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Predicting the side effects caused by drug combinations may facilitate the prescription of multiple medications in a clinical setting. So far, several prediction models of multidrug side effects based on knowledge graphs have been developed, showing good performance under constrained test conditions. However, these models usually focus on relationships between neighboring nodes of constituent drugs rather than whole nodes, and do not fully exploit the information about the occurrence of single drug side effects. The lack of learning the information on such relationships and single drug data may hinder improvement of performance. Moreover, compared with all possible drug combinations, the highly limited range of drug combinations used for model training prevents achieving high generalizability. To handle these problems, we propose a unified embedding-based prediction model using knowledge graph constructed with data of drug–protein and protein–protein interactions. Herein, single or multiple drugs or proteins are mapped into the same embedding space, allowing us to (1) jointly utilize side effect occurrence data associated with single drugs and multidrug combinations to train prediction models and (2) quantify connectivity strengths between drugs and other entities such as proteins. Due to these characteristics, it becomes also possible to utilize the quantified relationships between distant nodes, as well as neighboring nodes, of all possible multidrug combinations to regularize the models. Compared with existing methods, our model showed improved performance, especially in predicting the side effects of new combinations containing novel drugs that have no clinical information on polypharmacy effects. Furthermore, our unified embedding vectors have been shown to provide interpretability, albeit to a limited extent, for proteins highly associated with multidrug side effect.

Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.

Background Multidrug-resistant tuberculosis (MDR-TB) in HIV infected individuals is a serious threat to global efforts to combat tuberculosis. Inconsistent findings on the association between HIV infection and MDR-TB were present in many studies. We aimed to review existing data on the relationship between HIV infection and MDR-TB systematically to assess the contribution of HIV on MDR-TB worldwide. We also investigated the patterns of MDR-TB by age, country-wise income, study designs, and global regions. Methods We utilized PubMed, Google Scholar, and ScienceDirect databases to select eligible studies for meta-analysis that were published between January 1, 2010, and July 30, 2020. The random-effects model was used to obtain the pooled odds ratio of the crude association between HIV and MDR-TB with a 95% confidence interval. We investigated the potential publication-bias by checking funnel plot asymmetry and using the Egger’s test. Moreover, we assessed the heterogeneity using the I 2 statistic. Sensitivity analysis was performed based on sample size and adjustment factors. The protocol was registered with PROSPERO-CRD42019132752. Results We identified 1603 studies through a database search, and after subsequent eliminations we selected 54 studies including 430,534 TB patients. The pooled odds of MDR-TB was 1.42 times higher in HIV-positive patients than HIV-negative patients (OR=1.42,CI=1.17–1.71, I 2 =75.8%). Subgroup analysis revealed that the estimated pooled odds for South-East Asian countries was 1.86, which is the highest in WHO regions (OR=1.86,CI=1.30–2.67, I 2 =0.00%), followed by Europe and Africa. The effect estimate was found to be higher for primary MDR-TB (OR=2.76,CI=1.70–4.46, I 2 =0.00%). There was also a trend towards increased odds of MDR-TB for HIV patients older than 40 years (OR=1.56,CI=1.17–2.06). The association was found to be significant in high-burden TB countries (OR=1.75, CI=1.39–2.19) and in high-income countries (OR=1.55, CI=1.06–2.27). Conclusion Such findings indicate that HIV infection raises the risk of MDR-TB, and after contrasting it with the results of the earlier pooled study, it appeared to be an upward risk trend. Moreover, we found that the risk is the highest in the South-East Asian region. A balanced allocation of resources is needed to halt both primary and secondary MDR-TB, particularly in HIV infected people with 40 years of age and older.

Limited treatment options, long duration of treatment and associated toxicity adversely impact the physical and mental well-being of multidrug-resistant tuberculosis (MDR-TB) patients. Despite research advances in the microbiological and clinical aspects of MDR-TB, research on the psychosocial context of MDR-TB is limited and less understood. We searched the databases of PubMed, MEDLINE, Embase and Google Scholar to retrieve all published articles. The final manuscripts included in the review were those with a primary focus on psychosocial issues of MDR-TB patients. These were assessed and the information was thematically extracted on the study objective, methodology used, key findings, and their implications. Intervention studies were evaluated using components of the methodological and quality rating scale. Due to the limited number of studies and the multiple methodologies employed in the observational studies, we summarized these studies using a narrative approach, rather than conducting a formal meta-analysis. We used 'thematic synthesis' method for extracting qualitative evidences and systematically organised to broader descriptive themes. A total of 282 published articles were retrieved, of which 15 articles were chosen for full text review based on the inclusion criteria. Six were qualitative studies; one was a mixed methods study; and eight were quantitative studies. The included studies were divided into the following issues affecting MDR-TB patients: a) psychological issues b) social issues and economic issues c) psychosocial interventions. It was found that all studies have documented range of psychosocial and economic challenges experienced by MDR-TB patients. Depression, stigma, discrimination, side effects of the drugs causing psychological distress, and the financial constraints due to MDR-TB were some of the common issues reported in the studies. There were few intervention studies which addressed these psychosocial issues most of which were small pilot studies. There is dearth of large scale randomized psychosocial intervention studies that can be scaled up to strengthen management of MDR-TB patients which is crucial for the TB control programme. This review has captured the psychosocial and economic issues challenging MDR patients. However there is urgent need for feasible, innovative psychosocial and economic intervention studies that help to equip MDR-TB patients cope with their illness, improve treatment adherence, treatment outcomes and the overall quality of life of MDR-TB patients.

