Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Refine search result
12 1 - 50 of 63
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Akerlund, Anna
    et al.
    Div Clin Microbiol, Lab Med, Jönköping, Region Jonkopin, Sweden.;Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.;Linköping Univ Hosp, Dept Clin & Expt Med, Div Clin Microbiol, Linköping, Sweden..
    Petropoulos, Alexandros
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Malmros, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Giske, Christian G.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden..
    Blood culture diagnostics: a Nordic multicentre survey comparison of practices in clinical microbiology laboratories2022In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 28, no 5Article in journal (Refereed)
    Abstract [en]

    Objectives: Accurate and rapid microbiological diagnostics are crucial to tailor treatment and improve outcomes in patients with severe infections. This study aimed to assess blood culture diagnostics in the Nordic countries and to compare them with those of a previous survey conducted in Sweden in 2013. Methods: An online questionnaire was designed and distributed to the Nordic clinical microbiology laboratories (CMLs) (n = 76) in January 2018. Results: The response rate was 64% (49/76). Around-the-clock incubation of blood cultures (BCs) was supported in 82% of the CMLs (40/49), although in six of these access to the incubators around the clock was not given to all of the cabinets in the catchment area, and 41% of the sites (20/49) did not assist with satellite incubators. Almost half (49%, 24/49) of the CMLs offered opening hours for >= 10 h during weekdays, more commonly in CMLs with an annual output >= 30 000 BCs. Still, positive BCs were left unprocessed for 60-70% of the day due to restrictive opening hours. Treatment advice was given by 23% of CMLs (11/48) in >= 75% of the phone contacts. Rapid analyses (species identification and susceptibility testing with short incubation), performed on aliquots from positive cultures, were implemented in 18% of CMLs (9/49). Compared to 2013, species identification from subcultured colonies (<6 h) had become more common. Conclusions: CMLs have taken action to improve aspects of BC diagnostics, implementing satellite incubators, rapid species identification and susceptibility testing. However, the limited opening hours and availability of clinical microbiologists are confining the advantages of these changes. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

    Download full text (pdf)
    FULLTEXT01
  • 2.
    Allander, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Vickberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48-and NDM-Producing Escherichia coli and Klebsiella pneumoniae2022In: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 11, no 11, article id 1646Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 3.
    Behnke, Michael
    et al.
    Charite Univ Med Berlin, Natl Reference Ctr Surveillance Nosocomial Infect, Hindenburgdamm 27, D-12203 Berlin, Germany.;Free Univ Berlin, Hindenburgdamm 27, D-12203 Berlin, Germany.;Humboldt Univ, Inst Hyg & Environm Med, Hindenburgdamm 27, D-12203 Berlin, Germany..
    Valik, John Karlsson
    Karolinska Univ Hosp, Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden..
    Gubbels, Sophie
    Statens Serum Inst, Data Integrat & Anal Secretariat, Copenhagen, Denmark..
    Teixeira, Daniel
    Geneva Univ Hosp, Infect Control Programme, Geneva, Switzerland..
    Kristensen, Brian
    Statens Serum Inst, Dept Infect Dis Epidemiol & Prevent, Copenhagen, Denmark..
    Abbas, Mohamed
    Geneva Univ Hosp, Infect Control Programme, Geneva, Switzerland..
    van Rooden, Stephanie M.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.;Natl Inst Publ Hlth & Environm RIVM, Ctr Infect Dis Epidemiol & Surveillance, Bilthoven, Netherlands..
    Gastmeier, Petra
    Charite Univ Med Berlin, Natl Reference Ctr Surveillance Nosocomial Infect, Hindenburgdamm 27, D-12203 Berlin, Germany.;Free Univ Berlin, Hindenburgdamm 27, D-12203 Berlin, Germany.;Humboldt Univ, Inst Hyg & Environm Med, Hindenburgdamm 27, D-12203 Berlin, Germany..
    van Mourik, Maaike S. M.
    Univ Med Ctr Utrecht, Dept Med Microbiol & Infect Control, Utrecht, Netherlands..
    Information technology aspects of large-scale implementation of automated surveillance of healthcare-associated infections2021In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 27, no Suppl 1, p. S29-S39Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 4.
    Bulman, Zackery P.
    et al.
    Univ Illinois, Dept Pharm Practice, Chicago, IL 60612 USA..
    Wicha, Sebastian G.
    Univ Hamburg, Inst Pharm, Dept Clin Pharm, Hamburg, Germany..
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lenhard, Justin R.
    Calif Northstate Univ, Dept Clin & Adm Sci, Coll Pharm, Elk Grove, CA USA..
    Nation, Roger L.
    Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Melbourne, Vic, Australia..
    Theuretzbacher, Ursula
    Ctr Antiinfect Agents, Vienna, Austria..
    Derendorf, Hartmut
    Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Zeitlinger, Markus
    Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria..
    Landersdorfer, Cornelia B.
    Monash Univ, Ctr Med Use & Safety, Monash Inst Pharmaceut Sci, Melbourne, Vic, Australia..
    Bulitta, Jürgen B.
    Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Orlando, FL USA..
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Li, Jian
    Monash Univ, Monash Biomed Discovery Inst, Infect & Immun Program, Melbourne, Vic, Australia.;Monash Univ, Dept Microbiol, Melbourne, Vic, Australia..
    Tsuji, Brian T.
    Univ Buffalo, Dept Pharm Practice, Buffalo, NY USA..
    Research priorities towards precision antibiotic therapy to improve patient care2022In: LANCET MICROBE, ISSN 2666-5247, Vol. 3, no 10, p. e795-e802Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 5.
    Cojutti, Pier Giorgio
    et al.
    Univ Bologna, Dept Med & Surg Sci, Alma Mater Studiorum, Bologna, Italy.;IRCCS Azienda Osped Univ Bologna, Clin Pharmacol Unit, Bologna, Italy..
    Heffernan, Aaron J.
    Univ Queensland, Fac Med, Ctr Clin Res, Herston, Qld, Australia..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Della Siega, Paola
    Santa Maria della Misericordia Univ Hosp Udine, ASUFC, Infect Dis Clin, Udine, Italy..
    Tascini, Carlo
    Santa Maria della Misericordia Univ Hosp Udine, ASUFC, Infect Dis Clin, Udine, Italy..
    Roberts, Jason A.
    Univ Queensland, Fac Med, Ctr Clin Res, Herston, Qld, Australia.;Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia.;Metro North Hlth, Herston Infect Dis Inst HeIDI, Brisbane, Qld, Australia.;Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia.;Univ Montpellier, Nimes Univ Hosp, Div Anaesthesiol Crit Care Emergency & Pain Med, Nimes, France..
    Pea, Federico
    Univ Bologna, Dept Med & Surg Sci, Alma Mater Studiorum, Bologna, Italy.;IRCCS Azienda Osped Univ Bologna, Clin Pharmacol Unit, Bologna, Italy..
    Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients2023In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 67, no 3, article id e01665-22Article in journal (Refereed)
    Abstract [en]

    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.

  • 6.
    Dahdouh, Elias
    et al.
    Univ La Paz IdiPAZ, Inst Invest Sanitaria Hosp, Clin Microbiol & Parasitol Dept, Madrid 28046, Spain..
    Allander, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Falgenhauer, Linda
    Justus Liebig Univ Giessen, Inst Hyg & Environm Med, D-35392 Giessen, Germany..
    Iorga, Bogdan I.
    Univ Paris Saclay, CNRS UPR 2301, Inst Chim Subst Nat ICSN, F-91190 Gif Sur Yvette, France..
    Lorenzetti, Stefano
    Ist Super Sanita ISS, Dept Food Safety Nutr & Vet Publ Hlth, I-00161 Rome, Italy..
    Marcos-Alcalde, Inigo
    CSIC UAM, Ctr Biol Mol Severo Ochoa CBMSO, Mol Modeling Grp, Madrid 28049, Spain..
    Martin, Nathaniel, I
    Leiden Univ, Inst Biol Leiden IBL, Biol Chem Grp, Sylviusweg 72, NL-2333 BE Leiden, Netherlands..
    Martinez-Martinez, Luis
    Univ Hosp Reina Sofia, Unit Microbiol, Cordoba 14004, Spain.;Maimonides Biomed Res Inst Cordoba IMIBIC, Dept Agr Chem Edaphol & Microbiol, Cordoba 14004, Spain..
    Mingorance, Jesus
    Univ La Paz IdiPAZ, Inst Invest Sanitaria Hosp, Clin Microbiol & Parasitol Dept, Madrid 28046, Spain..
    Naas, Thierry
    Univ Paris Saclay, Dept Microbiol, Hop Bicetre, F-91190 Gif Sur Yvette, France..
    Rubin, Joseph E.
    Univ Saskatchewan Saskatoon, Dept Vet Microbiol, Saskatoon, SK S7N 5A2, Canada..
    Spyrakis, Francesca
    Univ Turin, Dept Drug Sci & Technol, I-10125 Turin, Italy..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Gomez-Puertas, Paulino
    CSIC UAM, Ctr Biol Mol Severo Ochoa CBMSO, Mol Modeling Grp, Madrid 28049, Spain..
    Computational Modeling and Design of New Inhibitors of Carbapenemases: A Discussion from the EPIC Alliance Network2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 17, article id 9746Article in journal (Other academic)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 7.
    Dittrich, Sabine
    et al.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland..
    Tadesse, Birkneh Tilahun
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland.;WHO, Special Programme Res & Training Trop Dis TDR, Ave Appia 20, CH-1211 Geneva 27, Switzerland.;Hawassa Univ, Dept Pediat, Coll Med & Hlth Sci, Hawassa, Ethiopia..
    Moussy, Francis
    WHO, 20 Ave Appia, CH-1211 Geneva 27, Switzerland..
    Chua, Arlene
    Tan Took Seng Hosp, Inst Infect Dis & Epidemiol, Singapore, Singapore..
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dolinger, David L.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland.;WHO, 20 Ave Appia, CH-1211 Geneva 27, Switzerland.;Tan Took Seng Hosp, Inst Infect Dis & Epidemiol, Singapore, Singapore..
    Page, Anne-Laure
    Epicentre, Epidemiol & Populat Hlth, Paris, France..
    Crump, John A.
    Univ Otago, Ctr Int Hlth, POB 56, Dunedin 9054, New Zealand.;Duke Univ, Duke Global Hlth Inst, Box 90519, Durham, NC 27708 USA.;Duke Univ, Med Ctr, Div Infect Dis & Int Hlth, Box 102359, Durham, NC 27710 USA..
    D'Acremont, Valerie
    Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland.;Univ Lausanne, Dept Ambulatory Care & Community Med, Bugnon 44, CH-1011 Lausanne, Switzerland..
    Bassat, Quique
    Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona, Spain.;CISM, Maputo, Mozambique..
    Lubell, Yoel
    Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand..
    Newton, Paul N.
    Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England.;Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit, Viangchan, Laos..
    Heinrich, Norbert
    Univ Munich LMU, Med Ctr, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res, Munich Partner Site,Leopoldstr 5, D-80802 Munich, Germany..
    Rodwell, Timothy J.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland..
    Gonzalez, Iveth J.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland..
    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 Consensus2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 8, article id e0161721Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 8. Dyar, O J
    et al.
    Beović, B
    Pulcini, C
    Tacconelli, E
    Hulscher, M
    Cookson, B
    ESCMID generic competencies in antimicrobial prescribing and stewardship: towards a European consensus.2019In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 25, no 1, p. 13-19Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 9. Helou, R. , I
    et al.
    Catho, Gaud
    Hop Univ Geneve, Dept Infect Dis, Geneva, Switzerland..
    Latif, Annabel Peyravi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Mouton, Johan
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    Hulscher, M.
    Radboud Univ Nijmegen, Sci Ctr Qual Healthcare IQ Healthcare, Radboud Inst Hlth Sci, Med Ctr, Nijmegen, Netherlands..
    Teerenstra, Steven
    Radboud Univ Nijmegen, Radboud Inst Hlth Sci, Dept Hlth Evidence, Med Ctr, Nijmegen, Netherlands..
    Conly, John
    Univ Calgary, Dept Med, Calgary, AB, Canada.;Alberta Hlth Serv, Calgary, AB, Canada..
    Huttner, Benedikt D.
    Hop Univ Geneve, Dept Infect Dis, Geneva, Switzerland..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Verbon, Annelies
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    Study protocol for an international, multicentre stepped-wedge cluster randomised trial to evaluate the impact of a digital antimicrobial stewardship smartphone application2020In: BMJ Open, E-ISSN 2044-6055, Vol. 10, no 6, article id e033640Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 10. Hong, Lisa T
    et al.
    Downes, Kevin J
    FakhriRavari, Alireza
    Abdul-Mutakabbir, Jacinda C
    Kuti, Joseph L
    Jorgensen, Sarah
    Young, David C
    Alshaer, Mohammad H
    Bassetti, Matteo
    Bonomo, Robert A
    Gilchrist, Mark
    Jang, Soo Min
    Lodise, Thomas
    Roberts, Jason A
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Zuppa, Athena
    Scheetz, Marc H
    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 Pharmacists2023In: Pharmacotherapy, ISSN 0277-0008, E-ISSN 1875-9114, Vol. 43, no 8, p. 736-739Article in journal (Refereed)
    Abstract [en]

