Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis.
OBJECTIVE
Ertapenem is FDA approved for the treatment of skin and skin-structure infections (SSSI), but its in vivo penetration into the interstitial space of soft tissues is unknown. The present microdialysis study was conducted to measure free, protein-unbound ertapenem concentrations in muscle and subcutaneous tissue.


METHODS
In a single-centre, prospective, open-label study six healthy volunteers (three females, 22-37 years) were treated with 1 g ertapenem given as a single intravenous dose. Microdialysis and plasma samples were collected before and at different time points up to 12 h after medication. Drug concentrations were determined by a validated LC-MS-MS method.


RESULTS
No serious or microdialysis-associated adverse events were observed. Ertapenem concentrations in plasma reached a maximum (C(max)) of 103.3 +/- 26.3 mg/L, a terminal elimination half-life (t(1/2)) of 3.8 +/- 0.6 h and an AUC(0-infinity) of 359.7 +/- 66.5 mg.h/L. Mean peak concentrations of free, protein-unbound ertapenem in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were much lower (C(max) = 6.7 +/- 4.1 and 4.0 +/- 1.6 mg/L, respectively). This degree of tissue distribution is consistent with high concentration-dependent plasma protein binding of ertapenem (84-96%). AUC(0-infinity) values for both muscle and adipose tissue were lower as well (39.7 +/- 24.8 and 18.6 +/- 4.6 mg.h/L). However, unbound interstitial fluid concentrations exceeded MIC(90) values for the important SSSI pathogens for 7 (subcutis) and 10 h (muscle) after dosing.


CONCLUSIONS
These results support the previously observed clinical efficacy of ertapenem in the treatment of SSSI.
Burkhardt
Olaf
O
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Brunner
Martin
M
Schmidt
Stephan
S
Grant
Maria
M
Tang
Yufei
Y
Derendorf
Hartmut
H
D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077727:Ertapenem; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis; D018482:Muscle, Skeletal / Q000378:metabolism*; D011446:Prospective Studies; D017192:Skin Diseases, Bacterial / Q000188:drug therapy / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism*; D014018:Tissue Distribution; D047090:beta-Lactams / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D000077727:Ertapenem