Plasma and Tissue Pharmacokinetics of Cefazolin in an Immature Porcine Modelof Pediatric Cardiac Surgery

Background: Surgical Site Infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts. The purpose of this study was to determine the plasma and tissue concentrations of standard-of-care peri-operative cefazolin dosing in an immature porcine model of cardiac surgery and cardiopulmonary bypass. Methods: Piglets (3-5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB+DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, non-compartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed. Results: Following the first intravenous dose, maximal cefazolin concentrations for plasma and tissue samples were similar between groups with peak tissue concentrations 15-30 minutes after administration. After the second cefazolin dose given with initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle and subcutaneous unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60-67% of the intraoperative time showed tissue cefazolin concentrations greater than16 μg/mL while this percentage was 78-79% for the CPB+DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP+DHCA (P=0.03). Conclusions: The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations.