Résumé
This thesis is a compilation of 11 of my prospectively designed studies plus extracts from 5 published reviews, focusing on pharmacokinetic (PK) aspects of antibiotics in ICU patients, all published in internationally peer-reviewed journals. Two papers investigated the pharmacokinetics of amicakin in adult and paediatric patients documenting the benefit of extended interval dosing. A following study on vancomycin demonstrated the differing pharmacokinetics during the course of a septic insult, day 2 pharmacokinetics differing from day 7. Two large PK studies on ciprofloxacin (a drug that has excellent tissue penetration) designed to address possible PK differences over time, could not demonstrate this difference in adults nor in two groups of paediatric patients where differences in body water are significant. My b-lactam antibiotic work has repeatedly demonstrated low serum levels at the end of the standard dosing interval. In view of b-lactam time-dependent kill characteristics we designed a continuous infusion protocol which we validated in a follow-up paper. An important study showed that some septic patients with "normal" serum creatinines can have very high creatinine clearances. It follows that drugs which are renally excreted will have high clearances and illustrates why many of the above patients had low serum levels of antibiotic, a reason why some ICU patients require different dosing to ward patients. The inflammatory response of infections involves endothelial damage and capillary permeability. With associated fluid shifts of severe sepsis and treatment thereof, the volume of distribution (Vd) of antibiotics that distribute into the extracellular space (aminoglycosides, glycopeptides) is high. Peak serum levels for these antibiotics are therefore lower than those found in non-critically ill and in normal volunteers. It is noteworthy that this change in Vd is not apparent with drugs that have good tissue penetration (e.g. ciprofloxacin). Due to the required fluid loading and inotropic use in septic patients, creatinine clearances and drug clearances are often raised. This results in low serum concentrations at the end of a standard dosing interval. We automatically assume that antibiotic prescribing data, collated from healthy volunteers and not so ill patients, can be transcribed into the Intensive Care Unit. This is not so.