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1.	Allander, Lisa, et al. (författare) Impact of porin deficiency on the synergistic potential of colistin in combination with β-lactam/β-lactamase inhibitors against Klebsiella pneumoniae Annan publikation (övrigt vetenskapligt/konstnärligt)
2.	Hong, Lisa T, et al. (författare) 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 Ingår i: Pharmacotherapy. - : John Wiley & Sons. - 0277-0008 .- 1875-9114. ; 43:8, s. 736-739 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).
3.	Hong, Lisa T., et al. (författare) 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 Ingår i: Pharmacotherapy. - : John Wiley & Sons. - 0277-0008 .- 1875-9114. ; 43:8, s. 740-777 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).
4.	Hong, Lisa T., et al. (författare) Response to comment on 'International consensus recommendations for the use of prolonged-infusion β-lactams 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 American (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists' 2024 Ingår i: Pharmacotherapy. - : Pharmacotherapy Publications. - 0277-0008 .- 1875-9114. ; 44:2, s. 208-209 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
5.	Allander, Lisa, et al. (författare) Evaluation of ceftazidime-avibactam in combination with colistin against KPC-2-producing Klebsiella pneumoniae with porin deficiency in static and dynamic time-kill experiments Annan publikation (övrigt vetenskapligt/konstnärligt)
6.	Allander, Lisa, et al. (författare) Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48-and NDM-Producing Escherichia coli and Klebsiella pneumoniae 2022 Ingår i: Antibiotics. - : MDPI. - 2079-6382. ; 11:11 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.
7.	Allander, Lisa (författare) β-lactam combinations against multidrug-resistant Enterobacterales : Exploring combination effects and resistance development 2023 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.
8.	Behnke, Michael, et al. (författare) Information technology aspects of large-scale implementation of automated surveillance of healthcare-associated infections 2021 Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 27:Suppl 1, s. S29-S39 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.
9.	Bulman, Zackery P., et al. (författare) Research priorities towards precision antibiotic therapy to improve patient care 2022 Ingår i: LANCET MICROBE. - : Elsevier. - 2666-5247. ; 3:10, s. e795-e802 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.
10.	Cojutti, Pier Giorgio, et al. (författare) Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients 2023 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 67:3 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.
11.	Dahdouh, Elias, et al. (författare) Computational Modeling and Design of New Inhibitors of Carbapenemases : A Discussion from the EPIC Alliance Network 2022 Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:17 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.
12.	Dittrich, Sabine, et al. (författare) 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 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8 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.
13.	Dyar, O J, et al. (författare) ESCMID generic competencies in antimicrobial prescribing and stewardship : towards a European consensus. 2019 Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 25:1, s. 13-19 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.
14.	Helou, R. , I, et al. (författare) Study protocol for an international, multicentre stepped-wedge cluster randomised trial to evaluate the impact of a digital antimicrobial stewardship smartphone application 2020 Ingår i: BMJ Open. - : BMJ PUBLISHING GROUP. - 2044-6055. ; 10:6 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.
15.	Jonsson, Anna-Karin, et al. (författare) A trial with IgY chicken antibodies to eradicate faecal carriage of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamases 2015 Ingår i: Infection Ecology & Epidemiology. - : Informa UK Limited. - 2000-8686. ; 5 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.
16.	Kurland, Siri, et al. (författare) Human plasma protein levels alter the in vitro antifungal activity of caspofungin : An explanation to the effect in critically ill? 2022 Ingår i: Mycoses. - : John Wiley & Sons. - 0933-7407 .- 1439-0507. ; 65:1, s. 79-87 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.
17.	Lagerbäck, Pernilla, et al. (författare) 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 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 71:8, s. 2321-2325 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.
18.	Lindström, Anna, 1961-, et al. (författare) Introducing the C-reactive protein point-of-care test : A conversation analytic study of primary care consultations for respiratory tract infection 2022 Ingår i: Social Science and Medicine. - : Elsevier. - 0277-9536 .- 1873-5347. ; 315 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.
19.	Ljungquist, Oskar, et al. (författare) Karbapenemresistenta Escherichia coli finns nu i Sverige 2013 Ingår i: Läkartidningen. - 0023-7205. ; , s. 32-33 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.
20.	Ljungquist, O, et al. (författare) Karbapenemresistenta Escherichia coli finns nu i Sverige : Carbapenem-resistant Escherichia coli now exist in Sweden 2013 Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 110:32/33, s. 1401-1402 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.
21.	Malmberg, Christer, et al. (författare) A Novel Microfluidic Assay for Rapid Phenotypic Antibiotic Susceptibility Testing of Bacteria Detected in Clinical Blood Cultures 2016 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:12 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.
22.	Malmberg, Christer, 1984- (författare) Development of a robust and rapid microfluidics-based antibiotic susceptibility test : From prototype to clinical implementation 2021 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.
23.	Malmberg, Christer, et al. (författare) Evaluation of the Speed, Accuracy and Precision of the QuickMIC Rapid Antibiotic Susceptibility Testing Assay With Gram-Negative Bacteria in a Clinical Setting 2022 Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 12 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.
24.	Malmberg, Christer, et al. (författare) Faster results, higher precision: Evaluating the QuickMIC rapid AST assay in a clinical setting 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.
25.	Malmberg, Christer, 1984-, et al. (författare) The T2Bacteria panel and rapid AST with bacteria pre-sampling for combined ID and AST before blood culture positivity 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.
26.	Malmros, Karin, et al. (författare) Comparison of antibiotic treatment guidelines for urinary tract infections in 15 European countries : Results of an online survey 2019 Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 54:4, s. 478-486 Tidskriftsartikel (refereegranskat)abstract Appropriate antibiotic use for urinary tract infections (UTIs) is important in order to provide effective and safe treatment while minimising the risk of antimicrobial resistance development. This survey was carried out to compare existing national guidelines for UTIs in Europe. Experts in 37 European countries were asked to participate. An electronic questionnaire was used to obtain information on treatment recommendations, factors considered important when setting guidelines, acceptable resistance rates for empirical therapy, evidence grading, and existing resistance surveillance for uropathogens. Treatment guidelines and antimicrobial susceptibility data were collected. In total, 22 experts (59%) responded to the survey. National guidelines were missing in four countries and data were incomplete in three cases. Fifteen national guidelines published between 2004 and 2017 were included in the analysis. Great variability was found between guidelines in the selection of antibiotics, dosing regimens and treatment duration. For example, 10 different antibiotics were recommended as first-line therapy for uncomplicated cystitis. National surveillance data on antimicrobial susceptibility of uropathogens were available in 13 of 15 countries. Resistance epidemiology could not explain the observed differences between guidelines, and comparison of resistance rates was hampered by variations in methods. This study revealed major differences in treatment guidelines for UTIs within Europe, indicating that there are opportunities for improvement. More clinical research and a more systematic and stratified approach to resistance surveillance, including also antibiotics that are currently not available in all countries, is needed.
27.	Maraolo, Alberto Enrico, et al. (författare) Organization and training at national level of antimicrobial stewardship and infection control activities in Europe : an ESCMID cross-sectional survey 2019 Ingår i: European Journal of Clinical Microbiology and Infectious Diseases. - : Springer. - 0934-9723 .- 1435-4373. ; 38:11, s. 2061-2068 Tidskriftsartikel (refereegranskat)abstract Antimicrobial stewardship (AMS) and Infection prevention and control (IPC) are two key complementary strategies that combat development and spread of antimicrobial resistance. The ESGAP (ESCMID Study Group for AMS), EUCIC (European Committee on Infection Control) and TAE (Trainee Association of ESCMID) investigated how AMS and IPC activities and training are organized, if present, at national level in Europe. From February 2018 to May 2018, an internet-based cross-sectional survey was conducted through a 36-item questionnaire, involving up to three selected respondents per country, from 38 European countries in total (including Israel), belonging to the ESGAP/EUCIC/TAE networks. All 38 countries participated with at least one respondent, and a total of 81 respondents. Education and involvement in AMS programmes were mandatory during the postgraduate training of clinical microbiology and infectious diseases specialists in up to one-third of countries. IPC was acknowledged as a specialty in 32% of countries. Only 32% of countries had both guidance and national requirements regarding AMS programmes, in contrast to 61% for IPC. Formal national staffing standards for AMS and IPC hospital-based activities were present in 24% and 63% of countries, respectively. The backgrounds of professionals responsible for AMS and IPC programmes varied tremendously between countries. The organization and training of AMS and IPC in Europe are heterogeneous and national requirements for activities are frequently lacking.
28.	Martson, A-G, et al. (författare) How to design a study to evaluate therapeutic drug monitoring in infectious diseases? 2020 Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 26:8, s. 1008-1016 Forskningsöversikt (refereegranskat)abstract Background: Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM.Objectives: We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM.Sources: The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM.Content: This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design.
