JAC Advance Access originally published online on January 18, 2009
Journal of Antimicrobial Chemotherapy 2009 63(3):553-559; doi:10.1093/jac/dkn541
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Original research |
Pharmacokinetic evaluation of linezolid in patients with major thermal injuries
1 Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust, Bristol BS10 5NB, UK 2 Service des brûlés, CHU Nantes, 30 Bd Monet, 44093 Nantes cedex 01, France 3 SGS, 3-5 rue Eugene Million, 75015 Paris, France 4 Service des brûlés, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris, France 5 Pfizer, 23-25 avenue du Dr Lannelongue, 75668 Paris cedex 14, France
Received 1 August 2008; returned 18 October 2008; revised 10 December 2008; accepted 16 December 2008
* Corresponding author. Tel: +44-117-9595653; Fax: +44-117-9593217; E-mail: andrew.lovering{at}nbt.nhs.uk
Aims: To evaluate the pharmacokinetics of linezolid following its administration in patients with major thermal injuries and in a group of healthy volunteers.
Methods: In an open-label, multicentre design with two parallel groups, a group of patients with major thermal injuries (>20% body area) and a group of age-, sex- and weight-matched healthy volunteers, subjects received a single 600 mg intravenous dose of linezolid. Serial blood and urine collections were made and the concentrations of linezolid in these samples were determined by HPLC. Non-compartmental analyses were used to describe the pharmacokinetic disposition of linezolid.
Results: Cmax concentrations and the volume of distribution at steady state (Vss) were not statistically different (P > 0.05) between the two groups of subjects. In contrast, values describing clearance [elimination rate constant (kel), t1/2 and mean residence time (MRT)] were significantly different (P < 0.05) in patients with thermal injuries compared with volunteers, which lead to an approximate reduction by half in AUC0–
from 98.1 mg·h/L (volunteers) to 42.5 mg·h/L (patients). Although renal clearance was similar in the two groups (24.7 ± 23 versus 30.6 ± 14.3 mL/min; P = 0.156), non-renal clearance was substantially increased (323 ± 191 versus 80.4 ± 27.5 mL/min) in the patients with thermal injuries, though this difference did not achieve statistical significance (P = 0.063).
Conclusions: The pharmacokinetics of linezolid are altered in patients with major thermal injuries, mainly as a result of increased non-renal clearance. These changes are of sufficient magnitude that linezolid concentrations may be sub-therapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.
Keywords: burns , human , oxazolidinone