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Monte Carlo simulations of cefepime in children receiving continuous kidney replacement therapy support continuous
H Rhodes Hambrick1,2,3,4, Nieko Punt5,6, Kathryn Pavia7,8,9
1Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue, Cincinnati, OH, 45229, USA. hhambrick@luriechildrens.org.
Insights
Continuous cefepime infusions (CI) achieve higher probability of target attainment (PTA) in pediatric patients on continuous kidney replacement therapy (CKRT). Dosing strategies must consider CKRT intensity and residual kidney function for optimal cefepime therapy in critically ill children.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Pediatric Critical Care
- Nephrology
Background:
- Sepsis frequently causes acute kidney injury (AKI) necessitating continuous kidney replacement therapy (CKRT).
- Continuous kidney replacement therapy (CKRT) significantly impacts drug pharmacokinetics (PK), including cefepime.
- Limited data exist on cefepime PK and pharmacodynamic (PD) target attainment in pediatric patients undergoing CKRT.
Purpose of the Study:
- To evaluate cefepime dosing strategies in pediatric patients receiving CKRT using Monte Carlo simulations (MCS).
- To determine the probability of target attainment (PTA) for various cefepime dosing regimens under different CKRT conditions.
Main Methods:
- A novel CKRT module was integrated into the Edsim++ software and a pediatric cefepime PK model.
- One thousand-fold Monte Carlo simulations (MCS) were conducted for pediatric patients (2-25 years, ≥10 kg).
- Simulations incorporated varying residual kidney function (eGFR 5 vs 30 mL/min/1.73 m²), CKRT effluent flow (2500 vs 8000 mL/h/1.73 m²), and fluid accumulation (0-30%).
Main Results:
- Continuous infusions (CI) of 100-150 mg/kg/day and 4-h infusions of 50 mg/kg achieved >90% PTA for 100% fT > 1x MIC under standard-dose CKRT with minimal kidney function.
- Achieving >90% PTA for 100% fT > 4x MIC required 150 mg/kg CI.
- Decreased PTA was observed with less frequent dosing, shorter infusions, higher-dose CKRT, and greater residual kidney function.
Conclusions:
- The developed CKRT module successfully simulated cefepime PK and PTA in pediatric patients on CKRT.
- Continuous infusions (CI) of cefepime are superior to intermittent dosing for achieving higher PTA, especially when targeting 100% fT > 4x MIC or utilizing high-dose CKRT.
- Optimized cefepime dosing strategies are crucial for effective treatment in critically ill children with AKI requiring CKRT.
Background:
Sepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT.
Methods:
We developed a CKRT "module" in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2-25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0-30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa.
Results:
Assuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100-150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function.
Conclusions:
Our new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.
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