Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function

Abstract

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (T fϾMIC ) for an MIC range of 0.25 to 16 g/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided Ͼ90% PTA for 75% T fϾMIC for an MIC of Յ4 g/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect.

Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens

“…The only comparators with equal activity were colistin and tigecycline, with the limitation that tigecycline was not active against P. aeruginosa. Finally, it should be emphasized that cefiderocol displays much favorable pharmacokinetic parameters (tissue diffusion and use in renal impairment) than colistin and tigecycline [19], which will be an important factor for choosing adequate therapy of infections due to multidrug infections.…”

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

“…Cefiderocol is a new siderophore cephalosporin that is active against MDR Gramnegative organisms, including carbapenemase-producing Enterobacteriaceae (370)(371)(372)(373)(374)(375). At a dose of 2 g every 8 h, it reaches Ͼ50% time above the MIC for MICs of up to 8 mg/liter (376). It has also been shown to be effective against KPC-and NDMproducing K. pneumoniae in a rat respiratory tract infection model, particularly when administered over 3 h (377).…”

Compassionate Use of Cefiderocol in the Treatment of an Intraabdominal Infection Due to Multidrug‐Resistant Pseudomonas aeruginosa: A Case Report

“…Second, our patient was maintained on hemodialysis for ESRD. Successful therapy utilizing the manufacturer‐recommended dose adjustment of cefiderocol for patients on hemodialysis suggests, at least in our case, appropriate pharmacodynamic target attainment and lends confidence to the provided dosing recommendations . Last, this is, to our knowledge, the first case of successful real‐world utilization of cefiderocol to treat a complicated intraabdominal infection with a MDR P. aeruginosa .…”

“…Successful therapy utilizing the manufacturer-recommended dose adjustment of cefiderocol for patients on hemodialysis suggests, at least in our case, appropriate pharmacodynamic target attainment and lends confidence to the provided dosing recommendations. 22 Last, this is, to our knowledge, the first case of successful real-world utilization of cefiderocol to treat a complicated intraabdominal infection with a MDR P. aeruginosa. To date, the patient has not experienced any complications or recurrence of infection and has been maintained off antimicrobial therapy for his intraabdominal infection for roughly 60 days.…”