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Cars, Otto
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Publications (10 of 61) Show all publications
Rochford, C., Sridhar, D., Woods, N., Saleh, Z., Hartenstein, L., Ahlawat, H., . . . Davies, S. (2018). Global governance of antimicrobial resistance. The Lancet, 391(10134), 1976-1978
Open this publication in new window or tab >>Global governance of antimicrobial resistance
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2018 (English)In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 391, no 10134, p. 1976-1978Article in journal, Editorial material (Other academic) Published
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-358128 (URN)10.1016/S0140-6736(18)31117-6 (DOI)000432440300010 ()29864011 (PubMedID)
Available from: 2018-08-28 Created: 2018-08-28 Last updated: 2018-08-28Bibliographically approved
Khan, D., Lagerbäck, P., Malmberg, C., Kristoffersson, A., Gullberg, E., Cao, S., . . . Friberg, L. E. (2018). Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli. International Journal of Antimicrobial Agents, 51(3), 399-406, Article ID S0924-8579(17)30392-8.
Open this publication in new window or tab >>Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli
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2018 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 51, no 3, p. 399-406, article id S0924-8579(17)30392-8Article in journal (Refereed) Published
Abstract [en]

Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection.

Keywords
Ciprofloxacin, Escherichia coli, PK/PD modelling, PK/PD predictions, Pharmacokinetics/Pharmacodynamics, Time–kill experiments
National Category
Pharmaceutical Sciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-343607 (URN)10.1016/j.ijantimicag.2017.10.019 (DOI)000427582000016 ()29127049 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme, FP7/2007-2013
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-05-18Bibliographically approved
Karvanen, M., Malmberg, C., Lagerbäck, P., Friberg, L. E. & Cars, O. (2018). Reply to Prim et al., "Is Colistin Susceptibility Testing Finally on the Right Track?" [Letter to the editor]. Antimicrobial Agents and Chemotherapy, 62(4), Article ID e02507-17.
Open this publication in new window or tab >>Reply to Prim et al., "Is Colistin Susceptibility Testing Finally on the Right Track?"
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2018 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 4, article id e02507-17Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2018
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-356888 (URN)10.1128/AAC.02507-17 (DOI)000428392100084 ()29588358 (PubMedID)
Available from: 2018-08-10 Created: 2018-08-10 Last updated: 2018-08-10Bibliographically approved
Tängdén, T., Pulcini, C., Aagaard, H., Balasegaram, M., Hara, G. L., Nathwani, D., . . . Cars, O. (2018). Unavailability of old antibiotics threatens effective treatment for common bacterial infections. Lancet. Infectious diseases (Print), 18(3), 242-244
Open this publication in new window or tab >>Unavailability of old antibiotics threatens effective treatment for common bacterial infections
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2018 (English)In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 18, no 3, p. 242-244Article in journal, Editorial material (Other academic) Published
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-351591 (URN)10.1016/S1473-3099(18)30075-6 (DOI)000425938000015 ()29485082 (PubMedID)
Available from: 2018-05-29 Created: 2018-05-29 Last updated: 2018-05-29Bibliographically approved
Tängdén, T., Karvanen, M., Friberg, L. E., Odenholt, I. & Cars, O. (2017). Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments. Infectious Diseases, 49(7), 521-527
Open this publication in new window or tab >>Assessment of early combination effects of colistin and meropenem against Pseudomonas aeruginosa and Acinetobacter baumannii in dynamic time-kill experiments
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2017 (English)In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 49, no 7, p. 521-527Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
Keywords
Gram-negative bacteria, time-kill experiments, checkerboards, synergy
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-322114 (URN)10.1080/23744235.2017.1296183 (DOI)000399555100006 ()28264618 (PubMedID)
Funder
AstraZeneca
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-19Bibliographically approved
Karvanen, M., Malmberg, C., Lagerbäck, P., Friberg, L. E. & Cars, O. (2017). Colistin is Extensively Lost during Standard in Vitro Experimental Conditions. Antimicrobial Agents and Chemotherapy, 61(11), Article ID e00857-17.
Open this publication in new window or tab >>Colistin is Extensively Lost during Standard in Vitro Experimental Conditions
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2017 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 11, article id e00857-17Article in journal (Refereed) Published
Abstract [en]

