Renal clearance is responsible for the elimination of a large number of water-soluble drugs and metabolites and is therefore of large importance when characterizing the pharmacokinetics of drugs.... Show moreRenal clearance is responsible for the elimination of a large number of water-soluble drugs and metabolites and is therefore of large importance when characterizing the pharmacokinetics of drugs. Renal clearance includes glomerular filtration, tubular secretion and reabsorption and each of these processes is subject to different developmental changes. To estimate the renal clearance of drugs in children, a thorough understanding of these developmental changes in the different subprocesses contributing to renal function is needed. Therefore the aim of the research described in this thesis was to characterize the developmental changes in renal function over the entire pediatric age range. To this end, a system-based pharmacology approach was applied implicating that within the models for the different subprocesses contributing to renal function a distinction was made between system-specific and drug-specific properties. The transition to a more system-based pharmacology approach and the combination of different strategies (extrapolation to other drugs, adult data or non-clinical data) will result in an approach focusing on the underlying system instead of focusing on the drugs and may facilitate development of pharmacokinetic models and evidence-based dosing regimens in the pediatric population. Show less
Since a decade, Clostridium difficile infection (CDI) has increased progressively in incidence and severity of disease. Currently, CDI is considered the leading cause of nosocomial diarrhoea,... Show moreSince a decade, Clostridium difficile infection (CDI) has increased progressively in incidence and severity of disease. Currently, CDI is considered the leading cause of nosocomial diarrhoea, associated with an increased duration of hospitalization, healthcare expenses, morbidity and mortality. This thesis describes our findings with outbreak control, diagnosis, identification of specific risk factors and treatment of CDI after the discovery of the emergence of C. difficile PCR-ribotype 027 in the Netherlands. The studies illustrate the role of antibiotics in relation to persistence, severeness and spreading of CDI. Antibiotics are shown to be a primary risk factor for the development of (ribotype-specific) CDI and an essential part of the outbreak control measures (__bundle-approach__), namely antibiotic stewardship. The use of antibacterials is a risk for selection of novel endemic C. difficile strains in e.g. animals, which introduce an increasing risk of alternative zoonotic transmission routes. Except for very mild CDI, which is clearly induced by usage of specific antibiotics, antibacterial treatment is advised. This thesis reviews the comparative effectiveness of the currently available treatment modalities, thereby providing evidence-based recommendations for CDI remedies. Treatment options include: oral and non-oral antibiotics, toxin-binding resins and polymers, immunotherapy, probiotics, faecal or bacterial intestinal transplantation. Show less
