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A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibacterial spectrum derived from both cephalosporin-like and quinolone-like activities, suggesting a dual mode of action. Studies to elucidate details of the mechanism of action have been inconclusive. Ciprofloxacin liberated as a consequence of bacterial enzyme-mediated reactions may contribute to the second mode of action, although some evidence indicates that the intact carbamate-linked bifunctional molecules may possess intrinsically both beta-lactam and quinolone activities.

Ro 24-4383 contains desacetylcefotaxime linked by a carbamate bond at the 3' position to ciprofloxacin. Ro 24-4383 was active against 99% of the 363 gram-positive and gram-negative aerobes tested in vitro, while the comparative agents cefotaxime and ciprofloxacin were active against 77 and 97%, respectively. The activities (ED50: mg/kg s.c.) of Ro 24-4383, cefotaxime and ciprofloxacin in systemic murine infections were: Escherichia coli 257, 1.4, less than 0.5, less than 0.2; Klebsiella pneumoniae A, 11, 30, 0.7; Enterobacter cloacae 5699, 3.2, 35, less than 0.2; Citrobacter freundii BS16, 3, 41, less than 0.5; Serratia marcescens SM, 35, greater than 100, 1.6; Pseudomonas aeruginosa 5712, 67, 100, 10; P. aeruginosa 8780, 33, 193, 3; Staphylococcus aureus Smith (oxacillin-susceptible), 12, 3.7, 1; S. aureus 753 (oxacillin-resistant), 28, greater than 100, 2; Streptococcus pneumoniae 6301, 10, 15, greater than 50, and S. pyogenes 4, 3.3, 1.6, 54. Ro 24-4383, although inactive against the S.-pneumoniae-induced pneumonia following one administration of the agent, was highly active (ED50 = 1.5) when three treatments were given following infection. Ro 24-4383 was active against the K.-pneumoniae-induced pneumonia (ED50 = 37), as well as the meningitis induced by S. pneumoniae (ED50 = 158) or K. pneumoniae (ED50 = 100). The protective effect of Ro 24-4383 was demonstrated when administered 8 h before infection with E. coli (ED50 = 37) and 4 h before infection with S. pyogenes (ED50 = 199).

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.

The in vitro activity of the dual-action antibacterial agent Ro 23-9424 was compared with those of cefotaxime, ceftazidime, ciprofloxacin, fleroxacin, imipenem, and amikacin against 358 aerobes and anaerobes. The MIC ranges, MICs for 50 and 90% of the strains (MIC50s and MIC90s), and percentage of strains susceptible for each agent at the recommended susceptible MIC breakpoint were determined for each genus. The MIC90s (micrograms per milliliter) of the agents against members of the family Enterobacteriaceae were as follows: ciprofloxacin, 0.063; Ro 23-9424, fleroxacin, and imipenem, 0.5; ceftazidime, 2; amikacin, 4; and cefotaxime, 16. The MIC90s (micrograms per milliliter) against Pseudomonas and Acinetobacter spp. were as follows: ciprofloxacin, 2; ceftazidime and imipenem, 8; Ro 23-9424, 16; fleroxacin, 32; amikacin, 64; and cefotaxime, 128. Against gram-positive bacteria, excluding the enterococci, the MIC90s (micrograms per milliliter) were as follows: ciprofloxacin, 1; imipenem, 4; Ro 23-9424 and fleroxacin, 8; amikacin, 64; and ceftazidime and cefotaxime, greater than 128. Against gram-positive bacteria, including the enterococci, the MIC90s changed only for the following agents: Ro 23-9424, 16 micrograms/ml; and amikacin, 128 micrograms/ml. Strains of Branhamella catarrhalis, Haemophilus influenzae, and Neisseria gonorrhoeae were 100% susceptible to Ro 23-9424, cefotaxime, ciprofloxacin, and fleroxacin, while the other three agents showed somewhat less activity only against N. gonorrhoeae. Against anaerobes, imipenem was the most effective agent, while the activities of the other six agents were variable.