title: In vivo evaluation of a dual-action antibacterial, Ro 23-9424, compared to cefotaxime and fleroxacin.
abstract: The dual-action antibacterial R 23-9424 (desacetylcefotaxime linked to the quinolone fleroxacin) is a new antibacterial agent with excellent in vitro activity. It was evaluated for in vivo efficacy in comparison with the cephalosporin cefotaxime and the quinolone component, fleroxacin. Ro 23-9424 demonstrated significant activity against all strains tested in systemic infections, including those strains resistant in vivo to cefotaxime (Staphylococcus aureus 753, Serratia marcescens SM and Pseudomonas aeruginosa 8780) and fleroxacin (Streptococcus pneumoniae 6301 and Streptococcus pyogenes. In prophylactic studies, Ro 23-9424 compared favorably with fleroxacin against Escherichia coli and with cefotaxime against S. pyogenes, but Ro 23-9424 was considerably more active than cefotaxime against E. coli and more active than fleroxacin against S. pyogenes. In a murine pneumonia model, Ro 23-9424 was equivalent in activity to cefotaxime against S. pneumoniae and more active than cefotaxime against Klebsiella pneumoniae. Fleroxacin was inactive against S. pneumoniae and about 20-fold more active than Ro 23-9424 against K. pneumoniae. In a murine meningitis infection caused by S. pneumoniae, Ro 23-9424 was 3 times as active as cefotaxime, while fleroxacin was inactive. When meningitis was induced by K. pneumoniae, Ro 23-9424 was as active as the quinolone, while cefotaxime was inactive. In a neutropenic (immunocompromised) model, Ro 23-9424 was more active than cefotaxime against P. aeruginosa and 5-fold less active than fleroxacin. In the control normal (immunocompetent) mouse infection, Ro 23-9424 was 3-fold more active than cefotaxime, but 10-fold less active than fleroxacin.
authors.affiliation: Department of Pharmacology and Chemotherapy, Hoffmann-La Roche Inc., Nutley, N.J.
authors.forename: G
authors.initials: G
authors.lastname: Beskid
authors.forename: J
authors.initials: J
authors.lastname: Siebelist
authors.forename: C M
authors.initials: CM
authors.lastname: McGarry
authors.forename: R
authors.initials: R
authors.lastname: Cleeland
authors.forename: K
authors.initials: K
authors.lastname: Chan
authors.forename: D D
authors.initials: DD
authors.lastname: Keith
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy*; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004755:Enterobacteriaceae; D016576:Fleroxacin / Q000031:analogs & derivatives; D024841:Fluoroquinolones; D007711:Klebsiella pneumoniae; D008581:Meningitis / Q000188:drug therapy; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced; D010403:Penicillin Resistance; D011014:Pneumonia / Q000188:drug therapy; D011550:Pseudomonas aeruginosa; D013211:Staphylococcus aureus; D013296:Streptococcus pneumoniae; D013297:Streptococcus pyogenes; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C060441:Ro-23-9424; D002939:Ciprofloxacin; D002439:Cefotaxime; D016576:Fleroxacin