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Tängdén, Thomas
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Publications (10 of 19) Show all publications
Montelin, H., Forsman, K.-J. & Tängdén, T. (2019). Retrospective evaluation of nitrofurantoin and pivmecillinam for the treatment of lower urinary tract infections in men. PLoS ONE, 14(1), Article ID e0211098.
Open this publication in new window or tab >>Retrospective evaluation of nitrofurantoin and pivmecillinam for the treatment of lower urinary tract infections in men
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0211098Article in journal (Refereed) Published
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.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-378740 (URN)10.1371/journal.pone.0211098 (DOI)000457037500099 ()30682092 (PubMedID)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Skarp, K.-P., Shams, A., Montelin, H., Lagerbäck, P. & Tängdén, T. (2019). Synergistic and bactericidal activities of mecillinam, amoxicillin and clavulanic acid combinations against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in 24-h time-kill experiments. International Journal of Antimicrobial Agents, 53(1), 74-79
Open this publication in new window or tab >>Synergistic and bactericidal activities of mecillinam, amoxicillin and clavulanic acid combinations against extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in 24-h time-kill experiments
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2019 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 53, no 1, p. 74-79Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2019
Keywords
Amdinocillin, Mecillinam, Synergy, Extended-spectrum beta-lactamase, ESBL, Urinary tract infection
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-375234 (URN)10.1016/j.ijantimicag.2018.09.011 (DOI)000455090800012 ()30236958 (PubMedID)
Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-01-29Bibliographically approved
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
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., Cojutti, P. G., Roberts, J. A. & Pea, F. (2018). Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens. Clinical Pharmacokinetics, 57(11), 1399-1405
Open this publication in new window or tab >>Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens
2018 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 57, no 11, p. 1399-1405Article in journal (Refereed) Published
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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-370009 (URN)10.1007/s40262-018-0638-5 (DOI)000447972300004 ()29546589 (PubMedID)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically 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
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
Tängdén, T., Martin, V. R., Felton, T. W., Nielsen, E. I., Marchand, S., Brueggemann, R. J., . . . Roberts, J. A. (2017). The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections. Intensive Care Medicine, 43(7), 1021-1032
Open this publication in new window or tab >>The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections
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2017 (English)In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 43, no 7, p. 1021-1032Article, review/survey (Refereed) Published
Abstract [en]

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/ pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.

Keywords
Individualised dosing, Antibiotics, Pharmacokinetics, Pharmacodynamics, Mathematical modelling
National Category
Pharmacology and Toxicology Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-333824 (URN)10.1007/s00134-017-4780-6 (DOI)000404020100007 ()
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2018-01-13Bibliographically 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
Jonsson, A.-K., Larsson, A., Tängdén, T., Melhus, Å. & Lannergård, A. (2015). A trial with IgY chicken antibodies to eradicate faecal carriage of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamases. Infection Ecology & Epidemiology, 5, Article ID 28224.
Open this publication in new window or tab >>A trial with IgY chicken antibodies to eradicate faecal carriage of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamases
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2015 (English)In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 28224Article in journal (Refereed) Published
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.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-266969 (URN)10.3402/iee.v5.28224 (DOI)26560861 (PubMedID)
Available from: 2015-11-15 Created: 2015-11-15 Last updated: 2017-12-01Bibliographically approved
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