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Antimicrobial Agents and Chemotherapy, August 2009, p. 3294-3301, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.00144-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Identifying Exposure Targets for Treatment of Staphylococcal Pneumonia with Ceftobiprole
Keith A. Rodvold,1
David P. Nicolau,2
Thomas P. Lodise,3
Mohammed Khashab,4
Gary J. Noel,5
James B. Kahn,3
Mark Gotfried,6,7
Sara A. Murray,6,7
Susan Nicholson,4
Somvadee Laohavaleeson,2
Pamela R. Tessier,2 and
G. L. Drusano3*
College of Pharmacy, University of Illinois, Chicago, Illinois,1 Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut,2 Ordway Research Institute, Albany, New York,3 Ortho-McNeil Janssen Scientific Affairs,4 Johnson & Johnson PRD, Raritan, New Jersey,5 University of Arizona School of Medicine,6 Pulmonary Associates, Phoenix, Arizona7
Received 30 January 2009/ Returned for modification 5 May 2009/ Accepted 12 May 2009
Ceftobiprole is a cephalosporin with potent activity against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). In order to treat patients with severe staphylococcal pneumonia, it is important to understand the drug exposure required to mediate the killing of multiple log10 cells in a preclinical-infection model. We measured drug exposure in terms of the percentage of penetration of the drug into epithelial lining fluid (ELF) and in terms of the time for which the drug concentration was above the MIC (time>MIC) in plasma and ELF. In a murine model of staphylococcal pneumonia, we demonstrated that ceftobiprole penetrated into ELF from the plasma at a median level of nearly 69% (25th to 75th percentile range, 25 to 187%), as indexed to the ratio of values for the area under the concentration-time curve in ELF and plasma. The total-drug times>MIC in ELF that were required to kill 1 log10 and 2 log10 CFU/g of lung tissue were 15% and 25% of the dosing interval. We also examined the penetration of ELF by ceftobiprole in volunteers, demonstrating mean and median penetration percentages of 25.5% and 15.3%, respectively (25th to 75th percentile range, 8 to 30%). Attainment rates were calculated for kill targets of 1 log10 and 2 log10 CFU/g, taken from the murine model, but using the volunteer ceftobiprole ELF penetration data. The standard dose for ceftobiprole is 0.5 g every 8 h as a 2-h infusion. The attainment rates remained above 90% for 1-log10 and 2-log10 CFU/g kill targets at MICs of 1 and 0.5 mg/liter, respectively. Taking the expectation over the distribution of ceftobiprole MICs for 4,958 MRSA isolates showed an overall target attainment of 85.6% for a 1-log10 CFU/g kill and 79.7% for a 2-log10 CFU/g kill. It is important to derive exposure targets in preclinical-infection models of the infection site so that these targets can be explored in clinical trials in order to optimize the probability of a good clinical outcome.
* Corresponding author. Mailing address: Ordway Research Institute, 150 New Scotland Ave., Albany, NY 12208. Phone: (518) 641-6410. Fax: (518) 641-6304. E-mail: gdrusano{at}ordwayresearch.org
Published ahead of print on 18 May 2009.
Antimicrobial Agents and Chemotherapy, August 2009, p. 3294-3301, Vol. 53, No. 8
0066-4804/09/$08.00+0 doi:10.1128/AAC.00144-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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