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

Abstract

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 (Cmin), 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 Cmin to MIC8 (fCmin/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 Cmin 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 fCmin/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 fCmin/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.

Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy

“…The optimal dosing should be adjusted based on CRRT modalities, MICs and flow rates (Chaijamorn et al, 2018). Extended infusion of cefepime improves the PK/PD target attainment (100% fT > MIC 8 ) during CVVH and CVVHD (Philpott et al, 2019). Dosing of 1-2 g q8-6h are recommended during CRRT under different modalities.…”

Clinical efficacy of regional citrate anticoagulation in continuous renal replacement therapy: systematic review and meta-analysis

“…Although frequent filter replacement can relieve blood clotting, it increases the cost of treatment for patients and also affects liver and kidney function (27). Therefore, there is a clinical need to find effective anticoagulant treatment methods that can be applied to the CRRT process to ensure the treatment effect of patients (28). Correct selection of anticoagulants and close clinical monitoring are very important to prevent complications.…”

Pharmacokinetics of Amoxicillin and Cefepime During Prolonged Intermittent Renal Replacement Therapy: A Case Report

“…Given the low amoxicillin clearance when the patient was not on PIRRT and the high plasma levels achieved during the sampling period despite RRT, a dose of 1 g every 8 hours on PIRRT and 1 g every 12 hours on non-PIRRT days would be recommended. [19][20][21][22][23][24] This neurotoxicity is attributed to an ability to cross the blood-brain barrier and exhibit concentration-dependent GABA antagonism.23 , 2⁴ Because this effect is concentration dependent, some studies suggest that a cefepime trough level of 36 mg/L is a highly accurate and sensitive threshold marker for cefepime-induced neurotoxicity, although this could be as low as 23 mg/L. 23,24 Supratherapeutic cefepime concentrations could have contributed to the encephalopathy in this case, especially as no dosage adjustments were made when the patient was not being dialysed.…”