| 1. |
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| 2. |
- Hong, Lisa T, et al.
(författare)
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International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics : Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists
- 2023
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Ingår i: Pharmacotherapy. - : John Wiley & Sons. - 0277-0008 .- 1875-9114. ; 43:8, s. 736-739
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Tidskriftsartikel (refereegranskat)abstract
- Intravenous β-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. β-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PI) can be applied during the administration of intravenous β-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of β-lactam PI developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug monitoring considerations, and the use of PI β-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of β-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).
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| 3. |
- Hong, Lisa T., et al.
(författare)
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International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics : Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists
- 2023
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Ingår i: Pharmacotherapy. - : John Wiley & Sons. - 0277-0008 .- 1875-9114. ; 43:8, s. 740-777
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Tidskriftsartikel (refereegranskat)abstract
- Intravenous & beta;-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. & beta;-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PIs) can be applied during the administration of intravenous & beta;-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of PI & beta;-lactams developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug-monitoring considerations, and the use of PI & beta;-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of & beta;-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).
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| 4. |
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| 5. |
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| 6. |
- Allander, Lisa, et al.
(författare)
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Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48-and NDM-Producing Escherichia coli and Klebsiella pneumoniae
- 2022
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Ingår i: Antibiotics. - : MDPI. - 2079-6382. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing Enterobacterales, but data remain inconclusive. This study evaluated the activity of double-carbapenem combinations against 51 clinical KPC-2-, OXA-48-, NDM-1, and NDM-5-producing Escherichia coli and Klebsiella pneumoniae and against constructed E. coli strains harboring genes encoding KPC-2, OXA-48, or NDM-1 in an otherwise isogenic background. Two-drug combinations of ertapenem, meropenem, and doripenem were evaluated in 24 h time-lapse microscopy experiments with a subsequent spot assay and in static time-kill experiments. An enhanced effect in time-lapse microscopy experiments at 24 h and synergy in the spot assay was detected with one or more combinations against 4/14 KPC-2-, 17/17 OXA-48-, 2/17 NDM-, and 1/3 NDM-1+OXA-48-producing clinical isolates. Synergy rates were higher against meropenem- and doripenem-susceptible isolates and against OXA-48 producers. NDM production was associated with significantly lower synergy rates in E. coli. In time-kill experiments with constructed KPC-2-, OXA-48- and NDM-1-producing E. coli, 24 h synergy was not observed; however, synergy at earlier time points was found against the KPC-2- and OXA-48-producing constructs. Our findings indicate that the benefit of double-carbapenem combinations against carbapenemase-producing E. coli and K. pneumoniae is limited, especially against isolates that are resistant to the constituent antibiotics and produce NDM.
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| 7. |
- Allander, Lisa
(författare)
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β-lactam combinations against multidrug-resistant Enterobacterales : Exploring combination effects and resistance development
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The β-lactam antibiotics are a cornerstone in treating bacterial infections, but the increasing prevalence of antibiotic resistance worldwide threatens their effectiveness. The main driver of β-lactam resistance is the production of β-lactamases, which are bacterial enzymes that inactivate the antibiotic. Moreover, resistance to multiple antibiotic classes is common in β-lactamase producing bacteria, further limiting treatment options. At the same time, few novel antibacterial agents are reaching the market. To address this challenge, antibiotic combination therapy is employed to enhance the effects of existing drugs against multidrug-resistant bacteria. Yet, there is a lack of knowledge regarding which antibiotics to combine to achieve the best effect. The investigations in this thesis evaluate the potential and limitations of combinations involving β-lactams, β-lactamase inhibitors and colistin against multidrug-resistant Enterobacterales in vitro. In the first paper, we investigated resistance mechanisms to three commonly used β-lactam/β-lactamase inhibitor combinations (BLBLIs) in an Escherichia coli strain encoding multiple β-lactamases. We found that β-lactamase gene amplifications were a key driver of resistance, with variations in the amplification pattern depending on the BLBLI combination. Clinical resistance could be reached by gene amplifications for ampicillin-sulbactam and piperacillin-tazobactam, whereas ceftazidime-avibactam resistance required multiple genetic changes. In the second paper, we evaluated the efficacy of double-carbapenem combinations against E. coli and Klebsiella pneumoniae producing carbapenemases (KPC-2, OXA-48, NDM-1, and NDM-5). Synergistic effects were most commonly observed against OXA-48-producing strains, whereas the efficacy was low against KPC-2 and negligible against NDM producers. In the third and fourth papers, we evaluated the antibacterial activity of colistin in combination with BLBLIs. Considering that reduced membrane permeability is associated with decreased susceptibility towards BLBLIs, adding colistin may be beneficial since its membrane-disrupting effect may increase the entry of other drugs. In paper three, we showed synergistic effects with colistin and ceftazidime-avibactam against a KPC-2-producing K. pneumoniae strain with porin deficiencies. However, when systematically assessing the impact of porin loss on the synergistic potential of colistin in combination with BLBLIs in paper four, we did not find any clear association between porin loss and synergy. These studies provide insight into the therapeutic potential and limitations of combinations, including β-lactam antibiotics against strains with different setups of resistance genes. More research is required to understand how to best use the newly introduced BLBLI combinations to preserve their activity and enhance the value of the available antibiotics for future generations.
