The prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho... Show moreThe prevalence of obesity (BMI >40 kg/m2) has increased rapidly over the recent years, not only in adults, but also in children and adolescents. Although it is well known that (patho)physiological changes in obese individuals can influence drug pharmacokinetics, implying adjusted doses, there is still a need for specific dose guidelines for many classes of drugs. In this thesis, the pharmacokinetics of the renally cleared antibiotics gentamicin, tobramycin and vancomycin, drugs for which it is well known that both the efficacy and toxicity of these drugs closely relate to blood concentrations, are studied in non-obese and (morbidly) obese adults, adolescents and children. We present practical dose recommendations for the obese adult, paediatric and adolescent populations. Furthermore, some important questions are addressed regarding the pharmacokinetics of drugs in obesity: can we use the lipophilicity of a drug to predict changes in volume of distribution? Which pitfalls have to be considered when using lean body weight as basis for drug dosing? And which methods for estimating glomerular filtration can predict the clearance of renally cleared drugs in obese patients? The work in this thesis provide some important steps in filling the current knowledge gaps regarding the pharmacokinetics of drugs in obesity. Show less
The aim of this thesis was to obtain insight into the epidemiology and molecular basis of multidrug resistance of Acinetobacter baumannii at the population level. To this aim a number of studies... Show moreThe aim of this thesis was to obtain insight into the epidemiology and molecular basis of multidrug resistance of Acinetobacter baumannii at the population level. To this aim a number of studies were performed on strains mainly from the Czech Republic (CR) which have shown in particular that (i) the vast majority of multidrug resistant (MDR) clinical isolates of A. baumannii from CR belong to clonal lineages termed EU clone I and II; (ii) these two clones have predominated among MDR hospital isolates in CR since at least 1991; (iii) recent emergence of A. baumannii resistance to carbapenems in CR was associated with the country-wide spread of a subclone of EU clone II; (iv) multidrug resistance is a general feature of strains of EU clones I and II, yet strains belonging to one clone may vary in the content of resistance genes; (v) upregulation of genes intrinsic to A. baumannii as well as horizontal acquisition of resistance genes can be sources of development of multidrug resistance and intraclonal diversification; (vi) the genes encoding the non-specific efflux system AdeABC are present in nearly all A. baumannii strains, yet the AdeABC overexpression is seen mostly in MDR strains harbouring additional resistance genes. Show less
