title: 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 (PD(50)) (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 512 mg/kg. PD(50) values were 16, 128 and 32 mg/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 4.15log(10)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.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS)/Hospital Universitario Virgen del Rocío/Universidad de Sevilla/CSIC, Sevilla, Spain. rlopezrojas@hotmail.com
authors.forename: R
authors.initials: R
authors.lastname: López-Rojas
authors.forename: J
authors.initials: J
authors.lastname: Sánchez-Céspedes
authors.forename: F
authors.initials: F
authors.lastname: Docobo-Pérez
authors.forename: J
authors.initials: J
authors.lastname: Domínguez-Herrera
authors.forename: J
authors.initials: J
authors.lastname: Vila
authors.forename: J
authors.initials: J
authors.lastname: Pachón
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000302:isolation & purification; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001770:Blood Bactericidal Activity; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D007928:Lethal Dose 50; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C556897:UB 8902; D002939:Ciprofloxacin