Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment.
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ABSTRACT:
SUBMITTER: de Vos M
PROVIDER: S-EPMC6518951 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bedaquiline is recommended by the World Health Organization for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). We pooled data from 5 cohorts of patients treated with bedaquiline in France, Georgia, Armenia, and South Africa and in a multicountry study. The rate of culture conversion to negative at 6 months (by the end of 6 months of treatment) was 78% (95% CI 73.5%-81.9%), and the treatment success rate was 65.8% (95% CI 59.9%-71.3%). Death rate was 11.7% (95% CI 7.0%-19.1%). Up to 91.1% (95% CI 82.2%-95.8%) of the patients experienced >1 adverse event, and 11.2% (95% CI 5.0%-23.2%) experienced a serious adverse event. Lung cavitations were consistently associated with unfavorable outcomes. The use of bedaquiline in MDR and XDR TB treatment regimens appears to be effective and safe across different settings, although the certainty of evidence was assessed as very low.
| S-EPMC6478224 | biostudies-literature
Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug Bedaquiline. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
2021-12-15 | GSE166546 | GEO
Project description:BACKGROUND:In 2012, the Food and Drug Administration approved use of bedaquiline fumarate as part of combination therapy for multidrug-resistant tuberculosis (MDR TB). We describe treatment outcomes, safety, and tolerability of bedaquiline in our case series. METHODS:Data on patients started on bedaquiline for MDR TB between September 2012 and August 2016 were collected retrospectively through 4 TB programs using a standardized abstraction tool. Data were analyzed using univariate methods. Adverse events were graded using the Common Terminology Criteria for Adverse Events. RESULTS:Of 14 patients, 7 (50%) had MDR, 4 (29%) had pre-extensively drug-resistant (XDR), and 3 (21%) had XDR TB. All had pulmonary TB, 5 (36%) had pulmonary and extrapulmonary TB, and 9/13 (69%) were smear positive. One patient (7%) had HIV coinfection, 5 (36%) had diabetes mellitus, and 5/14 (36%) had previous treatment TB. All patients were non-US-born and 5/14 (36%) had private insurance. All patients achieved sputum culture conversion within a mean of 71 days (26-116); 5 after starting bedaquiline. Twelve (86%) completed treatment and 1 (7%) moved out of the country. One patient (7%) had QTc prolongation >500 milliseconds and died 20 months after discontinuing bedaquiline of a cause not attributable to the drug. Common adverse events were peripheral neuropathy 7/14 (50%), not customarily associated with bedaquiline use, and QTc prolongation 6/14 (43%). CONCLUSIONS:Of 14 patients, 1 (7%) had an adverse event necessitating bedaquiline discontinuation. Safety, culture conversion, and treatment completion in this series (7%) support use of bedaquiline for the treatment of MDR/XDR TB.
| S-EPMC7350275 | biostudies-literature
Project description:Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and bedaquiline. Early data suggest a signal for low antiretroviral therapy adherence after this antiretroviral therapy switch. Mortality and other tuberculosis-specific benefits noted with bedaquiline treatment in multidrug and extensively drug-resistant tuberculosis HIV might be compromised by HIV viral failure, and emergent antiretroviral resistance. Programmatic responses, such as adherence support and dual pharmacovigilance, should be instituted; antiretroviral therapy initiation with fixed-dose combinations without bedaquiline drug interactions should be strongly considered.
| S-EPMC7155388 | biostudies-literature
Project description:We report the emergence of an atpE mutation in a clinical Mycobacterium tuberculosis strain. Genotypic and phenotypic bedaquiline susceptibility testing displayed variable results over time and ultimately were not predictive of treatment outcome. This observation highlights the limits of current genotypic and phenotypic methods for detection of bedaquiline resistance.
