Project title: Optimisation of antibiotic therapy in critically ill patients using population pharmacokinetic and pharmacodynamic modelling and simulation

Project aims:

For an effective fight of bacterial infections, a pathogen- and patient-specific treatment is needed. Not only the spectrum of activity, but also appropriate dosing and the resulting effective concentration-time profile at the site of infection of the antibiotic drug is important for the pathogen specific treatment. Between and within different bacterial species this effective concentration-time profile can vary. In addition, the drug-concentration-time profile associated to the same dosing regimen can differ within populations of patients. Especially in critically ill patients, large variability, due to physiological changes related to their state of disease, is observed. Since most dosing recommendations are based on clinical data of healthy volunteers or patients with a specific disease, dosing recommendations for critically ill patients on a scientific basis are challenging. The use of a uniform dosing regimen bears the risk of subtherapeutic or toxic concentration-time profiles and therefore the risk of treatment failure, adverse drug reactions and a further proceeding of bacterial resistance.  

Based on these considerations, my PhD project will focus on evaluating the pharmacokinetics and pharmacodynamics of frequently used antibiotics in critically ill patients. Based on both drug concentrations in serum and patient-specific characteristics a population pharmacokinetic, non-linear mixed-effects model is going to be developed. In a first step, the pharmacokinetics of the antibiotic is characterised, i.e. the typical concentration-time profile is described and different levels of variability between and within the patients are quantified. In a second step, covariates (such as demographics, physiological or disease-related parameters) are identified explaining the observed variabilities. The final pharmacometric model shall be used to examine currently used dosing regimens with a focus on effective concentration-time profiles of the antibiotic drug in critically ill patients and if needed to propose more effective dosing schemes. By this approach, it is intended to contribute to a successful treatment for every patient and to prevent a further emergence and spread of bacterial resistance.