29.	Montelin, Hanna, 1984- (författare) Antibiotic-Induced Damage on the Intestinal Microbiota and Treatment of Urinary Tract Infections Caused by ESBL- and Non-ESBL-Producing Bacteria 2024 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Therapeutic options for urinary tract infection (UTI) caused by Escherichia coli and Klebsiella pneumoniae are limited due to resistance against cephalosporins and carbapenems, which is typically mediated by the production of extended-spectrum β-lactamases (ESBLs) and carbapenemases. ESBL-producing bacteria are frequently co-resistant to other antibiotic classes, resulting in a shortage of treatment options. While all systemic antibiotic treatments are likely to disturb the microbiota and increase selection of resistance, evidence on the extent and persistence of such effects for different antibiotics is limited. The primary objective of this thesis was to investigate the therapeutic effect of carbapenem-sparing and narrow-spectrum oral antibiotics in the treatment of UTI, and to evaluate the impact of commonly used antibiotics on the intestinal microbiota. The first study investigated the efficacy of nitrofurantoin and pivmecillinam for lower UTI in men (n=171), with trimethoprim as a comparator. We concluded that nitrofurantoin and pivmecillinam are suitable for empirical treatment of lower UTIs in men, considering their high activity against Eschericha coli and limited impact on the microbiota. In a prospective multi-center study conducted at 15 infectious diseases hospital departments, patients (n=235) with UTI caused by ESBL-producing Enterobacterales were recruited. We aimed to evaluate clinical and microbiological treatment outcomes and relapse rates. The results indicate that carbapenem-sparing antibiotics were effective for UTI caused by ESBL-producing Enterobacterales and can be recommended for non-critically ill patients. Moreover, we noted that certain bacterial genetic features (e.g., ST131 in Eschericha coli and haemolysin) were associated with microbiological failure and relapse.In a randomized, controlled trial with healthy adults (n=86), we investigated the impact on the microbiota of five antibiotics (ceftibuten, ciprofloxacin, nitrofurantoin, pivmecillinam, trimethoprim-sulfamethoxazole) that are commonly used for UTI. Fecal samples were collected before and up to one year after five days of antibiotic treatment. Ciprofloxacin demonstrated significant immediate and long-term disruption of the intestinal microbiota in terms of diversity and taxonomy and stands out in comparison with the other antibiotics included in the study.In a prospective study, we investigated the intestinal microbiota in patients with hematological diseases undergoing hematopoietic stem cell transplantation (HSCT, n=88). Changes over time and during antibiotic treatment and potential associations between the intestinal microbiota at baseline and patient outcomes were explored. Oral ciprofloxacin demonstrated a significant impact on the intestinal microbiota, which was greater than the impact of intravenous broad-spectrum antibiotics. A low microbiome diversity at baseline was associated with neutropenic fever and antibiotic treatment following HSCT.
30.	Montelin, Hanna, et al. (författare) Antibiotic-induced microbiome disturbances in hematological patients undergoing hematopoietic stem cell transplantation: a prospective observational study 2024 Annan publikation (övrigt vetenskapligt/konstnärligt)
31.	Montelin, Hanna, 1984-, et al. (författare) Impact of ceftibuten, ciprofloxacin, nitrofurantoin, pivmecillinam and trimethoprim-sulphamethoxazole on the intestinal microbiota and resistome: a randomized controlled trial with healthy adults 2024 Annan publikation (övrigt vetenskapligt/konstnärligt)
32.	Montelin, Hanna, et al. (författare) Retrospective evaluation of nitrofurantoin and pivmecillinam for the treatment of lower urinary tract infections in men 2019 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Objectives: This study aimed to retrospectively assess the clinical outcome with nitrofurantoin and pivmecillinam for lower urinary tract infections (UTI) in men. Patients treated with trimethoprim were also included for comparison.Methods: All prescriptions of the study antibiotics to adult men in Uppsala County, Sweden, during 2012 were extracted. Data on patient characteristics, therapy, clinical outcome and microbiological results were obtained from the electronic medical records. The relative impact of antibiotic therapy, patient factors and pathogens on clinical outcome was assessed with univariate logistic regression using a 95% confidence interval (CI).Results: 832 prescriptions were identified, and 171 patients treated with nitrofurantoin (n = 69), pivmecillinam (n = 57) and trimethoprim (n = 45) met the inclusion criteria. Treatment failure occurred in one patient treated with nitrofurantoin and in four patients treated with pivmecillinam. New prescriptions of UTI antibiotics and relapse within 3 months after completion of therapy were more frequent with nitrofurantoin (34% and 15%) and pivmecillinam (30% and 17%) than trimethoprim (22 and 7%). However, these differences were not statistically significant and substantial heterogeneity was noted between the treatment groups. Urinary tract catheterization was associated with a higher risk for new antibiotic prescriptions (OR 2.34, 95% CI 1.14–4.80; P = 0.022) and prostate cancer was associated with a higher incidence of relapse (OR 3.01, 95% CI 1.09–8.29; P = 0.042).Conclusions: The clinical outcome with nitrofurantoin and pivmecillinam was acceptable in comparison with the results of previous studies. These antibiotics are suitable for empirical treatment of lower UTI in men considering their high activity against Escherichia coli and limited impact on the intestinal microbiota.
33.	Montelin, Hanna, 1984-, et al. (författare) Treatment, outcomes and characterization of pathogens in urinary tract infections caused by ESBL-producing Enterobacterales : a prospective multicentre study 2024 Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. Tidskriftsartikel (refereegranskat)abstract Objectives: Treatment options for urinary tract infections (UTIs) caused by ESBL-producing Enterobacterales are limited. Moreover, evidence to support therapeutic decisions is lacking. This study assessed current treatment strategies and patient and pathogen characteristics in relation to clinical and microbiological outcomes.Methods: Patients with UTI caused by ESBL-producing Enterobacterales were prospectively recruited by investigators at 15 infectious disease hospital departments. Data were collected on patient characteristics, treatments, clinical and microbiological cure 10–14 days after the end of treatment, and relapse within 3 months. Bacterial isolates were subjected to MIC determination and WGS.Results: In total, 235 patients (107 febrile UTI, 128 lower UTI) caused by Escherichia coli (n = 223) and Klebsiella spp. (n = 12) were included. Clinical and microbiological cure rates were 83% and 64% in febrile UTI, and 79% and 65% in lower UTI. Great variability in treatments was observed, especially in oral therapy for febrile UTI. No difference was seen in clinical outcomes with piperacillin/tazobactam (n = 28) compared with carbapenems (n = 41). Pivmecillinam was frequently used in lower UTI (n = 62), and was also associated with high clinical cure rates when used as initial therapy (10/10) or follow-up (7/8) for febrile UTI. Recurrent infection, diabetes mellitus and urogenital disease were associated (P < 0.05) with clinical failure and relapse. In E. coli, ST131 was significantly associated with relapse, and haemolysin with microbiological failure or relapse.Conclusions: Antibiotic treatments were highly variable. Patient and pathogen factors were identified as potential determinants of disease presentation and outcomes and may prove useful to guide individualized treatment and follow-up.