    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).

    Download full text (pdf)
    fulltext
  • 11.
    Hong, Lisa T.
    et al.
    Loma Linda Univ, Sch Pharm, Loma Linda, CA USA.;24745 Stewart St Shyrock Hall 205, Loma Linda, CA 92350 USA..
    Downes, Kevin J.
    Childrens Hosp Philadelphia, Philadelphia, PA USA..
    Fakhriravari, Alireza
    Loma Linda Univ, Sch Pharm, Loma Linda, CA USA..
    Abdul-Mutakabbir, Jacinda C.
    Loma Linda Univ, Sch Pharm, Loma Linda, CA USA.;Univ Calif San Diego, Div Clin Pharm & Black Diaspora & African Amer Stu, La Jolla, CA USA..
    Kuti, Joseph L.
    Hartford Hosp, Ctr Antiinfect Res & Dev, Hartford, CT USA..
    Jorgensen, Sarah
    Univ Toronto, Toronto, ON, Canada..
    Young, David C.
    Univ Utah, Coll Pharm, Salt Lake City, UT USA..
    Alshaer, Mohammad H.
    Univ Florida, Coll Pharm, Gainesville, FL USA..
    Bassetti, Matteo
    Univ Genoa, Genoa, Italy..
    Bonomo, Robert A.
    Cleveland Vet Affairs Med Ctr, Cleveland, OH USA.;Case Western Reserve Univ, Ctr Antimicrobial Resistance & Epidemiol Case VA C, Cleveland, OH USA..
    Gilchrist, Mark
    Natl Hlth Serv Trust, Imperial Coll Healthcare, London, England..
    Jang, Soo Min
    Loma Linda Univ, Sch Pharm, Loma Linda, CA USA..
    Lodise, Thomas
    Albany Coll Pharm & Hlth Sci, Albany, NY USA..
    Roberts, Jason A.
    Univ Queensland, Ctr Clin Res, Fac Med, Brisbane, Qld, Australia.;Metro North Hlth, Herston Infect Dis Inst, Brisbane, Qld, Australia.;Royal Brisbane & Womens Hosp, Dept Pharm & Intens Care, Brisbane, Qld, Australia.;Univ Montpellier, Nimes Univ Hosp, Div Anaesthesiol Crit Care Emergency & Pain Med, Nimes, France..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Zuppa, Athena
    Childrens Hosp Philadelphia, Philadelphia, PA USA..
    Scheetz, Marc H.
    Midwestern Univ, Coll Pharm, Pharmacometr Ctr Excellence, Downers Grove, IL USA.;Northwestern Mem Hosp, Dept Pharm, Chicago, IL USA..
    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 Pharmacists2023In: Pharmacotherapy, ISSN 0277-0008, E-ISSN 1875-9114, Vol. 43, no 8, p. 740-777Article in journal (Refereed)
    Abstract [en]

    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).

    Download full text (pdf)
    fulltext
  • 12.
    Hong, Lisa T.
    et al.
    Loma Linda Univ, Sch Pharm, 4745 Stewart St, Loma Linda, CA 92350 USA..
    Downes, Kevin J.
    Childrens Hosp Philadelphia, Philadelphia, PA USA..
    Fakhriravari, Alireza
    Loma Linda Univ, Sch Pharm, 4745 Stewart St, Loma Linda, CA 92350 USA..
    Abdul-Mutakabbir, Jacinda C.
    Loma Linda Univ, Sch Pharm, 4745 Stewart St, Loma Linda, CA 92350 USA.;Univ Calif San Diego, Div Clin Pharm, La Jolla, CA USA.;Univ Calif San Diego, Div Black Diaspora & African Amer Studies, La Jolla, CA USA..
    Kuti, Joseph L.
    Hartford Hosp, Ctr Antiinfect Res & Dev, Gainesville, FL USA..
    Jorgensen, Sarah
    Univ Toronto, Toronto, ON, Canada..
    Young, David C.
    Univ Utah, Coll Pharm, Salt Lake City, UT USA..
    Alshaer, Mohammad H.
    Univ Florida, Coll Pharm, Gainesville, FL USA..
    Bassetti, Matteo
    Univ Genoa, Genoa, Italy..
    Bonomo, Robert A.
    Cleveland Vet Affairs Med Ctr, Cleveland, OH USA.;Case Western Reserve Univ, Ctr Antimicrobial Resistance & Epidemiol Case VA C, Cleveland, OH USA..
    Gilchrist, Mark
    Imperial Coll Healthcare Natl Hlth Serv Trust, London, England..
    Jang, Soo Min
    Loma Linda Univ, Sch Pharm, 4745 Stewart St, Loma Linda, CA 92350 USA..
    Lodise, Thomas
    Albany Coll Pharm & Hlth Sci, Albany, NY USA..
    Roberts, Jason A.
    Univ Queensland, Fac Med, Ctr Clin Res, Brisbane, Qld, Australia.;Metro North Hlth, Herston Infect Dis Inst, Brisbane, Qld, Australia.;Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia.;Royal Brisbane & Womens Hosp, Dept Intens Care, Brisbane, Qld, Australia.;Univ Montpellier, Nimes Univ Hosp, Div Anaesthesiol Crit Care Emergency & Pain Med, Nimes, France..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Zuppa, Athena
    Childrens Hosp Philadelphia, Philadelphia, PA USA..
    Scheetz, Marc H.
    Midwestern Univ, Coll Pharm, Pharmacometr Ctr Excellence, Downers Grove, IL USA.;Northwestern Mem Hosp, Dept Pharm, Chicago, IL USA..
    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'2024In: Pharmacotherapy, ISSN 0277-0008, E-ISSN 1875-9114, Vol. 44, no 2, p. 208-209Article in journal (Other academic)
  • 13.
    Jonsson, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lannergård, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A trial with IgY chicken antibodies to eradicate faecal carriage of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamases2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 28224Article in journal (Refereed)
    Abstract [en]

    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.

