Continuous infusion of ceftolozane/tazobactam is associated with a higher probability of target attainment in patients infected with Pseudomonas aeruginosa, Abstract Ceftolozane/tazobactam (CTZ/TZ) exhibits time-dependent antimicrobial activity, and prolonged infusion can better achieve the pharmacodynamic target than an intermittent bolus. We aimed to compare the use of prolonged or continuous infusion with intermittent administration of CTZ/TZ for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. We performed a multicentric prospective cohort study to evaluate continuous, prolonged, or intermittent infusion of CTZ/TZ. We assessed the plasma concentration as a function of the duration of infusion and then performed a simulation of the percentage of patients who would reach the PK/PD targets, set at 100% ƒT> MIC or 100% ƒT>4 MIC. Seventy-two patients were enrolled with a median [IQR] age of 48.5 [32.4–63.2] years. Fifty-seven (79%) were hospitalized in an intensive care unit. Thirty-seven (51.4%) were immunosuppressed, and the in-hospital mortality rate was 15.2%. The major site of infection was the respiratory tract (66.7%). The PK/PD objectives (100% ƒT>4 MIC) were achieved for all patients infected with strains with CTZ/TZ MICs < 4 mg/L, regardless of the mode of administration. In contrast, intermittent bolus administration and prolonged infusion did not achieve the PK/PD objectives when the CTZ/TZ MICs were ≥ 4 mg/L. However, the PK/PD objectives (100% ƒT>4 MIC) were achieved for strains with MICs up to 8 mg/L in patients receiving continuous infusion of CTZ/TZ. A dosing regimen of 2 g/1 g CTZ/TZ administered every 8 h as a 1-h intravenous infusion, as currently recommended, did not provided adequate coverage to achieve a sufficient probability of target attainment for P. aeruginosa strains with MICs ≥ 4 mg/L.