| 1. |
- Becker, K., et al.
(författare)
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Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
- 2021
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Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
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Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. © 2021 The Author(s)
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| 2. |
- Becker, K., et al.
(författare)
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Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice
- 2021
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Ingår i: Clinical Microbiology and Infection. - : Elsevier B.V.. - 1198-743X .- 1469-0691. ; 27:9, s. 1315-
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Novel therapeutics are urgently required for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) causing critical infections with high mortality. Here we assessed the therapeutic potential of the clinical-stage drug candidate EBL-1003 (crystalline free base of apramycin) in the treatment of CRAB lung infections. Methods: The genotypic and phenotypic susceptibility of CRAB clinical isolates to aminoglycosides and colistin was assessed by database mining and broth microdilution. The therapeutic potential was assessed by target attainment simulations on the basis of time–kill kinetics, a murine lung infection model, comparative pharmacokinetic analysis in plasma, epithelial lining fluid (ELF) and lung tissue, and pharmacokinetic/pharmacodynamic (PKPD) modelling. Results: Resistance gene annotations of 5451 CRAB genomes deposited in the National Database of Antibiotic Resistant Organisms (NDARO) suggested >99.9% of genotypic susceptibility to apramycin. Low susceptibility to standard-of-care aminoglycosides and high susceptibility to EBL-1003 were confirmed by antimicrobial susceptibility testing of 100 A. baumannii isolates. Time–kill experiments and a mouse lung infection model with the extremely drug-resistant CRAB strain AR Bank #0282 resulted in rapid 4-log CFU reduction both in vitro and in vivo. A single dose of 125 mg/kg EBL-1003 in CRAB-infected mice resulted in an AUC of 339 h × μg/mL in plasma and 299 h × μg/mL in ELF, suggesting a lung penetration of 88%. PKPD simulations suggested a previously predicted dose of 30 mg/kg in patients (creatinine clearance (CLCr) = 80 mL/min) to result in >99% probability of –2 log target attainment for MICs up to 16 μg/mL. Conclusions: This study provides proof of concept for the efficacy of EBL-1003 in the treatment of CRAB lung infections. Broad in vitro coverage, rapid killing, potent in vivo efficacy, and a high probability of target attainment render EBL-1003 a strong therapeutic candidate for a priority pathogen for which treatment options are very limited. © 2020 The Author(s)
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| 3. |
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| 4. |
- Björn, Camilla, et al.
(författare)
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Efficacy and safety profile of the novel antimicrobial peptide PXL150 in a mouse model of infected burn wounds
- 2015
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 45:5, s. 519-524
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Tidskriftsartikel (refereegranskat)abstract
- The urgent need to develop novel antimicrobial therapies has stimulated interest in antimicrobial peptides as therapeutic candidates for the treatment of infectious diseases. The aim of this study was to evaluate the anti-infectious effect of the synthetic antimicrobial peptide PXL150, formulated in hydroxypropyl cellulose (HPC) gel, on Pseudomonas aeruginosa in vitro and in an in vivo mouse model of infected burn wounds as well as to assess the in vivo safety profile of PXL150 in rats and rabbits. Minimal microbicidal concentration analysis showed prominent efficacy of PXL150 against P. aeruginosa in vitro, which was further enhanced in formulating the peptide in HPC gel. Application of 1.25, 2.5, 5, 10 and 20 mg/g PXL150 in HPC gel twice daily for four consecutive days significantly reduced bacterial counts in the burn wounds compared with non-treated or placebo-treated controls. Continuous bioluminescence measurements of the bacteria revealed a pronounced anti-infective effect already at the first day post infection by PXL150 in concentrations of >= 2.5 mg/g. In the non-clinical safety studies, PXL150 showed a favourable safety profile following repeated administration systemically and locally in rats and rabbits, respectively. In conclusion, these data support that PXL150 has the potential to be an effective and safe drug candidate for the treatment of infected burn wounds. The findings encourage the progression of PXL150 as a novel topical treatment of microbial infections.
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| 5. |
- Fridholm, Björn, et al.
(författare)
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Kalman filter for adaptive learning of look-up tables with application to automotive battery resistance estimation
- 2016
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Ingår i: Control Engineering Practice. - : Elsevier BV. - 0967-0661 .- 1873-6939. ; 48, s. 78-86
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Tidskriftsartikel (refereegranskat)abstract
- In online automotive applications, look-up tables are often used to model nonlinearities in component models that are to be valid over large operating ranges. If the component characteristics change with ageing or wear, these look-up tables must be updated online. Here, a method is presented where a Kalman filter is used to update the entire look-up table based on local estimation at the current operating conditions. The method is based on the idea that the parameter changes observed as a component ages are caused by physical phenomena having effect over a larger part of the operating range that may have been excited. This means that ageing patterns at different operating points are correlated, and these correlations are used to drive a random walk process that models the parameter changes. To demonstrate properties of the method, it is applied to estimate the ohmic resistance of a lithium-ion battery. In simulations the complete look-up table is successfully updated without problems of drift, even in parts of the operating range that are almost never excited. The method is also robust to uncertainties, both in the ageing model and in initial parameter estimates.