  • 14.
    Kurland, Siri
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Shams, Ayda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Chryssanthou, Erja
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Breuer, Olof
    Karolinska Univ Hosp, Karolinska Inst, Dept Lab Med, Clin Pharmacol, Stockholm, Sweden..
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Human plasma protein levels alter the in vitro antifungal activity of caspofungin: An explanation to the effect in critically ill?2022In: Mycoses, ISSN 0933-7407, E-ISSN 1439-0507, Vol. 65, no 1, p. 79-87Article in journal (Refereed)
    Abstract [en]

    Background

    Recent 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.

    Objectives

    Fungal killing activity of caspofungin in vitro was investigated under varying levels of human plasma protein.

    Methods

    Time-kill studies were performed with clinically relevant caspofungin concentrations of 1-9 mg/L on four blood isolates of Cglabrata, three susceptible and one strain with reduced susceptibility, in human plasma and plasma diluted to 50% and 25% using Ringer's acetate.

    Results

    Enhanced 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.

    Conclusions

    Reduced 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.

    Download full text (pdf)
    fulltext
  • 15.
    Lagerbäck, Pernilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Khine, Wei W. T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Giske, C. G.
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Evaluation of antibacterial activities of colistin, rifampicin and meropenem combinations against NDM-1-producing Klebsiella pneumoniae in 24 h in vitro time-kill experiments2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 8, p. 2321-2325Article in journal (Refereed)
    Abstract [en]

    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.

  • 16.
    Lindström, Anna
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Scandinavian Languages.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Introducing the C-reactive protein point-of-care test: A conversation analytic study of primary care consultations for respiratory tract infection2022In: Social Science and Medicine, ISSN 0277-9536, E-ISSN 1873-5347, Vol. 315, article id 115493Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 17. Ljungquist, O
    et al.
    Kjölvmark, C
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Karbapenemresistenta Escherichia coli finns nu i Sverige: Carbapenem-resistant Escherichia coli now exist in Sweden2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 32/33, p. 1401-1402Article in journal (Refereed)
    Abstract [sv]

    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.

  • 18.
    Malmberg, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Gradientech AB.
    Flinkfeldt, Linnea
    Gradientech AB.
    Fernberg, Jenny
    Gradientech AB.
    Öhrn, Håkan
    Gradientech AB.
    Johansson, Cecilia
    Gradientech AB.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The T2Bacteria panel and rapid AST with bacteria pre-sampling for combined ID and AST before blood culture positivityManuscript (preprint) (Other academic)
    Abstract [en]

    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.

  • 19.
    Malmberg, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Gradientech AB, Uppsala, Sweden..
    Torpner, Jessie
    Gradientech AB, Uppsala, Sweden..
    Fernberg, Jenny
    Gradientech AB, Uppsala, Sweden..
    Ohrn, Hakan
    Gradientech AB, Uppsala, Sweden..
    Angstrom, Jonas
    Gradientech AB, Uppsala, Sweden..
    Johansson, Cecilia
    Gradientech AB, Uppsala, Sweden..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Evaluation of the Speed, Accuracy and Precision of the QuickMIC Rapid Antibiotic Susceptibility Testing Assay With Gram-Negative Bacteria in a Clinical Setting2022In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 12, article id 758262Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 20.
    Malmberg, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Torpner, Jessie
    Gradientech AB.
    Fernberg, Jenny
    Gradientech AB.
    Öhrn, Håkan
    Gradientech AB.
    Johansson, Cecilia
    Gradientech AB.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Faster results, higher precision: Evaluating the QuickMIC rapid AST assay in a clinical settingManuscript (preprint) (Other academic)
    Abstract [en]

    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.

  • 21.
    Malmberg, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Gradientech AB, Uppsala, Sweden..
    Yuen, Pikkei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Spaak, Johanna
    Gradientech AB, Uppsala, Sweden..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A Novel Microfluidic Assay for Rapid Phenotypic Antibiotic Susceptibility Testing of Bacteria Detected in Clinical Blood Cultures2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 12, article id e0167356Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 22.
    Malmros, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Huttner, Benedikt D.
    Univ Geneva, Geneva Univ Hosp, Div Infect Dis & Infect Control Program, Geneva, Switzerland;Univ Geneva, Fac Med, Geneva, Switzerland;European Soc Clin Microbiol & Infect Dis ESCMID, ESCMID Study Grp Antimicrobial Stewardship ESGAP, Basel, Switzerland.
    McNulty, Cliodna
    Publ Hlth England, Primary Care Unit, Gloucester, England.
    Rodriguez-Bano, Jesus
    European Soc Clin Microbiol & Infect Dis ESCMID, ESCMID Study Grp Antimicrobial Stewardship ESGAP, Basel, Switzerland;Hosp Univ Virgen Macarena, Enfermedades Infecciosas Microbiol & Med Preventi, Seville, Spain;Univ Seville, Dept Med, Seville, Spain.
    Pulcini, Celine
    Univ Lorraine, APEMAC, Nancy, France;Univ Lorraine, CHRU Nancy, Infect Dis Dept, Nancy, France.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. European Soc Clin Microbiol & Infect Dis ESCMID, ESCMID Study Grp Antimicrobial Stewardship ESGAP, Basel, Switzerland.
    Thalhammer, Florian
    Delvaux, Nicolas
    Heytens, Stefan
    Bjerrum, Lars
    Wuorela, Maarit
    Caron, Francois
    Wagenlehner, Florian
    Prins, Jan M.
    Haug, Jon Birger
    Kozlov, Roman
    Barac, Aleksandra
    Beovic, Bojana
    de Cueto, Marina
    Comparison of antibiotic treatment guidelines for urinary tract infections in 15 European countries: Results of an online survey2019In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 54, no 4, p. 478-486Article in journal (Refereed)
    Abstract [en]

    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.

