Christer Rimmler (1), Dagmar Horn (2), Christian Lanckohr (3), Sari Ceren (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:
Optimization of the perioperative antibiotic prophylaxis (PAP) is still a matter of debate. Despite existing guidelines and recommendations, there are important issues of uncertainty regarding the timing and dose before incision and the intraoperative follow-up administrations. Another issue is the tissue penetration of the antibiotics used for PAP. Therefore, we collected perioperative plasma and tissue samples from 25 patients receiving cefuroxime. To evaluate effects on the PK triggered by the alteration of physiological conditions during surgery, we included relevant changes in the final model.
Methods:
We collected plasma and lung tissue samples from 25 thoracical surgery patients (18 to 77 years). After induction of anesthesia, a dose of 1.5 g cefuroxime was administered intravenously. Another 1.5 g cefuroxime was given every 2.5 h thereafter. On the basis of our previous model [1] we used PK-Sim®/MoBi® [2] for population simulations and a scale-up from the fitted tissue concentrations to interstitial concentrations. We simulated alternative dosing regimens in varying populations (see below) and tested the difference between long-term infusions and standard short infusions. The simulated populations, which were in line with our study population, show different BMI levels, kidney functions, age and gender. For beta-lactams the relevant PD-target to achieve a maximal bactericidal and bacteriostatic effect, is the free drug concentration exceeding the pathogens minimal inhibitory concentration (MIC) for 60-70% and 35-40% of the time during the dosing interval in the targeted tissue. To reach this target, it is advocated that the blood concentrations should also exceed the MIC by a factor of 4 to 6 [3]. As targeted tissue we used the free unbound plasma and the lung interstitial unbound concentrations. Test pathogens for the definition of the MIC are Staphylococcus aureus and Escherichia coli which are most relevant for surgical side infections. The MIC values were taken from EUCAST Clinical Breakpoint Tables [4] and modified as described above.
Results:
The adjustment of the model according to the physiological changes during surgery improved the performance for the individual simulations (MPE = 1.4% and MAPE = 29.0%), with 84.5% of predicted plasma concentration being within 50% range of the observed values. The lung tissue concentrations could also be described adequately (MPE = 7.0%; MAPE = 34.3%). After subdividing the population into three groups accordning to their glomerular filtration rate (GFR) ranging from 40-80, 80-120 and 120-160 mL/min, the population simulations present adequate predictions as well (MPE = 10.4%; MAPE = 27.3%). In the low GFR population, the given dosing regimen leads to a protection for about 1.9 hours. However, in the middle and the high GFR group, the protection persist only 1.0 and 0.8 hours, respectively. In simulations, bolus of 1.5 g cefuroxime and long-term infusion of 3 g for 3 hours, leads to a protection for 4.6, 5.4 and 7.5 hours respectively, without giving more antibiotics as in the old dosing schedule in sum.
Conclusions:
We were able to give clear dose recommendations in the field of perioperative antibiotic prophylaxis. Our results show that the kinetics of cefuroxime is influenced by age and kidney status, not by gender, BMI or the surgery [1]). The use of cefuroxime for perioperative prophylaxis to prevent staphylococcal surgical site infections appears to be reasonable and recommendable. According to our results, the use of cefuroxime for perioperative prophylaxis against Escherichia coli in abdominal surgeries, using the described dosing regimes appears to be at least questionable. With our dose recommendations we provide a solution for this issue.
References:
[1] Rimmler C et al., Development of a PBPK Model to Predict the Tissue Concentrations of Cefuroxime During Surgery. PAGE, 2017.: Poster
[2] Eissing T et al., A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front Physiol, 2011. 2: p. 4.
[3] Drusano GL et al., AntimicrobialPharmacodynamics: Critical Interactions of`Bug and Drug`. Nature Reviews Microbiology, 2004.2: p 289-300
[4] The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 8.0, 2018. http://www.eucast.org
Reference: PAGE 27 (2018) Abstr 8440 [www.page-meeting.org/?abstract=8440]
Poster: Drug/Disease Modelling - Absorption & PBPK