Christoph Dorn1, David Petroff2,3, Nancy Neumann4, Alexander Kratzer5, Nahed El-Najjar6,7, Arne Dietrich3,8, Charlotte Kloft9, Markus Zeitlinger10, Martin G Kees11, Frieder Kees12, Hermann Wrigge3,4,13, Philipp Simon3,4. 1. Institute of Pharmacy, University of Regensburg, Regensburg, Germany. 2. Clinical Trial Centre, University of Leipzig, Leipzig, Germany. 3. Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany. 4. Department of Anaesthesiology and Intensive Care Medicine, University Hospital Leipzig, Leipzig, Germany. 5. Hospital Pharmacy, University Hospital Regensburg, Regensburg, Germany. 6. Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany. 7. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany. 8. Department of Surgery, University of Leipzig, Leipzig, Germany. 9. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany. 10. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 11. Department of Anaesthesiology, University Hospital Regensburg, Regensburg, Germany. 12. Department of Pharmacology, University of Regensburg, Regensburg, Germany. 13. Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, Halle, Germany.
Abstract
OBJECTIVES: To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. METHODS: Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. RESULTS: Thirteen obese patients (BMI 38-50 kg/m2) and 14 non-obese patients (BMI 0-29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). CONCLUSIONS: Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.
OBJECTIVES: To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. METHODS: Fifteen obesepatients undergoing bariatric surgery and 15 non-obesepatients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. RESULTS: Thirteen obesepatients (BMI 38-50 kg/m2) and 14 non-obesepatients (BMI 0-29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obesepatients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obesepatients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). CONCLUSIONS: Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obesepatients, the drug exposure in subcutaneous tissue was significantly lower in the obesepatients.
Authors: D Busse; P Simon; D Petroff; N El-Najjar; L Schmitt; D Bindellini; A Dietrich; M Zeitlinger; W Huisinga; R Michelet; H Wrigge; C Kloft Journal: Antimicrob Agents Chemother Date: 2022-05-23 Impact factor: 5.938
Authors: Sander G Kuiper; Anneke C Dijkmans; Erik B Wilms; Ingrid M C Kamerling; Jacobus Burggraaf; Jasper Stevens; Cees van Nieuwkoop Journal: J Antimicrob Chemother Date: 2020-11-01 Impact factor: 5.758
Authors: David Busse; André Schaeftlein; Alexander Solms; Luis Ilia; Robin Michelet; Markus Zeitlinger; Wilhelm Huisinga; Charlotte Kloft Journal: Pharm Res Date: 2021-03-15 Impact factor: 4.200