Cerebrospinal fluid penetration of ceftolozane/tazobactam in critically ill patients with an indwelling external ventricular drain.

The aim of this study was to describe the pharmacokinetics of ceftolozane/tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥ 18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0g ceftolozane/tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modelled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (Inter quartile range, IQR) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19-128) h*mg/L, and 323 (183-414) h*mg/L respectively. For tazobactam, these values were 5.6 (2-24) h*mg/L and 52 (36-80) h*mg/L, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2±0.26 for ceftolozane and tazobactam respectively. With the 3.0 g 8-houly regimen, ≥ 0.9 probability of target attainment (PTA) for 40% fT>MIC in the CSF was possible only when MICs were ≤ 0.25 mg/L. The CSF cumulative fractional response for P. aeruginosa susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1mg/L was 12%. The current maximal dose of ceftolozane/tazobactam (3.0 g 8-hourly) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/L).