INVITRO AND INVIVO ACTIVITY OF CARBAMATE-LINKED DUAL-ACTION ANTIBACTERIAL RO-24-4383

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, < 0.5, < 0.2; Klebsiella pneumoniae A, 11, 30, 0.7; Enterobacter cloacae 5699, 3.2, 35, < 0.2; Citrobacter freundii BS16, 3, 41, < 0.5; Serratia marcescens SM, 35, > 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, > 100, 2; Streptococcus pneumoniae 6301, 10, 15, > 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).