In vitro and in vivo 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, 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).
Beskid
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Department of Chemotherapy, Hoffmann-La Roche, Nutley, N.J.
Albrecht
H A
HA
Fallat
V
V
Keith
D D
DD
Lipschitz
E R
ER
McGarry
C M
CM
McGarry
D H
DH
Rossman
P
P
Siebelist
J
J
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000494:pharmacology; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D008581:Meningitis / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology
D000890:Anti-Infective Agents; C073906:Ro 24-4383; D002939:Ciprofloxacin; D002439:Cefotaxime