Ceftolozane/tazobactam exposure in critically ill patients undergoing continuous renal replacement therapy: a PK/PD approach to tailor dosing

Objectives: To investigate the influence of continuous renal replacement therapy (CRRT) intensity on the clearance of ceftolozane/tazobactam in critical care patients, and to evaluate if the reported doses would achieve an optimal pharmacokinetic/pharmacodynamic (PK/PD) target against Pseudomonas aeruginosa exhibiting different MICs. Methods: The MEDLINE-PubMed database was searched from inception to January 2020 to retrieve observational studies or case reports investigating the PK behaviour of ceftolozane/tazobactam during CRRT. Relevant CRRT settings and PK variables were extracted, and the influence of CRRT intensity on ceftolozane/tazobactam total clearance (CLtot) was determined by simple Linear regression. The optimal PK/PD target for the reported doses was deemed to be achieved when ceftolozane trough concentrations (C-min) were above the MIC (Less intensive target) or four times the MIC (intensive target) for P. aeruginosa. Results: Data from six studies including 11 patients (mean age 56.6 years) were analysed. Mean blood flow rate and effluent flow rate were 161.8 mL/min and 2383.4 mL/h, respectively. Ceftolozane C-min ranged from 25.8 to 79.4 mg/L. A significant correlation was found for ceftolozane CLtot and effluent flow rate (P= 0.027). The intensive PK/PD target was achieved by 100% and 50% of the reported doses for MIC, respectively, up to 4 and 8 mg/L. Conclusions: A significant correlation between effluent flow rate and ceftolozane clearance during CRRT could be identified. Higher dosing regimens coupled with continuous/extended infusion may be required in the case of higher CRRT intensity, deep-seated infections or poorly susceptible isolates. Larger studies assessing ceftolozane PK in different CRRT settings are warranted.

Automated summary

The study revealed a significant correlation between CRRT intensity and ceftolozane/tazobactam clearance, indicating that higher CRRT intensity may require higher doses to achieve optimal pharmacokinetic/pharmacodynamic (PK/PD) targets, especially in the case of deep-seated infections or poorly susceptible isolates. Further larger studies are needed to assess ceftolozane PK in different CRRT settings.