Pharmacokinetics and Pharmacodynamics of Ceftolozane/Tazobactam in Critically Ill Patients With Augmented Renal Clearance

•Augmented renal clearance (ARC) affects the pharmacokinetics (PK) of renally excreted drugs•Ceftolozane/tazobactam PK were evaluated in critically ill patients with ARC•In patients with ARC, 3 g ceftolozane/tazobactam met PK/pharmacodynamics targets•The 3 g thrice-daily dose of ceftolozane/tazobactam was adequate for patients with ARC To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection. ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated. Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (Vss) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and Vss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate. In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. NCT02387372