Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections.
OBJECTIVE
Physiological changes and local and systemic inflammation may affect plasma and tissue pharmacokinetics of antimicrobial agents in diabetics. The aim of the study was to investigate the penetration of linezolid into inflamed areas of infected diabetic foot wounds and the pharmacokinetics in the risk population of diabetics.


METHODS
Pharmacokinetics and tissue penetration of linezolid into inflamed diabetic foot infection (DFI) tissue were determined at steady state in 15 patients with diabetes type 2 and DFI following administration of multiple oral doses of 600 mg given every 12 h. Second debridement was performed on days 4-6, 3 h after linezolid administration. Linezolid concentrations were determined in perinecrotic wound tissue of inflamed diabetic foot by high-performance liquid chromatography (HPLC).


RESULTS
A mean maximum plasma concentration (C(max)) in plasma of 14.3 mg/L was attained at a median of 2.0 h [time to reach C(max) (T(max)) range 0.5-6.0 h). Area under the concentration time curve from zero to 12 h (AUC(0-12 h)) with a mean of 114.1 mgh/L and C(min) of 5.4 mg/L were achieved in patients with diabetes mellitus type 2. Penetration of linezolid into inflamed areas of DFI with tissue/plasma ratios of mean 101.7% [95% confidence interval (CI) 56; 148%] produced a mean concentration of 9.6 microg/g (95% CI 7.4; 11.8 microg/g) greater than those predicted to be effective against methicillin-resistant staphylococci [minimum concentration that inhibits 90% of organisms (MIC(90)) of 4 mg/L]. Tissue/plasma ratios correlated positive with systemic inflammation.


CONCLUSIONS
Plasma pharmacokinetics of linezolid in diabetics and adequate levels in inflamed areas of diabetic foot wound suggest that an oral dose of 600 mg bd of linezolid provides effective concentrations for treating methicillin-resistant Staphylococcus aureus (MRSA) in DFI.
Majcher-Peszynska
J
J
Center of Pharmacology and Toxicology, Institute of Clinical Pharmacology, University of Rostock, Schillingallee 70, 18057 Rostock, Germany. jolanta.majcher-peszynska@medizin.uni-rostock.de
Haase
G
G
Sass
M
M
Mundkowski
R
R
Pietsch
A
A
Klammt
S
S
Schareck
W
W
Drewelow
B
B
D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics*; D000368:Aged; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D017719:Diabetic Foot / Q000150:complications*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D000069349:Linezolid; D008297:Male; D016106:Methicillin Resistance; D008875:Middle Aged; D023303:Oxazolidinones / Q000009:adverse effects / Q000493:pharmacokinetics*; D010539:Permeability; D018461:Soft Tissue Infections / Q000188:drug therapy* / Q000378:metabolism; D013207:Staphylococcal Skin Infections / Q000188:drug therapy* / Q000378:metabolism
D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid