uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Little evidence for reversibility of trimethoprim resistance after a drastic reduction in trimethoprim use
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. (Infektionssjukdomar)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Show others and affiliations
2010 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 65, no 2, 350-360 p.Article in journal (Refereed) Published
Abstract [en]

Objectives The worldwide rapid increase in antibiotic-resistant bacteria has made efforts to prolong the lifespan of existing antibiotics very important. Antibiotic resistance often confers a fitness cost in the bacterium. Resistance may thus be reversible if antibiotic use is discontinued or reduced. To examine this concept, we performed a 24 month voluntary restriction on the use of trimethoprim-containing drugs in Kronoberg County, Sweden. Methods The intervention was performed on a 14 year baseline of monthly data on trimethoprim resistance and consumption. A three-parameter mathematical model was used to analyse the intervention effect. The prerequisites for reversion of resistance (i.e. fitness cost, associated resistance and clonal composition) were studied on subsets of consecutively collected Escherichia coli from urinary tract infections. Results The use of trimethoprim-containing drugs decreased by 85% during the intervention. A marginal but statistically significant effect on the increase in trimethoprim resistance was registered. There was no change in the clonal composition of E. coli and there was no measurable fitness cost associated with trimethoprim resistance in clinical isolates. The frequency of associated antibiotic resistances in trimethoprim-resistant isolates was high. Conclusions A lack of detectable fitness cost of trimethoprim resistance in vitro together with a strong co-selection of other antibiotics could explain the rather disappointing effect of the intervention. The result emphasizes the low possibility of reverting antibiotic resistance once established and the urgent need for the development of new antibacterial agents.

Place, publisher, year, edition, pages
Oxford University Press , 2010. Vol. 65, no 2, 350-360 p.
Keyword [en]
intervention, Escherichia coli, population dynamic
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-112599DOI: 10.1093/jac/dkp387ISI: 000273892600030PubMedID: 19900952OAI: oai:DiVA.org:uu-112599DiVA: diva2:286933
Epub ahead of print 8 November 2009Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2010-12-29Bibliographically approved
In thesis
1. Antibiotic Resistance and Population Dynamics of Escherichia coli in Relation to a Large Scale Antibiotic Consumption Intervention
Open this publication in new window or tab >>Antibiotic Resistance and Population Dynamics of Escherichia coli in Relation to a Large Scale Antibiotic Consumption Intervention
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic resistance challenges the practice and development of modern medicine. The aim of this thesis was to test the hypothesis that antibiotic resistance is reversible once the selection pressure of an antibiotic is removed. A decisive reduction (85%) in trimethoprim and trimethoprim-sulfamethoxazole over 24 months in Kronoberg County, Sweden, is described. The resistance baseline prior to the intervention and the effects of the intervention on resistance levels, trimethoprim resistance genes (dfr-genes) and population structure in Escherichia coli were studied.

The effects of different algorithms for excluding patient duplicate isolates were small but systematic. An identical algorithm was used throughout.

The drastic decrease in the use of trimethoprim containing drugs did not result in a corresponding decrease in trimethoprim resistance. This was true both for total trimethoprim resistance and for trimethoprim mono-resistance. The distributions of E. coli phenotypes, dfr-genes and E. coli sequence types were stable. The marginal effect on resistance rates was explained by a low fitness cost of trimethoprim resistance observed in vitro and the high levels of associated resistance in trimethoprim resistant isolates.

Trimethoprim resistance was, although widespread in the E. coli population, more common in certain E. coli sequence types. The distributions of dfr-genes were different in E. coli and K. pneumoniae and between different E. coli sequence types. These results indicate mechanisms related to the genetic back-bone of E coli to be important for the acquisition and persistence of antibiotic resistance.

The findings of this thesis indicates that, at least for some classes of antibiotics, we may have overestimated the usefulness of a strategy for reversing antimicrobial resistance based on the fitness cost of resistance. We have equally underestimated the conserving effects of associated resistance. The stability of the dfr-genes and E. coli sequence types underlines the importance of associated resistance and successful lineages in the spread and maintenance of antibiotic resistance in E. coli.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 81 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 512
reversibility, trimethoprim, dfr, associated resistance, MLST
National Category
Infectious Medicine Microbiology in the medical area Microbiology in the medical area
Research subject
Infectious Diseases
urn:nbn:se:uu:diva-112190 (URN)978-91-554-7700-4 (ISBN)
Public defence
2010-02-26, Universitetshuset, sal IV, Övre Slottsgatan, Uppsala, 13:00 (English)
Available from: 2010-02-02 Created: 2010-01-11 Last updated: 2010-02-02Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Sundqvist, MartinAndersson, Dan I.Cars, OttoKahlmeter, Gunnar
By organisation
Infectious DiseasesDepartment of Medical Biochemistry and MicrobiologyClinical Bacteriology
In the same journal
Journal of Antimicrobial Chemotherapy
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 409 hits
ReferencesLink to record
Permanent link

Direct link