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Nielsen, Elisabet I.
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Publications (10 of 32) Show all publications
Ungphakorn, W. (2018). Automated time-lapse microscopy a novel method for screening of antibiotic combination effects against multidrug-resistant Gram-negative bacteria. Clinical Microbiology and Infection, 24(7), Article ID 778.e7.
Open this publication in new window or tab >>Automated time-lapse microscopy a novel method for screening of antibiotic combination effects against multidrug-resistant Gram-negative bacteria
2018 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 24, no 7, article id 778.e7Article in journal (Refereed) Published
Abstract [en]

Objectives

Antibiotic combinations are often used for carbapenemase-producing Enterobacteriaceae (CPE) but more data are needed on the optimal selection of drugs. This study aimed to evaluate the feasibility of a novel automated method based on time-lapse microscopy (the oCelloScope, Philips BioCell A/S, Allerød, Denmark) to determine in vitro combination effects against CPE and to discuss advantages and limitations of the oCelloScope in relation to standard methods.

Methods

Four Klebsiella pneumoniae and two Escherichia coli were exposed to colistin, meropenem, rifampin and tigecycline, alone and in combination. In the oCelloScope experiments, a background corrected absorption (BCA) value of ≤8 at 24 h was used as a primary cut-off indicating inhibition of bacterial growth. A new approach was used to determine synergy, indifference and antagonism based on the number of objects (bacteria) in the images. Static time–kill experiments were performed for comparison.

Results

The time–kill experiments showed synergy with 12 of 36 regimens, most frequently with colistin plus rifampin. BCA values ≤8 consistently correlated with 24-h bacterial concentrations ≤6 log10 CFU/mL. The classification of combination effects agreed with the time–kill results for 33 of 36 regimens. In three cases, the interactions could not be classified with the microscopy method because of low object counts.

Conclusions

Automated time-lapse microscopy can accurately determine the effects of antibiotic combinations. The novel method is highly efficient compared with time–kill experiments, more informative than checkerboards and can be useful to accelerate the screening for combinations active against multidrug-resistant Gram-negative bacteria.

Keywords
Antibiotic combinations, Carbapenemases, Escherichia coli, Image analysis, Klebsiella pneumoniae, oCelloScope, Synergy, Time–kill experiments
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-343647 (URN)10.1016/j.cmi.2017.10.029 (DOI)000436640800021 ()29108951 (PubMedID)
Funder
Swedish Research CouncilAFA InsurancePublic Health Agency of Sweden
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-09-18Bibliographically approved
Senek, M., Nyholm, D. & Nielsen, E. I. (2018). Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients. European Journal of Clinical Pharmacology, 74(10), 1299-1307
Open this publication in new window or tab >>Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients
2018 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 10, p. 1299-1307Article in journal (Refereed) Published
Abstract [en]

Objectives: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates.

Methods: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson's disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies. The analysis was carried out using non-linear mixed effects modeling. Bodyweight was included on all disposition parameters according to allometric scaling. Potential influence of additional covariates was investigated using graphical evaluation and adjusted adaptive least absolute shrinkage and selection operator.

Results: Dispositions of levodopa and carbidopa were best described by a two- and one-compartment model respectively. Double-peak profiles were described using two parallel absorption compartments. Levodopa apparent clearance was found to decrease with increasing carbidopa dose (15% lower with 75 compared to 50mg of carbidopa) and disease stage (by 18% for Hoehn and Yahr 1 to 4). Carbidopa apparent clearance was found to decrease with age (28% between the age of 60 and 80years). An external evaluation showed the model to be able to reasonably well predict levodopa concentrations following multiple-dose microtablet administration in healthy subjects.

Conclusions: The presented models adequately described the PK of levodopa and carbidopa, following microtablet administration. The developed model may in the future be combined with a pharmacokinetic-pharmacodynamic target and used for individualized dose selection, utilizing the flexibility offered by the microtablets.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-343034 (URN)10.1007/s00228-018-2497-2 (DOI)000444387700009 ()29882153 (PubMedID)
Funder
VINNOVA
Available from: 2018-02-25 Created: 2018-02-25 Last updated: 2018-11-13Bibliographically 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
Netterberg, I., Karlsson, M. O., Nielsen, E. I., Quartino, A. L., Lindman, H. & Friberg, L. E. (2018). The risk of febrile neutropenia in breast cancer patients following adjuvant chemotherapy is predicted by the time course of interleukin-6 and C-reactive protein by modelling.. British Journal of Clinical Pharmacology, 84(3), 490-500
Open this publication in new window or tab >>The risk of febrile neutropenia in breast cancer patients following adjuvant chemotherapy is predicted by the time course of interleukin-6 and C-reactive protein by modelling.
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2018 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 84, no 3, p. 490-500Article in journal (Refereed) Published
Abstract [en]

