Cefiderocol in Critically Ill Patients with Multi-Drug Resistant Pathogens: Real-Life Data on Pharmacokinetics and Microbiological Surveillance

Abstract

Cefiderocol is a new siderophore-cephalosporin for the treatment of multi-drug resistant Gram-negative pathogens. As a reserve agent, it will and should be used primarily in critically ill patients in the upcoming years. Due to the novelty of the substance little data on the pharmacokinetics in critically ill patients with septic shock and renal failure (including continuous renal replacement therapy and cytokine adsorber therapy) is available. We performed therapeutic drug monitoring in a cohort of five patients treated with cefiderocol, to improve the knowledge on pharmacokinetics in this vulnerable patient population. As expected for a cephalosporin with predominantly renal elimination the maintenance dose could be reduced in patients with renal impairment or on continuous renal replacement therapy. The manufacturer's dosing instructions were sufficient to achieve a drug level well above the MIC. However, the addition of a cytokine adsorber might reduce serum levels substantially, so that in this context therapeutic drug monitoring and dose adjustment are recommended.

Keywords: cefiderocol; continuous veno-venous hemodialysis; critically ill patients; pharmacokinetics; therapeutic drug monitoring.

Figure 1

Clinical courses and cefiderocol levels of individual patients. The color scheme is applied consistently for all parts of the figure; blue = patient #1; green = patient #2; black = patient #3; red = patient #4; orange patient #5. (a) demonstrates individual courses of C-reactive protein for each patient. In addition, bars at the bottom indicate the duration of catecholamine therapy for each patient. (b–f) demonstrate the individual cefiderocol levels simulated based on the measured trough levels. Dotted horizontal lines denote the cut-off for sensitivity for the pathogen isolated from each patient according to EUCAST. Yellow bars present the durations of continuous renal replacement therapy. The daily cefiderocol dosage is displayed by dots at the bottom of each patients’ graph. Each dot denotes one gram of cefiderocol. Red arrows in part (f) indicate the change of CytoSorb^® cartridges with measured consecutive drops of cefiderocol plasma levels.