Surgical site infections (SSI) following cardiac surgery result in significant patient morbidity and mortality. Antimicrobial prophylaxis (AP) with cefazolin is a core strategy for preventing SSI. This was the first pharmacokinetic-pharmacodynamic study of guideline-recommended cefazolin AP in cardiac surgery with cardiopulmonary bypass (CPB).

In this non-interventional study, subjects (n = 55, 65 ± 10 years, 80 ± 19 mL/min/72kg) undergoing cardiac surgery received cefazolin AP and had blood samples collected at relevant times intraoperatively. Total and free cefazolin concentrations were measured by LC-MS/MS. Subjects were monitored for SSI during and after hospitalization. Total cefazolin concentrations at wound closure were compared to target concentrations ≥ 40 mg/L and risk factors for below-target concentrations identified. Free cefazolin concentrations were used to characterize cefazolin protein binding (PB). A population-pharmacokinetic model was constructed to characterize the pharmacokinetics of cefazolin during cardiac surgery. Finally, a pharmacodynamic analysis was conducted to investigate the relationship between cefazolin concentrations and SSI development.

Almost 10% of cefazolin concentrations at wound closure were < 40 mg/L. Shorter surgery duration, lower body weight and lower total cefazolin dose per hour of surgery were independently associated with below-target concentrations. A significant dose threshold of 7.6 mg/kgDW/h was identified and used to optimize the AP regimen, which demonstrated the inadequacy of 1-gram doses. The PB of cefazolin during surgery was 72 ± 8% compared to the usual 80%. PB saturation was observed during/post-CPB. The elimination rate constant was similar (0.35 ± 0.07 h-1), while the volume of distribution was higher (0.14 ± 0.05 L/kg) during cardiac surgery with CPB versus healthy volunteers. In the PD analysis, longer duration of surgery and lower total cefazolin closure concentrations were independently associated with SSI. Significant increases in risk of SSI were identified at thresholds of surgery duration > 5.8 hours and total closure concentrations < 104 mg/L.

Most importantly, the findings of this study were translated to clinical practice. An AP regimen designed to achieve target closure concentrations during cardiac surgery with CPB has been adopted where cefazolin AP consists of 2 grams (3 grams if ≥120 kg) preoperatively and re-dosed every 3 hours intraoperatively, with adjustments for renal function.