Abstract
BackgroundCefepime can be removed by continuous renal replacement therapy (CRRT) due to its pharmacokinetics. The purpose of this study is to define the optimal cefepime dosing regimens for critically ill patients receiving CRRT using Monte Carlo simulations (MCS).MethodsThe CRRT models of cefepime disposition during 48 h with different effluent rates were developed using published pharmacokinetic parameters, patient demographic data, and CRRT settings. Pharmacodynamic target was the cumulative percentage of a 48-h period of at least 70% that free cefepime concentration exceeds the four times susceptible breakpoint of Pseudomonas aeruginosa (minimum inhibitory concentration, MIC of 8). All recommended dosing regimens from available clinical resources were evaluated for the probability of target attainment (PTA) using MCS to generate drug disposition in a group of 5000 virtual patients for each dose. The optimal doses were defined as achieving the PTA at least 90% of virtual patients with lowest daily doses and the acceptable risk of neurotoxicity.ResultsOptimal cefepime doses in critically ill patients receiving CRRT with Kidney Disease: Improving Global Outcomes (KDIGO) recommended effluent rates were a regimen of 2 g loading dose followed by 1.5–1.75 g every 8 h for Gram-negative infections with a neurotoxicity risk of < 17%. Cefepime dosing regimens from this study were considerably higher than the recommended doses from clinical resources.ConclusionAll recommended dosing regimens for patients receiving CRRT from available clinical resources failed to achieve the PTA target. The optimal dosing regimens were suggested based on CRRT modalities, MIC values, and different effluent rates. Clinical validation is warranted.
Highlights
Cefepime can be removed by continuous renal replacement therapy (CRRT) due to its pharmacokinetics
Applying the aggressive target as Clinical Laboratory Standards Institute (CLSI) recommended minimum inhibitory concentration (MIC) breakpoint of 8 mg/L into the models, all recommended dosing regimens from clinical resources could not attain the targets with two different modalities
Considering efficacy from the probability of target attainment (PTA) target and the probability of developing neurotoxicity, the regimen of 2 g loading dose followed by 1.5–1.75 g every 8 h achieved the aforementioned targets of > 90% for all CRRT settings with Kidney Disease: Improving Global Outcomes (KDIGO) recommended effluent rates in a range of 20–25 mL/kg/h (Table 5)
Summary
Cefepime can be removed by continuous renal replacement therapy (CRRT) due to its pharmacokinetics. Pharmacokinetic changes in critically ill patients, such as increasing of volume of distribution and hypoalbuminemia, considerably reduce hydrophilic antimicrobial agent concentrations [5]. Cefepime dosing recommendations in critically ill patients are based on previously published pharmacokinetic studies [2, 5, 8, 9]. Li and colleagues gathered and analyzed 64 published pharmacokinetic studies in patients receiving CRRT. They revealed that those studies did not completely report key pharmacokinetic parameters to calculate extracorporeal clearance and design drug dosing in patient with CRRT such as type of CRRT modalities, effluent rate, blood flow rate, and extraction coefficient [10]. Neurotoxicity from high cefepime concentrations in patients with reduced renal function has been reported [11,12,13,14,15]
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