AIMS: Early identification of patients with febrile neutropenia (FN) is desirable for initiation of preventive treatment, such as with antibiotics. In this study, the time courses of two inflammation biomarkers, interleukin (IL)-6 and C-reactive protein (CRP), following adjuvant chemotherapy of breast cancer, were characterized. The potential to predict development of FN by IL-6 and CRP, and other model-derived and clinical variables, was explored.

METHODS: The IL-6 and CRP time courses in cycles 1 and 4 of breast cancer treatment were described by turnover models where the probability for an elevated production following initiation of chemotherapy was estimated. Parametric time-to-event models were developed to describe FN occurrence to assess: (i) predictors available before chemotherapy is initiated; (ii) predictors available before FN occurs; and (iii) predictors available when FN occurs.

RESULTS: The IL-6 and CRP time courses were successfully characterized with peak IL-6 typically occurring 2 days prior to CRP peak. Of all evaluated variables the CRP time course was most closely associated with the occurrence of FN. Since the CRP peak typically occurred at the time of FN diagnosis it will, however, have limited value for identifying the need for preventive treatment. The time course of IL-6 was the predictor that could best forecast FN events. Of the variables available at baseline, age was the best, although in comparison a relatively weak, predictor.

CONCLUSIONS: The developed models add quantitative knowledge about IL-6 and CRP and their relationship to the development of FN. The study suggests that IL-6 may have potential as a clinical predictor of FN if monitored during myelosuppressive chemotherapy.

Keywords
C-reactive protein, NONMEM, adjuvant chemotherapy, febrile neutropenia, interleukin-6
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-343812 (URN)10.1111/bcp.13477 (DOI)000424877400009 ()29178353 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-03-01 Created: 2018-03-01 Last updated: 2018-04-09Bibliographically approved
Johansson, A., Lindstedt, D., Roman, M., Thelander, G., Nielsen, E. I., Lennborn, U., . . . Kugelberg, F. C. (2017). A non-fatal intoxication and seven deaths involving the dissociative drug 3-MeO-PCP. Forensic Science International, 275, 76-82
Open this publication in new window or tab >>A non-fatal intoxication and seven deaths involving the dissociative drug 3-MeO-PCP
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2017 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 275, p. 76-82Article in journal (Refereed) Published
Abstract [en]

Introduction: 3-methoxyphencyclidine (3-MeO-PCP) appeared on the illicit drug market in 2011 and is an analogue of phencyclidine, which exhibits anesthetic, analgesic and hallucinogenic properties. In this paper, we report data from a non-fatal intoxication and seven deaths involving 3-MeO-PCP in Sweden during the period March 2014 until June 2016. Case descriptions: The non-fatal intoxication case, a 19-year-old male with drug problems and a medical history of depression, was found awake but tachycardic, hypertensive, tachypnoeic and catatonic at home. After being hospitalized, his condition worsened as he developed a fever and lactic acidosis concomitant with psychomotor agitation and hallucinations. After 22 h of intensive care, the patient had made a complete recovery. During his hospitalization, a total of four blood samples were collected at different time points. The seven autopsy cases, six males and one female, were all in their twenties to thirties with psychiatric problems and/or an ongoing drug abuse. Methods: 3-MeO-PCP was identified with liquid chromatography (LC)/time-of-flight technology and quantified using LC-tandem mass spectrometry. Results: In the clinical case, the concentration of 3-MeO-PCP was 0.14 mu g/g at admission, 0.08 mu g/g 2.5 h after admission, 0.06 mu g/g 5 h after admission and 0.04 mu g/g 17 h after admission. The half-life of 3-MeO-PCP was estimated to 11 h. In the autopsy cases, femoral blood concentrations ranged from 0.05 mu g/g to 0.38 mu g/g. 3-MeO-PCP was the sole finding in the case with the highest concentration and the cause of death was established as intoxication with 3-MeO-PCP. In the remaining six autopsy cases, other medications and drugs of abuse were present as well. Conclusion: Despite being scheduled in January 2015, 3-MeO-PCP continues to be abused in Sweden. Exposure to 3-MeO-PCP may cause severe adverse events and even death, especially if the user does not receive life-supporting treatment.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2017
Keywords
Dissociative drugs, Phencyclidine, 3-MeO-PCP, Intoxication, Postmortem blood concentrations
National Category
Forensic Science
Identifiers
urn:nbn:se:uu:diva-330757 (URN)10.1016/j.forsciint.2017.02.034 (DOI)000404011100011 ()28324770 (PubMedID)
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-03Bibliographically approved
Sadiq, M. W., Nielsen, E. I., Khachman, D., Conil, J.-M., Georges, B., Houin, G., . . . Friberg, L. E. (2017). A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection.. Journal of Pharmacokinetics and Pharmacodynamics, 44(2), 69-79
Open this publication in new window or tab >>A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection.
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2017 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 44, no 2, p. 69-79Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic-pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration-time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin's indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK-PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-318715 (URN)10.1007/s10928-016-9486-9 (DOI)000399036400002 ()27578330 (PubMedID)
Funder
Swedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme, 115156
Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2018-01-13Bibliographically approved
Nielsen, E. I., Khan, D. D., Cao, S., Lustig, U., Hughes, D., Andersson, D. I. & Friberg, L. E. (2017). Can a pharmacokinetic/pharmacodynamic (PKPD) model be predictive across bacterial densities and strains?: External evaluation of a PKPD model describing longitudinal in vitro data. Journal of Antimicrobial Chemotherapy, 72(11), 3108-3116
Open this publication in new window or tab >>Can a pharmacokinetic/pharmacodynamic (PKPD) model be predictive across bacterial densities and strains?: External evaluation of a PKPD model describing longitudinal in vitro data
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2017 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 11, p. 3108-3116Article in journal (Refereed) Published
Abstract [en]