  • 23.
    Maraolo, Alberto Enrico
    et al.
    Univ Naples Federico II, Sect Infect Dis, Dept Clin Med & Surg, Naples, Italy..
    Ong, David S. Y.
    Dept Med Microbiol & Infect Control, Franciscus Gasthuis Vlietland, Kleiweg 500, NL-3045 PM Rotterdam, Netherlands.;Univ Utrecht, Univ Med Ctr Utrecht, Dept Epidemiol, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Cimen, Cansu
    Ardahan Publ Hosp, Infect Dis & Clin Microbiol Clin, Minist Hlth, Ardahan, Turkey..
    Howard, Philip
    Leeds Teaching Hosp NHS Trust, Leeds, W Yorkshire, England..
    Kofteridis, Diamantis P.
    Univ Hosp Herakl, Dept Internal Med, Fac Med, Iraklion, Greece..
    Schouten, Jeroen
    Radboud Univ Nijmegen, Sci Ctr Qual Healthcare, IQ Healthcare, Med Ctr, Nijmegen, Netherlands..
    Mutters, Nico T.
    Univ Freiburg, Inst Infect Prevent & Hosp Epidemiol, Med Ctr, Fac Med, Freiburg, Germany..
    Pulcini, Celine
    Univ Lorraine, APEMAC & Infect Dis Dept, Nancy, France.;CHRU Nancy, Nancy, France..
    Harxhi, Arjan
    Organization and training at national level of antimicrobial stewardship and infection control activities in Europe: an ESCMID cross-sectional survey2019In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 38, no 11, p. 2061-2068Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 24.
    Martson, A-G
    et al.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Sturkenboom, M. G. G.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands..
    Stojanova, J.
    Univ Valparaiso, Interdisciplinary Ctr Hlth Studies CIESAL, Valparaiso, Chile..
    Cattaneo, D.
    ASST Fatebenefratelli Sacco Univ Hosp, Dept Lab Med, Unit Clin Pharmacol, Milan, Italy..
    Hope, W.
    Univ Liverpool, Antimicrobial Pharmacodynam & Therapeut, Liverpool, Merseyside, England.;Royal Liverpool Broadgreen Univ Hosp Trust, Liverpool, Merseyside, England..
    Marriott, D.
    St Vincents Hosp, Sydney, NSW, Australia..
    Patanwala, A. E.
    Univ Sydney, Sydney Pharm Sch, Sydney, NSW, Australia.;Royal Prince Alfred Hosp, Sydney, NSW, Australia..
    Peloquin, C. A.
    Univ Florida, Coll Pharm, Emerging Pathogens Inst, Infect Dis Pharmacokinet Lab, Gainesville, FL USA..
    Wicha, S. G.
    Univ Hamburg, Inst Pharm, Dept Clin Pharm, Hamburg, Germany..
    van der Werf, T. S.
    Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis & TB, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Roberts, J. A.
    Univ Queensland, Fac Med, Ctr Clin Res, Brisbane, Qld, Australia.;Univ Queensland, Ctr Translat Antiinfect Pharmacodynam, Sch Pharm, Brisbane, Qld, Australia.;Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia.;Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia.;Univ Montpellier, Nimes Univ Hosp, Div Anaesthesiol Crit Care Emergency & Pain Med, Nimes, France..
    Neely, M. N.
    Childrens Hosp Los Angeles, Lab Appl Pharmacokinet & Bioinformat, Los Angeles, CA 90027 USA..
    Alffenaar, J-WC.
    How to design a study to evaluate therapeutic drug monitoring in infectious diseases?2020In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 26, no 8, p. 1008-1016Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 25.
    Montelin, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Camporeale, Angela
    Hallgren, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Angelin, Martin
    Hogvall, Jonas
    Östholm Balkhed, Åse
    Vading, Malin
    Giske, Christian G
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Treatment, outcomes and characterization of pathogens in urinary tract infections caused by ESBL-producing Enterobacterales: a prospective multicentre studyIn: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091Article in journal (Refereed)
    Abstract [en]

    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.

  • 26.
    Montelin, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Forsman, Karl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Retrospective evaluation of nitrofurantoin and pivmecillinam for the treatment of lower urinary tract infections in men2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 1, article id e0211098Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 27.
    Nauclér, P.
    et al.
    Department of Medicine, Solna, Karolinska Institutet, and Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Huttner, A.
    Division of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland.
    van Werkhoven, C. H.
    Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
    Singer, M.
    Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK.
    Tattevin, P.
    Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France.
    Einav, S.
    Department of Intensive Care, Shaare Zedek Medical Center, Jerusalem, Israel.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Impact of time to antibiotic therapy on clinical outcome in patients with bacterial infections in the emergency department: implications for antimicrobial stewardship2021In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 27, no 2, p. 175-181Article, review/survey (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 28.
    Olsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Allander, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Shams, Ayda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Al-Farsi, Hissa
    Karolinska Inst, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden..
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Activity of polymyxin B combinations against genetically well-characterised Klebsiella pneumoniae producing NDM-1 and OXA-48-like carbapenemases2023In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 62, no 5, article id 106967Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 29.
    Olsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Hong, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Al-Farsi, Hissa
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
    Giske, Christian G
    Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Interactions of polymyxin B in combination with aztreonam, minocycline, meropenem and rifampicin against Escherichia coli producing NDM and OXA-48-group carbapenemases2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 12, article id 01065-21Article in journal (Refereed)
    Abstract [en]

    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.

  • 30.
    Olsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Malmberg, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zhao, Chenyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    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.2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, article id dkad394Article in journal (Refereed)
    Abstract [en]

    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.