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| 6. |
- Fridholm, Björn, et al.
(författare)
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Robust recursive impedance estimation for automotive lithium-ion batteries
- 2016
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Ingår i: Journal of Power Sources. - : Elsevier BV. - 0378-7753 .- 1873-2755. ; 304, s. 33-41
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Tidskriftsartikel (refereegranskat)abstract
- Recursive algorithms, such as recursive least squares (RLS) or Kalman filters, are commonly used in battery management systems to estimate the electrical impedance of the battery cell. However, these algorithms can in some cases run into problems with bias and even divergence of the estimates. This article illuminates problems that can arise in the online estimation using recursive methods, and lists modifications to handle these issues. An algorithm is also proposed that estimates the impedance by separating the problem in two parts; one estimating the ohmic resistance with an RLS approach, and another one where the dynamic effects are estimated using an adaptive Kalman filter (AKF) that is novel in the battery field. The algorithm produces robust estimates of ohmic resistance and time constant of the battery cell in closed loop with SoC estimation, as demonstrated by both in simulations and with experimental data from a lithium-ion battery cell.
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| 7. |
- Fridholm, Björn, et al.
(författare)
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Robustness comparison of battery state of charge observers for automotive applications
- 2014
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Ingår i: IFAC Proceedings Volumes (IFAC-PapersOnline). - : IFAC Secretariat. - 1474-6670. - 9783902823625 ; , s. 2138-2146
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Konferensbidrag (refereegranskat)abstract
- This paper compares the robustness of three different battery State of Charge (SoC) estimation algorithms: the Extended Kalman Filter (EKF), the Unscented Kalman Filter (UKF) and the H∞ filter. Their performance when subject to disturbances such as parameter uncertainties, different sensor noise characteristics and sensitivity to tuning of the filter are examined. Simulations show that the appropriate choice of observer algorithm will depend on battery chemistry as well as on the intended application. For batteries with a strong correlation between SoC and OCV, the UKF is robust to disturbances such as sensor bias. The H∞ observer shows performance on par with the UKF but the variability of the estimation errors are larger. The EKF is a good all-round choice.
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| 8. |
- Gustafsson, Jonas, et al.
(författare)
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A demonstration of monitoring and measuring data centers for energy efficiency using opensource tools
- 2018
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Ingår i: e-Energy 2018 - Proceedings of the 9th ACM International Conference on Future Energy Systems. - New York, NY, USA : ACM. - 9781450357678 ; , s. 506-512
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Konferensbidrag (refereegranskat)abstract
- Data centers are complex systems that require sophisticated operational management approaches to provide the availability of digital services against the backdrop of cost and energy efficiency. To achieve this, data center telemetry data is required since, as is commonly said it is not possible to manage what cannot be measured. This paper details how it is possible to construct the key data center infrastructure management (DCIM) elements of monitoring and measuring by a combination of available opensource software tools that permit both scalability and an environment where analytics can be employed on the data center operation, which can offer relevant insight into energy efficient operational practices.
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| 9. |
- Hellström, Björn, 1959-, et al.
(författare)
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Acoustic Design Artifacts and Methods for Urban Soundscapes
- 2008
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Ingår i: The 15th International Congress on Sound and Vibration In: International Journal of Acoustics & Vibration. ; , s. 52-52
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Konferensbidrag (refereegranskat)abstract
- The research question is: “How to develop and apply acoustic artifacts and design methodologies for improving soundscapes in urban outdoor spaces?” In the project, this research question is limited to two specific types of urban outdoor spaces – city-park and city-square – and to two types of acoustic design artifacts. These are: I. Dynamic promotion of qualitative site specific sounds (e.g., the overall site specific sonic atmosphere, sounds from human activities, birds and fountains), which creates an improved soundscape. II. Sound-art installations, that creates delimited auditory sub-spaces within the park/square. The purpose and method is: 1. To provide two case-studies of artistic soundscape improvement, one in a noise polluted city-park and one in a city-square. The case-studies will serve as models for future applications of the new acoustic design artifacts. 2. To create and validate an innovative acoustic design methodology based on state-of-the-art real-time acoustic simulation tools integrated into the design process. The methodology will be validated in psychoacoustic listening experiments and field studies. 3. To determine the potential of the two acoustic design artifacts (I Dynamic promotion of qualitative site specific sounds, and II Sound-art installations) for providing pleasant and restorative soundscapes, in order to strengthening the social interaction as well as the spatial and aesthetical qualities in noise polluted city parks/squares. The present project beats a new track by combining acoustic design with sound art research, integrating methodologies based on real-time acoustic simulation and application of psychoacoustic methodology for validating simulations and for evaluating perceptual, emotional and behavioural effects on visitors to public open spaces. The ongoing research project, financed by the Swedish Research Council, is executed by the University College of Arts, Crafts and Design (Konstfack), Gösta Ekman Laboratory – Stockholm University and Karolinska Institutet and the Interactive Institute, all in Stockholm, Sweden.
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