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

AbstractOBJECTIVES:
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 (3)H-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.
AuthorsKeith Miller, Christopher Storey, William J Stubbings, Anthony M Hoyle, Joanne K Hobbs, Ian Chopra
JournalThe Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 55 Issue 4 Pg. 579-82 (Apr 2005) ISSN: 0305-7453 [Print] England
PMID15722396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • CB 181963
  • Carrier Proteins
  • Cephalosporins
  • Penicillin-Binding Proteins
Topics
  • Anti-Bacterial Agents (metabolism, pharmacology)
  • Bacterial Proteins (physiology)
  • Biofilms (drug effects)
  • Carrier Proteins (physiology)
  • Cephalosporins (metabolism, pharmacology)
  • Methicillin Resistance
  • Microbial Sensitivity Tests
  • Penicillin-Binding Proteins (metabolism)
  • Protein Binding (physiology)
  • Staphylococcus aureus (drug effects, metabolism)

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