cefmenoxime and cefbuperazone

In previous papers (Y. Ikeda and T. Nishino, Antimicrob. Agents Chemother. 32:1073-1077, 1988; Y. Ikeda, T. Nishino, and T. Tanino, Antimicrob. Agents Chemother. 31:865-869, 1987), we reported that many of the 7-aminothiazolyl cephalosporins, such as cefmenoxime, showed paradoxically reduced activity against Proteus vulgaris at higher concentrations, whereas these paradoxical effects were not observed for other types of cephalosporins, such as cefbuperazone and cefoperazone. In this study, we compare the therapeutic effect of cefmenoxime with that of cefbuperazone and explore the in vivo paradoxical effect of cefmenoxime by using an experimental infection model in mice. In an intraperitoneal infection with P. vulgaris 11, the survival rate with cefmenoxime was increased to 43% at 3.13 mg/kg but was lower at higher doses. On the other hand, cefbuperazone did not show such a paradoxical therapeutic effect. In mice infected with P. vulgaris 11, cefmenoxime levels in both serum and peritoneal washings were rapidly reduced and beta-lactamase activities in the peritoneal cavity were increased at higher cefmenoxime doses. These findings suggested that high levels of cefmenoxime at the infection site induced increased production of beta-lactamase, which then rapidly inactivated the antibiotic. We conclude that the paradoxical therapeutic effect of cefmenoxime against P. vulgaris occurs by the same mechanisms as the in vitro effect and that the high beta-lactamase inducibility and low beta-lactamase stability may account for the paradoxical therapeutic effect of cefmenoxime against P. vulgaris.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Cefmenoxime; Cephamycins; Male; Mice; Mice, Inbred ICR; Proteus Infections; Proteus vulgaris

The growth-inhibitory effect of cefmenoxime against Proteus vulgaris was studied by using the broth dilution and paper disk diffusion methods. Cefmenoxime showed growth-inhibitory activity against Proteus vulgaris at low concentrations but not at high concentrations up to a certain limit. This paradoxical antibacterial activity was not observed with cefoperazone and cefbuperazone. The induction of beta-lactamase by cefmenoxime and the rate of hydrolysis of cefmenoxime in the culture broth were proportional to the initial concentration of this antibiotic. At high initial concentrations, cefmenoxime was rapidly inactivated. On the other hand, neither cefoperazone nor cefbuperazone was inactivated irrespective of concentration. We conclude that cefmenoxime induces beta-lactamase in P. vulgaris, perhaps accounting for its paradoxical antibacterial effect.

Topics: beta-Lactamases; Cefmenoxime; Cefoperazone; Cefotaxime; Cephamycins; Drug Resistance, Microbial; Enzyme Induction; Microbial Sensitivity Tests; Proteus vulgaris