Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin

Abstract

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent in vitro activity and in vivo efficacy against most gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In phase 1 studies, cefiderocol demonstrated linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours, and a protein binding of 58% in human plasma. Cefiderocol is a time-dependent cephalosporin; the probability of a target attainment at ≥75% of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL is likely to be achieved at the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients. As expected, renal function markers were the most influential covariates for the pharmacokinetics of cefiderocol for patients with renal impairment or augmented renal clearance (ARC). Dose adjustment is recommended for patients with impaired renal function, and additionally, in ARC patients with creatinine clearance >120 mL/minute, a more frequent dosing regimen (ie, 2 g every 6 hours) was predicted to achieve the target fT > MIC. The single and multiple doses of cefiderocol tested were well tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT interval prolongation nor drug–drug interaction via organic anion transporters was demonstrated in healthy subjects. Cefiderocol is being investigated in phase 3 clinical studies for the treatment of infections caused by carbapenem-resistant bacteria.

Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin

“…Overall, cefiderocol time-dependent in vivo efficacy in various preclinical infection models has been established for carbapenem-resistant pathogens, which was predicted by its in vitro potency and supported by a reliable PK/PD profile. Safety information on cefiderocol is discussed by Katsube et al [51] and Echols et al [52] in this supplement.…”

Cefiderocol: A Novel Siderophore Cephalosporin Defeating Carbapenem-resistant Pathogens

“…These data demonstrated a very high rate of susceptibility to cefiderocol, importantly in P. aeruginosa , A. baumannii , and S. maltophilia . Supporting its high potency against a wide range of carbapenem-susceptible and -resistant pathogens, preclinical pharmacokinetic/pharmacodynamic (PK/PD) studies established that the PD driver of its efficacy is the fraction of time during which the concentration of cefiderocol remains above the minimum inhibitory concentration (ƒT/MIC), thereby establishing a target PD parameter of 75% ƒT > MIC as discussed in the article by Katsube et al [23]. In phase 1 clinical studies, a linear and predictable PK profile of cefiderocol was established, with minimal accumulation during multiple dosing, primarily renal clearance, and a low risk of drug–drug interactions [23].…”

“…Supporting its high potency against a wide range of carbapenem-susceptible and -resistant pathogens, preclinical pharmacokinetic/pharmacodynamic (PK/PD) studies established that the PD driver of its efficacy is the fraction of time during which the concentration of cefiderocol remains above the minimum inhibitory concentration (ƒT/MIC), thereby establishing a target PD parameter of 75% ƒT > MIC as discussed in the article by Katsube et al [23]. In phase 1 clinical studies, a linear and predictable PK profile of cefiderocol was established, with minimal accumulation during multiple dosing, primarily renal clearance, and a low risk of drug–drug interactions [23]. The article by Echols et al presents an update on cefiderocol development, describing late-stage clinical trials for the treatment of patients with complicated urinary tract infection or acute pyelonephritis, nosocomial pneumonia, and bloodstream infections [24].…”

Compassionate Use of Cefiderocol to Treat a Case of Prosthetic Joint Infection Due to Extensively Drug-Resistant Enterobacter hormaechei

“…In these studies, cefiderocol MICs of the tested strains were inferior to the provisional susceptibility breakpoint of ≤4 mg/L used for Enterobacterales, P. aeruginosa, Stenotrophomonas maltophilia and Acinetobacter spp., and proposed by the Clinical & Laboratory Standards Institute (CLSI), based on preclinical pharmacokinetic and pharmacodynamics studies [10].…”