Multidrug-resistant Tuberculosis (MDR TB) is emerging public health concern globally. Lost to follow-up (LTFU) is one of the key challenge in MDRTB treatment. In 2013, 18% of MDR TB patients were reported LTFU in India. A qualitative study was conducted to obtain better understanding of both patient and provider related factors for LTFU among MDR TB treatment. Qualitative semi-structured personal interviews were conducted with 20 MDRTB patients reported as LTFU and 10 treatment providers in seven districts linked to Nagpur Drug resistant TB Centre (DRTBC) during August 2012-February 2013. Interviews were transcribed and inductive content analysis was performed to derive emergent themes. We found multiple factors influencing MDR TB treatment adherence. Barriers to treatment adherence included drug side effects, a perceived lack of provider support, patient financial constraints, conflicts with the timing of treatment services, alcoholism and social stigma. Patient adherence to treatment is multi-factorial and involves individual patient factors, provider factors, and community factors. Addressing issue of LTFU during MDRTB treatment requires enhanced efforts towards resolving medical problems like adverse drug effects, developing short duration treatment regimens, reducing pill burden, motivational counselling, flexible timings for DOT services, social, family support for patients & improving awareness about disease.

Background. Clofazimine (Cfz) has shown activity against Mycobacterium tuberculosis, including multidrug-resistant (MDR) strains in vitro and in animal studies. Here we evaluate the clinical efficacy and tolerability of using Cfz to treat MDR tuberculosis in China. Methods. We enrolled 105 patients who had sputum culture-positive MDR tuberculosis in 6 major tuberculosis specialty hospitals in China. Patients were randomly assigned to either the Cfz therapy group (n = 53) or control group (n = 52). Patients in the 2 groups were given 21 months of individual-based chemotherapy regimens based on medication history and drug susceptibility test results. The Cfz therapy group regimens incorporated 100 mg of Cfz once daily for 21 months. Results. Three patients in each group discontinued therapy because of side effects or other reasons. Sputum culture conversion to negative was earlier in patients who received Cfz compared with controls (P = .042 by log-rank test). Chest computed tomography showed cavitary changes in 46 patients in the Cfz therapy group and 45 in the control group. Cavity closure was earlier in patient who received Cfz compared with controls (P = .047 by log-rank test). The treatment success rate in the Cfz group was 73.6%, higher than that in control group (53.8%; P = .035). Side effects in skin only occurred in the Cfz group. The rates of skin discoloration and ichthyosis were 94.3% and 47.2%, respectively. Conclusions. Using Cfz to treat MDR tuberculosis promotes cavity closure, accelerates sputum culture conversion, and improves treatment success rates.

Hypothyroidism is one of the adverse drug reactions that associated with Multidrug Resistant Tuberculosis (MDR-TB) medications. Extremely variable magnitude of hypothyroidism in MDR-TB patients has been reported from different parts of the world. However, there is no evidence that tried to estimate the pooled prevalence of hypothyroidism to confirm the rareness of hypothyroidism in MDR-TB patients on treatment. Therefore, we did a systematic review and meta-analysis to estimate the prevalence of hypothyroidism in MDR-TB patients on treatment, and to summarize the demographic and clinical characteristics of the patients. We conducted a systematic review and meta-analysis on studies reported around the world on the prevalence of hypothyroidism in MDR-TB patients on treatment. We searched electronic databases: PubMed/Medline, EMBASE, CINAHL, Science Direct, Academic Search Complete and Google scholar for English language articles without limiting publication year. We also reviewed the bibliographies of relevant studies and conducted an electronic search for relevant conference abstracts. Eligible studies were cross-sectional and cohort studies that included at least five participants. We used a random-effects model to estimate the pooled prevalence of hypothyroidism. The registration number of this review study protocol is CRD42018109237. We included 30 studies and pooled data on a total of 6,241 MDR-TB patients. The crude prevalence of hypothyroidism was extremely heterogeneous. The pooled prevalence of hypothyroidism in MDR-TB patients on treatment was 17.0% (95% CI: 13.0-20.0). Ethionamide and para-aminosalicylic acid (PAS) were the most frequently reported drugs that associated with the occurrence of hypothyroidism. This review revealed that hypothyroidism is not a rare adverse drug reaction in MDR-TB patients on treatment. Ethionamide and PAS were the most frequently reported drugs that associated with the occurrence of hypothyroidism. Screening of hypothyroidism in MDR-TB patients on treatment is important while targeting patients on Ethionamide and PAS based treatment regimen.

Management of multidrug-resistant tuberculosis (MDR-TB) is a significant challenge to the global healthcare system due to the complexity and long duration of the MDR-TB treatment. This study analyzed the safety of patients on longer injectable-based MDR-TB treatment regimens using active pharmacovigilance data. We conducted an observational, prospective study based on active pharmacovigilance within the national TB program. A total of 659 MDR-TB patients were enrolled and followed up at 9 TB- hospitals in 9 provinces of all 3 regions in Vietnam between 2014 and 2016. Patients received a treatment regimen (standardized or individualized) based on their drug susceptibility test result and their treatment history. Baseline and follow-up information was collected at the start and during treatment. Adverse events (AE) were defined and classified as serious adverse events (SAEs) or otherwise. Multivariate Cox regression following the Iterative Bayesian Model Averaging algorithm was performed to identify factors associated with AE occurrence. Out of 659 patients assessed, 71.3% experienced at least one AE, and 17.5% suffered at least one SAE. The most common AEs were gastrointestinal disorders (38.5%), arthralgia (34.7%), and psychiatric disorders (30.0%). The proportion of patients with nephrotoxicity and hearing loss or vestibular disorders were 7.4% and 15.2%, respectively. 13.1% of patients required modifications or interruption of one or more drugs. In 77.7% of patients, treatment was completed successfully, while 9.3% lost to follow-up, in 3.0% treatment failed, and 7.4% died. Some significant risk factors for nephrotoxicity included diabetes mellitus (HR = 8.46 [1.91-37.42]), renal dysfunction (HR = 8.46 [1.91-37.42]), alcoholism (HR = 13.28 [5.04-34.99]), and a higher average daily dose of injectable drugs (HR = 1.28 [1.14-1.43]). While a majority of patients on the longer injectable-based regimens experienced non-serious AEs during MDR-TB treatment, one in six patients experienced at least an SAE. Active TB drug-safety monitoring is useful to understand the safety of MDR-TB treatment and explore the risk factors for toxicity. All-oral, shorter MDR-TB regimens might be able to reduce the inconvenience, discomfort, and toxicity of such regimens and increase adherence and likelihood of successful completion.

Approximately 30,000 children (<15 years) develop multidrug-resistant (MDR) tuberculosis (TB) each year. MDR-TB severely impacts the lives of children and their families, yet data exploring their experiences are limited. We describe the experiences of children routinely treated for MDR-TB and their caregivers throughout their MDR-TB journeys in Cape Town, South Africa. We conducted a series of three in-depth qualitative interviews (48 interviews in total) with 17 children (<15 years) and/or their caregivers between April 2021 and September 2021. We selected children who had been routinely treated for MDR-TB between 2018 and 2021. We applied a deductive, thematic analysis to case summaries with illustrative examples from interviews. Children had negative experiences throughout their MDR-TB journey, before their diagnosis, during the diagnostic process, through treatment, and beyond treatment completion. Children and their caregivers experienced delays in acquiring accurate and timely MDR-TB diagnosis; stating lack of symptom recognition and repeated referrals between health facilities. Once on treatment, caregivers experienced challenges administering MDR-TB medication as children resisted taking their medications due to poor palatability, tolerability, and negative side effects. Some caregivers reported that, beyond treatment, children experienced extended physical challenges such as shortness of breath. Additionally, MDR-TB diagnosis and treatment negatively affected family life, as caregivers adjusted household spending toward foods that facilitated ingestion and mitigated side effects. Caregivers also juggled between attending to their children's MDR-TB care and other household priorities. There are multifactorial challenges experienced by children and their caregivers throughout their MDR-TB journey. Research is needed to develop holistic interventions for child-caregiver-centred psychosocial support to mitigate the negative impact of MDR-TB on children and their caregivers through prevention, earlier diagnosis, and simpler, child-friendly regimens. [1112,3].

Multi-drug-resistant tuberculosis (MDR-TB) is one of the biggest challenges worldwide to end tuberculosis. It is vital to understand the challenges and opportunities of patients during MDR-TB treatment to enhance prevention and control efforts. The gap in research on the challenges and opportunities of patients during the screening, diagnosis, referral, and follow-up of MDR-TB prompted this study. The purpose of the study was to assess the challenges and opportunities for patients with MDR-TB during the diagnosis and treatment of MDR-TB in the Oromia region of Ethiopia. A qualitative approach was applied. The data were collected from 30 MDR-TB patients from 1 to 30 April 2022 using semi-structured interviews after written informed consent was signed by each participant to understand the challenges and opportunities of MDR-TB treatment. Data was analysed by thematic analysis using ATLAS.ti software. This article identifies challenges that include delays in diagnosis and treatment initiation due to inadequate diagnostic services, physical inaccessibility, and financial problems faced by patients to pay for transport, food, diagnosis, and accommodation. Other challenges included lack of psychosocial support, shortage of healthcare providers, poor communication, drug side effects, and interruption of food and housing support. In addition, participants mentioned opportunities, which include the availability of free diagnosis, treatment, and admission; availability of transport; food and housing allowance; and use of an ambulance for referral. This study filled a research gap in Ethiopia by identifying challenges and opportunities during the MDR-TB treatment program. The MDR-TB treatment program should focus on improving inadequate screening and resources, shortage of healthcare providers, delays in the referral process, and non-compliance of patients.