Risk of Underexposure and Lack of Efficacy of Cefiderocol by Reduced Dosing in Japanese Patients With Gram-Negative Bacterial Infections

Abstract
Background: Recently, a cost-saving, dose-reducing strategy for cefiderocol against gram-negative bacteria with low cefiderocol minimum inhibitory concentrations (MICs) was proposed as an alternative to the standard dosing (ie, 2 g every 8 hours, 3-hours infusion). The objectives of this article are to summarize the available evidence on the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics of cefiderocol to support the rationale of the approved dosing and to assess any risk of underexposure with reduced doses (ie, 1 g every 8 hours or 12 hours) regarding higher cefiderocol MICs.

Methods: Published data from phase 1-3 clinical, preclinical effectiveness, and surveillance studies were reviewed, and new population PK simulations were conducted.

Results: Most carbapenem-resistant gram-negative isolates displayed cefiderocol MICs up to 4 mg/L. Single or multiple doses of cefiderocol, up to 4 g, were tested in phase 1 clinical studies, which confirmed a linear PK profile, low metabolism, renal clearance, and penetration into the lungs and soft tissues. Phase 2-3 randomized controlled clinical studies have demonstrated the efficacy and safety of cefiderocol at 2 g every 8 hours or renally adjusted doses versus comparators in patients with complicated urinary tract infections, nosocomial pneumonia, and bloodstream infection/sepsis caused by various carbapenem-susceptible or -resistant gram-negative pathogens. Population PK models incorporating clinical data predicted that the approved dosing regimen of cefiderocol, in contrast to reduced doses, would achieve high probability of target attainment against gram-negative isolates, with cefiderocol MICs of 2-4 mg/L across various infection types and patient populations.

Conclusions: Administering low-dose cefiderocol to reduce treatment-related costs will lead to treatment failure and prolonged hospitalization and incur further expenses. Therefore, the approved cefiderocol dosing regimen is strongly recommended.