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| 8. |
- Behnke, Michael, et al.
(författare)
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Information technology aspects of large-scale implementation of automated surveillance of healthcare-associated infections
- 2021
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Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 27:Suppl 1, s. S29-S39
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Healthcare-associated infections (HAI) are a major public health concern. Monitoring of HAI rates, with feedback, is a core component of infection prevention and control programmes. Digitalization of healthcare data has created novel opportunities for automating the HAI surveillance process to varying degrees. However, methods are not standardized and vary widely between different healthcare facilities. Most current automated surveillance (AS) systems have been confined to local settings, and practical guidance on how to implement large-scale AS is needed. Methods: This document was written by a task force formed in March 2019 within the PRAISE network (Providing a Roadmap for Automated Infection Surveillance in Europe), gathering experts in HAI surveillance from ten European countries. Results: The document provides an overview of the key e-health aspects of implementing an AS system of HAI in a clinical environment to support both the infection prevention and control team and information technology (IT) departments. The focus is on understanding the basic principles of storage and structure of healthcare data, as well as the general organization of IT infrastructure in surveillance networks and participating healthcare facilities. The fundamentals of data standardization, interoperability and algorithms in relation to HAI surveillance are covered. Finally, technical aspects and practical examples of accessing, storing and sharing healthcare data within a HAI surveillance network, as well as maintenance and quality control of such a system, are discussed. Conclusions: With the guidance given in this document, along with the PRAISE roadmap and governance documents, readers will find comprehensive support to implement large-scale AS in a surveillance network.
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| 9. |
- Bulman, Zackery P., et al.
(författare)
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Research priorities towards precision antibiotic therapy to improve patient care
- 2022
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Ingår i: LANCET MICROBE. - : Elsevier. - 2666-5247. ; 3:10, s. e795-e802
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections. It is this salient paradox that points to key future directions for research in antibiotic therapeutics. This Personal View discusses six priority areas for antibiotic pharmacology research: (1) antibiotic-pathogen interactions, (2) antibiotic targets for combination therapy, (3) mechanistic models that describe the time-course of treatment response, (4) understanding and modelling of host response to infection, (5) personalised medicine through therapeutic drug management, and (6) application of these principles to support development of novel therapies. Innovative approaches that enhance our understanding of antibiotic pharmacology and facilitate more accurate predictions of treatment success, coupled with traditional pharmacology research, can be applied at the population level and to individual patients to improve outcomes.
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| 10. |
- Cojutti, Pier Giorgio, et al.
(författare)
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Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients
- 2023
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 67:3
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in kidney transplant patients. A population PK/PD model was developed with Monolix. Ganciclovir concentrations and CMV viral loads were obtained retrospectively from kidney transplant patients receiving routine clinical care. Ten thousand Monte Carlo simulations were performed with the licensed dosages adjusted for renal function to assess the probability of attaining a viral load target of <= 290 and <= 137 IU/mL. Fifty-seven patients provided 343 ganciclovir concentrations and 328 CMV viral loads for PK/PD modeling. A one-compartment pharmacokinetic model coupled with an indirect viral turnover growth model with stimulation of viral degradation pharmacodynamic model was devised. Simulations showed that 1- and 2-log(10) reduction of CMV viral load mostly occurred between a median of 5 to 6 and 12 to 16 days, respectively. The licensed dosages achieved a probability of reaching the viral load target >= 90% at days 35 to 49 and 42 to 56 for the thresholds of <= 290 and <= 137 IU/mL, respectively. Simulations indicate that in patients with an estimated glomerular filtration rate of 10 to 24 mL/min/1.73m(2), a dose increase to 450 mg every 36 h may reduce time to optimal viral load target to days 42 and 49 from a previous time of 49 and 56 days for the thresholds of <= 290 and <= 137 IU/mL, respectively. Currently licensed dosages of valganciclovir for preemptive therapy of CMV infection may achieve a viral load reduction within the first 2 weeks, but treatment should continue for >= 35 days to ensure viral load suppression.
