Margreke JE Brill(1,5), Aletta PI Houwink(2), Christiaan Vos(1), Stephan Schmidt(3), René J Wiezer(4), Bert van Ramshorst(4), Eric PA van Dongen(3), Catherijne AJ Knibbe(1,5)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (2) Department of Anaesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands; (3) Center for Pharmacometrics & System Pharmacology, Department of Pharmaceutics, University of Florida, U.S.A. (4) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands; (5) Division of Pharmacology, Leiden/ Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
Objectives: Morbidly obese patients are prone to surgical site infections. To reduce the risk of infection a prophylactic antibiotic agent is administered before initial surgical incision to attain adequate levels of antibiotic in the bloodstream and subcutaneous tissues. For gastric surgery, cefazolin is the prophylactic antibiotic agent of choice. Currently it is unknown how morbid obesity affects cefazolin pharmacokinetics, particularly in view of tissue penetration. In this study, we aimed to investigate the pharmacokinetics of unbound serum and subcutaneous tissue cefazolin concentrations in morbidly obese patients.
Methods: Eight morbidly obese patients with a median BMI of 45.4 (41-57) kg/m2 and 6 normal weight patient with a median BMI of 28.7 (24-31) kg/m2 participated in the study. At induction of anesthesia, patients received cefazolin 2 gram i.v.. Unbound serum concentrations were measured at T=0, 5, 10, 30, 60, 120 and 240 min. Using microdialysis, samples to measure unbound cefazolin concentrations in subcutaneous adipose tissue of the abdomen were collected every 20 minutes until 240 minutes after dosing. In the analysis, unbound cefazolin serum concentration profiles of 19 morbidly obese patients were considered [1]. The influence of body weight and other covariates on cefazolin pharmacokinetics in serum and subcutaneous tissue were evaluated using population pharmacokinetic modeling with NONMEM VI.
Results: The AUCtissue/AUCserum ratio was 0.87 ± 0.4 in morbidly obese and 1.11 ± 0.3 in normal weight patients (p=0.16), however time above minimal inhibitory concentration of 90% of Staphylococcus Aureus species in Europe, 1 mg/L, was 100% until 4 hours after dose for all patients. A one compartment model for cefazolin in serum with a one compartment model of cefazolin in subcutaneous tissue best described the data. Body weight was a significant covariate for central volume of distribution (decrease in -2LL of 11 points) and for clearance (decrease in -2LL of 5 points) and was able to explain 23% and 3% of the inter individual variability, respectively. No other covariates were found.
Conclusions: We found that body weight is of strong influence on cefazolin central volume of distribution and of slight influence on clearance. This implicates lower unbound cefazolin serum and subcutaneous adipose tissue concentrations with increasing body weight.
References:
[1] van Kralingen S, Taks M, Diepstraten J, et al. Pharmacokinetics and protein binding of cefazolin in morbidly obese patients. Eur J Clin Pharmacol. 2011 Oct;67(10):985-92.
Reference: PAGE 21 () Abstr 2515 [www.page-meeting.org/?abstract=2515]
Poster: Infection