Background: Pharmacokinetic/pharmacodynamic (PKPD) models developed based on data from in vitro time-kill experiments have been suggested to contribute to more efficient drug development programmes and better dosing strategies for antibiotics. However, for satisfactory predictions such models would have to show good extrapolation properties. Objectives: To evaluate if a previously described mechanism-based PKPD model was able also to predict drug efficacy for higher bacterial densities and across bacterial strains. Methods: A PKPD model describing the efficacy of ciprofloxacin on Escherichia coli was evaluated. The predictive performance of the model was evaluated across several experimental conditions with respect to: (i) bacterial start inoculum ranging from the standard of similar to 10(6) cfu/mL up to late stationary-phase cultures; and (ii) efficacy for seven additional strains (three laboratory and four clinical strains), not included during the model development process, based only on information regarding their MIC. Model predictions were performed according to the intended experimental protocol and later compared with observed bacterial counts. Results: The mechanism-based PKPD model structure developed based on data from standard start inoculum experiments was able to accurately describe the inoculum effect. The model successfully predicted the time course of drug efficacy for additional laboratory and clinical strains based on only the MIC values. The model structure was further developed to better describe the stationary phase data. Conclusions: This study supports the use of mechanism-based PKPD models based on preclinical data for predictions of untested scenarios.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2017
National Category
Pharmaceutical Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-340705 (URN)10.1093/jac/dkx269 (DOI)000413464200019 ()28961946 (PubMedID)
Funder
Swedish Foundation for Strategic Research
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-02-21Bibliographically approved
Kurland, S., Furebring, M., Löwdin, E., Nielsen, E. I. & Sjölin, J. (2017). Elimination ability of caspofungin in critically ill patients in relation to liver dysfunction in an ICU setting. Mycoses (Berlin), 60, 225-225
Open this publication in new window or tab >>Elimination ability of caspofungin in critically ill patients in relation to liver dysfunction in an ICU setting
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2017 (English)In: Mycoses (Berlin), ISSN 0933-7407, E-ISSN 1439-0507, Vol. 60, p. 225-225Article in journal, Meeting abstract (Other academic) Published
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-346551 (URN)000411715800387 ()
Available from: 2018-03-21 Created: 2018-03-21 Last updated: 2018-03-21Bibliographically approved
Abrantes, J. A., Nielsen, E. I., Korth-Bradley, J., Harnisch, L. & Jönsson, S. (2017). Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa. Clinical Pharmacology and Therapeutics, 102(6), 977-988
Open this publication in new window or tab >>Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
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2017 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 6, p. 977-988Article in journal (Refereed) Published
Abstract [en]

This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-342208 (URN)10.1002/cpt.716 (DOI)000414921800026 ()28437834 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-20Bibliographically 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
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