JAC Advance Access originally published online on April 9, 2008
Journal of Antimicrobial Chemotherapy 2008 62(1):156-160; doi:10.1093/jac/dkn133
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Original research |
In vitro pharmacodynamics of novel rifamycin ABI-0043 against Staphylococcus aureus
1 Laboratory for Antimicrobial Pharmacodynamics, 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 2 Roswell Park Cancer Institute, Departments of Pharmacy and Medicine, Buffalo, NY 14263, USA
Received 27 November 2007; returned 20 December 2007; revised 15 February 2008; accepted 16 February 2008
* Correspondence address. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, NY, USA. Tel: +1-716-881-7543; Fax: +1-716-849-6890; E-mail: btsuji{at}buffalo.edu
Objectives: 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 
16x MIC against all isolates. Bacterial reductions were greatest at 64x MIC against MRSA and MSSA isolates, as a >4 log10 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 EC50 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.
Keywords: S. aureus , rifalazil , benzoxazinorifamycin
Present address. Roche Pharmaceuticals, Nutley, NJ, USA.