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| 11. |
- Dahdouh, Elias, et al.
(författare)
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Computational Modeling and Design of New Inhibitors of Carbapenemases : A Discussion from the EPIC Alliance Network
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:17
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The EPIC consortium brings together experts from a wide range of fields that include clinical, molecular and basic microbiology, infectious diseases, computational biology and chemistry, drug discovery and design, bioinformatics, biochemistry, biophysics, pharmacology, toxicology, veterinary sciences, environmental sciences, and epidemiology. The main question to be answered by the EPIC alliance is the following: "What is the best approach for data mining on carbapenemase inhibitors and how to translate this data into experiments?" From this forum, we propose that the scientific community think up new strategies to be followed for the discovery of new carbapenemase inhibitors, so that this process is efficient and capable of providing results in the shortest possible time and within acceptable time and economic costs.
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| 12. |
- Dittrich, Sabine, et al.
(författare)
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Target Product Profile for a Diagnostic Assay to Differentiate between Bacterial and Non-Bacterial Infections and Reduce Antimicrobial Overuse in Resource-Limited Settings : An Expert Consensus
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Acute fever is one of the most common presenting symptoms globally. In order to reduce the empiric use of antimicrobial drugs and improve outcomes, it is essential to improve diagnostic capabilities. In the absence of microbiology facilities in low-income settings, an assay to distinguish bacterial from non-bacterial causes would be a critical first step. To ensure that patient and market needs are met, the requirements of such a test should be specified in a target product profile (TPP). To identify minimal/optimal characteristics for a bacterial vs. non-bacterial fever test, experts from academia and international organizations with expertise in infectious diseases, diagnostic test development, laboratory medicine, global health, and health economics were convened. Proposed TPPs were reviewed by this working group, and consensus characteristics were defined. The working group defined non-severely ill, non-malaria infected children as the target population for the desired assay. To provide access to the most patients, the test should be deployable to community health centers and informal health settings, and staff should require <2 days of training to perform the assay. Further, given that the aim is to reduce inappropriate antimicrobial use as well as to deliver appropriate treatment for patients with bacterial infections, the group agreed on minimal diagnostic performance requirements of >90% and >80% for sensitivity and specificity, respectively. Other key characteristics, to account for the challenging environment at which the test is targeted, included: i) time-to-result <10 min (but maximally <2 hrs); ii) storage conditions at 0-40 degrees C, <= 90% non-condensing humidity with a minimal shelf life of 12 months; iii) operational conditions of 5-40 degrees C, <= 90% non-condensing humidity; and iv) minimal sample collection needs (50-100 mu L, capillary blood). This expert approach to define assay requirements for a bacterial vs. non-bacterial assay should guide product development, and enable targeted and timely efforts by industry partners and academic institutions.
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| 13. |
- Dyar, O J, et al.
(författare)
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ESCMID generic competencies in antimicrobial prescribing and stewardship : towards a European consensus.
- 2019
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Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 25:1, s. 13-19
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop a consensus-based set of generic competencies in antimicrobial prescribing and stewardship for European prescribers through a structured consensus procedure.METHODS: The RAND-modified Delphi procedure comprised two online questionnaire rounds, a face-to-face meeting between rounds, and a final review. Our departure point was a set of competencies agreed previously by consensus among a UK multi-disciplinary panel, and which had been subsequently revised through consultation with ESCMID Study Group representatives. The 46 draft competency points were reviewed by an expert panel consisting of specialists in infectious diseases and clinical microbiology, and pharmacists. Each proposed competency was assessed using a nine-point Likert scale, for relevance as a minimum standard for all independent prescribers in all European countries.RESULTS: A total of 65 expert panel members participated, from 24 European countries (one to six experts per country). There was very high satisfaction (98%) with the final competencies set, which included 35 competency points, in three sections: core concepts in microbiology, pathogenesis and diagnosing infections (11 points); antimicrobial prescribing (20 points); and antimicrobial stewardship (4 points).CONCLUSIONS: The consensus achieved enabled the production of generic antimicrobial prescribing and stewardship competencies for all European independent prescribers, and of possible global utility. These can be used for training and can be further adapted to the needs of specific professional groups.
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| 14. |
- Helou, R. , I, et al.
(författare)
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Study protocol for an international, multicentre stepped-wedge cluster randomised trial to evaluate the impact of a digital antimicrobial stewardship smartphone application
- 2020
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Ingår i: BMJ Open. - : BMJ PUBLISHING GROUP. - 2044-6055. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionWith the widespread use of electronic health records and handheld electronic devices in hospitals, informatics-based antimicrobial stewardship interventions hold great promise as tools to promote appropriate antimicrobial drug prescribing. However, more research is needed to evaluate their optimal design and impact on quantity and quality of antimicrobial prescribing.Methods and analysisUse of smartphone-based digital stewardship applications (apps) with local guideline directed empirical antimicrobial use by physicians will be compared with antimicrobial prescription as per usual as primary outcome in three hospitals in the Netherlands, Sweden and Switzerland. Secondary outcomes will include antimicrobial use metrics, clinical and process outcomes. A multicentre stepped-wedge cluster randomised trial will randomise entities defined as wards or specialty regarding time of introduction of the intervention. We will include 36 hospital entities with seven measurement periods in which the primary outcome will be measured in 15 participating patients per time period per cluster. At participating wards, patients of at least 18 years of age using antimicrobials will be included. After a baseline period of 2-week measurements, six periods of 4 weeks will follow in which the intervention is introduced in 6 wards (in three hospitals) until all 36 wards have implemented the intervention. Thereafter, we allow use of the app by everyone, and evaluate the sustainability of the app use 6 months later.Ethics and disseminationThis protocol has been approved by the institutional review board of each participating centre. Results will be disseminated via media, to healthcare professionals via professional training and meetings and to researchers via conferences and publications.Trial registration numberClinicalTrials.gov registry (NCT03793946). Stage; pre-results.
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| 15. |
- Jonsson, Anna-Karin, et al.
(författare)
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A trial with IgY chicken antibodies to eradicate faecal carriage of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamases
- 2015
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Ingår i: Infection Ecology & Epidemiology. - : Informa UK Limited. - 2000-8686. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is an emerging therapeutic challenge, especially in the treatment of urinary tract infections. Following an outbreak of CTX-M-15 Klebsiella pneumoniae in Uppsala, Sweden, an orphan drug trial on IgY chicken antibodies was undertaken in an attempt to eradicate faecal carriage of ESBL-producing K. pneumoniae and Escherichia coli.METHODS: Hens were immunised with epitopes from freeze-dried, whole-cell bacteria (ESBL-producing K. pneumoniae and E. coli) and recombinant proteins of two K. pneumoniae fimbriae subunits (fimH and mrkD). The egg yolks were processed according to good manufacturing practice and the product was stored at-20°C until used. Using an internal database from the outbreak and the regular laboratory database, faecal carriers were identified and recruited from May 2005 to December 2013. The participants were randomised in a placebo-controlled 1:1 manner.RESULTS: From 749 eligible patients, 327 (44%) had deceased, and only 91 (12%) were recruited and signed the informed consent. In the initial screening performed using the polymerase chain reaction, 24 participants were ESBL positive and subsequently randomised and treated with either the study drug or a placebo. The study was powered for 124 participants. Because of a very high dropout rate, the study was prematurely terminated. From the outbreak cohort (n=247), only eight patients were screened, and only one was positive with the outbreak strain in faeces.CONCLUSIONS: The present study design, using IgY chicken antibodies for the eradication of ESBL-producing K. pneumonia and E. coli, was ineffective in reaching its goal due to high mortality and other factors resulting in a low inclusion rate. Spontaneous eradication of ESBL-producing bacteria was frequently observed in recruited participants, which is consistent with previous reports.
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| 16. |
- Kurland, Siri, et al.
(författare)
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Human plasma protein levels alter the in vitro antifungal activity of caspofungin : An explanation to the effect in critically ill?
- 2022
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Ingår i: Mycoses. - : John Wiley & Sons. - 0933-7407 .- 1439-0507. ; 65:1, s. 79-87
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRecent studies have shown low caspofungin concentrations in critically ill patients. In some patients, the therapeutic target, area under the total plasma concentration curve in relation to the minimal inhibition concentration (AUCtot/MIC), seems not to be achieved and therapeutic drug monitoring (TDM) has been proposed. Caspofungin is highly protein-bound and the effect of reduced plasma protein levels on pharmacodynamics has not been investigated.ObjectivesFungal killing activity of caspofungin in vitro was investigated under varying levels of human plasma protein.MethodsTime-kill studies were performed with clinically relevant caspofungin concentrations of 1-9 mg/L on four blood isolates of C. glabrata, three susceptible and one strain with reduced susceptibility, in human plasma and plasma diluted to 50% and 25% using Ringer's acetate.ResultsEnhanced fungal killing of the three susceptible strains was observed in plasma with lower protein content (p < .001). AUCtot/MIC required for a 1 log10 CFU/ml kill at 24 h in 50% and 25% plasma was reduced with 36 + 12 and 80 + 9%, respectively. The maximum effect was seen at total caspofungin concentrations of 4–9 × MIC. For the strain with reduced susceptibility, growth was significantly decreased at lower protein levels.ConclusionsReduced human plasma protein levels increase the antifungal activity of caspofungin in vitro, most likely by increasing the free concentration. Low plasma protein levels in critically ill patients with candidemia might explain a better response to caspofungin than expected from generally accepted target attainment and should be taken into consideration when assessing TDM based on total plasma concentrations.
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| 17. |
- Lagerbäck, Pernilla, et al.
(författare)
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Evaluation of antibacterial activities of colistin, rifampicin and meropenem combinations against NDM-1-producing Klebsiella pneumoniae in 24 h in vitro time-kill experiments
- 2016
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 71:8, s. 2321-2325
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the activity of colistin alone or in double and triple combination with rifampicin and meropenem against NDM-1-producing Klebsiella pneumoniae. Eight isolates of NDM-1-producing K. pneumoniae were exposed to clinically relevant antibiotic concentrations in 24 h time-kill experiments. Three colistin concentrations were used for two of the strains. Resistance development was assessed with population analysis and sequencing of the mgrB and pmrB genes. Initial killing was achieved with colistin alone, but with considerable regrowth at 24 h. Combinations including colistin and rifampicin were bacteriostatic or bactericidal against all strains. Colistin plus meropenem was bactericidal against one strain, but, overall, meropenem showed little additive effects. Higher concentrations of colistin did not enhance antibacterial activity. Resistant populations and deletion or mutations in the mgrB and pmrB genes were frequently detected in endpoint samples after exposure to colistin alone. Based on the results of this and previous studies, the combination of colistin and rifampicin seems promising and should be further explored in vivo and considered for clinical evaluation. Meropenem seems less useful in the treatment of infections caused by high-level carbapenem-resistant NDM-1-producing K. pneumoniae. Higher colistin concentrations did not result in significantly better activity, suggesting that combination therapy might be superior to monotherapy also when colistin is prescribed using high-dose regimens in accordance with current recommendations.
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| 18. |
- Lindström, Anna, 1961-, et al.
(författare)
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Introducing the C-reactive protein point-of-care test : A conversation analytic study of primary care consultations for respiratory tract infection
- 2022
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Ingår i: Social Science and Medicine. - : Elsevier. - 0277-9536 .- 1873-5347. ; 315
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Tidskriftsartikel (refereegranskat)abstract
- The C-reactive protein point-of-care test (CRP-POCT) can help distinguish between viral and bacterial infection and has been promoted as a strategy to improve antimicrobial stewardship. The test is widely used in Sweden. National guidelines advocate conservative use in primary care consultations with patients presenting with symptoms of respiratory tract infection (RTI). Previous research suggests low adherence to guidelines. We provide new insights into the communication surrounding the CRP-POCT by documenting how the decision to administer the test is interactionally motivated and organized in Swedish primary care. The data consists of video-recordings of RTI-consultations. A CRP-POCT was performed in nearly two thirds of the consultations and our study is focused on a subset where the test is ordered by a medical doctor. We find that doctors order the test during the transition from or after physical examination, a practice that aligns with national guidelines. Guidelines indicate that pathological findings from physical examination are warrants for ordering the test but we only found one example where this was communicated to the patient. A more prevalent pattern was that doctors ordered the CRP-POCT even though the outcome of the physical examination was assessed as normal. Our analyses of these show that doctors can provide the rationale for ordering the test in subtle ways and that failure to provide a rationale is treated as a noticeable absence. We also find that the CRP-POCT can be used to reconcile the contrast between the normal physical examination and the patient's problem presentation. Doctors can also order the test in ways that position the CRP-POCT as criterial for antibiotic prescription. Consultations where the patients described the symptoms as particularly severe and/or persistent were more likely to engender elaborate accounts than consultations where patients presented their symptoms as less problematic.
