Mizuho Asada1, Masashi Nagata2,3, Tomohiro Mizuno4, Tokujiro Uchida5, Hiromitsu Takahashi1, Koshi Makita5, Hirokuni Arai4, Shinichi Kijima6, Hirotoshi Echizen7, Masato Yasuhara8. 1. Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan. 2. Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan. mna-mpha@tmd.ac.jp. 3. Department of Pharmacokinetics and Pharmacodynamics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. mna-mpha@tmd.ac.jp. 4. Department of Cardiovascular Surgery, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 5. Department of Anesthesiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 6. Office of Advanced Evaluation with Electronic Data, Pharmaceuticals and Medical Devices Agency (PMDA), Tokyo, Japan. 7. Meiji Pharmaceutical University, Tokyo, Japan. 8. Department of Pharmacokinetics and Pharmacodynamics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Abstract
PURPOSE: The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin. METHODS: Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated. RESULTS: A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (Bmax). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8 mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16 mg/L was proposed. CONCLUSION: PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.
PURPOSE: The aims of the present study were to establish a population pharmacokinetic (PPK) model of cefazolin for adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to assess the probability of target attainment (PTA) for the prophylaxis of surgical site infection (SSI) using cefazolin. METHODS: Adult patients who underwent cardiac surgery with CPB were enrolled in the prospective study. Blood samples for plasma cefazolin assay were collected, and total and unbound drug concentrations were measured and analysed using the nonlinear mixed-effects modelling (NONMEM) software considering saturable plasma protein binding. Using the PPK model, plasma unbound cefazolin concentration-time courses with current prophylaxis protocols were simulated, and the PTA for common SSI pathogens was estimated. RESULTS: A total of 199 blood samples were obtained from 27 patients. A one-compartment model with first-order elimination plus an on/off CPB compartment best described the data. The population mean for systemic drug clearance (CL) was reduced and that for the volume of distribution (V) was increased during CPB compared with the pre-CPB values. CPB-induced hypoalbuminemia was associated with reduced maximum protein binding (Bmax). The simulation studies suggested that the current dosing protocols are insufficient for attaining PTA > 0.9 throughout surgery against pathogens with minimum inhibitory concentrations (MICs) >8 mg/L. A new dosing protocol that achieves a PTA > 0.9 for pathogens with a MIC of 16 mg/L was proposed. CONCLUSION: PPK modelling with simulation may be valuable for devising a cefazolin prophylaxis protocol for patients undergoing cardiac surgery with CPB.
Entities:
Keywords:
Cardiopulmonary bypass; Cefazolin; Plasma protein binding; Population pharmacokinetics
Authors: Jonathan R Edwards; Kelly D Peterson; Yi Mu; Shailendra Banerjee; Katherine Allen-Bridson; Gloria Morrell; Margaret A Dudeck; Daniel A Pollock; Teresa C Horan Journal: Am J Infect Control Date: 2009-12 Impact factor: 2.918
Authors: Dale W Bratzler; E Patchen Dellinger; Keith M Olsen; Trish M Perl; Paul G Auwaerter; Maureen K Bolon; Douglas N Fish; Lena M Napolitano; Robert G Sawyer; Douglas Slain; James P Steinberg; Robert A Weinstein Journal: Am J Health Syst Pharm Date: 2013-02-01 Impact factor: 2.637
Authors: Divna Calic; Robert E Ariano; Rakesh C Arora; Hilary P Grocott; Ted M Lakowski; Ryan Lillico; Sheryl A Zelenitsky Journal: J Antimicrob Chemother Date: 2018-03-01 Impact factor: 5.790
Authors: Sandra I Berríos-Torres; Craig A Umscheid; Dale W Bratzler; Brian Leas; Erin C Stone; Rachel R Kelz; Caroline E Reinke; Sherry Morgan; Joseph S Solomkin; John E Mazuski; E Patchen Dellinger; Kamal M F Itani; Elie F Berbari; John Segreti; Javad Parvizi; Joan Blanchard; George Allen; Jan A J W Kluytmans; Rodney Donlan; William P Schecter Journal: JAMA Surg Date: 2017-08-01 Impact factor: 14.766
Authors: Alexandra Douglas; Mahdi Altukroni; Andrew A Udy; Michael S Roberts; Kersi Taraporewalla; Jason Jenkins; Jeffrey Lipman; Jason A Roberts Journal: BMC Anesthesiol Date: 2011-02-22 Impact factor: 2.217