No abstract

Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biological properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decomposition product, desacetyl cefotaxime, Ro 23-9424 bound at c2 ,ug/ml to the essential penicillin-binding proteins lb and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureus. In E. coli, Keith, 28th ICAAC, abstr. no. 448, 1988

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 4). 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. Ro 23-9424 is a new dual-action agent in which a cephalosporin moiety with the same 7-acylamino substituent as ceftriaxone and cefotaxime is linked by an ester bond to the quinolone fleroxacin at the 3'-methyl position. This dual action antibacterial agent is one of a series of cephalosporins with quinolones esterified at the 3' position (H.

Ro 23-9424 is a dual-action cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position. The new compound has broad and potent antibacterial activity in vitro and in vivo, reflecting contributions from both the , (-lactam Ro 23-9424 is a cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position (1). Ro 23-9424 has broad and potent antibacterial activity in vitro (2, 9, 12) and in vivo (3). The antibacterial spectrum reflects contributions of both the cephalosporin moiety (notably, streptococci) and the quinolone moiety (notably, ,-lactamase-overproducing strains). Ro 23-9424 binds to penicillin-binding proteins and inhibits replicative DNA biosynthesis (8). These observations have led to the use of the term "dual-action cephalosporins" for Ro 23-9424 and analogous compounds (1,8).It was originally proposed by O'Callaghan et al. (15) that the second "warhead" of such a cephalosporin, in this case, the fleroxacin moiety of Ro 23-9424, is released when the ,-lactam ring is opened by a bacterial enzyme, such as a P-lactamase. In the case of Ro 23-9424, active quinolone may also be released by enzymatic or nonenzymatic hydrolysis of the ester linkage. It is well known that 3'-acetoxy cephalosporins, such as cephalothin, cephapirin, and cefotaxime, are deesterified in vivo to form 3-hydroxymethylcephalosporins (4, 5, 19). These metabolites have antibacterial activity, but they are less potent than the acetylated cephalosporins. Hydrolysis of the ester bond of Ro 23-9424 presumably results in the formation of fleroxacin and the 3-hydroxymethylcephalosporin desacetylcefotaxime, both of which have antibacterial activity. The extent to which Ro 23-9424 exerts the proposed mechanism of action in vivo (wherein the quinolone is released by a bacterial process), or acts as a combination of active metabolites, is therefore determined by its pharmacokinetic properties. This study *