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 (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.

The Role of Cefepime in the Treatment of Extended-Spectrum Beta-Lactamase Infections.

OBJECTIVE: To review the efficacy of cefepime for use in infections caused by extended-spectrum beta-lactamase (ESBL)-producing organisms. DATA SOURCES: A PubMed literature search (May 2000 to June 2017) was performed using the keyword cefepime and the MeSH terms beta-lactamases, cephalosporinases, and Enterobacteriaceae infections. STUDY SELECTION AND DATA EXTRACTION: All human, English language studies evaluating cefepime use for the treatment of ESBL-producing Escherichia coli and Klebsiella pneumoniae infections were included. DATA SYNTHESIS: Studies assessing the use of cefepime for ESBL infections are few, and clinical studies are limited by design and sample size. The largest pharmacokinetic/pharmacodynamic study, a Monte Carlo simulation using data from the U.S. SENTRY antimicrobial surveillance program, evaluating cefepime use for infections due to ESBL-producing organisms found a 95% to 100% probability of target attainment with traditional cefepime dosing regimens. Most clinical studies found that patients treated with cefepime empirically and definitively had higher rates of mortality than those treated with carbapenems. However, in concordance with other studies reporting minimum inhibitory concentration (MIC) data, lower MICs were associated with lower mortality. CONCLUSIONS: Cefepime should be avoided for empiric treatment of suspected ESBL infections and should only be considered for definitive treatment if the MIC ≤1 µg/mL. However, the site and severity of infection, local resistance patterns, and patient-specific risk factors should also help guide antimicrobial selection.