Document Detail

Identifying exposure targets for treatment of staphylococcal pneumonia with ceftobiprole.
MedLine Citation:
PMID:  19451287     Owner:  NLM     Status:  MEDLINE    
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 log(10) 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 log(10) and 2 log(10) 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 log(10) and 2 log(10) 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-log(10) and 2-log(10) 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-log(10) CFU/g kill and 79.7% for a 2-log(10) 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.
Keith A Rodvold; David P Nicolau; Thomas P Lodise; Mohammed Khashab; Gary J Noel; James B Kahn; Mark Gotfried; Sara A Murray; Susan Nicholson; Somvadee Laohavaleeson; Pamela R Tessier; G L Drusano
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Publication Detail:
Type:  Journal Article     Date:  2009-05-18
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  53     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-20     Completed Date:  2009-10-19     Revised Date:  2013-01-14    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3294-301     Citation Subset:  IM    
College of Pharmacy, University of Illinois, Chicago, Illinois, USA.
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MeSH Terms
Anti-Bacterial Agents / blood,  pharmacokinetics*,  therapeutic use*
Bronchoalveolar Lavage Fluid / chemistry
Cephalosporins / blood,  pharmacokinetics*,  therapeutic use*
Disease Models, Animal
Epithelium / metabolism
Monte Carlo Method
Pneumonia, Staphylococcal / drug therapy*
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Cephalosporins; 5T97333YZK/ceftobiprole

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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