Colistin adheres to a range of materials, including plastics in labware. The loss caused by adhesion influences an array of methods detrimentally, including MIC assays and in vitro time-kill experiments. The aim of this study was to characterize the extent and time course of colistin loss in different types of laboratory materials during a simulated time-kill experiment without bacteria or plasma proteins present. Three types of commonly used large test tubes, i.e., soda-lime glass, polypropylene, and polystyrene, were studied, as well as two different polystyrene microplates and low-protein-binding microtubes. The tested concentration range was 0.125 to 8 mg/liter colistin base. Exponential one-phase and two-phase functions were fitted to the data, and the adsorption of colistin to the materials was modeled with the Langmuir adsorption model. In the large test tubes, the measured start concentrations ranged between 44 and 102% of the expected values, and after 24 h, the concentrations ranged between 8 and 90%. The half-lives of colistin loss were 0.9 to 12 h. The maximum binding capacities of the three materials ranged between 0.4 and 1.1 μg/cm2, and the equilibrium constants ranged between 0.10 and 0.54 ml/μg. The low-protein-binding microtubes showed start concentrations between 63 and 99% and concentrations at 24 h of between 59 and 90%. In one of the microplates, the start concentrations were below the lower limit of quantification at worst. In conclusion, to minimize the effect of colistin loss due to adsorption, our study indicates that low-protein-binding polypropylene should be used when possible for measuring colistin concentrations in experimental settings, and the results discourage the use of polystyrene. Furthermore, when diluting colistin in protein-free media, the number of dilution steps should be minimized.

Keywords
Colistin adsorption degradation
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-197722 (URN)10.1128/AAC.00857-17 (DOI)000413558300063 ()28893773 (PubMedID)
Funder
VINNOVASwedish Foundation for Strategic Research
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2018-02-20Bibliographically approved
Pulcini, C., Beovic, B., Beraud, G., Carlet, J., Cars, O., Howard, P., . . . Sharland, M. (2017). Ensuring universal access to old antibiotics: a critical but neglected priority. Clinical Microbiology and Infection, 23(9), 590-592
Open this publication in new window or tab >>Ensuring universal access to old antibiotics: a critical but neglected priority
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2017 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 23, no 9, p. 590-592Article in journal, Editorial material (Other academic) Published
National Category
Infectious Medicine Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-334996 (URN)10.1016/j.cmi.2017.04.026 (DOI)000407933400002 ()28522030 (PubMedID)
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2017-11-29Bibliographically approved
Ungphakorn, W., Malmberg, C., Lagerbäck, P., Cars, O., Nielsen, E. I. & Tängdén, T. (2017). Evaluation of automated time-lapse microscopy for assessment of in vitro activity of antibiotics. Journal of Microbiological Methods, 132, 69-75
Open this publication in new window or tab >>Evaluation of automated time-lapse microscopy for assessment of in vitro activity of antibiotics
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2017 (English)In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 132, p. 69-75Article in journal (Refereed) Published
Abstract [en]

This study aimed to evaluate the potential of a new time-lapse microscopy based method (oCelloScope) to efficiently assess the in vitro antibacterial effects of antibiotics. Two E. con and one P. aeruginosa strain were exposed to ciprofloxacin, colistin, ertapenem and meropenem in 24-h experiments. Background corrected absorption (BCA) derived from the oCelloScope was used to detect bacterial growth. The data obtained with the oCelloScope were compared with those of the automated Bioscreen C method and standard time-kill experiments and a good agreement in results was observed during 6-24 h of experiments. Viable counts obtained at 1, 4, 6 and 24 h during oCelloScope and Bioscreen C experiments were well correlated with the corresponding BCA and optical density (OD) data. Initial antibacterial effects during the first 6 h of experiments were difficult to detect with the automated methods due to their high detection limits (approximately 105 CFU/mL for oCelloScope and 107 CFU/mL for Bioscreen C), the inability to distinguish between live and dead bacteria and early morphological changes of bacteria during exposure to ciprofloxacin, ertapenem and meropenem. Regrowth was more frequently detected in time-kill experiments, possibly related to the larger working volume with an increased risk of preexisting or emerging resistance. In comparison with Bioscreen C, the oCelloScope provided additional information on bacterial growth dynamics in the range of 105 to 107 CFU/mL and morphological features. In conclusion, the oCelloScope would be suitable for detection of in vitro effects of antibiotics, especially when a large number of regimens need to be tested.

