Target site pharmacokinetics of antiinfectives in the treatment of serious gram positive infections

This book contains investigations on the pharmacokinetics of antiinfectives at the site of infection. Vancomycin was studied in in vitro experiments to enable the conduction of clinical trials investigating its PK by using the microdialysis approach. A rapid and reliable HPLC assay capable of measuring vancomycin concentrations in microdialysate and plasma is presented. Linezolid was investigated in two in vivo studies. In the first study, microdialysis was applied to corticancellous bone tissue of healthy sows after single intravenous linezolid infusion. The feasibility and validity of the microdialysis technique in bone tissue was assessed and the pharmacokinetics in bone tissue was investigated. In the second study, a clinical trial was conducted in order to assess the pharmacokinetics of linezolid in healthy volunteers and septic patients after single and multiple dosing using a population pharmacokinetic approach. Unbound linezolid concentrations were determined in plasma as well as the interstitium of subcutaneous adipose tissue and skeletal muscle applying the microdialysis technique. The analysis is focused on mechanistic interpretation of the observed pharmacokinetic characteristics, resulting in a thorough characterisation of linezolid pharmacokinetics including covariate relations. The results might be used to guide further linezolid dose selection and might therefore help to improve individual therapy and outcome of serious infections in the critically ill.