US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800.

Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy.

In this report, we describe our scientific approach for including effluent flow rate (QE )-based dosing recommendations of cefiderocol for patients receiving continuous renal replacement therapy (CRRT) in the product labeling. The total clearance (CL) of cefiderocol in patients receiving CRRT was estimated as the sum of patients' nonrenal clearance (CLnonrenal ) and extracorporeal clearance by CRRT (CLCRRT ), based on the following rationale: (a) The renal clearance (CLrenal ) of cefiderocol is assumed to be negligible in patients receiving CRRT, (b) CLnonrenal represents the CRRT patients' own remaining systemic clearance and is estimated from the observed clearance in participants with creatinine clearance (CLcr) < 15 mL/minute without undergoing hemodialysis, and (c) CLCRRT was estimated by the product of unbound (free) fraction of plasma drug concentration (fu ) and QE because the free fraction of low-molecular-weight compounds like cefiderocol (752 Da) can be completely filtered by CRRT, regardless of CRRT modality. Hence, cefiderocol CL in CRRT patients was calculated by the equation of CL = CLnonrenal + fu × QE . Accordingly, the cefiderocol dosing regimens for patients receiving CRRT in clinically relevant ranges of QE were determined with the goal of achieving an average daily area under the concentration-time curve (AUC) observed in patients not receiving CRRT. Subsequently, pharmacokinetic (PK) simulations demonstrated that cefiderocol PK profiles following the QE -based dosing in patients receiving CRRT would be similar to those in patients not receiving CRRT.