Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy

• DOI: 10.1007/s40262-021-01086-y
• Publication Date: 2021-11-18T06:02:49Z
• Authors: Eric Wenzler; David Butler; Xing Tan; Takayuki Katsube; Toshihiro Wajima
• Keywords: Renal replacement therapy; Pharmacodynamics

The need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable large part to subtherapeutic antimicrobial exposure failure achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol a novel siderophore cephalosporin broad vitro activity against resistant pathogens often used treat patients, including those receiving CRRT, despite the lack data guide dosing this population. aim study was evaluate PK PD cefiderocol vivo CRRT provide optimal recommendations. dialytic clearance evaluated via an established model across various modes, filter types, effluent flow rates. were combined from nine while phase III trials. Optimal regimens their respective probability attainment (PTA) assessed population Bayesian estimation 1000-subject Monte Carlo simulations at each rate. overall mean sieving/saturation coefficient 0.90 all rates, points fluid dilution tested. Adsorption negligible 10.9%. Three-way analysis variance (ANOVA) multiple linear regression analyses demonstrated that rate primary driver can be calculate doses required match systemic observed normal function. these rate-based trials revealed comparable (± standard deviation) area under concentration-time curve values as function (1709 ± 539 mg·h/L vs. 1494 58.4 mg·h/L; p = 0.26). confirmed achieved >90% PTA minimum inhibitory concentrations ≤4 mg/L rates 0.5 5 L/h. developed work have been incorporated into prescribing information cefiderocol, making it first only labeled Future studies warranted confirm efficacy safety regimens.