| S-EPMC9045433 | biostudies-literature
Project description:BackgroundActive smoking increases the risk of tuberculosis (TB) infection 2 to 2.5 times and is significantly associated with recurrent TB and TB mortality. Observational studies have shown associations between smoking and poor TB treatment outcomes such as increased loss to follow-up rate, severity of disease, drug resistance and slow smear conversion. Since most smoking-related immunologic abnormalities are reversible within six weeks of stopping smoking, smoking cessation may have substantial positive effects on TB treatment outcomes, TB relapse and future lung disease.ObjectivesTo analyse the effect of tobacco smoking cessation interventions (SCIs) on the treatment outcomes of people with adult pulmonary TB.Search methodsWe searched the Cochrane Tobacco Addiction Group Specialised Register using free-text and MeSH terms for TB and antitubercular treatment. We also searched MEDLINE and EMBASE using the same topic-related terms, combined with the search terms used to identify trials of tobacco cessation interventions from the Specialised Register. We also searched reference list of articles and reviews, the Conference Paper Index, clinicaltrials.gov and grey literature. The searches are current to 29th July 2015.Selection criteriaIndividual and cluster-randomised controlled trials (RCTs), regardless of date, language and publication status, studies of adults with pulmonary TB on first-line anti-tubercular drugs, with interventions at either an individual or a population level, delivered separately or as part of a larger tobacco control package. This included any type of behavioural or pharmaceutical intervention or both for smoking cessation.Data collection and analysisUsing the eligibility criteria, two authors independently checked the abstracts of retrieved studies for relevance, and acquired full trial reports of candidates for inclusion. The authors resolved any disagreements on eligibility by mutual consent, or by recourse to a third author. Two authors intended to independently extract study data from eligible studies into a data extraction form and compare the findings, synthesise data using risk ratios, and assess risk of bias using standard Cochrane methodologies. However, we found no eligible trials.Main resultsThere were no randomised controlled trials that met the eligibility criteria. A number of potentially eligible studies are underway, and we will assess them for inclusion in the next update of this review.Authors' conclusionsThere is a lack of high-quality evidence, i.e. RCTs, that tests the effectiveness of cessation interventions in improving TB treatment outcomes. There is a need for good-quality randomised controlled trials that assess the effect of SCIs on TB treatment outcomes in both the short and long term. Establishing such an evidence base would be an essential step towards the implementation of SCIs in TB control programmes worldwide.
| S-EPMC7386791 | biostudies-literature
Project description:Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT prolongation) were simulated for 5,000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (Cmax) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety, respectively, of the reloading strategies. Bedaquiline weekly AUC and M2 Cmax deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than 2 weeks, no new loading dose is needed. For interruptions with durations between 2 weeks and 1 month, 1 month and 1 year, and longer than 1 year, reloading periods of 3 days, 1 week, and 2 weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with -16.4% to -59.8% without reloading for interruptions of 2 weeks and 1 year, respectively, without increasing M2 Cmax. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.
| S-EPMC8923200 | biostudies-literature
Project description:BackgroundDrug-resistant tuberculosis (DR-TB) is considered to be a public health threat and is difficult to cure, requiring a lengthy treatment with potent, potentially toxic drugs. The novel antimicrobial agent bedaquiline has shown promising results for patients with DR-TB, improving the rate of culture conversion and reducing TB-related mortality. However, increasing numbers of cases with acquired bedaquiline resistance (ABR) have been reported in recent years.MethodsThis systematic review aimed to assess the frequency of ABR and characteristics of patients acquiring it. Studies showing data on sequential bedaquiline drug-susceptibility testing in patients treated with a bedaquiline-containing regimen were included. The databases CENTRAL, PubMed and Embase were manually searched, and 866 unique records identified, eventually leading to the inclusion of 13 studies. Phenotypic ABR was assessed based on predefined MIC thresholds and genotypic ABR based on the emergence of resistance-associated variants.ResultsThe median (IQR) frequency of phenotypic ABR was 2.2% (1.1%-4.6%) and 4.4% (1.8%-5.8%) for genotypic ABR. Among the studies reporting individual data of patients with ABR, the median number of likely effective drugs in a treatment regimen was five, in accordance with WHO recommendations. In regard to the utilization of important companion drugs with high and early bactericidal activity, linezolid was included in the regimen of most ABR patients, whereas the usage of other group A (fluoroquinolones) and former group B drugs (second-line injectable drugs) was rare.ConclusionsOur findings suggest a relevant frequency of ABR, urging for a better protection against it. Therefore, treatment regimens should include drugs with high resistance-preventing capacity through high and early bactericidal activity.
| S-EPMC8963286 | biostudies-literature
Project description:We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.
| S-EPMC5621558 | biostudies-literature
Project description:We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.
| S-EPMC6709449 | biostudies-literature