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Antimicrobial Agents and Chemotherapy, July 2009, p. 2773-2776, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01409-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Soft-Tissue Penetration of Ceftobiprole in Healthy Volunteers Determined by In Vivo Microdialysis{triangledown}

April Barbour,1 Stephan Schmidt,1 Sreedharan Nair Sabarinath,1 Maria Grant,2 Christoph Seubert,3 Donna Skee,4 Bindu Murthy,4 and Hartmut Derendorf1*

Department of Pharmaceutics, University of Florida, 1600 Southwest Archer Road, Room P3-20, P.O. Box 100494, Gainesville, Florida 32610,1 Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32610-0267,2 Department of Anesthesiology, University of Florida, Gainesville, Florida 32610-0254,3 Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey4

Received 21 October 2008/ Returned for modification 5 February 2009/ Accepted 8 April 2009

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 (fAUCmuscle/fAUCplasma of 0.69 ± 0.13) and s.c. adipose tissue (fAUCs.c.adipose/fAUCplasma 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.

* Corresponding author. Mailing address: Department of Pharmaceutics, University of Florida, 1600 SW Archer Rd., Room P3-20, P.O. Box 100494, Gainesville, FL 32610. Phone: (352) 273-7856. Fax: (352) 273-7854. E-mail: hartmut{at}cop.ufl.edu

{triangledown} Published ahead of print on 13 April 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2773-2776, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01409-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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