34.	Nauclér, P., et al. (författare) Impact of time to antibiotic therapy on clinical outcome in patients with bacterial infections in the emergency department : implications for antimicrobial stewardship 2021 Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 27:2, s. 175-181 Forskningsöversikt (refereegranskat)abstract BACKGROUND: Rapid initiation of antibiotic treatment is considered crucial in patients with severe infections such as septic shock and bacterial meningitis, but may not be as important for other infectious syndromes. A better understanding of which patients can tolerate a delay in start of therapy is important for antibiotic stewardship purposes.OBJECTIVES: To explore the existing evidence on the impact of time to antibiotics on clinical outcomes in patients presenting to the emergency department (ED) with bacterial infections of different severity of illness and source of infection.SOURCES: A literature search was performed in the PubMed/MEDLINE database using combined search terms for various infectious syndromes (sepsis/septic shock, bacterial meningitis, lower respiratory tract infections, urinary tract infections, intra-abdominal infections and skin and soft tissue infections), time to antibiotic treatment, and clinical outcome.CONTENT: The literature search generated 8828 hits. After screening titles and abstracts and assessing potentially relevant full-text papers, 60 original articles (four randomized controlled trials, 43 observational studies) were included. Most articles addressed sepsis/septic shock, while few studies evaluated early initiation of therapy in mild to moderate disease. The lack of randomized trials and the risk of confounding factors and biases in observational studies warrant caution in the interpretation of results. We conclude that the literature supports prompt administration of effective antibiotics for septic shock and bacterial meningitis, but there is no clear evidence showing that a delayed start of therapy is associated with worse outcome for less severe infectious syndromes.IMPLICATIONS: For patients presenting with suspected bacterial infections, withholding antibiotic therapy until diagnostic results are available and a diagnosis has been established (e.g. by 4-8 h) seems acceptable in most cases unless septic shock or bacterial meningitis are suspected. This approach promotes the use of ecologically favourable antibiotics in the ED, reducing the risks of side effects and selection of resistance.
35.	Olsson, Anna, et al. (författare) Activity of polymyxin B combinations against genetically well-characterised Klebsiella pneumoniae producing NDM-1 and OXA-48-like carbapenemases 2023 Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 62:5 Tidskriftsartikel (refereegranskat)abstract Background: Combination therapy can enhance the activity of available antibiotics against multidrug-resistant Gram-negative bacteria. This study assessed the effects of polymyxin B combinations against carbapenemase-producing Klebsiella pneumoniae ( K. pneumoniae).Methods: Twenty clinical K. pneumoniae strains producing NDM-1 (n = 8), OXA-48-like (n = 10), or both NDM-1 and OXA-48-like (n = 2) carbapenemases were used. Whole-genome sequencing was applied to detect resistance genes (e.g. encoding antibiotic-degrading enzymes) and sequence alterations influ-encing permeability or efflux. The activity of polymyxin B in combination with aztreonam, fosfomycin, meropenem, minocycline, or rifampicin was investigated in 24-hour time-lapse microscopy experiments. Endpoint samples were spotted on plates with and without polymyxin B at 4 x MIC to assess resistance development. Finally, associations between synergy and bacterial genetic traits were explored.Results: Synergistic and bactericidal effects were observed with polymyxin B in combination with all other antibiotics: aztreonam (11 of 20 strains), fosfomycin (16 of 20), meropenem (10 of 20), minocy-cline (18 of 20), and rifampicin (15 of 20). Synergy was found with polymyxin B in combination with fosfomycin, minocycline, or rifampicin against all nine polymyxin-resistant strains. Wildtype mgrB was associated with polymyxin B and aztreonam synergy (P = 0.0499). An absence of arr-2 and arr-3 was associated with synergy of polymyxin B and rifampicin (P = 0.0260). Emergence of populations with reduced polymyxin B susceptibility was most frequently observed with aztreonam and meropenem.Conclusion: Combinations of polymyxin B and minocycline or rifampicin were most active against the tested NDM-1 and OXA-48-like-producing K. pneumoniae. Biologically plausible genotype-phenotype as-sociations were found. Such information might accelerate the search for promising combinations and guide individualised treatment.
36.	Olsson, Anna, et al. (författare) Efficacy of Antibiotic Combinations against Multidrug-Resistant Pseudomonas aeruginosa in Automated Time-Lapse Microscopy and Static Time-Kill Experiments 2020 Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 64:6 Tidskriftsartikel (refereegranskat)abstract Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa. We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampin, temocillin, thiamphenicol, or trimethoprim by automated time-lapse microscopy using predefined cutoff values indicating inhibition of growth (<= 10(6) CFU/ml) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments. All strains were intermediate or resistant to polymyxin B, antipseudomonal beta-lactams, ciprofloxacin, and amikacin. Genes encoding beta-lactamases (e.g., bla(PAO) and bla(OXA-50)) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol, and trimethoprim. Time-kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations.
37.	Olsson, Anna (författare) Exploring the interactions of antibiotic combinations against multidrug-resistant Gram-negative bacteria 2021 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Antimicrobial resistance is emerging and available treatment options are lacking. Antibiotics is a cornerstone in modern medicine where medical procedures such as surgery, care of premature babies or treatment of cancer is dependent on efficient drugs. The need for novel treatment alternatives is increasing as bacteria continue to develop new resistance mechanisms.The main goal of this thesis was to screen for antimicrobial combinations efficient against Gram-negative bacteria. The complex membrane structure of Gram-negative bacteria is very protective against antimicrobial activity making many antibiotics ineffective. Polymyxin B was therefore used as a main component in the combinations evaluated due to its membrane disruptive mode of action. Previously neglected or disused antibiotics was used in combination with polymyxin B as a part of a Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) called CO-ACTION. The prevailing theory of polymyxin B combinations is that the membrane disruptive effect will facilitate entry of a second antibiotic and reduce efflux activity. In contrast, the combination will not be as efficient in the presence of bacterial enzymatic activity as the resistance mechanism is not affected by changes in the membrane composition. To increase knowledge on underlying mechanisms behind the success of antimicrobial combinations an extensive genetic analysis was performed. Several promising polymyxin B combinations were found which could offer a treatment option in caring for severely ill patients for which few alternatives exist. Associations between genetic background and efficient bacterial killing was also established. The chance of synergistic effect by the combination was increased if the antibiotic used in combination with polymyxin B could normally not enter the bacterial cell or in presence of resistance mechanisms increasing efflux activity. This thesis highlights the fact that only phenotypical antimicrobial susceptibility testing would not be used in forecasting the success of antimicrobial combinations. Information on antimicrobial susceptibility in combination with knowledge on resistance mechanisms present and how it influences the antibiotics used in combination is equally important. With this work increased knowledge on genetic background of resistance mechanisms and bacterial killing by polymyxin B combinations and was provided. Antimicrobial combinations offer an interesting feature when no other treatment alternatives are available. The lack of diagnostics in forecasting the success of combination therapy in a clinical microbiology lab is of concern. The knowledge obtained in this work contributes to the general knowledge on antimicrobial combinations and provides an example of how to evaluate their effect.
38.	Olsson, Anna, et al. (författare) Interactions of polymyxin B in combination with aztreonam, minocycline, meropenem and rifampicin against Escherichia coli producing NDM and OXA-48-group carbapenemases 2021 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:12 Tidskriftsartikel (refereegranskat)abstract Carbapenemase-producing Enterobacterales pose an increasing medical threat. Combination therapy is often used for severe infections; however, there is little evidence supporting the optimal selection of drugs. This study aimed to determine the in vitro effects of polymyxin B combinations against carbapenemase-producing Escherichia coli. The interactions of polymyxin B in combination with aztreonam, meropenem, minocycline or rifampin against 20 clinical isolates of NDM and OXA-48-group-producing E. coli were evaluated using time-lapse microscopy; 24-h samples were spotted on plates with and without 4× MIC polymyxin B for viable counts. Whole-genome sequencing was applied to identify resistance genes and mutations. Finally, potential associations between combination effects and bacterial genotypes were assessed using Fisher's exact test. Synergistic and bactericidal effects were observed with polymyxin B and minocycline against 11/20 strains and with polymyxin B and rifampin against 9/20 strains. The combinations of polymyxin B and aztreonam or meropenem showed synergy against 2/20 strains. Negligible resistance development against polymyxin B was detected. Synergy with polymyxin B and minocycline was associated with genes involved in efflux (presence of tet[B], wild-type soxR, and the marB mutation H44Q) and lipopolysaccharide synthesis (eptA C27Y, lpxB mutations, and lpxK L323S). Synergy with polymyxin B and rifampin was associated with sequence variations in arnT, which plays a role in lipid A modification. Polymyxin B in combination with minocycline or rifampin frequently showed positive interactions against NDM- and OXA-48-group-producing E. coli. Synergy was associated with genes encoding efflux and components of the bacterial outer membrane.
