Pharmacokinetics and Pharmacodynamics of Extended-Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open-Label Study

Study objective: To evaluate extended-infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD).

Design: Prospective, open-label, PK study.

Setting: Intensive care units at a large, academic, tertiary-care medical center.

Patients: Ten critically ill adults who were receiving cefepime 2 g intravenously every 8 hours as a 4-hour infusion while receiving CVVH (eight patients) or CVVHD (two patients).

Intervention: Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady-state) cefepime doses.

Measurements and main results: Reversed-phase high-performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half-life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (C_min ), and minimum inhibitory concentration breakpoint of 8 µg/ml for the pathogen (MIC₈ ) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC₈ (100% fT > MIC₈ ), 100% fT > 4 × MIC₈ (optimal), percentage of time fT > 4 × MIC₈ (%fT > 4 × MIC₈ ) at steady state, and ratio of C_min to MIC₈ (fC_min /MIC₈ ). Total CRRT effluent flow rate was a mean ± SD of 30.1 ± 5.4 ml/kg/hr, CRRT clearance was 39.6 ± 9.9 ml/min, and half-life was 5.3 ± 1.7 hours. Sieving coefficient or saturation coefficient were 0.83 ± 0.13 and 0.69 ± 0.22, respectively. First and steady-state dose C_min were 23.4 ± 10.1 µg/ml and 45.2 ± 14.6 µg/ml, respectively. All patients achieved 100% fT > MIC₈ on first and steady-state doses. First and steady-state dose 100% fT > 4 × MIC₈ were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT > 4 × MIC₈ at steady state was 97.5%. The fC_min /MIC₈ was 2.92 ± 1.26 for the first dose and 5.65 ± 1.83 at steady state.

Conclusion: Extended-infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT > MIC₈ in all patients and an appropriate fC_min /MIC₈ for both first and steady-state doses. All but one patient achieved 100% fT > 4 × MIC₈ at steady state. No significant differences were observed in PK properties between first and steady-state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population.