From Penicillin Binding Proteins to Community Interventions : Mathematical and Statistical Models Related to Antibiotic Resistance

Sammanfattning: 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.