Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass

Saeed A Alqahtani; Abdullah S Alsultan; Hussain M Alqattan; Ahmed Eldemerdash; Turki B Albacker

doi:10.1128/AAC.02241-17

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass

Antimicrob Agents Chemother. 2018 Mar 27;62(4):e02241-17. doi: 10.1128/AAC.02241-17. Print 2018 Apr.

Authors

Saeed A Alqahtani^{1

2}, Abdullah S Alsultan^{3

2}, Hussain M Alqattan⁴, Ahmed Eldemerdash⁵, Turki B Albacker⁴

Affiliations

¹ Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia saeed@ksu.edu.sa.
² Clinical Pharmacokinetics and Pharmacodynamics Unit, King Saud University Medical City, Riyadh, Saudi Arabia.
³ Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁴ Cardiac Surgery Department, King Fahad Cardiac Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁵ Cardiac Anesthesia Department, King Fahad Cardiac Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Abstract

The purpose of this study was to investigate the population pharmacokinetics (PK) of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix (version 4.4) software. Pharmacokinetic-pharmacodynamic (PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples from 78 patients were analyzed. The PK for cefuroxime were best described by a two-compartment model with between-subject variability on clearance, the volume of distribution of the central compartment, and the volume of distribution of the peripheral compartment. The clearance of cefuroxime was related to creatinine clearance (CL_CR). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of the percentage of the time that the free concentration is maintained above the MIC during a dosing interval (fT_MIC) of 65% for an MIC of 8 mg/liter in patients with a CL_CR of 30, 60, or 90 ml/min, whereas this dosing regimen failed to achieve the PK-PD target in patients with a CL_CR of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CL_CR values required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CL_CR values (≤30 ml/min).

Keywords: CABG; Monte Carlo simulation; antibiotic prophylaxis; cefuroxime; pharmacokinetics-pharmacodynamics; population PK; β-lactams.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Anti-Bacterial Agents / pharmacokinetics*
Anti-Bacterial Agents / therapeutic use*
Cardiopulmonary Bypass / methods*
Cefuroxime / pharmacokinetics*
Cefuroxime / therapeutic use*
Chromatography, High Pressure Liquid
Coronary Artery Bypass / methods*
Female
Humans
Male
Microbial Sensitivity Tests
Middle Aged
Monte Carlo Method
Young Adult
beta-Lactams / pharmacokinetics
beta-Lactams / therapeutic use

Substances

Anti-Bacterial Agents
beta-Lactams
Cefuroxime