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| 19. |
- Ljungquist, Oskar, et al.
(författare)
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Karbapenemresistenta Escherichia coli finns nu i Sverige
- 2013
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Ingår i: Läkartidningen. - 0023-7205. ; , s. 32-33
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Escherichia coli som producerar ESBLCARBA, vilket bryter ner karbapenemer, har blivit allt vanligare utomlands. Stammar som producerar NDM-1 uppfattas som ett stort hot, eftersom de är multiresistenta och ökar snabbt globalt. De fall av NDM-1 som tidigare påvisats i Sverige har isolerats från patienter som blivit koloniserade i samband med resa eller vård utomlands. Vi presenterar här det första kända fallet av sepsis med NDM-1-producerande E coli i Sverige. Det krävs en hög beredskap på samtliga vårdenheter för att hantera en ökad förekomst av multiresistenta tarmbakterier. Karbapenemer bör användas restriktivt för att undvika selektion av ESBLCARBA-producerande stammar.
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| 20. |
- Ljungquist, O, et al.
(författare)
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Karbapenemresistenta Escherichia coli finns nu i Sverige : Carbapenem-resistant Escherichia coli now exist in Sweden
- 2013
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 110:32/33, s. 1401-1402
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Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli som producerar ESBLCARBA, vilket bryter ner karbapenemer, har blivit allt vanligare utomlands. Stammar som producerar NDM-1 uppfattas som ett stort hot, eftersom de är multiresistenta och ökar snabbt globalt. De fall av NDM-1 som tidigare påvisats i Sverige har isolerats från patienter som blivit koloniserade i samband med resa eller vård utomlands. Vi presenterar här det första kända fallet av sepsis med NDM-1-producerande E coli i Sverige. Det krävs en hög beredskap på samtliga vårdenheter för att hantera en ökad förekomst av multiresistenta tarmbakterier. Karbapenemer bör användas restriktivt för att undvika selektion av ESBLCARBA-producerande stammar.
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| 21. |
- Malmberg, Christer, et al.
(författare)
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A Novel Microfluidic Assay for Rapid Phenotypic Antibiotic Susceptibility Testing of Bacteria Detected in Clinical Blood Cultures
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Background Appropriate antibiotic therapy is critical in the management of severe sepsis and septic shock to reduce mortality, morbidity and health costs. New methods for rapid antibiotic susceptibility testing are needed because of increasing resistance rates to standard treatment. Aims The purpose of this study was to evaluate the performance of a novel microfluidic method and the potential to directly apply this method on positive blood cultures. Methods Minimum inhibitory concentrations (MICs) of ciprofloxacin, ceftazidime, tigecycline and/or vancomycin for Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus were determined using a linear antibiotic concentration gradient in a microfluidic assay. Bacterial growth along the antibiotic gradient was monitored using automated time-lapse photomicrography and growth inhibition was quantified by measuring greyscale intensity changes in the images. In addition to pure culture MICs, vancomycin MICs were determined for S. aureus from spiked and clinical blood cultures following a short centrifugation step. The MICs were compared with those obtained with the Etest and for S. aureus and vancomycin also with macrodilution. Results The MICs obtained with the microfluidic assay showed good agreement internally as well as with the Etest and macrodilution assays, although some minor differences were noted between the methods. The time to possible readout was within the range of 2 to 5 h. Conclusions The examined microfluidic assay has the potential to provide rapid and accurate MICs using samples from positive clinical blood cultures and will now be tested using other bacterial species and antibiotics.
