Clinical pharmacokinetics of temocillin : a way to optimize personalized dosing

Antibiotic resistance in Enterobacteriaceae is increasing worldwide, in particular through the production of extended-spectrum beta-lactamases, leading to therapeutic failures and excessive use of last-resort antibiotics. Given this alarming situation, temocillin, a penicillin derived from ticarcillin but showing stability to many extended-spectrum beta-lactamases, could represent a useful carbapenem-sparing drug. Yet many unanswered questions remain regarding its dosing, because its pharmacokinetic and pharmacodynamic profiles have not been studied in details and according to the current standards. First, temocillin shows a high and saturable binding to plasma proteins in the range of clinically achievable concentrations, which complicates dose optimization based on pharmacokinetic and pharmacodynamic concepts, as only the unbound form of β–lactams is microbiologically active. Second, no data supporting dosing regimens are available in paediatric patients, the current dose being based on a simple scaling-down of the typical adult daily dose. Third, there is only few data concerning the distribution of temocillin in tissues and fluids, which is important for infections that are not localized in the bloodstream. Within this framework, five original works have been carried out to fill this gap through two major objectives. 1. To better characterize temocillin plasma protein binding including in patients, 2. To assess tissue penetration of temocillin through fluid effusions from infected sites in critically ill adult and paediatric patients, and to develop pharmacokinetic and pharmacodynamic models and to perform Monte Carlo simulations to assess the probability pharmacodynamics target attainment of temocillin in plasma and tissue in order to propose optimized dosing regimens. We showed that temocillin protein binding is saturable over the range of clinically achievable concentrations, and depends on the albumin concentration in the patient’s plasma. We then demonstrated that the penetration of temocillin is reasonable in the ascitic fluid of both adult and paediatric patients (46 and 82% respectively), and that plasma and ascitic concentrations depend on the renal clearance of the patient and of the weight in children. On these bases, we propose dosing regimens optimized to reach pharmacokinetic and pharmacodynamic targets against susceptible organisms.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 202