Cerebrospinal fluid concentrations of ceftaroline and ceftazidime/avibactam in healthy volunteers: Pharmacokinetics and probability of target attainment

Objectives

This study measured the penetration of ceftaroline and ceftazidime/avibactam into cerebrospinal fluid (CSF) to evaluate the potential of both drugs for treatment of central nervous system (CNS) infections.

Methods

In this prospective, single-centre pharmacokinetic (PK) study, 24 healthy volunteers equally divided into two groups received four doses of either 600 mg ceftaroline fosamil or 2000/500 mg ceftazidime/avibactam as intravenous infusions over 2 h at 8 h intervals for 4 doses. Plasma samples were obtained on both study days and CSF was sampled once per subject at either 2 h, 4 h or 8 h after the start of the last infusion via lumbar puncture. PK data were analysed using non-compartmental analysis, as well as using a population PK modelling approach. Monte Carlo simulations were performed to calculate probability of PK-pharmacodynamic (PK-PD) target attainment.

Results

Two-compartment models described the plasma PK data for all three compounds. The ratios between the estimated distribution clearances into and out of the CSF were 0.021, 0.083 and 0.071 for ceftaroline, ceftazidime and avibactam, respectively, indicating limited CSF penetration. Ceftaroline and ceftazidime PK-PD targets were not attained in CSF for minimum inhibitory concentrations around commonly used susceptibility breakpoints, but exposure appears sufficient to treat several pathogens commonly causing CNS infections. Avibactam concentrations were well below reported threshold concentrations that are required for activity.

Conclusion

In healthy subjects, ceftaroline, ceftazidime and avibactam poorly distribute to CSF. Nonetheless, CSF exposure of both cephalosporins might be sufficient to cover certain, but not all, pathogens causative of CNS infections.