In vitro pharmacodynamics of novel rifamycin ABI-0043 against Staphylococcus aureus

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 ≥16× MIC against all isolates. Bacterial reductions were greatest at ≥64× 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.