39.	Olsson, Anna, et al. (författare) Synergy of polymyxin B and minocycline against KPC-3- and OXA-48-producing Klebsiella pneumoniae in dynamic time-kill experiments : agreement with in silico predictions. 2023 Ingår i: Journal of Antimicrobial Chemotherapy. - 0305-7453 .- 1460-2091. Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: Combination therapy is often used for carbapenem-resistant Gram-negative bacteria. We previously demonstrated synergy of polymyxin B and minocycline against carbapenem-resistant Klebsiella pneumoniae in static time-kill experiments and developed an in silico pharmacokinetic/pharmacodynamic (PK/PD) model. The present study assessed the synergistic potential of this antibiotic combination in dynamic experiments.METHODS: Two clinical K. pneumoniae isolates producing KPC-3 and OXA-48 (polymyxin B MICs 0.5 and 8 mg/L, and minocycline MICs 1 and 8 mg/L, respectively) were included. Activities of the single drugs and the combination were assessed in 72 h dynamic time-kill experiments mimicking patient pharmacokinetics. Population analysis was performed every 12 h using plates containing antibiotics at 4× and 8× MIC. WGS was applied to reveal resistance genes and mutations.RESULTS: The combination showed synergistic and bactericidal effects against the KPC-3-producing strain from 12 h onwards. Subpopulations with decreased susceptibility to polymyxin B were frequently detected after single-drug exposures but not with the combination. Against the OXA-48-producing strain, synergy was observed between 4 and 8 h and was followed by regrowth. Subpopulations with decreased susceptibility to polymyxin B and minocycline were detected throughout experiments. For both strains, the observed antibacterial activities showed overall agreement with the in silico predictions.CONCLUSIONS: Polymyxin B and minocycline in combination showed synergistic effects, mainly against the KPC-3-producing K. pneumoniae. The agreement between the experimental results and in silico predictions supports the use of PK/PD models based on static time-kill data to predict the activity of antibiotic combinations at dynamic drug concentrations.
40.	Paul, Mical, et al. (författare) European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine) 2022 Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 28:4, s. 521-547 Tidskriftsartikel (refereegranskat)abstract ScopeThese ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy.MethodsAn expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak).RecommendationsThe guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, β-lactam/β-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.
41.	Skarp, Kari-Pekka, et al. (författare) Synergistic and bactericidal activities of mecillinam, amoxicillin and clavulanic acid combinations against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in 24-h time-kill experiments 2019 Ingår i: International Journal of Antimicrobial Agents. - : ELSEVIER SCIENCE BV. - 0924-8579 .- 1872-7913. ; 53:1, s. 74-79 Tidskriftsartikel (refereegranskat)abstract This study aimed to evaluate the potential synergistic and bactericidal effects of mecillinam in combination with amoxicillin and clavulanic acid against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. Eight clinical E. coli isolates with varying susceptibility to mecillinam [minimum inhibitory concentrations (MICs) of 0.125 mg/L to >256 mg/L] and high-level resistance to amoxicillin (MICs > 256 mg/L) were used. Whole-genome sequencing was performed to determine the presence of beta-lactamase genes and mutations in the cysB gene. The activities of single drugs and the combinations of two or three drugs were tested in 24-h time-kill experiments. Population analysis was performed for two strains before and after experiments. Only one strain had a mutation in the cysB gene resulting in an amino acid substitution. With the two-drug combinations, initial killing was observed both with mecillinam and amoxicillin when combined with clavulanic acid. Synergy was observed with mecillinam and clavulanic acid against one strain and with amoxicillin and clavulanic acid against three strains. However, following significant re-growth, a bactericidal effect was found only with amoxicillin and clavulanic acid against two strains. Pre-existing subpopulations with elevated mecillinam MICs were detected before experiments and were selected with mecillinam alone or in two-drug combinations. In contrast, the three-drug combination showed enhanced activity with synergy against six strains, a bactericidal effect against all eight strains, and suppression of resistance during 24-h antibiotic exposure. This combination may be of clinical interest in the treatment of urinary tract infections caused by ESBL-producing E. coli.
42.	Sütterlin, Susanne, et al. (författare) Silver resistance genes are overrepresented among Escherichia coli isolates with CTX-M production 2014 Ingår i: Applied and Environmental Microbiology. - 0099-2240 .- 1098-5336. ; 80:22, s. 6863-6869 Tidskriftsartikel (refereegranskat)abstract Members of the Enterobacteriaceae with extended-spectrum beta-lactamases (ESBLs) of the CTX-M type have disseminated rapidly in recent years and have become a threat to public health. In parallel with the CTX-M type expansion, the consumption and widespread use of silver-containing products has increased. To determine the carriage rates of silver resistance genes in different Escherichia coli populations, the presence of three silver resistance genes (silE, silP, and silS) and genes encoding CTX-M-, TEM-, and SHV-type enzymes were explored in E. coli isolates of human (n = 105) and avian (n = 111) origin. The antibiotic profiles were also determined. Isolates harboring CTX-M genes were further characterized, and phenotypic silver resistance was examined. The silE gene was present in 13 of the isolates. All of them were of human origin. Eleven of these isolates harbored ESBLs of the CTX-M type (P = 0.007), and eight of them were typed as CTX-M-15 and three as CTX-M-14. None of the silE-positive isolates was related to the O25b-ST131 clone, but 10 out of 13 belonged to the ST10 or ST58 complexes. Phenotypic silver resistance (silver nitrate MIC > 512 mg/liter) was observed after silver exposure in 12 of them, and a concomitant reduced susceptibility to piperacillin-tazobactam developed in three. In conclusion, 12% of the human E. coli isolates but none of the avian isolates harbored silver resistance genes. This indicates another route for or level of silver exposure for humans than that caused by common environmental contamination. Since silE-positive isolates were significantly more often found in CTX-M-positive isolates, it is possible that silver may exert a selective pressure on CTX-M-producing E. coli isolates.
