Perioperative pharmacokinetics of piperacillin during liver transplantation

There have been few evaluations of the perioperative pharmacokinetics of antibiotics. Piperacillin (PPR) is a widely prescribed ureidopenicillin of established efficacy against enterobacteria and P. aeruginosa. The serum pharmacokinetics and perioperative safety of PPR were evaluated in 8 patients hospitalized for an orthotopic liver transplantation. The subjects were given a 60 mg/kg infusion of PPR once every 8 hours. PPR was assayed by HPLC and data were analyzed by a noncompartmental method. There were no adverse events during surgery. It seems that kinetics of PPR showed no variation during the anhepatic period. However, transplants notably modified the kinetics of PPR in comparison with data previously published in healthy volunteers. Trends were as follows: flattening of Cmax and prolongation of T1/2 (2.2 h vs 0.92 h). This phenomenon seems to be due to a marked increase in V(area) (44.0 1 vs 16.2 1) while C1 were similar. The increase in V(area) is probably the combined results of multiple factors including blood loss, vascular filling, combined prescription of vasoactive drugs, and, obviously, the surgical procedure itself. Concentrations of PPR were after 4 hours below (i.e. 5/8 patients) the MIC of P. aeruginosa (i.e. < or = 16 micrograms/ml). From 6 hours onwards antibacterial cover was insufficient against the majority of enterobacteria (i.e. < or = 8 micrograms/ml). This inadequate protection included the critical anhepatic period. Measured concentrations achieved by the initial dosage regimen were compared to those obtained by simulation using modified dosing pattern in order to ensure circulating levels constantly of 16 micrograms/ml or more. This leads to a suggested modified dosage pattern in which PPR would be given as 1 dose of 60 mg/kg every 4 hours. Under these conditions the expected concentrations should be constantly over 16 micrograms/ml and any risk of systemic accumulation is excluded.