  • 31.
    Olsson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Wistrand-Yuen, Pikkei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Efficacy of Antibiotic Combinations against Multidrug-Resistant Pseudomonas aeruginosa in Automated Time-Lapse Microscopy and Static Time-Kill Experiments2020In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 64, no 6, article id e02111-19Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 32. Paul, Mical
    et al.
    Carrara, Elena
    Retamar, Pilar
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Bitterman, Roni
    Bonomo, Robert A.
    de Waele, Jan
    Daikos, George L.
    Akova, Murat
    Harbarth, Stephan
    Pulcini, Celine
    Garnacho-Montero, José
    Seme, Katja
    Tumbarello, Mario
    Lindemann, Paul Christoffer
    Gandra, Sumanth
    Yu, Yunsong
    Bassetti, Matteo
    Mouton, Johan W.
    Tacconelli, Evelina
    Rodríguez-Baño, Jesús
    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)2022In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 28, no 4, p. 521-547Article in journal (Refereed)
    Abstract [en]

    Scope

    These 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.

    Methods

    An 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).

    Recommendations

    The 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.

  • 33.
    Skarp, Kari-Pekka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Shams, Ayda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Montelin, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    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 experiments2019In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 53, no 1, p. 74-79Article in journal (Refereed)
    Abstract [en]

    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.

  • 34.
    Swartling, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Hedenstierna laboratory.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Therapeutic drug monitoring of vancomycin and meropenem: Illustration of the impact of inaccurate information in dose administration time2023In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 63, no 1, article id 107032Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    fulltext
  • 35.
    Sütterlin, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Edquist, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Adler, Marlen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Drobni, Mirva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Silver resistance genes are overrepresented among Escherichia coli isolates with CTX-M production2014In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 80, no 22, p. 6863-6869Article in journal (Refereed)
    Abstract [en]

    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.

  • 36.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae: Treatment, Selection and International Spread2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The prevalence of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum beta-lactamases (ESBLs) and carbapenemases is increasing worldwide. Therapeutic options for infections with these bacteria are limited not only by the production of ESBLs and carbapenemases, which confer resistance to cephalosporins and carbapenems, but also by frequent co-resistance to other antibiotics. The overall aim of this thesis was to obtain a better understanding of multidrug-resistant E. coli and K. pneumoniae in relation to epidemiology, selection and susceptibility to antibiotic therapy.

    In a prospective study ESBL-producing E. coli was found to spread easily through international travel. Twenty-four of 100 Swedes travelling outside Northern Europe acquired ESBL-producing E. coli in the intestinal flora. The risk was highest for travelers visiting India and those suffering from gastroenteritis during travel.

    To minimize selection of ESBL-producing K. pneumoniae during a hospital outbreak with these bacteria, an educational antibiotic intervention was performed at Uppsala University Hospital in 2006. The primary aim of the intervention was to reduce the consumption of parenteral cephalosporins. An immediate and radical reduction of cephalosporins was demonstrated with interrupted time series analysis. The outbreak declined during 2007 and no increased resistance to replacement antibiotics was detected.

    The impact of ESBL production on the antibacterial activity of ertapenem was studied in time-kill experiments. It was shown that porin-deficient subpopulations with reduced susceptibility to ertapenem frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics.

    Further, the antibacterial effects of antibiotic combinations against four strains of K. pneumoniae producing carbapenemases of the metallo-beta-lactamase type were studied in time-kill experiments. Double and triple combinations of aztreonam, fosfomycin, meropenem, rifampin and colistin at clinically relevant static concentrations were effective despite that the bacteria were frequently resistant to the individual drugs. These results indicate that there is a largely unexplored potential of antibiotic combination therapy for multidrug-resistant K. pneumoniae.

    List of papers
    1. 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
    Open this publication in new window or tab >>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 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, no 9, p. 3564-3568Article in journal (Refereed) Published
    Abstract [en]

    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-135414 (URN)10.1128/AAC.00220-10 (DOI)000281005900005 ()
    Available from: 2010-12-07 Created: 2010-12-06 Last updated: 2022-01-28Bibliographically approved
    2. Radical reduction of cephalosporin use at a tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae
    Open this publication in new window or tab >>Radical reduction of cephalosporin use at a tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae
    Show others...
    2011 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 66, no 5, p. 1161-1167Article in journal (Refereed) Published
    Abstract [en]

    Objectives: During an outbreak of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae at our hospital, we performed an educational antibiotic intervention aimed at reducing prescriptions of second- and third-generation cephalosporins and preventing increased use of fluoroquinolones and carbapenems. In this report, we describe the implementation strategy used and evaluate the intervention effect according to Cochrane recommendations. Methods: New recommendations for empirical intravenous antibiotic treatment were communicated to prescribers throughout the hospital by infectious diseases physicians working with Strama (the Swedish strategic programme against antibiotic resistance). No restrictive measures were used. The intervention effect was analysed with interrupted time series (ITS) regression analysis of local and national monthly antibiotic sales data. Results: A radical immediate and sustained reduction was demonstrated for the cephalosporins targeted in the intervention, whereas consumption of piperacillin/tazobactam and penicillin G increased substantially. Fluoroquinolone and carbapenem use was essentially unchanged. The ESBL outbreak subsided and no increased resistance to piperacillin/tazobactam was detected in K. pneumoniae, Escherichia coli or Pseudomonas aeruginosa blood isolates during the 2.5 year follow-up. Conclusions: Our study clearly demonstrates that an educational intervention can have an immediate and profound effect on antibiotic prescription patterns at a large tertiary hospital. ITS regression analysis of local and national antibiotic sales data was valuable to readily assess the immediate and sustained effects of the intervention.

    Keywords
    interrupted time series, ESBLs, piperacillin/tazobactam
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-152851 (URN)10.1093/jac/dkr053 (DOI)000289584000031 ()
    Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2022-01-28Bibliographically approved
    3. 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
    Open this publication in new window or tab >>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
    Show others...
    2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 6, p. 1319-1326Article in journal (Refereed) Published
    Abstract [en]

    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-197878 (URN)10.1093/jac/dkt044 (DOI)000319468900016 ()23478794 (PubMedID)
    Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06Bibliographically approved
    4. Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiment
    Open this publication in new window or tab >>Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiment
    Show others...
    2014 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 3, p. 1757-1762Article in journal (Refereed) Published
    Abstract [en]

    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.