43.	Swartling, Maria, et al. (författare) Therapeutic drug monitoring of vancomycin and meropenem : Illustration of the impact of inaccurate information in dose administration time 2023 Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 63:1 Tidskriftsartikel (refereegranskat)abstract Objectives: To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and meropenem, and to explore the influence of drug and patient characteristics, and TDM sampling strategies.Methods: Bedside observations of errors in documented dose administration times were collected. Population pharmacokinetic simulations were performed for vancomycin and meropenem, evaluating different one- and two-sampling strategies for populations with estimated creatinine clearance (CLcr) of 30, 80 or 130 mL/min. The impact of errors was evaluated as the proportion of individuals incorrectly considered to have reached the target.Results: Of 143 observed dose administrations, 97% of doses were given within ±30 min of the documented time. For vancomycin, a +30 min error was predicted to result in a 0.1-3.9 percentage point increase of cases incorrectly evaluated as reaching area under the concentration-time curve during a 24-hour period (AUC24)/minimum inhibitory concentration (MIC) >400, with the largest increase for patients with augmented renal clearance and peak and trough sampling. For meropenem, a +30 min error resulted in a 1.3-6.4 and 0-20 percentage point increase of cases incorrectly evaluated as reaching 100% T>MIC, and 50% T>MIC, respectively. Overall, mid-dose and trough sampling was most favourable for both antibiotics.Conclusions: For vancomycin, simulations indicate that TDM-based target attainment evaluation is robust with respect to the observed errors in dose administration time of ±30 min; however, the errors had a potentially clinically important impact in patients with augmented renal clearance. For meropenem, extra measures to promote correct documentation are warranted when using TDM, as the impact of errors was evident even in patients with normal renal function.
44.	Tängdén, Thomas, et al. (författare) A genome-wide association study in a large community-based cohort identifies multiple loci associated with susceptibility to bacterial and viral infections 2022 Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12 Tidskriftsartikel (refereegranskat)abstract There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. Genome-wide association studies using large population cohorts can be a first step towards identifying patients prone to infectious diseases and targets for new therapies. Genetic variants associated with clinically relevant entities of bacterial and viral infections (e.g., abdominal infections, respiratory infections, and sepsis) in 337,484 participants of the UK Biobank cohort were explored by genome-wide association analyses. Cases (n = 81,179) were identified based on ICD-10 diagnosis codes of hospital inpatient and death registries. Functional annotation was performed using gene expression (eQTL) data. Fifty-seven unique genome-wide significant loci were found, many of which are novel in the context of infectious diseases. Some of the detected genetic variants were previously reported associated with infectious, inflammatory, autoimmune, and malignant diseases or key components of the immune system (e.g., white blood cells, cytokines). Fine mapping of the HLA region revealed significant associations with HLA-DQA1, HLA-DRB1, and HLA-DRB4 locus alleles. PPP1R14A showed strong colocalization with abdominal infections and gene expression in sigmoid and transverse colon, suggesting causality. Shared significant loci across infections and non-infectious phenotypes in the UK Biobank cohort were found, suggesting associations for example between SNPs identified for abdominal infections and CRP, rheumatoid arthritis, and diabetes mellitus. We report multiple loci associated with bacterial and viral infections. A better understanding of the genetic determinants of bacterial and viral infections can be useful to identify patients at risk and in the development of new drugs.
45.	Tängdén, Thomas, et al. (författare) Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments 2017 Ingår i: Infectious Diseases. - : TAYLOR & FRANCIS LTD. - 2374-4235 .- 2374-4243. ; 49:7, s. 521-527 Tidskriftsartikel (refereegranskat)abstract Background: In view of the paucity of clinical evidence, in vitro studies are needed to find antibiotic combinations effective against multidrug-resistant Gram-negative bacteria. Interpretation of in vitro effects is usually based on bacterial growth after 24h in time-kill and checkerboard experiments. However, the clinical relevance of the effects observed in vitro is not established. In this study we explored alternative output parameters to assess the activities of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii. Methods: Four strains each of P. aeruginosa and A. baumannii were exposed to colistin and meropenem, alone and in combination, in 8h dynamic time-kill experiments. Initial (1h), maximum and 8h bacterial reductions and the area under the bacterial time-kill curve were evaluated. Checkerboards, interpreted based on fractional inhibitory concentration indices after 24h, were performed for comparison. Results: In the time-kill experiments, the combination resulted in enhanced 1h, maximum and 8h bacterial reductions against 2, 3 and 5 of 8 strains, respectively, as compared to the single drugs. A statistically significant reduction in the area under the time-kill curve was observed for three strains. In contrast, the checkerboards did not identify synergy for any of the strains. Conclusions: Combination effects were frequently found with colistin and meropenem against P. aeruginosa and A. baumannii in time-kill experiments but were not detected with the checkerboard method. We propose that the early dynamics of bacterial killing and growth, which may be of great clinical importance, should be considered in future in vitro combination studies.
