Paradoxical antibacterial activity of cefmenoxime against Proteus vulgaris

Abstract

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 I8-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 I8-lactamase in P. vulgaris, perhaps accounting for its paradoxical antibacterial effect.Cefmenoxime (CMX) is one of the new type of cephalosporins which have excellent antibacterial activity against gram-positive and gram-negative bacteria including Proteus vulgaris (10). However, like cefotaxime and cefotiam, CMX is comparatively unstable to 13-lactamase produced by P. vulgaris (10).In 1948, Eagle and Musselman (2) reported that the antibacterial activity of penicillin G against gram-positive cocci was paradoxically reduced as its concentration was increased. Similar phenomena against gram-positive cocci have been reported by others (9, 16). This effect is generally known as the "Eagle effect." Regarding gram-negative bacteria, a paradoxical effect of mecillinam against Providencia stuartii was reported in 1976 (4). However, the mechanism of this paradoxical effect has not been explained sufficiently.In studying the antibacterial activity of P-lactam antibiotics, we observed an interesting phenomenon in P. vulgaris: whereas growth was found in the presence of CMX at high concentrations, no growth occurred at low concentrations. This paper deals with the paradoxical effect of CMX on P.vulgaris.MATERIALS AND METHODS Antibiotics. CMX, prepared by Takeda Pharmaceutical Co., Ltd., Osaka, Japan, and cefoperazone (CPZ) and cefbuperazone (CBPZ), both prepared by Toyama Chemical Co., Ltd., Tokyo, Japan, were used as test antibiotics.Bacterial strains. The strains of P. vulgaris used in this study were all derived from clinical materials obtained in Japan.Paradoxical effect of drugs. (i) Broth dilution method. A series of tubes containing doubling dilutions of antibiotics in sensitivity broth (Eiken Chemical Co., Ltd., Tokyo, Japan) were inoculated with P. vulgaris at an inoculum size of 106 cells per ml. The tubes were incubated at 37°C for 18 h, and visible growth was observed.(ii) Paper disk method. Sensitivity disk agar (Eiken Chemical Co., Ltd.) molten at 45°C was inoculated with organisms * Corresponding author. Preparation of I8-lactamase. An overnight culture in brain heart infusion broth (Difco Laboratories, Detroit, Mich.) was diluted 10-fold with the same medium and incubated with shaking at 37°C for 2 h. Then 10 ,ug of cefmetazol per ml was added as ...

Paradoxical activity of beta-lactam antibiotics against Proteus vulgaris in experimental infection in mice

“…However, several exceptions to this trend have been reported (3,9,13). In previous papers (4,5), we reported that some 7-aminothiazolyl-type cephalosporins showed paradoxically reduced activities against Proteus vulgaris when they were present at high concentrations. Indeed, it has been difficult to demonstrate such paradoxical antibacterial activity clinically, but it appears that the in vivo paradoxical effect can be confirmed by using an experimental infection model.…”

Paradoxical antibacterial activities of beta-lactams against Proteus vulgaris: mechanism of the paradoxical effect

“…P. vulgaris 11, a strain that has been described previously (4), and P. vulgaris 11-S, a P-lactamase-noninducing mutant of P. vulgaris 11, were used in this study. P. vulgaris 11-S was derived by mutagenesis with selection, based on its susceptibility to cephaloridine and ampicillin.…”

“…The P-lactamase activity was determined by the modified microiodometric method of Novick (8) for piperacillin or the spectrophotometric method (12) Induction activity for the ,-lactamase. The P-lactamaseinducing activity was determined by a previously described method (4). An overnight culture of P. vulgaris in sensitivity broth was diluted 20-fold with the same medium and incubated with shaking at 37°C for 2 h. Then, various concentrations of antibiotics were added as the ,-lactamase inducers.…”

“…The broth dilution method was used for susceptibility testing (4 Preparation of j8-lactamase. ,-Lactamase was prepared by a previously described method (4).…”

“…The broth dilution method was used for susceptibility testing (4 Preparation of j8-lactamase. ,-Lactamase was prepared by a previously described method (4). A final concentration at 10 ,ug of cefmetazole per ml was added into the logarithmicphase culture of P. vulgaris as a 1-lactamase inducer.…”