Absorption, distribution and excretion of Cefmenoxime (SCE-1365), a novel broad-spectrum cephalosporin, in mice, rats, rabbits and dogs.

The activity of cefmenoxime (SCE-1365), 7,8-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid, was compared with that of other cephalosporins. Cefinenoxime exhibited high activity against a wide variety of gram-positive and gramnegative bacteria. The in vitro activity of cefmenoxime against Streptococcus pyogenes, Haemophilus influenzae, and Enterobacteriaceae, including indolepositive Proteus, Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii, was 10 to 1,000 times greater than that of several other cephalosporins. Against Pseudomonas aeruginosa, cefmenoxime showed activity two to four times that of sulbenicillin and carbenicillin but less than that of cefsulodin. Variation in pH, addition of horse serum, and type of growth medium had definite effects on the activity of cefmenoxime, and the inoculum size affected the activity against bacterial species. In Escherichia coli cefmenoxime showed marked affinity for penicillin-binding protein 3 (PBP-3), followed by PBP-1 (1A and 1B). This affinity profile was well correlated with its filamentous cell-forming activity under extremely low drug concentrations and with its bactericidal activity against microorganisms. The high in vitro activity of cefmenoxime was reflected in the degree of protection observed in mice infected intraperitoneally with a wide variety of gram-positive and gram-negative bacteria. Furthermore, cefmenoxime showed good therapeutic activity against infection models in mice such as respiratory tract infection caused by Klebsiellapneumoniae and urinary tract infection caused by Proteus mirabilis.In recent years, with the increasing use of cephalosporins, an increasing number of infections caused by cephalosporin-resistant bacteria have been observed. The present report concerns the activity of cefmenoxime (SCE-1365),

Section: Resultsmentioning

confidence: 91%

Cefmenoxime (SCE-1365), a novel broad-spectrum cephalosporin: in vitro and in vivo antibacterial activities

Tsuchiya¹,

Kondo²,

Kida³

et al. 1981

“…Cefmenoxime, a new cephalosporin, differs from cefotaxime by having a methyltetrazolthio group in the 3 position instead of an acetoxymethyl group (11). Like cefotaxime, cefmenoxime displays a broad spectrum of activity against both gram-positive and gram-negative bacteria in vitro (3, 8, 10, ime has greater activity than cefotaxime in mice infected with various species of the family Enterobacteriaceae (12).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of cefmenoxime in experimental Escherichia coli bacteremia and meningitis

Kim¹

1985

Cefmenoxime, a new semisynthetic cephalosporin structurally similar to cefotaxime, was evaluated for its activities in vitro and in vivo against a Kl Escherichia coli strain in comparison with activities of cefotaxime and ampicillin. In vitro the MICs and MBCs of both cefmenoxime and cefotaxime were the same, 1/16th and 1/32nd those of ampicillin, respectively. The efficacies of cefmenoxime and cefotaxime against experimentally induced E. coli bacteremia and meningitis in newborn rats were similar and significantly better than that of ampicillin as judged by bactericidal titers of blood and cerebrospinal fluid, rapidity of clearance of bacteria from blood and cerebrospinal fluid, and incidence of meningitis in animals with bacteremias. The efficacy of cefmenoxime or cefotaxime measured by impact on mortality was influenced by the size of bacterial populations. The mortality was significantly greater in rats with bacterial counts before therapy of .106 CFU/ml of blood than in animals with lower counts. Overall, the in vivo efficacy of cefmenoxime was similar to that of cefotaxime; thus it could be useful in the therapy of neonatal E. coli infection.It has been shown previously that experimental Escherichia coli bacteremia and meningitis induced in the newborn rat is suitable for evaluating in vivo efficacies of various antimicrobial agents, particular in terms of rates of bacterial clearance from blood and cerebrospinal fluid (CSF) and of mortality (4-6). In these studies, it has been shown the activity of armpicillin against E. coli Kl is limited (4, 5), but that of cefotaxime is excellent. Results of recent studies, however, have shown that the outcome of E. coli infections in this model treated with cefotaxime is not significantly better than that of a conventional therapeutic regimen, ampicillin-gentamicin (K. S. Kim, submitted for publication). Recently, Tsuchiya et al. (12) have shown that cefmenoxime, a new cephalosporin structurally similar to cefotaxime, has greater protective and therapeutic activities than cefotaxime against members of the family Enterobacteriaceae in mice despite their similar activities in vitro. The present study was therefore performed to examine the activity of cefmenoxime in vitro and in vivo against E. coli and to compare the results with those of cefotaxime and ampicillin. MATERIALS AND METHODSOrganisms. A serum-resistant E. coli Kl strain (C5) isolated from the CSF ofa newborn infant with meningitis was used in this study.In vitro studies. The MICs and MBCs were measured in Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) by a macrobroth dilution mpethQd (13). Antimicrobial agents tested were cefmenoxime hydrochloride (Abbott Laboratories, TAP Pharmaceuticals, North Chicago, Ill.), ampicillin trihydrate (Bristol Laboratories, Syracuse, N.Y.) and cefotaxime sodium (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.). All antibiotic solutions were serially twofold diluted from 16 to 0.03 ,ug/ml in Mueller-Hinton broth. Late logarithmic-phase cultures of strain C5 c...