Keywords
Gram-negative bacteria, PKPD, Bacterial morphology, oCelloScope, Bioscreen C, Time-kill experiments
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-317690 (URN)10.1016/j.mimet.2016.11.001 (DOI)000393017100012 ()27836633 (PubMedID)
Funder
AFA InsurancePublic Health Agency of Sweden
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Pulcini, C., Mohrs, S., Beovic, B., Gyssens, I., Theuretzbacher, U. & Cars, O. (2017). Forgotten antibiotics: a follow-up inventory study in Europe, the USA, Canada and Australia. International Journal of Antimicrobial Agents, 49(1), 98-101
Open this publication in new window or tab >>Forgotten antibiotics: a follow-up inventory study in Europe, the USA, Canada and Australia
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2017 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 49, no 1, p. 98-101Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to update a 2011 survey, conducted on behalf of the ESCMID Study Group for Antibiotic Policies (ESGAP), studying the availability of old but clinically useful antibiotics in North America, Europe and Australia. This follow-up survey was performed in 2015 in 40 countries among specialists from the pharmaceutical, infectious diseases and microbiology sectors in North America, Europe and Australia in order to assess the availability through usual marketing processes of 36 systemic antibiotics (addition of 3 antibiotics compared with the 2011 survey) selected for their ability to treat infections caused by resistant bacteria and their unique value for specific criteria. The questionnaire was sent by e-mail to national contacts belonging to ESGAP and ReAct networks. In all, 39 of the 40 countries participated in this survey. The number of available antibiotics differed considerably from one drug to another as well as from one country to another (e.g. 7 antibiotics available in Estonia, 24 in France). Overall, 25/36 selected antibiotics were marketed in 20/39 countries or less. From 2011 to 2015 (data available for both periods in 37 countries for 33 antibiotics), the number of available selected antibiotics increased in 13 countries and decreased in 17. In conclusion, despite the ongoing bacterial resistance crisis, the situation regarding the availability of 'forgotten antibiotics' has worsened since 2011. Urgent measures are needed to ensure better availability of these antibiotics on a global scale as a conservation measure to ensure sustainable and responsible use of antibiotics. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Bacterial resistance, Drug approval, Drug marketing, Antibiotic stewardship
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-319293 (URN)10.1016/j.ijantimicag.2016.09.029 (DOI)000396429300014 ()27887966 (PubMedID)
Available from: 2017-04-11 Created: 2017-04-11 Last updated: 2017-11-29Bibliographically approved
Malmberg, C., Yuen, P., Spaak, J., Cars, O., Tängdén, T. & Lagerbäck, P. (2016). A Novel Microfluidic Assay for Rapid Phenotypic Antibiotic Susceptibility Testing of Bacteria Detected in Clinical Blood Cultures. PLoS ONE, 11(12), Article ID e0167356.
Open this publication in new window or tab >>A Novel Microfluidic Assay for Rapid Phenotypic Antibiotic Susceptibility Testing of Bacteria Detected in Clinical Blood Cultures
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0167356Article in journal (Refereed) Published
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.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-316968 (URN)10.1371/journal.pone.0167356 (DOI)000392754300025 ()27974860 (PubMedID)
Funder
AFA InsuranceVINNOVA, 2014-03512
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-11-29Bibliographically approved
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