title: Antistaphylococcal activity of the novel cephalosporin CB-181963 (CAB-175).
abstract: OBJECTIVE
  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.
authors.affiliation: Antimicrobial Research Centre and School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Miller
authors.forename: Christopher
authors.initials: C
authors.lastname: Storey
authors.forename: William J
authors.initials: WJ
authors.lastname: Stubbings
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Hoyle
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Hobbs
authors.forename: Ian
authors.initials: I
authors.lastname: Chopra
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000502:physiology; D018441:Biofilms / Q000187:drug effects; D002352:Carrier Proteins / Q000502:physiology; D002511:Cephalosporins / Q000378:metabolism / Q000494:pharmacology*; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C489158:CB 181963; D002352:Carrier Proteins; D002511:Cephalosporins; D046915:Penicillin-Binding Proteins