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Antimicrob Agents Chemother. 2019 Oct 28. pii: AAC.01655-19. doi: 10.1128/AAC.01655-19. [Epub ahead of print]

A population pharmacokinetic model-guided evaluation of ceftolozane/tazobactam dosing in critically ill patients undergoing continuous venovenous hemodiafiltration.

Author information

1
University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia.
2
School of Pharmacy, Centre for Translational Anti-infective Pharmacodynamics, The University of Queensland, Brisbane, Australia.
3
Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia.
4
Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes France.
5
University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia j.roberts2@uq.edu.au.
6
Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Abstract

The aim of this work was to describe optimised dosing regimens of ceftolozane/tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane/tazobactam and CVVHDF. Unbound drug concentrations were measured from serial pre-filter blood, post-filter blood and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modelling and dosing simulations were preformed using Pmetrics®. A four compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratio for ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30 respectively. Model estimated CVVHDF clearances were 2.7 ± 0.8 and 3.0 ± 0.6 L/h respectively. Residual non-CVVHDF clearances were 0.6 ± 0.5 and 3.3 ±0.9 L/h, respectively. In the initial 24 h, doses as low as 0.75g 8-hourly enable fractional target attainment of ≥ 85% for empiric coverage against Pseudomonas aeruginosa considering 40 % fT>MIC target. For 100 % fT>MIC, at least 1.5 g 8-hourly is required. The median (interquartile range) steady state trough ceftolozane concentrations for simulated 1.5g and 3.0g 8-hourly regimens were 28 (21-42) and 56 (42-84) mg/L, respectively. The corresponding tazobactam concentrations were 6.1 (5.5-6.7) and 12.1 (11.0-13.4) mg/L, respectively. We suggest a front-loaded regimen with a single 3.0 g loading dose followed by 0.75 g 8-hourly for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.

PMID:
31658965
DOI:
10.1128/AAC.01655-19
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