bedaquiline and Drug-Related-Side-Effects-and-Adverse-Reactions

Tuberculosis is still one of the top causes of infection-related death globally. Drug-resistant tuberculosis has a high mortality rate and is still a serious public health concern around the world. The appearance of multidrug-resistant and extensively drug-resistant strains of tuberculosis has increased the need for new therapeutic options against these strains. Most of the drugs used to treat them have been poorly tested and have serious negative effects. Patients with drug-resistant tuberculosis have been fighting for access to experimental medications, particularly bedaquiline.. The study aimed to summarise the existing evidence of bedaquiline's safety on drugresistant tuberculosis treatment outcome and look for bedaquiline-related adverse drug reactions in the Pharmacovigilance Programme of India and World Health Organisation - Uppsala Monitoring Centre database.. We searched the PubMed database for relevant studies on the safety profile of bedaquiline used in the treatment of drug-resistant tuberculosis and bedaquiline-related adverse drug reactions in the Pharmacovigilance Programme of India and World Health Organisation - Uppsala Monitoring Centre database published up to April 25, 2022.. A total of 190 abstracts were identified through the Pubmed database. In a list of 157 fulltext eligible articles assessed, 149 were excluded as they did not meet the inclusion criteria. The complete articles of the remaining 8 studies were further evaluated. There were 4 prospective cohorts, 2 retrospective cohorts, and 2 case series.. Pharmacovigilance and medication safety monitoring of newer treatments, like bedaquiline, are critical for enhancing treatment support and adherence, especially among drugresistant tuberculosis patients.

Topics: Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Humans; India; Prospective Studies; Retrospective Studies; Tuberculosis; Tuberculosis, Multidrug-Resistant

Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.. We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.. 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.. Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.. Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

Topics: Adult; Aminosalicylic Acid; Antitubercular Agents; Canada; Clofazimine; Diarylquinolines; Drug-Related Side Effects and Adverse Reactions; Female; Fluoroquinolones; Humans; Incidence; Linezolid; Male; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

TB still represents a serious public health problem. The latest reports estimate an incidence of 8.7 million cases in 2011 and 1.4 million deaths. Drug resistance contributed an estimated 630,000 cases of multidrug-resistant TB, making control of the disease harder. Recent reports show cases of TB that were almost resistant to all available antibiotics. Therefore, there is an urgent need to develop new anti-TB drugs with the potential of reducing the current length of treatment. Bedaquiline, formerly TMC207, is a new diarylquinoline antibiotic with specific activity against Mycobacterium tuberculosis and several nontuberculous mycobacteria. It acts by inhibiting ATP synthase, interfering with the energy generation needed by the bacterial cell. Based on clinical evaluations for safety, tolerability and efficacy, bedaquiline has recently received accelerated approval for the treatment of pulmonary multidrug-resistant TB in adults. This article will review the main aspects related to the chemistry, microbiology, pharmacology, efficacy and tolerability of bedaquiline.

Topics: Adenosine Triphosphate; Antitubercular Agents; Diarylquinolines; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Energy Metabolism; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Bedaquiline is a novel adenosine triphosphate synthase inhibitor anti-tuberculosis drug. Bedaquiline belongs to the class of diarylquinolines, which are antituberculosis drugs that are quite different mechanistically from quinolines and flouroquinolines. The fact that relatively similar chemical drugs produce different mechanisms of action is still not widely understood. To enhance discrimination in favor of bedaquiline, a new approach using eight-score principal component analysis (PCA), provided by a ChemGPS-NP model, is proposed. PCA scores were calculated based on 35 + 1 different physicochemical properties and demonstrated clear differences when compared with other quinolines. The ChemGPS-NP model provided an exceptional 100 compounds nearest to bedaquiline from antituberculosis screening sets (with a cumulative Euclidian distance of 196.83), compared with the different 2Dsimilarity provided by Tanimoto methods (extended connective fingerprints and the Molecular ACCess System, showing 30% and 182% increases in cumulative Euclidian distance, respectively). Potentially similar compounds from publicly available antituberculosis compounds and Maybridge sets, based on bedaquiline's eight-dimensional similarity and different filtrations, were identified too.

Topics: Antitubercular Agents; Biological Products; Cluster Analysis; Computational Biology; Databases, Chemical; Diarylquinolines; Drug-Related Side Effects and Adverse Reactions; Forecasting; Humans; Models, Theoretical; Principal Component Analysis; Quantitative Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant

World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP).. AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort.. By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75-169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually.. Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

Topics: Adult; Antitubercular Agents; China; Diarylquinolines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Safety; Tuberculosis, Multidrug-Resistant

Indonesia is one of the top 20 countries with the highest prevalence of drug resistant tuberculosis (DR-TB) worldwide with a percentage of new cases of 2.4% and retreatment of 13%. Bedaquiline (BDQ) is one of the drugs that used in the individual long regimen treating DR-TB. BDQ is also combined with levofloxacin (LFX) and/or clofazimine (CFZ) that can cause QTc interval prolongation. The aim was to study the differences in the use of BDQ regimens to the lengthening of the QTc interval and to study risk factors (diabetes, hypokalemia, sex, BMI, and age) in BDQ regimen.. This study was an observational retrospective study with a total sampling method, which was conducted at Dr. Soetomo General Hospital Surabaya. Samples from this study were patients diagnosed with DR-TB at Dr. Soetomo General Hospital Surabaya in the period of January 2015-December 2019 who used BDQ regimen and met the inclusion criteria. The ECG data were analyzed from the mean of each group (BDQ regimen and risk factors), also analyzed using statistical analysis.. Data obtained from total sample in this study were 73 patients. The most widely used different regimens in this study were the combination of BDQ + LFX by 36 patients (49.3%), BDQ + LFX + CFZ by 16 patients (21.9%), BDQ by 11 patients (15.1%) and BDQ + CFZ 10 patients (13.7%). Out of 73 patients, 52 patients (71.2%) experienced lengthening of the QT interval and grade 1 of QTc interval prolongation occurred in most patients and also the onset was mostly one month after using BDQ regimen. The side effects of QTc interval prolongation from groups of combination and risk factors were no difference in each month (p>0.05).. This study can be concluded that there were no differences in the QTc prolongation between the groups of BDQ regimen (BDQ, BDQ + LFX, BDQ + CFZ and BDQ + LFX + CFZ) and the groups of risk factors.

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Humans; Long QT Syndrome; Retrospective Studies; Tuberculosis, Multidrug-Resistant

Bedaquiline, a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB), is recommended for a duration of 24 weeks. There are scarce data on patients treated with this drug outside clinical trials.All MDR-TB patients who started treatment from January 1, 2011 to December 31, 2013 and received ≥30 days of bedaquiline were included in a multicentre observational cohort.Among 45 MDR-TB patients, 53% harboured isolates resistant to both fluoroquinolones and second-line injectables, and 38% harboured isolates resistant to one of these drug classes. Median bedaquiline treatment duration was 361 days and 33 patients (73%) received prolonged (>190 days) bedaquiline treatment. Overall, 36 patients (80%) had favourable outcome, five were lost to follow-up, three died, and one failed and acquired bedaquiline resistance. No cases of recurrence were reported. Severe and serious adverse events were recorded in 60% and 18% of patients, respectively. Values of Fridericia-corrected QT interval (QTcF) >500 ms were recorded in 11% of patients, but neither arrhythmias nor symptomatic cardiac side-effects occurred. Bedaquiline was discontinued in three patients following QTcF prolongation. No significant differences in outcomes or adverse events rates were observed between patients receiving standard and prolonged bedaquiline treatment.Bedaquiline-containing regimens achieved favourable outcomes in a large proportion of patients. Prolonged bedaquiline treatment was overall well tolerated in this cohort.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug-Related Side Effects and Adverse Reactions; Female; France; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Multivariate Analysis; Mycobacterium tuberculosis; Retrospective Studies; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Bedaquiline is a new antibiotic that was approved for the treatment of multidrug-resistant (MDR) tuberculosis. We aimed to evaluate the short-term microbiological efficacy and the tolerability profile of bedaquiline.. We performed a retrospective cohort study among patients with MDR tuberculosis receiving bedaquiline for compassionate use between January 2010 and July 2013 and evaluated at 6 months of bedaquiline treatment.. A total of 35 patients with MDR tuberculosis were included in the study. Nineteen (54%) had extensively drug-resistant (XDR) tuberculosis, and 14 (40%) had isolates resistant to fluoroquinolones (Fqs) or second-line injectables. Bedaquiline was associated with a median of 4 (range, 2-5) other drugs, including linezolid in 33 (94%) cases. At 6 months of bedaquiline treatment, culture conversion was achieved in 28 of 29 (97%) cases with culture-positive pulmonary tuberculosis at bedaquiline initiation. Median time to culture conversion was 85 days (range, 8-235 days). Variables independently associated with culture conversion were treatment with a Fq (P = .01), absence of lung cavities (P < .001), and absence of hepatitis C virus infection (P = .001). A total of 7 patients (20%) experienced a ≥60-ms increase in QT interval, leading to bedaquiline discontinuation in 2 (6%) cases. Severe liver enzyme elevation occurred in 2 patients (6%). During the study period, 1 death (3%) occurred and was reported as unrelated to tuberculosis or antituberculosis treatment.. The use of bedaquiline combined with other active drugs has the potential to achieve high culture conversion rates in complicated MDR and XDR tuberculosis cases, with a reassuring safety profile at 6 months of treatment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cohort Studies; Compassionate Use Trials; Diarylquinolines; Drug-Related Side Effects and Adverse Reactions; Extensively Drug-Resistant Tuberculosis; Female; France; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Treatment Outcome; Young Adult