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| 22. |
- Malmberg, Christer, 1984-
(författare)
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Development of a robust and rapid microfluidics-based antibiotic susceptibility test : From prototype to clinical implementation
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Even though bacteria normally are rapidly cleared from the blood by the immune system, a blood stream infection may arise, in turn possibly leading to sepsis and septic shock. Sepsis is a life-threatening condition, where the inflammatory response to infection targets tissues and organs. Mortality in sepsis is very high, at 25-30%, but can be reduced by early and appropriate antibiotic treatment. The time until appropriate antibiotic therapy is started impacts mortality and morbidity to a large extent, from 1-7% increase in mortality per hour of delayed treatment in sepsis and septic shock. However, with increasing antimicrobial resistance globally, the likelihood of successful treatment is continuously reduced. Antimicrobial resistance emphasizes the need for diagnostics to guide therapy, but traditional antimicrobial susceptibility testing is often inadequate in time-critical disease such as sepsis. Subsequently, there is an urgent need for new, more rapid and accurate antibiotic susceptibility tests. One challenge to improving the speed of phenotypic susceptibility testing is the need to rapidly, accurately and non-invasively capture data from a very large collection of cells. Furthermore, development of new diagnostic methods for patients in critical condition, such as sepsis, demands high reliability and accuracy of the method – a false test result can lead to suboptimal therapy, and in turn increased morbidity and ultimately death. This thesis presents a series of prototype rapid antibiotic susceptibility testing (AST) systems using a low-magnification, wide-field optical setup with high cell-mass resolution for simultaneously quantifying bacterial growth rates of tens of thousands of bacterial cell clusters growing in antibiotic gradients generated using microfluidics. Performance data from spiked reference blood samples show that the analytical performance of the system is good, with mean essential agreement of 83.2% against reference methods. The average time to result for the reference dataset was 180 min. For clinical samples, the method was demonstrated to have high categorical agreement with disc diffusion (94.9%), as tested at Uppsala University Hospital. Furthermore, the time from patient sampling until test result availability (turnaround-time) was reduced by 40%. The thesis concludes with a discussion of the recent experimental work and a summary concerning the potential applications of this technology. In summary, rapid diagnostics capable of shorter turnaround times could enable earlier de-escalation of broad-spectrum empirical therapy, as well as enable rapid adjustments to treatments when coverage is lacking. This is likely to reduce mortality as well as healthcare costs associated with increasing resistance.
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| 23. |
- Malmberg, Christer, et al.
(författare)
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Evaluation of the Speed, Accuracy and Precision of the QuickMIC Rapid Antibiotic Susceptibility Testing Assay With Gram-Negative Bacteria in a Clinical Setting
- 2022
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The rapidly changing landscape of antimicrobial resistance poses a challenge for empirical antibiotic therapy in severely ill patients and highlights the need for fast antibiotic susceptibility diagnostics to guide treatment. Traditional methods for antibiotic susceptibility testing (AST) of bacteria such as broth microdilution (BMD) or the disc diffusion method (DDM) are comparatively slow and show high variability. Rapid AST methods under development often trade speed for resolution, sometimes only measuring responses at a single antibiotic concentration. QuickMIC is a recently developed lab-on-a-chip system for rapid AST. Here we evaluate the performance of the QuickMIC method with regard to speed, precision and accuracy in comparison to traditional diagnostic methods. 151 blood cultures of clinical Gram-negative isolates with a high frequency of drug resistance were tested using the QuickMIC system and compared with BMD for 12 antibiotics. To investigate sample turnaround time and method functionality in a clinical setting, another 41 clinical blood culture samples were acquired from the Uppsala University Hospital and analyzed on site in the clinical laboratory with the QuickMIC system, and compared with DDM for 8 antibiotics routinely used in the clinical laboratory. The overall essential agreement between MIC values obtained by QuickMIC and BMD was 83.4%, with an average time to result of 3 h 2 min (SD: 24.8 min) for the QuickMIC method. For the clinical dataset, the categorical agreement between QuickMIC and DDM was 96.8%, whereas essential and categorical agreement against BMD was 91.0% and 96.7%, respectively, and the total turnaround time as compared to routine diagnostics was shown to be reduced by 40% (33 h vs. 55 h). Interexperiment variability was low (average SD: 44.6% from target MIC) compared to the acceptable standard of +/- 1 log(2) unit (i.e. -50% to +100% deviation from target MIC) in BMD. We conclude that the QuickMIC method can provide rapid and accurate AST, and may be especially valuable in settings with high resistance rates, and for antibiotics where wildtype and antibiotic-resistant bacteria have MIC distributions that are close or overlapping.
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| 24. |
- Malmberg, Christer, et al.
