Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial

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/m(2)) and 14 non-obese patients (BMI 0-29 kg/m(2)) 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(infinity) 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(infinity) 1052 +/- 394 versus 1929 +/- 725 mg.h/L, P=0.0010). The tissue/plasma ratio (AUC(ISF)/AUC(plasma)) 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