Pre-clinical studies of a new quinolone (UB-8902) against Acinetobacter baumannii resistant to ciprofloxacin

Abstract: The in vitro activity and in vivo efficacy of a new ciprofloxacin derivative (UB-8902) were evaluated. In vitro time–kill curves were performed for ciprofloxacin (CIP), moxifloxacin (MXF) and UB-8902 against CIP-susceptible (Ab58) and CIP-resistant (Ab661 and Ab33) Acinetobacter baumannii strains. UB-8902 showed similar bactericidal activity to CIP and MXF against these strains. In the in vivo experiments in mice, the toxicity of UB-8902, its 50% protective dose (PD50) (peritoneal sepsis model), its pharmacokinetic/pharmacodynamic (PK/PD) parameters and its efficacy in a pneumonia model were studied. The maximum tolerated dose of UB-8902 was 512mg/kg. PD50 values were 16, 128 and 32mg/kg for Ab58, Ab661 and Ab33, respectively. Pharmacokinetic parameters of UB-8902 were similar to MXF and were lower than those for CIP, whilst pharmacodynamic parameters were better than CIP. In the pneumonia model, UB-8902 decreased the bacterial lung concentration [4.62 colony-forming units (CFU)/g and 4.15log10 CFU/g] and positive blood cultures (60% and 62.5%) for Ab58 and Ab33, respectively, compared with the control. In conclusion, UB-8902 presents bactericidal activity against A. baumannii strains resistant to CIP. Moreover, it is effective at reducing mortality in a model of peritoneal sepsis with a dose lower than the toxic one, and it is efficacious in a murine pneumonia model. [Copyright &y& Elsevier]