(författare)
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Faster results, higher precision: Evaluating the QuickMIC rapid AST assay in a clinical setting
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The rapidly changing landscape of antimicrobial resistance poses a challenge for empirical therapy and highlights the need for fast antibiotic susceptibility diagnostics to guide treatment. Traditional methods for antibiotic susceptibility testing (AST) of bacteria such as broth microdilution (BMD) or the disc diffusion method (DDM) are comparatively slow and with high variability. Rapid AST methods under development often trade speed for resolution, sometimes only measuring responses at a single antibiotic concentration. QuickMIC is a recently developed lab-on-a-chip system for rapid AST. Here we evaluate the performance of the QuickMIC method with regard to speed, precision and accuracy in comparison to traditional diagnostic methods. 151 blood cultures of clinical Gram-negative isolates with a high frequency of resistant bacteria were tested with the QuickMIC system and compared with BMD for 12 antibiotics. To investigate sample turnaround time and functionality in a clinical setting, another 41 clinical blood culture samples were acquired from the Uppsala University Hospital and analyzed on site in the clinical laboratory with the QuickMIC system and compared with DDM for 8 antibiotics routinely used in the clinical laboratory. The overall essential agreement between MIC values obtained by QuickMIC and BMD was 83.2%, with times to result of 3 h 2 min (SD: 24.8 min) for the QuickMIC method. For the clinical dataset, the categorical agreement was 94.9%, and the total turnaround time as compared to routine diagnostics reduced by 40% (33 h vs. 55 h). Interexperiment variability was low (average SD: 44.6% from target MIC) compared to the acceptable standard of ±1 log2 unit (-50% to +100% deviation from target MIC) in BMD. We conclude that the QuickMIC method can be used to rapidly guide therapy, and may be especially valuable for antibiotics where wildtype and resistant MIC distributions are close or overlapping or in settings with high background resistance.
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| 25. |
- Malmberg, Christer, 1984-, et al.
(författare)
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The T2Bacteria panel and rapid AST with bacteria pre-sampling for combined ID and AST before blood culture positivity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Rapid diagnostic methods are important for antibiotic stewardship and for improving quality of care in severe infections. New non-culture based methods for bacterial identification (ID) within hours directly from blood sampling are becoming available, such as the T2Bacteria panel. However, blood cultures remain necessary for bacteria isolation and follow-up analysis such as antibiotic susceptibility testing (AST). QuickMIC is a rapid diagnostic tool under development, capable of AST at very low bacterial concentrations. Here we evaluate a combined rapid ID/AST diagnostic workflow using the T2Bacteria panel and the QuickMIC AST system.Materials/methods: Two diagnostic workflows were simulated, a “standard” workflow using blood culture followed by MALDI-TOF MS (MS) and AST by broth microdilution (BMD); or a “rapid” workflow using T2Bacteria followed by AST using QuickMIC. Clinically derived strains of Escherichia coli (n = 5), Klebsiella pneumoniae (n = 9), Acinetobacter baumannii (n = 6), Pseudomonas aeruginosa (n = 5), Enterococcus faecalis (n=1) and Staphylococcus aureus (n =12) were inoculated in horse blood and used to simultaneously start blood cultures as well as analyses using the T2Bacteria panel. After identification of bacteria-containing blood cultures using the T2Bacteria panel, the cultures were sampled for analysis using rapid AST using QuickMIC. Further, after blood culture positivity, MS was performed. Specificity, sensitivity and turnaround times were compared between the two workflows, and QuickMIC results were compared to results obtained using the BMD method with regard to categorical and essential agreement.Results: The rapid diagnostic workflow was significantly faster than the standard workflow (9.5±2.5h vs. 52.9±0.4h, p<0.001), and significantly faster for Gram-negative compared to Gram-positive bacteria (7.4±0.6h vs 12.2±0.4h, p<0.001). For 68% of the samples, the rapid ID/AST result was available before blood culture positivity (86% for Gram-negatives, 45% for Gram-positives). For 100% of the samples, ID/AST results from the rapid workflow were available before ID by MS. Diagnostic sensitivity/specificity at the species level were 94.7%/99.5% and 97.4%/100% for analysis from the T2Bacteria panel or MS, respectively. QuickMIC results took on average 167±15 min, and categorical agreement to BMD was 70.9% (Gram-negative bacteria) and 72.8% (Gram-positive bacteria).Conclusions: We conclude that QuickMIC has the potential to be a suitable companion diagnostic to the T2Bacteria panel for delivering rapid ID/AST results to enable same-workshift results for improved antibiotic stewardship and quality of care.
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