Pharmacokinetic evaluation of linezolid in patients with major thermal injuries.
OBJECTIVE
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
C(max) concentrations and the volume of distribution at steady state (V(ss)) were not statistically different (P > 0.05) between the two groups of subjects. In contrast, values describing clearance [elimination rate constant (k(el)), t(1/2) 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 AUC(0-infinity) 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.
Lovering
A M
AM
Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust, Bristol, UK. andrew.lovering@nbt.nhs.uk
Le Floch
R
R
Hovsepian
L
L
Stephanazzi
J
J
Bret
P
P
Birraux
G
G
Vinsonneau
C
C
D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002056:Burns; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000069349:Linezolid; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry*; D013997:Time Factors; D014556:Urine / Q000737:chemistry*; D055815:Young Adult
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid