Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis.
BACKGROUND
Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens.


OBJECTIVE
To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients.


METHODS
We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 microg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 microg/mL), Bacteroides fragilis (MIC 2.0 microg/mL), and Peptostreptococcus magnus (MIC 1.0 microg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated.


RESULTS
Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 microg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 microg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (> or =6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 microg/mL) as well as the strain of VRE and P. magnus.


CONCLUSIONS
Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC > or =4.0 microg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.
Stein
Gary E
GE
Department of Medicine, Michigan State University, B320 Life Sciences Building, East Lansing, MI 48824-1317, USA. steing@msu.edu
Schooley
Sharon L
SL
Peloquin
Charles A
CA
Kak
Vivek
V
Havlichek
Daniel H
DH
Citron
Diane M
DM
Tyrrell
Kerin L
KL
Goldstein
Ellie J C
EJ
D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002481:Cellulitis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006207:Half-Life; D006801:Humans; D000069349:Linezolid; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009765:Obesity / Q000150:complications*; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D015610:Serum Bactericidal Test; D017192:Skin Diseases, Bacterial / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D018461:Soft Tissue Infections / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid