 9.56 fL), with a mean difference of -3.37 ± 12.29 g/dL. The mean MCH and MCHC levels were also slightly lower in DR-TB patients (26.17 ± 3.44 pg and 30.41 ± 1.92 g/dL, respectively), but the differences were not statistically significant. The WBC count was similar in both groups (8.20 ± 3.80 × 10^9 /L and 8.45 ± 3.63 × 10^9 /L, respectively). Conclusion: The mean hemoglobin levels were significantly lower in DR-TB patients than in DS-TB patients which may be due to the increased inflammation associated with DR-TB. The WBC count was similar in both groups, suggesting that the immune system is responding similarly to the infection in both DR-TB and DS-TB patients. Recommendation: In the meantime, healthcare providers should be aware of these potential differences and use them to inform their diagnosis and treatment of patients with tuberculosis.

Beyond the diagnosis of drug-resistant Tuberculosis in Norway: patients' experiences before, during and after treatment.

BACKGROUND: This study aims to explore the varied experiences of patients with drug-resistant tuberculosis in Norway. The study emphasizes challenges and implications of being diagnosed with drug-resistant tuberculosis, including the impact on psychosocial health during the diagnosis, disease, treatment, isolation and recovery phases. Norway is a low endemic country of tuberculosis. Most patients are immigrants, and some of them have recently arrived in the country. Patients undergoing treatment for drug-resistant tuberculosis endure prolonged and demanding treatment that could affect their psychosocial health. METHODS: This qualitative study conducted 16 in-depth interviews with individuals aged 18 years and above who were diagnosed with drug-resistant tuberculosis. All participants completed the treatment between 2008 and 2020. Fourteen participants were immigrants, and eight of them had resided in Norway for less than four years before diagnosis. Data analysis followed the six-phase reflexive thematic analysis framework, focusing on identifying patterns in participants' experiences, thoughts, expectations and attitudes. RESULTS: The narratives of the participants highlighted the complexities of navigating the diagnosis of drug-resistant tuberculosis, treatment, side effects and life after treatment. Immigrants encountered additional challenges, including language barriers and adapting to new social environments. All participants reported experiencing physical health issues that additionally affected their mental health and social activity. Several participants had a delayed or prolonged diagnosis that complicated their disease trajectory. Participants with suspected or confirmed contagious pulmonary tuberculosis underwent hospital isolation for periods ranging from weeks to six months. The participants reported mental health issues, social isolation and stigma, however few were offered follow-up by a psychologist. Many participants had persistent problems at the time of the interviews. Three main themes emerged from the analysis: Delayed and prolonged diagnosis; Psychosocial impact of isolation during treatment; The life after tuberculosis. CONCLUSION: This study highlights the enduring impact of drug-resistant tuberculosis on patients and the significance of timely diagnosis, psychosocial support and post-treatment follow-up. The participants universally faced serious implications of the disease, including stigma and isolation. Participants who experienced delayed diagnosis, reflected on missed early intervention opportunities. We recommend further research in low endemic countries to evaluate the international and local recommendations on psychosocial support.

Advancements in Artificial Intelligence for the Diagnosis of Multidrug Resistance and Extensively Drug-Resistant Tuberculosis: A Comprehensive Review.

Tuberculosis (TB) remains a significant global health concern, particularly with the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Traditional methods for diagnosing drug resistance in TB are time-consuming and often lack accuracy, leading to delays in appropriate treatment initiation and exacerbating the spread of drug-resistant strains. In recent years, artificial intelligence (AI) techniques have shown promise in revolutionizing TB diagnosis, offering rapid and accurate identification of drug-resistant strains. This comprehensive review explores the latest advancements in AI applications for the diagnosis of MDR-TB and XDR-TB. We discuss the various AI algorithms and methodologies employed, including machine learning, deep learning, and ensemble techniques, and their comparative performances in TB diagnosis. Furthermore, we examine the integration of AI with novel diagnostic modalities such as whole-genome sequencing, molecular assays, and radiological imaging, enhancing the accuracy and efficiency of TB diagnosis. Challenges and limitations surrounding the implementation of AI in TB diagnosis, such as data availability, algorithm interpretability, and regulatory considerations, are also addressed. Finally, we highlight future directions and opportunities for the integration of AI into routine clinical practice for combating drug-resistant TB, ultimately contributing to improved patient outcomes and enhanced global TB control efforts.

Drug-Resistant Tuberculosis Case-Finding Strategies: Scoping Review.

BACKGROUND: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. OBJECTIVE: We therefore assessed the available literature on DR-TB case-finding strategies. METHODS: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp). RESULTS: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. CONCLUSIONS: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.

How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial.

Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.

Prevalence of tuberculosis infection among contacts of drug-resistant tuberculosis patients: A systematic review and meta-analysis.

INTRODUCTION: Contact investigations with drug-susceptible tuberculosis (DS-TB) patients have demonstrated a high prevalence of tuberculosis infection (TBI). However, the prevalence of TBI among individuals in close contact with drug-resistant tuberculosis (DR-TB) patients is poorly understood. This systematic review and meta-analysis aimed to determine the prevalence of TBI among household and non-household contacts of DR-TB patients. METHOD AND ANALYSIS: We searched five databases (Medline, Embase, Scopus, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL)) from inception to 2 June 2023. All studies that reported the prevalence of TBI among DR-TB contacts were included in the study. A random-effects meta-analysis was conducted to estimate the pooled prevalence of TBI with a 95% confidence interval (CI). Sub-group analyses were conducted using study characteristics as covariates. RESULTS: Thirty studies involving 7659 study participants from 19 countries were included. The pooled prevalence of TBI among DR-TB contacts was 36.52% (95% CI: 30.27-42.77). The sub-group analysis showed considerable heterogeneity in the estimates, with the highest prevalence reported in Southeast Asia (80.74%; 95% CI: 74.09-87.39), household contacts (38.60%; 95% CI: 30.07-47.14), lower-middle-income countries (LMICs) (54.72; 95% CI: 35.90, 73.55), children (43.27%; 95% CI: 25.50, 61.04), and studies conducted between 2004 and 2012 (45.10; 95% CI: 32.44, 57.76). CONCLUSION: The prevalence of TBI among DR-TB contacts was high, with substantial regional variations. Further research is needed to determine the drug susceptibility status of TBI in DR-TB contacts. PROTOCOL REGISTRATION: The protocol is registered in PROSPERO (CRD42023390339).

Impact of Xpert MTB/RIF implementation in tuberculosis case detection and control in Brazil: a nationwide intervention time-series analysis (2011-2022).

Background: Since 2014, Brazil has gradually implemented the Xpert MTB/RIF (Xpert) test to enhance early tuberculosis (TB) and drug-resistant (DR-TB) detection and control, yet its nationwide impact remains underexplored. Our study conducts an intervention time-series analysis (ITSA) to evaluate how the Xpert's implementation has improved TB and DR-TB detection nationwide. Methods: 1,061,776 cases from Brazil's National TB Registry (2011-2022) were reviewed and ITSA (2011-2019) was used to gauge the impact of the Xpert's adoption on TB and DR-TB notification. Granger Causality and dynamic regression modelling determined if incorporating Xpert testing as an external regressor enhanced forecasting accuracy for Brazil's future TB trends. Findings: Xpert implementation resulted in a 9.7% increase in TB notification and substantial improvements in DR-TB (63.6%) and drug-susceptible TB (92.1%) detection compared to expected notifications if it had not been implemented. Xpert testing counts also presented a time-dependent relationship with DR-TB detection post-implementation, and improved predictions in forecasting models, which depicted a potential increase in TB and DR-TB detection in the next six years. Interpretation: This study underscores the critical role of Xpert's adoption in boosting TB and DR-TB detection in Brazil, reinforcing the case for its widespread use in disease control. Improvements in prediction accuracy resulting from integrating Xpert data are crucial for allocating resources and reducing the incidence of TB. By acknowledging Xpert's role in both disease control and improving predictions, we advocate for its expanded use and further research into advanced molecular diagnostics for effective TB and DR-TB control. Funding: FIOCRUZ.

Assessing the quality of life in patients with drug-resistant tuberculosis: a cross-sectional study.

BACKGROUND: This study investigated the current status of the quality of life (QOL) of drug-resistant tuberculosis (DR-TB) patients in Nanjing, China, and analyzed the influencing factors. METHODS: The survey was conducted among patients with DR-TB who were hospitalized in the tuberculosis department of the Second Hospital of Nanjing (Nanjing Public Health Medical Center) from July 2022 to May 2023. The Chinese version of the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire was used to investigate the QOL levels of patients with DR-TB, and a multiple linear regression model was used to analyze the QOL influencing factors. RESULTS: A total of 135 patients participated in the study; 69.6% were male, the average age was 46.30 ± 17.98 years, 13.33% had an education level of elementary school or below, and 75.56% were married. The QOL scores were 51.35 ± 17.24, 47.04 ± 20.28, 43.89 ± 17.96, and 35.00 ± 11.57 in the physiological, psychological, social, and environmental domains, respectively. The differences between the four domain scores and the Chinese normative results were statistically significant (P < 0.05). The results of multiple linear regression analysis showed that the factors related to the physiological domain included residence, family per-capita monthly income, payment method, adverse drug reactions (ADRs), and comorbidities; psychological domain correlates included educational level, family per-capita monthly income, course of the disease, and caregivers; social domain correlates included age and comorbidities; and factors related to the environmental domain included age, education level, and comorbidities. CONCLUSIONS: In Nanjing, China, patients with younger age, higher education level, living in urban areas, high family per-capita monthly income, no adverse drug reactions, no comorbidities, and having caregivers have better quality of life. Future interventions to improve the quality of life of patients with drug-resistant tuberculosis could be tailored to a specific factor.

Clinical Drug-Resistant Cutaneous Tuberculosis Presenting as Lupus Vulgaris Ulcerative Type in an Indian Female With Poncet's Disease: A First-of-Its-Type Report.

Tuberculosis of the skin is rare and a difficult diagnosis. Moreover, recurrent episodes of mycobacterial infection in the skin with Poncet's disease are rarely reported in females. Herein, the first of its type case of clinical drug-resistant tuberculosis of the skin in an Indian female is presented. She had a history of cutaneous tuberculosis five times in the past. At the sixth time, she came with complaints of an ulcerative lesion over her right forearm and cubital fossa with left knee swelling. The paucibacillary nature of the infection made the diagnosis exceedingly challenging. However, a detailed clinical examination with a suspicion of drug resistance resulted in management with significant clinical improvement.

Impact of line probe assay-based molecular testing on individualized treatment in patients with rifampicin-resistant tuberculosis: data from the prospective INNOVA4TB cohort study in Ukraine.

BACKGROUND: Ukraine remains a high World Health Organization priority country for drug-resistant tuberculosis (TB). Rifampicin-resistant TB (RR-TB) has a more protracted, more complicated, and more expensive treatment. In 2021, Ukraine reported 4025 RR-TB cases - 5.4 times more (751) than all 30 European Union/ European Economic Area countries together. OBJECTIVES: The objective of the study was to determine the diagnostic accuracy of line probe assay (LPA), AID Autoimmun Diagnostika GmbH, for detecting resistance to anti-TB drugs and its clinical application for selecting treatment regimens. DESIGN: A prospective observational cohort study. METHODS: From May 2019 to June 2020, we consecutively enrolled patients with active TB hospitalized at the Regional Phthisiopulmonology Center (Vinnytsia, Ukraine), aged between 18 and 82 years. The LPA was performed in the Genetic Research Laboratory at National Pirogov Memorial Medical University, Vinnytsia, Ukraine. RESULTS: A total of 84 clinical specimens and 97 culture isolates from 126 TB patients were tested during the study. Accuracy (95% confidence interval) of LPA for clinical samples in comparison with phenotypic drug susceptibility test (DST) was 80.1 (68.5-89.0) for isoniazid (H), 74.7 (62.4-84.6) for rifampicin (R), 74.4 (62.5-84.1) for ethambutol, 71.4 (41.9-91.6) for streptomycin, 84.6 (62.4-96.5) for prothionamide/ethionamide, and 84.6 (73.6-92.3) for levofloxacin (Lfx), respectively. We found a significantly higher sensitivity of LPA for H, R, and Lfx for the culture isolates compared to clinical specimens (p < 0.05). LPA detected different mutations in 6 out of 17 (35.5%) patients susceptible to R by Xpert. A shorter treatment regimen with an injectable agent demonstrated a low suitability rate of 5% (8/156) in a cohort of RR-TB patients from Ukraine. CONCLUSION: Initial LPA testing accurately identifies resistance to anti-TB drugs and facilitates the selection of an appropriate treatment regimen, minimizing exposure to empirical therapy.

Study about the impact of rapid resistance detection on the treatment of patients with tuberculosis in Ukraine written by healthcare and biomedical professionals to better understand how we can improve the results of treatment and to prevent spreading of resistant bacteriaWhy was the study done? Ukraine has over 4000 patients with tuberculosis (TB) resistant to at least one drug (rifampicin) - five times that of all 30 European Union/European Economic Area countries combined. Unfortunately, only about 60% of such patients have been successfully treated in 2019. At that time, the majority of people suffering from tuberculosis in Ukraine, after checking resistance to rifampicin, initially received standard combinations of the first-line or second-line anti-TB medicines before the result of traditionally used tests (usually few weeks later) became available to individualize the treatment. Alternatively, the sputum could be transported to some overloaded reference laboratories located hundreds of km away from the treatment places.What did the researchers do? The INNOVA4TB team implemented rapid diagnostics of drug resistance in routine practice, guiding key antibiotics use in TB patients. A total of 181 samples from 126 individuals were tested during 2019-2020.What did the researchers find? This new diagnostic technology accurately detected resistance to 9 anti-TB drugs in sputum samples. It could be helpful to select appropriate TB treatment regimens, reducing time for decision from 1 month up to 2 days. Recommended at the study time 9-month shorter standardized treatment regimen with injectable agent was suitable only for 5% of patients for whom it was indicated in Vinnytsia region of Ukraine.What do the findings mean? The study has demonstrated successful implementation of the new molecular diagnostic technology from scratch in a country with restricted resources and limited TB laboratory capacity. This test can facilitate optimal distribution of available wards among patients with different profiles of resistance and correct choice between treatment options.

Advanced integrative molecular platform for high-throughput screening of drug-resistant tuberculosis.

A real time-polymerase chain reaction-based test in lyophilized form, was developed to simultaneously identify Mycobacterium tuberculosis complex (MTC) by targeting IS6110, rrs as dual markers, as well as mutations causing rifampicin and isoniazid resistance. The test was evaluated for pulmonary and non-pulmonary specimens from sample isolation to PCR analysis. The test demonstrated limit of detection of 25 CFU/mL for MTB, 200 CFU/mL for rpoB and inhA/katG targets with >95 % CI. The specificity for MTC was supported by a comprehensive clinical validation (n = 100). This load-and-go molecular platform, with features of high throughput, long shelf-life, room temperature storage provides simultaneous detection of MTC and its drug-resistant mutations in minimal time. The test named "PathoDetect TM MTB-RIF and INH resistance detection kit" has been approved by Central Drugs Standard Control Organisation, Indian Council of Medical Research and would have implications for tuberculosis elimination programs.

Validation and application of an online extraction and liquid chromatography tandem mass spectrometry assay for the analysis of delamanid and its DM-6705 metabolite in human breast milk.

We developed and validated a bioanalytical assay to quantify delamanid and its key metabolite (DM-6705) in breast milk and aimed to quantify the secretion of these compounds in breast milk. Due to the hydrophobic nature of the analytes, special care was taken during sample preparation to prevent the formation of fatty deposits during protein precipitation. This was followed by online solid phase extraction and liquid chromatography with tandem mass spectrometry for detection. A Restek Viva BiPh C18 column (1.0 mm×50 mm, 5 µm) was used for extraction while chromatographic separation was performed using a Waters Xterra MS C18 (2.1 mm×100 mm, 5 µm) analytical column with an isocratic mobile phase consisting of acetonitrile, methanol, and 5 mM ammonium carbonate. The mass spectrometric detection of the analytes was performed using an AB Sciex 3200 mass spectrometer employing electrospray ionisation in the positive mode with multiple reaction motoring of the relevant precursor and product ions. Delamanid-d4 and OPC-14714 were used as internal standards. A quadratic (weighted 1/x concentration) regression was used to fit calibration curves for delamanid and DM-6705 over the concentration range of 10.0 - 1000 ng/mL. The intra- and inter-day validation accuracies of the quality control samples were between 92.1% and 98.3% for delamanid, and 97.0% and 102.8% for DM-6705. The percentage coefficient of variation (precision) was less than 7.8%. To our knowledge, this is the first report describing the concentrations of delamanid and DM-6705 in the breast milk of patients treated for rifampicin-resistant tuberculosis.

Discordant results between Xpert MTB/RIF assay and Bactec MGIT 960 culture system regarding the detection of rifampin-resistant Mycobacterium tuberculosis isolates in Wenzhou, China.

This study aimed to assess the possible causes of discordant results between Xpert MTB/RIF (Xpert) and Bactec MGIT 960 Culture System (MGIT960) regarding rifampicin (RIF) susceptibility in Mycobacterium tuberculosis. Patients with previous RIF-resistant tuberculosis who were admitted to Wenzhou Central Hospital from January 2020 to December 2022 were enrolled. The isolates obtained from these patients were subjected to RIF susceptibility tests using Xpert and MGIT960, and the minimum inhibitory concentration (MIC) of RIF was determined by the MYCOTB MIC plate test. Additionally, molecular docking and molecular dynamics (MD) simulations were performed to evaluate the binding efficacy of rpoB and RIF based on rpoB mutations detected in the isolates with discordant RIF susceptibility results. A total of 28 isolates with discordant RIF susceptibility test results were detected, 15 of them were RIF susceptible with MICs ≤ 0.5 µg/mL. Twelve out of 15 isolates contained borderline RIF resistance-associated mutations [L430P (n = 6), H445N (n = 6)], 1 isolate had D435Y and Q429H double mutation, and the remaining 2 isolates had a silent (Q432Q) mutation. Compared with the affinity of RIF toward the wild type (WT) (-45.83 kcal/mol) by MD, its affinity toward L452P (-55.52 kcal/mol), D435Y (-47.39 kcal/mol), L430P (approximately -69.72 kcal/mol), H445N (-49.53 kcal/mol), and Q429H (-55.67 kcal/mol) increased. Borderline RIF resistance-associated mutations were the main cause for the discordant RIF susceptibility results between Xpert and MGIT960, and the mechanisms of the resistance need further investigated.IMPORTANCEThis study is aimed at assessing discordant results between Xpert MTB/RIF (Xpert) assay and Bactec MGIT 960 Culture System (MGIT960) regarding the detection of rifampicin (RIF)-resistant Mycobacterium tuberculosis isolates in Wenzhou, China. The discordant results of RIF between these two assays were mainly caused by borderline RIF resistance-associated mutations, subsequently by silent mutations of rpoB. Borderline RIF resistance- associated mutations detected in our study were demonstrated to not be affected by the affinity of rpoB and RIF by molecular dynamics, and the mechanism of resistance was needed to be clarified. For the discordant results of RIF by Xpert and MGIT960 that occurred, rpoB DNA sequencing was recommended to investigate its association with resistance to RIF.

Cycles of antibiotic use and emergent antimicrobial resistance in the South African tuberculosis programme (1950-2021): A scoping review and critical reflections on stewardship.

