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 (Cmin) 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 56.6years) were analysed. Mean blood flow rate and effluent flow rate were 161.8mL/min and 2383.4mL/h, respectively. Ceftolozane Cmin ranged from 25.8 to 79.4mg/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 8mg/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.