Soft-tissue penetration of ceftobiprole in healthy volunteers determined by in vivo microdialysis.
Ceftobiprole is a promising new broad-spectrum cephalosporin with activity against several multidrug-resistant gram-positive and gram-negative species, including methicillin-resistant Staphylococcus aureus. In order to make efficacy predications against these resistant bacteria in soft-tissue infections, i.e., skin and skin structure infections, ceftobiprole's ability to reach the site of action should be explored. Therefore, a microdialysis study was conducted in 12 healthy volunteers to determine the penetration of ceftobiprole into skeletal muscle and subcutaneous (s.c.) adipose tissue after a single intravenous dose of 500 mg. Plasma and tissue interstitial space fluid (ISF) drug concentrations were measured for 24 h from the start of the 2-h intravenous infusion. Pharmacokinetic parameters were determined using noncompartmental analysis. The penetration of ceftobiprole into the ISF of tissues was assessed by comparing the ratios between tissue and plasma of the free drug area under the concentration-time curve (fAUC). It was found that ceftobiprole distributes into the muscle (fAUC(muscle)/fAUC(plasma) of 0.69 +/- 0.13) and s.c. adipose tissue (fAUC(s.c.adipose)/fAUC(plasma) of 0.49 +/- 0.28). The concentrations in both skeletal muscle and s.c. adipose tissue met the efficacy breakpoint (percentage of the time that free drug concentrations remained above the MIC) for at least 40% of the 8-h dosing interval for organisms with a MIC of 2 mg/liter. Therefore, ceftobiprole qualifies as a potential agent with drug penetration capabilities to treat complicated skin and skin structure infections due to both gram-negative and gram-positive pathogens with MICs equal to or below 2 mg/liter.
Barbour
April
A
Department of Pharmaceutics, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Schmidt
Stephan
S
Sabarinath
Sreedharan Nair
SN
Grant
Maria
M
Seubert
Christoph
C
Skee
Donna
D
Murthy
Bindu
B
Derendorf
Hartmut
H
D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis; D018482:Muscle, Skeletal / Q000378:metabolism; D055815:Young Adult
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C443755:ceftobiprole