Ceftolozane/Tazobactam Pharmacokinetics in a Critically Ill Adult Receiving Continuous Renal Replacement Therapy

Abstract

Limited data are available on ceftolozane/tazobactam dosing in patients receiving continuous renal replacement therapy (CRRT). Thus we performed a pharmacokinetic analysis of intravenous ceftolozane/tazobactam in a critically ill patient receiving CRRT at our medical center. A 47-year-old critically ill man with multidrug-resistant Pseudomonas aeruginosa pneumonia, bacteremia, and osteomyelitis was receiving ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) every 8 hours while receiving continuous venovenous hemodiafiltration (CVVHDF). After the fifth dose of ceftolozane/tazobactam, plasma samples were obtained at 1-, 2-, 4-, 6-, and 8-hour time points. Two additional post-hemodialysis filter plasma samples were obtained to assess CVVHDF clearance. The maximum and minimum plasma concentrations for ceftolozane were 163.9 μg/ml and 79.4 μg/ml, respectively. The area under the plasma concentration-time curve from 0-8 hours (AUC ) was 689 μg hour/ml; the plasma half-life was 13.3 hours. The ceftolozane CVVHDF clearance and total clearance were 2.4 L/hour and 2.9 L/hour, respectively. Compared with a patient with normal renal function, this patient receiving CVVHDF had decreased ceftolozane clearance. A ceftolozane/tazobactam dosage of 1.5 g every 8 hours should adequately achieve a desired drug concentration above the minimum inhibitory concentration of 8 μg/ml for the treatment of pneumonia. Additional pharmacokinetic data are needed to confirm our results and for alternative forms of CRRT.

PK/PD Target Attainment With Ceftolozane/Tazobactam Using Monte Carlo Simulation in Patients With Various Degrees of Renal Function, Including Augmented Renal Clearance and End-Stage Renal Disease

“…Second, this study was limited by the lack of clinical data to support the findings in ARC, severe renal impairment, and ESRD. Recent case studies, however, have reported successful clinical outcomes in patients with more severe renal impairment [28, 29]. Third, this study was based on population PK models and simulations with characteristics from patients not critically ill, though still infected, or from patients with ESRD who were otherwise healthy.…”

Ex vivo Ceftolozane/Tazobactam Clearance during Continuous Renal Replacement Therapy

“…Overall, ceftolozane/tazobactam drug exposure, as measured by the area under the concentration-time curve (AUC), was reduced by 66/56%, respectively, with a standard hemodialysis session [6]. Case reports of ceftolozane/tazobactam use in patients with acute kidney injury (AKI) treated with continuous renal replacement therapy (CRRT) have been published, but no dosing recommendations have been made [7,8]. Ceftolozane and tazobactam are both relatively small molecules (molecular weights of 666 and 322 Daltons) with similar volumes of distribution (13.5 and 18.2 L) and low plasma protein binding rates (16-21 and 30%, respectively) [4,9,10].…”

Persistent Bacteremia fromPseudomonas aeruginosawithIn VitroResistance to the Novel Antibiotics Ceftolozane-Tazobactam and Ceftazidime-Avibactam

“…A recent publication on a multidrug-resistant P. aeruginosa bacteremia was reported by Bremmer and colleagues, but the isolate was susceptible to ceftolozane-tazobactam [4]. In our current report, a rapid development of antibiotic resistance was observed despite appropriate antimicrobial therapy and, intriguingly, with resistance to ceftazidime-avibactam and ceftolozane-tazobactam, agents that have been only recently approved by the US Food and Drug Administration.…”