Résumé
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 3.0 g 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 modeled 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 (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (fAUC(0-inf)) in the CSF and plasma were 30 (19 to 128) h.mg/liter and 323 (183 to 414) h.mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h.mg/liter and 52 (36 to 80) h.mg/liter, 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 regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of >= 0.9 for 40% fT(>MIC) in the CSF was possible only when MICs were <= 0.25 mg/liter. The CSF cumulative fractional response for Pseudomonas aeruginosa-susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT(>1 mg/liter) was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) 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/liter).