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INFECTIOUS DISEASES

Pharmacokinetics and Pharmacodynamics of Linezolid in Obese Patients with Cellulitis

Professor of Medicine and Pharmacology, Michigan State University, East Lansing, MI

Sharon L Schooley, BS

Senior Research Associate, Michigan State University

Charles A Peloquin, PharmD

Director, Infectious Disease Pharmacokinetic Laboratory, National Jewish Medical and Research Center, Denver, CO

Vivek Kak, MD

Assistant Professor of Medicine, Michigan State University

Daniel H Havlichek, MD

Associate Professor of Medicine and Microbiology, Michigan State University

Diane M Citron, BS

Associate Director, RM Alden Research Laboratory, Santa Monica, CA

Kerin L Tyrrell, BS

Microbiologist, RM Alden Research Laboratory

Ellie JC Goldstein, MD

Director, RM Alden Research Laboratory

Reprints: Dr. Stein, Department of Medicine, Michigan State University, B320 Life Sciences Bldg., East Lansing, MI 48824-1317, fax 517/353-1922, steing{at}msu.edu

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 µg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 µg/mL), Bacteroides fragilis (MIC 2.0 µg/mL), and Peptostreptococcus magnus (MIC 1.0 µg/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 µg/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 µg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 µg/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 4.0 µg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.

Key Words: linezolid, obesity, pharmacodynamics, pharmacokinetics

Published Online, February 8, 2005. www.theannals.com, DOI 10.1345/aph.1E484

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