Cefepime pharmacokinetics in critically ill children and young adults undergoing continuous kidney replacement therapy.

OBJECTIVES: Cefepime is an antibiotic commonly used to treat sepsis and is cleared by renal excretion. Cefepime dosing requires adjustment in patients with decreased kidney function and in those receiving continuous kidney replacement therapy (CKRT). We aimed to characterize cefepime PK in a diverse cohort of critically ill paediatric patients on CKRT. METHODS: Patients were identified from an ongoing pharmacokinetic/pharmacodynamic (PK/PD) study of beta-lactam antibiotics, and were included if they had received at least two cefepime doses in the ICU and were on CKRT for at least 24 h. PK parameters were estimated using MwPharm++ with Bayesian estimation and a paediatric population PK model. Target attainment was assessed as time of free cefepime concentrations above minimum inhibitory concentration (fT > 1× or 4 × MIC). RESULTS: Seven patients were included in the study (ages 2 to 20 years). CKRT indications included liver failure (n = 1), renal failure (n = 4) and fluid overload (n = 2). Total effluent flow rates ranged from 1833 to 3115 (mean 2603) mL/1.73 m2/h, while clearance was 2.11-3.70 (mean 3.0) L/h/70 kg. Effluent flows were lower, but clearance and fT > MIC were similar to paediatric data published previously. Using Pseudomonas aeruginosa MIC breakpoints, all patients had 100% of dosing interval above MIC, but only one had 100% of dosing interval above 4× MIC. CONCLUSIONS: Since most patients failed to attain stringent targets of 100% fT > 4×  MIC, model-informed precision dosing may benefit such patients.

Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model.

OBJECTIVES: WCK 5222 combines cefepime with zidebactam, a ß-lactam enhancer that binds PBP2 and inhibits class A and C ß-lactamases. The efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR Pseudomonas aeruginosa was investigated in a neutropenic murine pneumonia model. METHODS: Nineteen MDR isolates of P. aeruginosa (cefepime MICs ≥64 mg/L) were studied. MICs of zidebactam and WCK 5222 ranged from 4 to 512 mg/L and from 4 to 32 mg/L, respectively. Dosing regimens of cefepime and zidebactam alone and in combination that achieved epithelial lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2 g of cefepime/1 g of zidebactam every 8 h (1 h infusion) were utilized; controls were vehicle-dosed. Lungs were intranasally inoculated with 107-108 cfu/mL bacterial suspensions. Mice were dosed subcutaneously 2 h after inoculation for 24 h, then lungs were harvested. RESULTS: In vitro MIC was predictive of in vivo response to WCK 5222 treatment. Mean±SD changes in bacterial density at 24 h compared with 0 h controls (6.72±0.50 log10 cfu/lungs) for 13 isolates with WCK 5222 MICs ≤16 mg/L were 1.17±1.00, -0.99±1.45 and -2.21±0.79 log10 cfu/lungs for cefepime, zidebactam and WCK 5222, respectively. Against these isolates, zidebactam yielded >1 log10 cfu/lungs reductions in 8/13, while activity was enhanced with WCK 5222, producing >2 log10 cfu/lungs reductions in 10/13 and >1 log10 cfu/lungs reductions in 12/13. Among isolates with WCK 5222 MICs of 32 mg/L, five out of six showed a bacteriostatic response. CONCLUSIONS: Human-simulated bronchopulmonary exposure of WCK 5222 is effective against MDR P. aeruginosa at MIC ≤16 mg/L in a murine pneumonia model. These data support the clinical development of WCK 5222 for pseudomonal lung infections.

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.