title: In vitro pharmacodynamics of novel rifamycin ABI-0043 against Staphylococcus aureus.
abstract: OBJECTIVE
  ABI-0043 is a novel benzoxazinorifamycin derivative, which derives its potent bactericidal activity by the specific inhibition of bacterial RNA polymerase. We evaluated the in vitro pharmacodynamics and bactericidal activity of ABI-0043 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA).
  
  
  METHODS
  Using time-kill studies at a wide range of concentrations of ABI-0043, we evaluated the killing activity against four clinical isolates of S. aureus over 24 h. An integrated pharmacokinetic/pharmacodynamic area measure was applied to all cfu data and was fitted to a Hill-type mathematical model to evaluate pharmacodynamics.
  
  
  RESULTS
  Bacterial killing for ABI-0043 occurred rapidly and in a concentration-dependent manner. Bactericidal activity was achieved within 4 h at > or =16 x MIC against all isolates. Bacterial reductions were greatest at > or =64 x MIC against MRSA and MSSA isolates, as a >4 log(10) cfu/mL reduction was observed as early as 2 h, and sustained throughout 24 h. The pharmacodynamics of ABI-0043 was well described by a Hill-type model, with a steep sigmoidicity constant and a low EC(50) against all isolates.
  
  
  CONCLUSIONS
  ABI-0043 displayed rapid and sustained bactericidal activity against S. aureus clinical isolates. ABI-0043 represents a promising antistaphylococcal agent to combat serious S. aureus infections. Further, pharmacokinetic, pharmacodynamic and in vivo studies are warranted to determine its ultimate place in antibacterial therapy.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences and The New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, NY 14260, USA. btsuji@buffalo.edu
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Yang
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Kelchlin
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016106:Methicillin Resistance; D050296:Microbial Viability; D012294:Rifamycins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013997:Time Factors
chemical_list: C518212:ABI 0043; D000900:Anti-Bacterial Agents; D012294:Rifamycins