The emergent threat of antimicrobial resistance (AMR) has resulted in debates around the use and preservation of effective antimicrobials. Concerns around AMR reflect a history of increasing dependence on antibiotics to address disease epidemics rooted in profound structural and systemic challenges. In the context of global health, this process, often referred to as pharmaceuticalisation, has commonly occurred within disease programmes, of which lessons are vital for adding nuance to conversations around antimicrobial stewardship. Tuberculosis (TB) is a notable example. A disease which accounts for one-third of AMR globally and remains the leading cause of death from a single infectious agent in many low - and middle-income countries, including South Africa. In this scoping review, we chart TB science in South Africa over 70 years of programming. We reviewed published manuscripts about the programme and critically reflected on the implications of our findings for stewardship. We identified cycles of programmatic responses to new drug availability and the emergence of drug resistance, which intersected with cycles of pharmaceuticalisation. These cycles reflect the political, economic, and social factors influencing programmatic decision-making. Our analysis offers a starting point for research exploring these cycles and drawing out implications for stewardship across the TB and AMR communities.

Drug-Resistant Bone, Joint and Spine Tuberculosis: Evolution of Diagnosis and Treatment.

Background: Drug resistant (DR) osteoarticular TB (OATB) is a challenge in view of it being deep seated lesion and paucibacillary disease. Case definition, investigation protocol, treatment of proven DR and those cases where DR could not be demonstrated lacks clarity and evidence. Hence, a series of studies were conducted to develop an algorithm to investigate and treat therapeutically refractory disease (TRD) or presumptive drug resistance (PDR) cases of OATB. Patients and methods: 6 studies were conducted. Study one and two evaluated criteria to label TRD/PDR. Three subsequent studies were conducted where TDR/PDR or fresh cases of OATB cases were investigated by AFB smear, Bactec/liquid culture, histology and genotypic DST by CBNAAT & LPA. Sixth study was a retrospective evaluation of all DR cases treated for proven or clinical drug resistance (CDR). Results: Patient of bone/spine TB on ATT for 5 months or more show poor clinico-radiological treatment response as worsening of lesion, increased spinal deformity, persistent discharging sinus/ulcer, appearance of fresh lesion, recurrence of previous lesion, wound dehiscence of post-operative surgical scar cab labelled as PDR cases. These cases on histology ascertained TB and were proven DR on genotypic and phenotypic DST and are treated successfully. The patients of histologically ascertained TB and no/indeterminate phenotypic and genotypic DST were successfully treated as clinical drug resistance on MDR protocol. Conclusions: We described an algorithm. We must suspect PDR(TRD) based on criteria described. The tissue must be procured and submitted for AFB smear, histology and phenotypic and genotypic DST for diagnosis of TB. Genotypic and phenotypic DST will be useful to prove (90% instances) type of drug resistance. Remaining on strong clinical suspicion of DR and yet inconclusive on phenotypic/genotypic DST (<10%), may be treated as CDR as MDR. The adverse drug reactions and hepatic side-effects should be monitored diligently and these cases to be treated till healed status is demonstrated.

Role of therapeutic drug monitoring in the treatment of multi-drug resistant tuberculosis.

Tuberculosis (TB) is a leading cause of mortality worldwide, and resistance to anti-tuberculosis drugs is a challenge to effective treatment. Multi-drug resistant TB (MDR-TB) can be difficult to treat, requiring long durations of therapy and the use of second line drugs, increasing a patient's risk for toxicities and treatment failure. Given the challenges treating MDR-TB, clinicians can improve the likelihood of successful outcomes by utilizing therapeutic drug monitoring (TDM). TDM is a clinical technique that utilizes measured drug concentrations from the patient to adjust therapy, increasing likelihood of therapeutic drug concentrations while minimizing the risk of toxic drug concentrations. This review paper provides an overview of the TDM process, pharmacokinetic parameters for MDR-TB drugs, and recommendations for dose adjustments following TDM.

Pathological findings in respiratory organs and blood circulation in patients with isolated DRTB and DRTB/HIV/AIDS co-infection (according to autopsy data).