    National Category
    Infectious Medicine Microbiology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-183597 (URN)10.1128/AAC.00741-13 (DOI)000332175100061 ()
    Available from: 2012-10-31 Created: 2012-10-30 Last updated: 2018-01-12Bibliographically approved
    Download full text (pdf)
    fulltext
  • 37.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Adler, Marlen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 6, p. 1319-1326Article in journal (Refereed)
    Abstract [en]

    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.

  • 38.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    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 Volunteers2010In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, no 9, p. 3564-3568Article in journal (Refereed)
    Abstract [en]

    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.

  • 39. Tängdén, Thomas
    et al.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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.2010In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, no 54, p. 3564-3568Article in journal (Refereed)
  • 40.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cojutti, Pier Giorgio
    Santa Maria della Misericordia Univ, Inst Clin Pharmacol, ASUIUD, Udine, Italy;Univ Udine, Dept Med, Udine, Italy.
    Roberts, Jason A.
    Royal Brisbane & Womens Hosp, Dept Intens Care Med, Brisbane, Qld, Australia;Royal Brisbane & Womens Hosp, Dept Pharm, Brisbane, Qld, Australia;Univ Queensland, Ctr Clin Res, Fac Med, Level 3,Ned Hanlon Bldg, Herston, Qld 4029, Australia;Univ Queensland, Ctr Antiinfect Translat Pharmacodynam, Sch Pharm, Level 3,Ned Hanlon Bldg, Herston, Qld 4029, Australia.
    Pea, Federico
    Santa Maria della Misericordia Univ, Inst Clin Pharmacol, ASUIUD, Udine, Italy;Univ Udine, Dept Med, Udine, Italy.
    Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens2018In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 57, no 11, p. 1399-1405Article in journal (Refereed)
    Abstract [en]

    Background and ObjectivesValganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations.MethodsTherapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively. A non-parametric pharmacokinetic analysis and Monte Carlo simulations to determine the probabilities of reaching an area under the drug concentration-time curve (AUC) target of 40-50mg<bold>h</bold>/L with various dosing regimens at different levels of renal function were conducted using the Pmetrics package for R.ResultsThis study included 792 ganciclovir concentration measurements derived from 97 patients. A one-compartment oral absorption model best described the data. The final covariate model was as follows: CL(ganciclovir)=TVCLx(CLCR/51)(0.75), where CL is the clearance, TVCL is the typical value of ganciclovir clearance, creatinine clearance (CLCR) according to the Cockcroft-Gaultt equation and 51 is the mean CLCR determined in the study. In the simulations, the probability of reaching the targeted AUC was insufficient when using the recommended dosing regimens for prophylaxis, especially in patients with impaired renal function at CLCR<50mL/min.ConclusionsHigher doses of valganciclovir corrected to renal function are suggested for use as oral prophylaxis for CMV infection in kidney transplant recipients. Further study is required to establish TDM targets to ensure adequate drug concentrations while avoiding potentially toxic drug exposures.

  • 41.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ullberg, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Neurosurgical Gram-Negative Bacillary Ventriculitis and Meningitis: A Retrospective Study Evaluating the Efficacy of Intraventricular Gentamicin Therapy in 31 Consecutive Cases2011In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 52, no 11, p. 1310-1316Article in journal (Refereed)
    Abstract [en]

    Background. Gram-negative bacillary (GNB) ventriculitis and meningitis are rare but serious complications after neurosurgery. Prospective studies on antibiotic treatment for these infections are lacking, and retrospective reports are sparse. At our hospital in Uppsala, Sweden, meropenem has been recommended as empirical therapy since 1996, with the addition of intraventricular gentamicin in cases that do not respond satisfactorily to treatment. In this study, we retrospectively compare the efficacy of combination treatment with intraventricular gentamicin to that of systemic antibiotics alone. In addition, we report our experience of meropenem for the treatment of GNB ventriculomeningitis. Methods. Adult consecutive patients with gram-negative bacteria isolated from cerebrospinal fluid during a 10-year period and with postneurosurgical GNB ventriculitis or meningitis were included retrospectively. Data were abstracted from the medical records. Results. Thirty-one patients with neurosurgical GNB ventriculitis or meningitis and follow-up for 3 months were identified. The main intravenous therapies were meropenem (n = 24), cefotaxime (n = 3), ceftazidime (n = 2), imipenem (n = 1), and trimethoprim-sulfamethoxazole (n = 1). Thirteen patients were given combination treatment with appropriate intraventricular gentamicin. These patients had a higher cure rate and a lower relapse rate than did those treated with intravenous antibiotics alone (P = .03). Relapse occurred in 0 of 13 patients treated intraventricularly and in 6 of 18 patients treated with systemic antibiotics alone. The mortality rate was 19%; 3 patients in each group died, but in no case was death considered to be attributable to meningitis. Conclusions. Our results support combination treatment with intraventricular gentamicin for postneurosurgical GNB ventriculomeningitis. Meropenem seems to be an effective and safe alternative for the systemic antibiotic treatment of these neurointensive care infections.

  • 42. Tängdén, Thomas
    et al.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ullberg, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Neurosurgical gram-negative bacillary ventriculitis and meningitis: a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases.2011In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, no 52, p. 10-16Article in journal (Refereed)
  • 43.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Eriksson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Svennblad, Bodil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Radical reduction of cephalosporin use at a tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae2011In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 66, no 5, p. 1161-1167Article in journal (Refereed)
    Abstract [en]

    Objectives: During an outbreak of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae at our hospital, we performed an educational antibiotic intervention aimed at reducing prescriptions of second- and third-generation cephalosporins and preventing increased use of fluoroquinolones and carbapenems. In this report, we describe the implementation strategy used and evaluate the intervention effect according to Cochrane recommendations. Methods: New recommendations for empirical intravenous antibiotic treatment were communicated to prescribers throughout the hospital by infectious diseases physicians working with Strama (the Swedish strategic programme against antibiotic resistance). No restrictive measures were used. The intervention effect was analysed with interrupted time series (ITS) regression analysis of local and national monthly antibiotic sales data. Results: A radical immediate and sustained reduction was demonstrated for the cephalosporins targeted in the intervention, whereas consumption of piperacillin/tazobactam and penicillin G increased substantially. Fluoroquinolone and carbapenem use was essentially unchanged. The ESBL outbreak subsided and no increased resistance to piperacillin/tazobactam was detected in K. pneumoniae, Escherichia coli or Pseudomonas aeruginosa blood isolates during the 2.5 year follow-up. Conclusions: Our study clearly demonstrates that an educational intervention can have an immediate and profound effect on antibiotic prescription patterns at a large tertiary hospital. ITS regression analysis of local and national antibiotic sales data was valuable to readily assess the immediate and sustained effects of the intervention.

