Intrapulmonary penetration of ceftolozane/tazobactam and ceftazidime/avibactam administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial.

BACKGROUND

Ceftolozane/tazobactam (TOL/TAZ) and ceftazidime-avibactam (CAZ/AVI) are increasingly used to treat pneumonia caused by multidrug-resistant Gram-negative bacilli. However, data on intrapulmonary penetration to confirm dosing adequacy are limited. Therefore, the aim of this study was to compare epithelial lining fluid (ELF) penetration and pharmacokinetic/pharmacodynamic (PK/PD) target attainment of TOL/TAZ versus CAZ/AVI administered by continuous infusion (CI) in critically ill patients with nosocomial pneumonia.

METHODS

Single-center, open-label, randomized pharmacokinetic (PK) study. Thirty patients were randomized 1:1 to receive 6 g/3 g of TOL/TAZ or 6 g/1.5 g of CAZ/AVI administered by CI. A population PK model was constructed using plasma and ELF concentrations. Lung penetration was estimated based on the ratio AUC0-8ELF/AUC0-8plasma. Simulations were performed to estimate the probability of attaining predefined joint ELF PK/PD target defined as free concentration 100% fT> minimum inhibitory concentration (MIC) for the β-lactam component and 100% fT> concentration threshold (CT) for the β-lactamase inhibitors, among relevant MIC scenarios. Three different dosing regimens (low, standard and high) were evaluated for each combination.

RESULTS

A total of 298 plasma and 58 ELF samples were analyzed. The median [IQR] age, body mass index, and creatinine clearance were 77 [9.8] years, 26.48 [5.5] kg/m², and 76.0 [96.0] mL/min, respectively. Median intrapulmonary penetration was 0.66 [0.32] for ceftolozane, 0.41 [0.30] for ceftazidime 0.44 [0.05] for tazobactam and 0.44 [0.46] for avibactam. Under the prespecified ELF PK/PD target, standard dosing achieved adequate target attainment for both combinations. Simulations showed that all CAZ/AVI regimens achieved high ELF target attainment under conservative inhibitor threshold assumptions (assuming ceftazidime MIC = 8 mg/L and avibactam CT =1 mg/L), whereas for TOL/TAZ (assuming ceftolozane MIC = 4 mg/L and tazobactam CT 2 mg/L) at least the standard-dose regimen was required. More aggressive target scenarios reduced the probability of target attainment, particularly for inhibitor thresholds of 4 mg/L and for Enterobacterales-oriented joint targets.

CONCLUSIONS

In critically ill adults with nosocomial pneumonia receiving TOL/TAZ or CAZ/AVI by CI, standard doses achieved ELF exposures consistent with dual PK/PD target attainment against all susceptible isolates. Interindividual variability and the risk of plasma overexposure support individualized dosing and consideration of therapeutic drug monitoring.

TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT No. 2021-006908-32). Registered 10 February 2022; https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-006908-32/ES .