ro-23-9424 and Bacterial-Infections

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.

Topics: Animals; Anti-Infective Agents; Bacterial Infections; Cefotaxime; Ciprofloxacin; Drug Evaluation, Preclinical; Enterobacteriaceae; Fleroxacin; Fluoroquinolones; Klebsiella pneumoniae; Meningitis; Mice; Neutropenia; Penicillin Resistance; Pneumonia; Pseudomonas aeruginosa; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Time Factors

The in vitro activity of Ro 23-9424, which is desacetyl-cefotaxime linked to fleroxacin, was compared with the activities of cefotaxime, desacetyl-cefotaxime, fleroxacin, ofloxacin, and ciprofloxacin. It inhibited the majority of members of the family Enterobacteriaceae, except for some Serratia marcescens, Citrobacter freundii, and Enterobacter cloacae strains, at less than or equal to 0.25 microgram/ml and had an MIC for 90% of strains tested (MIC90) of 8 micrograms/ml against Pseudomonas aeruginosa. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited at less than or equal to 0.25 microgram/ml. Ninety percent of the staphylococci were inhibited at less than or equal to 4 micrograms/ml, except for some methicillin-resistant Staphylococcus aureus isolates. The MIC90S of Ro 23-9424 for Enterococcus faecalis and Listeria monocytogenes were greater than or equal to 16 micrograms/ml. Ninety percent of Clostridium perfringens isolates were inhibited by less than or equal to 2 micrograms/ml, whereas Bacteroides fragilis had an MIC90 of 32 micrograms/ml. There was a minimal inoculum size effect. The MICs and MBCs were either identical or within a twofold dilution. The MICs of Ro 23-9424 for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Staphylococcus aureus increased 16- to 128-fold after 2 weeks of transfer in the presence of Ro 23-9424, showing that the presence of two agents does not prevent resistance.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Bacterial Infections; Cefotaxime; Ciprofloxacin; Drug Resistance, Microbial; Fleroxacin; Fluoroquinolones; Humans; Microbial Sensitivity Tests