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JAC Advance Access originally published online on February 18, 2005
Journal of Antimicrobial Chemotherapy 2005 55(4):579-582; doi:10.1093/jac/dki003
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

Antistaphylococcal activity of the novel cephalosporin CB-181963 (CAB-175)

Keith Miller, Christopher Storey{dagger}, William J. Stubbings, Anthony M. Hoyle, Joanne K. Hobbs and Ian Chopra*

Antimicrobial Research Centre and School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, UK

* Corresponding author. Tel: +44-113-343-5604; Fax: +44-113-343-3167; Email: i.chopra{at}leeds.ac.uk

Objectives: We examined the antistaphylococcal activity of the novel cephalosporin CB-181963 (formerly known as CAB-175), with emphasis on its microbiological activity and penicillin-binding protein specificities.

Methods: Using established procedures, we examined the activity of CB-181963 against methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains of Staphylococcus aureus in both planktonic and biofilm culture. We also determined whether CB-181963 exhibited a post-antibiotic effect (PAE). A radioactive competition assay with 3H-labelled benzylpenicillin was used to determine penicillin-binding protein (PBP) affinities of CB-181963, including binding to PBP2a from MRSA. The potential for emergence of CB-181963-resistant mutants in MSSA and MRSA strains was examined using plating procedures.

Results: CB-181963 showed excellent activity against MRSA strains resistant to other cephalosporins in both planktonic and biofilm cultures. However, in common with other cephalosporins it was unable to eradicate biofilms. CB-181963 had a short PAE compared with other ß-lactam antibiotics. CB-181963 retained activity against a strain expressing type A ß-lactamase and demonstrated affinity for PBP2a of MRSA. Mutants resistant to CB-181963 were not recovered in either MSSA or MRSA.

Conclusions: CB-181963 is a potent antistaphylococcal agent with better activity against MRSA than other cephalosporins. The anti-MRSA activity is correlated with elevated binding to PBP2a. CB-181963 may have a role in the treatment of staphylococcal infections, including those caused by MRSA and in the prophylaxis of biofilm-associated MSSA and MRSA infections. However, because of its short PAE, CB-181963 may have to be administered more frequently than other ß-lactam antibiotics, or given via prolonged infusion.

Keywords: methicillin-resistant Staphylococcus aureus , penicillin-binding proteins


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