| 1. |
- Singh, K. P., et al.
(author)
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Clinical standards for the management of adverse effects during treatment for TB
- 2023
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In: The International Journal of Tuberculosis and Lung Disease. - : International Union Against Tuberculosis and Lung Disease. - 1027-3719 .- 1815-7920. ; 27:7, s. 506-519
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Journal article (peer-reviewed)abstract
- BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitiv-ity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person -centred, consensus-based approach to minimise the impact of AE TB treatment.
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| 2. |
- Alffenaar, J. W. C., et al.
(author)
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Clinical standards for the dosing and management of TB drugs
- 2022
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In: The International Journal of Tuberculosis and Lung Disease. - Paris, France : International Union Against Tuberculosis and Lung Disease. - 1027-3719 .- 1815-7920. ; 26:6, s. 483-
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Journal article (other academic/artistic)abstract
- Background: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice' for dosing and management of TB drugs.Methods: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.Results: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.Conclusion: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.
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| 3. |
- Reed, R. A., et al.
(author)
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Anthology of the Development of Radiation Transport Tools as Applied to Single Event Effects
- 2013
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In: IEEE Transactions on Nuclear Science. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9499 .- 1558-1578. ; 60:3, s. 1876-1911
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Journal article (peer-reviewed)abstract
- This anthology contains contributions from eleven different groups, each developing and/or applying Monte Carlo-based radiation transport tools to simulate a variety of effects that result from energy transferred to a semiconductor material by a single particle event. The topics span from basic mechanisms for single-particle induced failures to applied tasks like developing websites to predict on-orbit single event failure rates using Monte Carlo radiation transport tools.
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| 4. |
- van den Elsen, SHJ, et al.
(author)
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Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study
- 2020
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In: BMJ open. - : BMJ. - 2044-6055. ; 10:6, s. e035350-
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Journal article (peer-reviewed)abstract
- Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls.Methods and analysisPatients aged 18 years or older with sputum smear and culture-positive pulmonary MDR-TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if >80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM.Ethics and disseminationEthical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal.Trial registration numberClinicalTrials.gov Registry (NCT03409315).
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| 5. |
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| 6. |
- Akkerman, V., et al.
(author)
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Flow-flame interaction in a closed chamber
- 2008
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In: Physics of Fluids. - : AIP Publishing. - 1070-6631 .- 1089-7666. ; 20:5, s. 21-
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Journal article (peer-reviewed)abstract
- Numerous studies of flame interaction with a single vortex and recent simulations of burning in vortex arrays in open tubes demonstrated the same tendency for the turbulent burning rate proportional to U-rms lambda(2/3), where U-rms is the root-mean-square velocity and lambda is the vortex size. Here, it is demonstrated that this tendency is not universal for turbulent burning. Flame interaction with vortex arrays is investigated for the geometry of a closed burning chamber by using direct numerical simulations of the complete set of gas-dynamic combustion equations. Various initial conditions in the chamber are considered, including gas at rest and several systems of vortices of different intensities and sizes. It is found that the burning rate in a closed chamber (inverse burning time) depends strongly on the vortex intensity; at sufficiently high intensities it increases with U-rms approximately linearly in agreement with the above tendency. On the contrary, dependence of the burning rate on the vortex size is nonmonotonic and qualitatively different from the law lambda(2/3). It is shown that there is an optimal vortex size in a closed chamber, which provides the fastest total burning rate. In the present work, the optimal size is six times smaller than the chamber height.
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| 7. |
- Borisov, S, et al.
(author)
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Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report
- 2019
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 54:6
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Journal article (peer-reviewed)abstract
- The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.
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| 8. |
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| 9. |
- Keutzer, Lina, et al.
(author)
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Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment
- 2023
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In: Pharmaceuticals. - : MDPI. - 1424-8247. ; 16:11
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Journal article (peer-reviewed)abstract
- Long-term usage of linezolid can result in adverse events such as peripheral neuropathy, anemia and thrombocytopenia. Therapeutic drug monitoring data from 75 drug-resistant tuberculosis patients treated with linezolid were analyzed using a time-to-event (TTE) approach for peripheral neuropathy and anemia and indirect response modelling for thrombocytopenia. Different time-varying linezolid pharmacokinetic exposure indices (AUC0-24h,ss, Cav, Cmax and Cmin) and patient characteristics were investigated as risk factors. A treatment duration shorter than 3 months was considered dropout and was modelled using a TTE approach. An exposure-response relationship between linezolid Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0-24h. The final TTE dropout model indicated an association between linezolid Cmin and dropout. New safety targets for each adverse event were proposed which can be used for individualized linezolid dosing. According to the model predictions at 6 months of treatment, a Cmin of 0.11 mg/L and 1.4 mg/L should not be exceeded to keep the cumulative probability to develop anemia and peripheral neuropathy below 20%. The AUC0-24h should be below 111 h center dot mg/L or 270 h center dot mg/L to prevent thrombocytopenia and severe thrombocytopenia, respectively. A clinical utility assessment showed that the currently recommended dose of 600 mg once daily is safer compared to a 300 mg BID dosing strategy considering all four safety endpoints.
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