Abstract
BACKGROUND: Cefiderocol is the first antibiotic with effluent flow rate-based dosing recommendations outlined in the product label for patients receiving continuous renal replacement therapy (CRRT). We aimed to investigate the population pharmacokinetics of cefiderocol among patients receiving CRRT and validate these dosing recommendations. METHODS: A multicenter, prospective cefiderocol pharmacokinetic study among intensive care unit patients receiving CRRT was conducted (2022-2023). Blood sampling was performed at steady-state and cefiderocol concentrations were assayed by validated liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analyses were conducted in Pmetrics using R software. The free time above the minimum inhibitory concentration (f T > MIC) and total daily area under the concentration time curve (AUC(daily)) were calculated. RESULTS: Fourteen patients with effluent flow rates ranging from 2.1 to 5.1 L/h were enrolled. Cefiderocol concentrations best fitted a 2-compartment model. Mean ± standard deviation (SD) parameter estimates for clearance, central compartment volume, and intercompartment transfer constants (k(12) and k(21)) were 3.5 ± 1.5 L/hour, 10.7 ± 8.4 L, 3.9 ± 1.8 hours(-1), and 2.2 ± 2.2 hours(-1), respectively. With simulations based on product label dosing recommendations, all patients achieved 100% fT > MIC up to MIC 8 mg/L with an AUC(daily) (mean ± SD) of 1444 ± 423 mg × hour/L. Cefiderocol was well tolerated among the 14 patients. CONCLUSIONS: The current package insert dosing recommendations resulted in pharmacodynamically optimized cefiderocol exposures. Cefiderocol concentrations exceeded relevant MIC breakpoints in all patients at each effluent flow rate, and AUC(daily) was within the range observed in patients in the phase 3 clinical trials, suggestive of a safe and therapeutic drug profile.