Tuberculosis remains a major global health concern, especially in the context of emerging drug-resistant strains and the high prevalence of HIV/AIDS. Understanding the pathomorphologic changes associated with DRTB and its coinfection with HIV/AIDS is crucial for designing effective diagnostic, preventive, and therapeutic interventions. The objectives of this study were to assess the pathomorphologic changes, investigate lung function and blood circulation, and explore risk factors and clinical predictors associated with cor pulmonale in patients with DRTB and DRTB/HIV/AIDS co-infections. The study included 72 patients, with 28 having isolated DRTB and 44 having DRTB/HIV/AIDS co-infections. Microscopic examination of lung tissue samples from isolated DRTB patients revealed fibrous and productive changes with inflammatory infiltration. Histological examination of the myocardium in these patients showed hypertrophy and diffuse cardiosclerosis. Patients with DRTB/HIV/AIDS co-infections exhibited extensive destructive changes in lung tissue, along with dystrophy of cardiomyocytes and focal lymphohistiocytic infiltration in the myocardium. The frequency of cor pulmonale formation was significantly higher in the co-infection group (22.7%) compared to the isolated DRTB group (10.7%). Histological samples suggested that co-infection with HIV/AIDS exacerbates myocardial damage caused by DRTB. This research demonstrates the distinct pathomorphologic changes observed in the lung tissue and myocardium of patients with isolated DRTB and DRTB/HIV/AIDS co-infections. The study findings support the association between co-infection and increased risk of cor pulmonale development. Understanding the mechanisms underlying these differences will help identify potential therapeutic targets to mitigate myocardial damage in patients with DRTB and its co-infection.

A pregnant woman with pre-XDR PTB giving birth to a healthy newborn: A case report.

We reported a late-pregnancy woman with pre-XDR PTB who had not received regular anti-tuberculosis treatment prior to delivery. Despite this, she successfully delivered a premature baby who exhibited normal growth and development, and subsequently completed her anti-tuberculosis treatment. This report suggests that delayed treatment for pre-XDR TB during late pregnancy does not necessarily increase the risk of treatment failure for the mother or the risk of neonatal tuberculosis.

The clinical profile and outcomes of drug resistant tuberculosis in Central Province of Zambia.

BACKGROUND: The emergence of Drug Resistant Tuberculosis (DR-TB) is one of the main public health and economic problems facing the world today. DR-TB affects mostly those in economically productive years and prevents them from being part of the workforce needed for economic growth. The aim of this study was to determine the Clinical Profile and Outcomes of DR-TB in Central Province of Zambia. METHODS: This was a retrospective cross sectional study that involved a review of records of patients with confirmed DR-TB who were managed at Kabwe Central Hospital's Multi-Drug Resistant TB (MDR-TB) Ward from the year 2017 to 2021. 183 patients were managed during this period and all were recruited in the study. Data was collected from DR-TB registers and patient files and then entered in SPSS version 22 where all statistical analyses were performed. RESULTS: The study revealed that the prevalence of DR-TB among registered TB patients in Central Province was 1.4%. Majority of those affected were adults between the ages of 26 and 45 years (63.9%). The study also found that more than half of the patients were from Kabwe District (60.7%). Other districts with significant number of cases included Kapiri Mposhi 19 (10.4%), Chibombo 12 (6.6%), Chisamba 10 (5.5%), Mumbwa 7 (3.8%) and Mkushi 7 (3.8%). Furthermore, the analysis established that most of the patients had RR-TB (89.6%). 9.3% had MDR-TB, 0.5% had IR-TB and 0.5% had XDR-TB. RR-TB was present in 93.8% of new cases and 88.9% of relapse cases. MDR-TB was present in 6.2% of new cases and 10% of relapse cases. With regard to outcomes of DR-TB, the investigation revealed that 16.9% of the patients had been declared cured, 45.9% had completed treatment, 6% were lost to follow up and 21.3% had died. Risk factors for mortality on multivariate analysis included age 36-45 years (adjusted odds ratio [aOR] 0.253, 95% CI [0.70-0.908] p = 0.035) and male gender (aOR 0.261, 95% CI [0.107-0.638] p = 0.003). CONCLUSION: The research has shown beyond doubt that the burden of DR-TB in Central Province is high. The study recommends putting measures in place that will help improve surveillance, early detection, early initiation of treatment and proper follow up of patients.