  • 44.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Löwdin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Werner, Sonja
    Korsallergi mellan penicilliner och övriga betalaktam­antibiotikaRisken är betydligt mindre än man tidigare trott: [Cross allergy between penicillins and other beta lactam antibiotics--the risk is much less than previously thought]2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, article id C9A4Article in journal (Refereed)
    Abstract [sv]

    Vid misstänkt IgE-medierad allergi mot antibiotika bör ansvarig läkare dokumentera substans, symtom och förlopp i journalen, informera patienten och skriva remiss för allergiutredning.Patienter med anafylaxi, angio-ödem eller annan livshotande reaktion mot penicillin bör inte ånyo behandlas med penicilliner eller andra betalaktamantibio-tika.Risken för korsallergi mot cefa-losporiner och karbapenemer hos patienter med misstänkt penicillinallergi är betydligt lägre än vad man tidigare har trott.Till patienter med lindriga symtom och låg misstanke om IgE-medierad penicillinallergi kan man särskilt vid allvarliga infektioner överväga att ge beta-laktamantibiotika direkt eller efter provdos.

  • 45.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Giske, C G
    Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 277, no 5, p. 501-512Article, review/survey (Refereed)
    Abstract [en]

    The prevalence of carbapenem-resistant Gram-negative bacilli is on the rise worldwide, posing a major public health threat. Previously, this was mostly a problem in Pseudomonas and Acinetobacter, but during the last decade, carbapenem resistance has escalated in medically important species such as Klebsiella pneumoniae and Escherichia coli. In particular, the rising trend in E. coli is of concern, as this may lead to almost untreatable community-acquired infections. Resistance is conferred by carbapenemases, which are beta-lactamases that can breakdown essentially all beta-lactams. Moreover, bacteria carrying these resistance determinants are often resistant to other treatment options, due to the frequent co-acquisition of non-beta-lactam resistance genes located on the same mobile genetic elements. The detection of carbapenemase-producing Enterobacteriaceae (CPE) is a challenge, because some carbapenemases produce relatively discrete levels of carbapenem resistance. Current clinical evidence for treatment guidance is limited and based on retrospective observational studies and case reports. Existing data support the use of combination therapy for treatment of severe infections caused by CPE. Combination regimens including colistin, carbapenems, tigecycline, aminoglycosides and fosfomycin have been used. Randomized controlled studies of combination regimens are ongoing and may help to determine the optimal therapy. Novel beta-lactamase inhibitors may also have a role in future treatment of these infections. Strict infection control measures including isolation or cohort care of affected patients as well as contact tracing and active screening are needed to curb the spread of CPE. In this review, we provide a clinical perspective on the management of patients infected or colonized with CPE.

  • 46.
    Tängdén, Thomas Grenholm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 149-153Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 47.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Rao, Abhiram S.
    Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA..
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA..
    A genome-wide association study in a large community-based cohort identifies multiple loci associated with susceptibility to bacterial and viral infections2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 2582Article in journal (Refereed)
    Abstract [en]

    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.

    Download full text (pdf)
    FULLTEXT01
  • 48.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Hickman, Rachel A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Forsberg, Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Giske, Christian G.
    Inst. för klinisk mikrobiologi, Karolinska Institutet, Stockholm.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Evaluation of Double- and Triple-Antibiotic Combinations for VIM- and NDM-Producing Klebsiella pneumoniae by In Vitro Time-Kill Experiment2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 3, p. 1757-1762Article in journal (Refereed)
    Abstract [en]

    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.

  • 49.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Karvanen, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Odenholt, Inga
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments2017In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 49, no 7, p. 521-527Article in journal (Refereed)
    Abstract [en]

    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.

  • 50.
    Tängdén, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lundberg, Carina Vingsbo
    Statens Serum Inst, Dept Bacteria Parasites & Fungi, Copenhagen, Denmark..
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Huttner, Angela
    Geneva Univ Hosp, Div Infect Dis, Geneva, Switzerland..
    How preclinical infection models help define antibiotic doses in the clinic2020In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 56, no 2, p. 106008-, article id 106008Article in journal (Refereed)
    Abstract [en]

    Appropriate dosing of antibiotics is key in the treatment of bacterial infections to ensure clinical efficacy while avoiding toxic drug concentrations and minimizing emergence of resistance. As collection of sufficient clinical evidence is difficult for specific patient populations, infection types and pathogens, market authorization, dosing strategies and recommendations often rely on data obtained from in vitro and animal experiments. The aim of this review is to provide an overview of commonly used preclinical infection models, including their strengths and limitations. In vitro, static and dynamic time-kill experiments are the most frequently used methods for assessing pharmacokinetic/pharmacodynamic (PK/PD) associations. Limitations of in vitro models include the inability to account for the effects of the immune system, and uncertainties in clinically relevant bacterial concentrations, growth conditions and the implications of emerging resistant bacterial populations during experiments. Animal experiments, most commonly murine lung and thigh infections models, are considered a necessary link between in vitro data and the clinical situation. However, there are differences in pathophysiology, immunology, and PK between species. Mathematical modeling in which preclinical data are integrated with human population PK can facilitate translation of preclinical data to the patient's clinical situation. Moreover, PK/PD modeling and simulations can help in the design of clinical trials aiming to establish optimal dosing regimens to improve patient outcomes. (C) 2020 The Authors. Published by Elsevier B.V.

    Download full text (pdf)
    fulltext
12 1 - 50 of 63
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf