Cefoperazone/sulbactam therapeutic drug monitoring in patients with liver cirrhosis: Potential factors affecting the pharmacokinetic/pharmacodynamic target attainment

Objectives: Cefoperazone/sulbactam trough concentration (C_min) varies widely in cirrhotic patients. The objective of this study was to describe the characteristics of C_min and to identify factors associated with the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of cefoperazone/sulbactam in cirrhotic patients. Methods: Data were collected retrospectively from cirrhotic patients who received cefoperazone/sulbactam treatment. The C_min was measured using a validated liquid chromatography-tandem mass spectrometry. The PK/PD target of 100% fT > MIC was used for cefoperazone/sulbactam. Multivariate logistic regression and classification and regression tree (CART) analysis were performed to identify the factors affecting the PK/PD target attainment in these patients. Results: Cefoperazone and sulbactam C_min were measured simultaneously in 103 plasma samples from 70 cirrhotic patients. Cefoperazone and sulbactam C_min were 89.27 ± 44.38 mg/L and 10.09 ± 13.01 mg/L, respectively. The PK/PD target of 100% fT > MIC was achieved in 47.1% (33/70) patients for cefoperazone and in 28.6% (20/70) patients for sulbactam. The CART analysis revealed that cefoperazone C_min was likely to reach the PK/PD target in patients with serum bilirubin levels between 26.15 μmol/L and 99.15 μmol/L. Inversely, lower cefoperazone C_min was observed in patients with bilirubin levels ≤26.15 μmol/L and serum albumin >38.45 g/L or in patients with bilirubin levels >99.15 μmol/L and creatinine clearance (CrCl) >139.13 mL/min. Additionally, patients had higher sulbactam C_min when CrCl was below 62.85 mL/min. Conclusions: This study shows that current cefoperazone/sulbactam dosage regimens may result in inadequate plasma concentrations in cirrhotic patients. We recommend monitoring the C_min of cefoperazone/sulbactam to ensure efficacy of cefoperazone/sulbactam treatment.