Effect of Blood Product Resuscitation on the Pharmacokinetics of Ampicillin-Sulbactam during Orthotopic Liver Transplantation.

Abstract

Background: Ampicillin-sulbactam is a piperacillin-tazobactam-sparing alternative antibiotic administered as surgical prophylaxis during orthotopic liver transplant (OLT), but limited data are available describing its pharmacokinetics and impact of blood product resuscitation. The purpose of this study was to determine the intra-operative pharmacokinetics of ampicillin-sulbactam in patients during OLT and evaluate the effects of blood resuscitation on exposure. Patients and Methods: This was a pharmacokinetic study in 10 OLT patients receiving ampicillin-sulbactam surgical prophylaxis. A 5,000-patient Monte Carlo simulation was conducted to identify optimal ampicillin-sulbactam regimens. Linear regression assessed association between blood product administration and ampicillin exposures. Results: Ampicillin and sulbactam concentrations best fitted two-compartment models. Mean ampicillin pharmacokinetic parameters were central compartment volume (Vc): 6.9 ± 2.0 L, clearance (CL): 26.6 ± 18.4 L/h, and inter-compartmental rate constants (k12 and k21): 4.8 ± 2.6 and 2.3 ± 1.4 h-1. Sulbactam pharmacokinetic parameters were Vc: 8.1 ± 2.7 L, CL: 26.1 ± 7.4 L/h, k12 and k21: 4.9 ± 1.0 and 2.8 ± 1.1 h-1. Participants received between 500 and 23,642 mL of total blood product. No statistical relations were observed between blood product administration and exposures (R2 0.00-0.26). Ampicillin-sulbactam 2/1 g every two hours and 2/1 g bolus followed by 6/3 g continuous infusion provided acceptable probability of target attainment up to minimum inhibitory concentrations (MICs) of 16 and 32 mcg/mL, respectively. Conclusions: High and frequent ampicillin-sulbactam doses are required to maintain 100% fT > MIC at relevant MICs during OLT and no impact of blood product resuscitation was observed on ampicillin exposure. These are the first data available to guide ampicillin-sulbactam dosing in patients undergoing OLT.