Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • 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
From Penicillin Binding Proteins to Community Interventions: Mathematical and Statistical Models Related to Antibiotic Resistance
Stockholm University, Faculty of Science, Department of Mathematics.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic resistance has become a major public health concern and mathematical models are important analytical tools for the understanding, evaluation and prediction of the resistance problem and related control strategies.

The risk of emerging antibiotic resistance and selection has rarely been a concern in the design of antibiotic drug dosing regimens. In the first paper, a selection of antibiotic resistant subpopulations for different antibiotic dosing regimens was studied in vitro. The demonstrated complex relationship was influenced by both the rise of new mutants and a postantibiotic effect (PAE) (continued inhibition of bacterial growth after removal of the antibiotic drug). By constructing a mathematical model that incorporated biologically relevant parameters, we were able to assess the risks of resistance development under different dosing strategies.

In the second paper, the model for PAEs is further developed to determine the implications for different dosing regimens. The result challenges the conventional notion that long PAEs promote extended drug dosing intervals and it allows new hypotheses to be tested experimentally based on the findings from the theoretical framework.

Since PAE experiments often are time-consuming and laborious, very few studies have been reporting variation for this phenomenon. In the third paper, an extension to capture the stochastic behavior of bacterial population growth under drug exposure is made. The stochastic nature of the model is also an important complement to the existing deterministic models on drug dose drug effect relationships.

The last paper describes a controlled clinical intervention study aiming at determining whether the frequency of trimethoprim resistance in E. coli can be decreased by a sudden and drastic reduction in trimethoprim use. In addition to evaluating the intervention effect, the model, given estimated parameters, is also used for predicting other interesting outcomes.

Place, publisher, year, edition, pages
Stockholm: Matematiska institutionen , 2009. , 132 p.
Keyword [en]
antibiotic resistance, mathematical modeling, pharmacokinetics, pharmacodynamics, penicillin binding protein, postantibiotic effect, reversibility, selection, community intervention
National Category
Probability Theory and Statistics
Research subject
Mathematical Statistics
Identifiers
URN: urn:nbn:se:su:diva-8477ISBN: 978-91-7155-809-1 (print)OAI: oai:DiVA.org:su-8477DiVA: diva2:200337
Public defence
2009-02-27, sal 14, hus 5, Kräftriket, Stockholm, 13:00
Opponent
Supervisors
Available from: 2009-02-05 Created: 2009-01-27Bibliographically approved
List of papers
1. Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-Resistant Escherichia coli
Open this publication in new window or tab >>Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-Resistant Escherichia coli
2005 In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, Vol. 49, no 12, 5081-5091 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25710 (URN)
Note
Part of urn:nbn:se:su:diva-8477Available from: 2009-02-05 Created: 2009-01-27Bibliographically approved
2. Modeling the Mechanism of Postantibiotic Effect and Determining Implications for Dosing Regimens
Open this publication in new window or tab >>Modeling the Mechanism of Postantibiotic Effect and Determining Implications for Dosing Regimens
2009 (English)In: Journal of Mathematical Biology, ISSN 0303-6812, E-ISSN 1432-1416, Vol. 59, no 5, 1416-1432 p.Article in journal (Refereed) Published
Abstract [en]

A stochastic model is proposed to explain one possible underlying mechanism of the postantibiotic effect (PAE). This phenomenon, of continued inhibition of bacterial growth after removal of the antibiotic drug, is of high relevance in the context of optimizing dosing regimens. One clinical implication of long PAE lies in the possibility of increasing intervals between drug administrations. The model describes the dynamics of synthesis, saturation and removal of penicillin binding proteins (PBPs). High fractions of saturated PBPs are in the model associated with a lower growth capacity of bacteria. An analytical solution for the bivariate probability of saturated and unsaturated PBPs is used as a basis to explore optimal antibiotic dosing regimens. Our finding that longer PAEs do not necessarily promote for increased intervals between doses, might help for our understanding of data provided from earlier PAE studies and for the determination of the clinical relevance of PAE in future studies.

Keyword
Antibiotic resistance - Kolmogorov equations - Penicillin binding proteins - Postantibiotic effect
National Category
Mathematics Other Mathematics
Identifiers
urn:nbn:se:su:diva-25711 (URN)10.1007/s00285-009-0249-8 (DOI)000269058000007 ()
Note
Part of urn:nbn:se:su:diva-8477Available from: 2009-02-05 Created: 2009-01-27 Last updated: 2017-12-13Bibliographically approved
3. A multi-type branching model with varying environments for for Bacterial Dynamics with Postantibiotic Effect
Open this publication in new window or tab >>A multi-type branching model with varying environments for for Bacterial Dynamics with Postantibiotic Effect
2009 (English)In: Journal of Theoretical Biology, ISSN 0022-5193, Vol. 256, no 1, 58-64 p.Article in journal (Refereed) Published
Abstract [en]

A multi-type branching process with varying environment was used to construct a pharmacokinetic/pharmacodynamic (PK/PD) model that captures the postantibiotic effect (PAE) seen in bacterial populations after exposure of antibiotics. This phenomenon of continued inhibition of bacterial growth even after removal of the antibiotic from the growth medium is of high relevance in the context of optimizing dosing regimens. The clinical implication of long PAEs lies in the interesting possibility of increasing the intervals between drug administrations.

The model structure is generalizable to most types of antibiotics and is useful both as a theoretical framework for understanding the time properties of PAE and to explore optimal antibiotic dosing regimens. Data from an in vitro study with Escherichia coli exposed to different dosing regimens of cefotaxime were used to evaluate the model.

Identifiers
urn:nbn:se:su:diva-25712 (URN)10.1016/j.jtbi.2008.09.023 (DOI)000261706800005 ()
Note
Part of urn:nbn:se:su:diva-8477Available from: 2009-02-05 Created: 2009-01-27 Last updated: 2012-05-07Bibliographically approved
4. Marginal effect on antibiotic resistance following a drastic reduction in trimethoprim use in a community
Open this publication in new window or tab >>Marginal effect on antibiotic resistance following a drastic reduction in trimethoprim use in a community
Show others...
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-25713 (URN)
Note
Part of urn:nbn:se:su:diva-8477Available from: 2009-02-05 Created: 2009-01-27Bibliographically approved

Open Access in DiVA

No full text

By organisation
Department of Mathematics
Probability Theory and Statistics

Search outside of DiVA

GoogleGoogle Scholar

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 920 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • 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