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JAC Advance Access published online on February 18, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki003
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JAC © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved
Received October 14, 2004
Revised December 6, 2004
Accepted December 6, 2004

Original article

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

Keith Miller 1, Christopher Storey 1, William J. Stubbings 1, Anthony M. Hoyle 1, Joanne K. Hobbs 1, and Ian Chopra 1*

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

* To whom correspondence should be addressed.
Ian Chopra, E-mail: i.chopra{at}leeds.ac.uk


  Abstract

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 {beta}-lactam antibiotics. CB-181963 retained activity against a strain expressing type A {beta}-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 {beta}-lactam antibiotics, or given via prolonged infusion.

Keywords: methicillin-resistant Staphylococcus aureus; penicillin-binding proteins.
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