Christer Rimmler (1), Dagmar Horn (2), Christian Lanckohr (3), Miriam Mittrup (3), Manfred Fobker (4), Georg Hempel (1)
(1) Institute of Pharmaceutical and Medicinal Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Germany, (2) Department of Pharmacy, University Hospital of Münster, Münster, Germany, (3) Institute of Hygiene, University Hospital of Münster, Münster, Germany, (4) Department of Laboratory Medicine, University Hospital of Münster, Münster, Germany
Objectives: There is a wide discrepancy describing the influence of a cardiopulmonary bypass (CPB) on drugs used during surgery (e.g. the perioperative antibiotic prophylaxis (PAP)). Despite existing guidelines and recommendations, there are important issues of uncertainty regarding the timing and dose before incision and the intraoperative follow-up administrations. In order to assess the influence of CPB, we analysed plasma samples collected from patients receiving cefuroxime during surgery.
Methods: We collected 278 plasma samples from 23 patients aged 45 to 82 years during cardiopulmonary bypass surgeries and at follow up on ICU. After induction of anesthesia, a dose of 1.5 g cefuroxime was administered intravenously. Another 1.5 g cefuroxime was given at start of the CPB and three further doses were administered at ICU every 6 hours. To identify relevant covariates, a PopPK model using NONMEM® was developed. To gain deeper insight in the physiological changes during surgery, triggered by the CPB, we included relevant changes in our previous PBPK model (System Pharmacology®) [1]. For beta-lactams, the relevant PD-target to achieve a maximal bactericidal effect is the free drug concentration exceeding the pathogens minimal inhibitory concentration (MIC) for 100% of the time during the dosing interval. To reach this target, it is advocated that the blood concentrations should also exceed the MIC by a factor of 2 to 5 [2]. Test pathogens for the definition of the MIC are S. aureus and E. coli, which are most relevant for surgical side infections. MIC values were taken from EUCAST Clinical Breakpoint Tables [3].
Results: Relevant covariates were the estimated glomerular filtration rate influencing the clearance and albumin influencing the rate of distribution. Furthermore, there is a high intraindividual variability in the clearance during the different occasions (before, during CPB and on ICU). The CPB itself has no significant influence, neither on clearance nor on volume of distribution. This finding could by confirmed by the CPB-PBPK-model. The large and rapid expansion of the blood pool with the extra volume through the CPB-system leads to a small drop of the plasma concentrations, which is negligible over the time. Therefore no relevant changes in the AUC or Cmin occurred. According to PopPK or PBPK simulations using the described dosing regime, patients during surgery are well protected against S. aureus, whereas a protection against E.coli is not sufficient. Redosing at start of the CPB is necessary to cover the period of surgery. During the subsequent time on ICU, no sufficient protection is maintained for both pathogens. A bolus of 1 g cefuroxime in addition to continuous infusion of 0.5 g/h during the time of surgery results in an adequate protection for E.coli (0.5 g bolus for S.aureus), without increasing the total dose of cefuroxime.
Conclusion: Our results show that the kinetics of cefuroxime is influenced by age and kidney status, not by gender, BMI or the evaluated types of surgery [1]. The use of cefuroxime for perioperative prophylaxis to prevent staphylococcal surgical site infections appears to be reasonable. However, perioperative prophylaxis against E.coli in abdominal surgeries is not sufficient using the actual dosing regime. We recommend an alternative regimen with 1 g bolus loading dose and continuous infusion of 0.5 g per hour.
References:
[1] Rimmler C et al., Evaluating New Dosing Strategies for the Use of Cefuroxime in Perioperative Antibiotic Prophylaxis using PBPK. PAGE, 2018.: Poster
[2] Heffernan A. J. et al., Individualising Therapy to Minimize Bacterial Multidrug Resistance. Drugs, 2018. 78: p 621-641
[3] The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 9.0, 2019. http://www.eucast.org
Reference: PAGE 28 (2019) Abstr 8906 [www.page-meeting.org/?abstract=8906]
Poster: Drug/Disease Modelling - Infection