Population Pharmacokinetics of Prophylactic Cefazolin in Cardiac Surgery with Standard and Minimally Invasive Extracorporeal Circulation

Abstract

The objectives of this study were to develop a population pharmacokinetic model of prophylactically administered cefazolin in patients undergoing cardiac surgery with and without the use of the cardiopulmonary bypass of both existing types—standard (ECC) and minimallyu invasive extracorporeal circulation (MiECC)—and to propose cefazoline dosing optimization based on this model. A total of 65 adult patients undergoing cardiac surgery were recruited to this clinical trial. A prophylactic cefazolin dose of 2 g was intravenously administered before surgery. Blood samples were collected using a rich sampling design and cefazolin serum concentrations were measured using the HPLC/UV method. The pharmacokinetic population model was calculated using a nonlinear mixed-effects modeling approach, and the Monte Carlo simulation was used to evaluate the PK/PD target attainment. The population cefazolin central volume of distribution (Vd) of 4.91 L increased by 0.51 L with each 1 m2 of BSA, peripheral Vd of 22.07 L was reduced by 0.77 L or 0.79 L when using ECC or MiECC support, respectively, while clearance started at 0.045 L/h and increased by 0.49 L/h with each 1 mL/min/1.73 m2 of eGFR. ECC/MiECC was shown to be covariate of cefazolin Vd, but without relevance to clinical practice, while eGFR was most influential for the PK/PD target attainment. The standard dose of 2 g was sufficient for PK/PD target attainment throughout surgery in patients with normal renal status or with renal impairment. In patients with augmented renal clearance, an additive cefazolin dose should be administered 215, 245, 288 and 318 min after the first dose at MIC of 4, 3, 2 and 1.5 mg/L, respectively.

Surgical Antibiotic Prophylaxis: A Proposal for a Global Evidence-Based Bundle

“…Because cefazolin is hydrophilic, penetration into tissue is not dose-dependent. Therefore, high cefazolin doses may not be necessary in obese patients [47][48][49]. In contrast, cefoxitin is not as hydrophilic as cefazolin and higher doses of cefoxitin may be required for obese patients.…”

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“…As an example [79], cefazolin, given as a single 2 g IV bolus 3-5 min before skin incision and provides protective cefazolin concentrations (>MIC of methicillin-susceptible S. aureus) for 4.8 h, longer than the duration of most bariatric procedures (regardless of body mass index, thus obviating the need for intraoperative redosing at 4 h. Because cefazolin is water-soluble (volume of distribution (Vd) = 0.2 L/Kg) [80], penetration into adipose tissue is not dose-dependent. Therefore, extremely high-dose cefazolin (i.e., 3-4 g) is unnecessary [78,79,81,82]. In contrast, cefoxitin is not as hydrophilic (Vd = 12 L/Kg) [83,84], and higher doses may be required.…”