Optimal dosage regimens of cefiderocol administered by short, prolonged or continuous infusion: a PK/PD simulation study

Abstract Background and objectives Cefiderocol approved dosages are based on a prolonged infusion (PI) of 3 h that may not be adequate in all settings The objective of this study was to identify alternative cefiderocol dosage regimens based on short infusion (SI) or continuous infusion (CI). Methods We performed 1000-patient pharmacokinetic/pharmacodynamic (PK/PD) simulations based on a reference population model. Drug penetration into the epithelial lining fluid (ELF) was considered for pneumonia. For various stages of creatinine clearance (CLCR), we simulated the recommended PI as well as various SI (1 h-infusion) and CI regimens. The PK/PD targets were set at 75% or 100% of the dosing interval during which the free concentration of cefiderocol was above the MIC (fT > MIC) in plasma and ELF. The PTAs were computed considering the cefiderocol MIC breakpoint (2 mg/L). Results In plasma, all recommended PI regimens were associated with a PTA ≥ 90%. Some SI regimens also showed acceptable PTAs. CI regimens were associated with high PTAs, even for doses as low as 2 g over 24 h and in patients with high CLCR. Recommended dosages failed to achieve acceptable PTAs in ELF for the 100% fT > MIC target in patients with CLCR ≥ 90 mL/min. CI regimens showed the highest PTAs for the high target, but high doses of 6 to 8 g over 24 h were required in patients with CLCR ≥ 90 mL/min. Conclusions We identified SI and CI regimens of cefiderocol that may be useful alternatives to the PI regimens in some patients. Continuous administration of cefiderocol may be especially relevant for patients with pneumonia. However, further clinical evaluation is necessary.