Cerebrospinal Fluid Penetration of Ceftolozane-Tazobactam in Critically Ill Patients with an Indwelling External Ventricular Drain

• Published in: Antimicrobial agents and chemotherapy Vol. 65; no. 1
• Main Authors: Sime, Fekade B, Lassig-Smith, Melissa, Starr, Therese, Stuart, Janine, Pandey, Saurabh, Parker, Suzanne L, Wallis, Steven C, Lipman, Jeffrey, Roberts, Jason A
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 16.12.2020
• Subjects: Clinical Therapeutics; tazobactam; cerebrospinal fluid; meningitis; ceftolozane-tazobactam; ceftolozane; ventriculitis; CSF penetration
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01698-20

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 ( AUC ) 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% T in the CSF was possible only when MICs were ≤0.25 mg/liter. The CSF cumulative fractional response for -susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% T 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).