46.	Tängdén, Thomas, et al. (författare) Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiment 2014 Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 58:3, s. 1757-1762 Tidskriftsartikel (refereegranskat)abstract Combination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM- and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h time-kill experiments. Double- and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin, meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a >= 2 log(10) decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a >= 3 log(10) decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam, fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin, meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.
47.	Tängdén, Thomas, et al. (författare) Foreign Travel Is a Major Risk Factor for Colonization with Escherichia coli Producing CTX-M-Type Extended-Spectrum beta-Lactamases : a Prospective Study with Swedish Volunteers 2010 Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 54:9, s. 3564-3568 Tidskriftsartikel (refereegranskat)abstract Foreign travel has been suggested to be a risk factor for the acquisition of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. To our knowledge, this has not previously been demonstrated in a prospective study. Healthy volunteers traveling outside Northern Europe were enrolled. Rectal swabs and data on potential travel-associated risk factors were collected before and after traveling. A total of 105 volunteers were enrolled. Four of them did not complete the study, and one participant carried ESBL-producing Escherichia coli before travel. Twenty-four of 100 participants with negative pretravel samples were colonized with ESBL-producing Escherichia coli after the trip. All strains produced CTX-M enzymes, mostly CTX-M-15, and some coproduced TEM or SHV enzymes. Coresistance to several antibiotic subclasses was common. Travel to India was associated with the highest risk for the acquisition of ESBLs (88%; n = 7). Gastroenteritis during the trip was an additional risk factor (P = 0.003). Five of 21 volunteers who completed the follow-up after 6 months had persistent colonization with ESBLs. This is the first prospective study demonstrating that international travel is a major risk factor for colonization with ESBL-producing Enterobacteriaceae. Considering the high acquisition rate of 24%, it is obvious that global efforts are needed to meet the emergence and spread of CTX-M enzymes and other antimicrobial resistances.
48.	Tängdén, Thomas, 1976-, et al. (författare) Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extended-spectrum beta-lactamases: a prospective study with Swedish volunteers. 2010 Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; :54, s. 3564-3568 Tidskriftsartikel (refereegranskat)
49.	Tängdén, Thomas, et al. (författare) Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model 2013 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 68:6, s. 1319-1326 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES:Ertapenem resistance is increasing in Enterobacteriaceae. The production of extended-spectrum β-lactamases (ESBLs) and reduced expression of outer membrane porins are major mechanisms of resistance in ertapenem-resistant Klebsiella pneumoniae. Less is known of ertapenem resistance in Escherichia coli. The aim of this study was to explore the impact of ESBL production in E. coli on the antibacterial activity of ertapenem.METHODS:Two E. coli strains, with and without ESBL production, were exposed to ertapenem in vitro for 48 h at concentrations simulating human pharmacokinetics with conventional and higher dosages.RESULTS:Isolates with non-susceptibility to ertapenem (MICs 0.75-1.5 mg/L) were detected after five of nine time-kill experiments with the ESBL-producing strain. All of these isolates had ompR mutations, which reduce the expression of outer membrane porins OmpF and OmpC. Higher dosage did not prevent selection of porin-deficient subpopulations. No mutants were detected after experiments with the non-ESBL-producing strain. Compared with other experiments, experiments with ompR mutants detected in endpoint samples showed significantly less bacterial killing after the second dose of ertapenem. Impaired antibacterial activity against E. coli with ESBL production and ompR mutation was also demonstrated in time-kill experiments with static antibiotic concentrations.CONCLUSIONS: The combination of ESBL production and porin loss in E. coli can result in reduced susceptibility to ertapenem. Porin-deficient subpopulations frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Inappropriate use of ertapenem should be avoided to minimize the risk of selection of ESBL-producing bacteria with reduced susceptibility to carbapenems.
50.	Tängdén, Thomas Grenholm (författare) Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria 2014 Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 119:2, s. 149-153 Forskningsöversikt (refereegranskat)abstract Combination antibiotic therapy for Gram-negative sepsis is controversial. The present review provides a brief summary of the existing knowledge on combination therapy for severe infections with multidrug-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae. Empirical combination antibiotic therapy is recommended for severe sepsis and septic shock to reduce mortality related to inappropriate antibiotic treatment. Because definitive combination therapy has not been proven superior to monotherapy in meta-analyses, it is generally advised to de-escalate antibiotic therapy when the antibiotic susceptibility profile is known, although it cannot be excluded that some subgroups of patients might still benefit from continued combination therapy. Definitive combination therapy is recommended for carbapenemase-producing Enterobacteriaceae and should also be considered for severe infections with Pseudomonas and Acinetobacter spp. when beta-lactams cannot be used. Because resistance to broad-spectrum beta-lactams is increasing in Gram-negative bacteria and because no new antibiotics are expected to become available in the near future, the antibacterial potential of combination therapy should be further explored. In vitro data suggest that combinations can be effective even if the bacteria are resistant to the individual antibiotics, although existing evidence is insufficient to support the choice of combinations and explain the synergistic effects observed. In vitro models can be used to screen for effective combinations that can later be validated in animal or clinical studies. Further, in the absence of clinical evidence, in vitro data might be useful in supporting therapeutic decisions for severe infections with multidrug-resistant Gram-negative bacteria.

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