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Fluoroquinolones for children : filling the gap

Book - Dissertation

Fluoroquinolones, a class of antibiotics, are regularly prescribed to children for treatment and prophylaxis of complex infections. At the moment when ciprofloxacin, which is one of the first fluoroquinolones, was launched in the 1980s, it had not been tested in the pediatric population. This is not uncommon. During traditional drug development processes, the effects and safety of medicines have been studied in adults, given the numerous ethical and practical challenges of pediatric drug research. Experiments in young animals were performed as an attempt to study the safety of fluoroquinolones in children. Unfortunately, severe cartilage tissue damages and growth deformities were observed in these animals, particularly in beagle dogs. This resulted in a class label warning for the usage of fluoroquinolones in children, in 1995. Nevertheless, during the past two decades, many children have been prescribed a fluoroquinolone. These prescriptions are usually so-called off-label, which means that either the indication for its prescription or its dosage has not formally been studied. Off-label prescribing is undesirable. However, in previous post-marketing studies of children to whom fluoroquinolones were administered, it turned out that fluoroquinolones unlikely result in cartilage tissue lesions and growth deformities in humans. At the beginning of this PhD project, there was a gap in knowledge about the working of fluoroquinolones in children. Therefore, the main aim of this thesis was to enhance the pharmacological knowledge of fluoroquinolones within the pediatric population. In the first paper, a retrospective drug utilization study, we analyzed for which reasons hospitalized children were prescribed a fluoroquinolone, in the setting of two university hospitals. The most common reasons were central nervous infections, prophylaxis of febrile neutropenia, and soft tissue infections. Furthermore, about 30% of the prescriptions were dosed inadequately, with underdosing being the most frequent. We found that particularly young children were at risk for receiving an underdosed prescription. In the second paper, a prospective population pharmacokinetic study, we investigated which dose of ciprofloxacin is adequate for treating complicated urinary tract infection. We proved that conventional dose recommendations result in a major undertreatment of children whose urinary tract infection was caused by Pseudomonas aeruginosa. Because pathophysiological alterations had a major influence on ciprofloxacin metabolism, in paper 3 we modeled these changes in a physiologically based pharmacokinetic model, in order to better predict ciprofloxacin exposure in these children. This model demonstrated its adequacy in simulating different dosing scenarios for children older than 3 months with complicated urinary tract infection. To provide improved dosing advices for children with both different diseases and other fluoroquinolones, we wrote a systematic review (paper 4), in which pharmacokinetic parameters of systemic fluoroquinolones in children were analyzed. We found multiple disease related characteristics that should be considered when dosing fluoroquinolones for children. From the previous studies it can be concluded that a correct indication and an adequate dose are the cornerstone of an antibiotic prescription. Since children's involvement in clinical trials is often perceived as controversial, we investigated in paper 5 how scientists deal with basic ethical principles in their studies.
Publication year:2019
Accessibility:Closed