“…Each subject was given a single 500-mg dose of cefmenoxime base, containing 48. 5 ,uCi of 14C, intramuscularly into the upper, outer quadrant of the buttock. The subjects were fasted for a minimum of 2 h before and after drug administration, and the activity of the subjects was limited during the first 2 h after dosing.…”

Section: Methodsmentioning

confidence: 99%

“…Radioactivity has also been found in the bile of rats and dogs after intravenous or intramuscular administration of [14C]cefmenoxime (4). Characterization of the radioactivity showed it to consist largely of unmetabo- (4)(5)(6).…”

Section: Plasmamentioning

confidence: 99%

See 1 more Smart Citation

Metabolism of [14C]Cefmenoxime in normal subjects after intramuscular administration

Machinist¹,

Bopp²,

Quinn³

1984

The metabolism of cefmenoxime (SCE-1365) was studied in four healthy male volunteers after intramuscular administration of a single 500-mg dose of the '4C-labeled drug. Plasma levels of total radioactivity and cefmenoxime peaked at 0.5 and 1.0 h, corresponding to 16.5 ,ug eq/ml and 15.8 ,ug/ml, respectively. Thereafter, parent drug levels declined rapidly, with a terminal elimination half-life of ca. 1.5 h. No significant differences were noted between total radioactivity and parent drug levels up to 2 h after drug administration. After 3 h, low but persistent levels of radioactivity were significantly greater than parent drug levels, indicating metabolism or degradation of cefmenoxime. The terminal elimination half-life of total radioactivity was estimated to be ca. 40 h. The radioactive plasma metabolite(s) remaining at the end of the 5-day study represented only 1% of the administered dose. Urinary excretion was the major route of elimination of cefmenoxime, accounting for ca. 86% of the dose in 12 h. Analysis of cefmenoxime in urine by total radioactivity, high-pressure liquid chromatography, and a microbiological assay showed that 80 to 92% of the excreted dose was parent drug. Radioactivity was also excreted into the feces via the bile and represented ca. 11% of the dose after 5 days. Although extensive degradation of cefmenoxime was found in fecal samples, it was proposed that this may be due to the metabolic activity of the intestinal flora rather than in vivo biotransformation in the liver. This study supports the concept that cefmenoxime undergoes minimal metabolism in humans and is excreted largely as unchanged drug.Studies on the metabolic fate of cefmenoxime have been conducted previously in mice, rats, rabbits, and dogs (4-6). The purpose of this investigation was to determine the metabolism of cefmenoxime in normal human subjects following intramuscular administration of a single dose of radiolabeled drug. MATERIALS AND METHODSDrug. Cefmenoxime (sodium salt) was synthesized with 14C in the 2-position of the thiazole ring (N. Hayashi, personal communication; Fig. 1). The material had a specific activity of 26 pCi/mg and was at least 97% radiochemically pure. The infrared and nuclear magnetic resonance spectra were consistent with the proposed structure. The dose solution was prepared by making appropriate dilutions of the radiolabeled drug with unlabeled cefmenoxime base. Under sterile conditions, the drug mixture was filtered, and fractions were transferred to individual vials. The contents of the vials were frozen and lyophilized.Drug administration. Four adult male volunteers (weight, 68 to 92 kg) participated in the study. On the day of dosing, each vial was reconstituted in sterile water for injection so that each milliliter of solution contained 250 mg of cefmenoxime base and 24.2 ,uCi of 14C. Each subject was given a single 500-mg dose of cefmenoxime base, containing 48.5 ,uCi of 14C, intramuscularly into the upper, outer quadrant of the buttock. The subjects were fasted for a minimum of 2 h...