Population pharmacokinetic model-based dosing proposal for ampicillin prophylaxis in cardiac surgery patients with cardiopulmonary bypass

Abstract

The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m² was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.

Keywords:

• Antibiotic prophylaxis
• ampicillin
• cardiopulmonary bypass
• nonlinear mixed-effects modelling
• pharmacokinetics
• cardiac surgery patients

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval statement

The study was approved by the local Ethics Committee of the University Hospital in Olomouc under the No. 17-31540 A on June 16, 2016, and follows the principles of the Declaration of Helsinki.

Patient consent statement

Written informed consent was obtained from all subjects before enrolment.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

The study was supported by the grant No. 17-31540 A from the Czech Health Research Council. This work was funded by Agentura Pro Zdravotnický Výzkum České Republiky.