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Cephradine, the first generation cephalosporin, is active against a wide range of Gram-positive and Gram-negative bacteria including penicillinase-producing Staphylococci. Since the presence of complexing ligand may affect the bioavailability of a metal in the blood or tissues, therefore, in order to study the probable interaction of cephradine with essential and trace elements present in human body, cephradine has been reacted with cobalt, copper, zinc and cadmium metal halides in L:M ratio of 2:1 in methanol and the products recrystallized from suitable solvents to pure crystals of consistent melting points. Infrared and ultraviolet studies of these complexes were carried out and compared with ligand. Magnetic susceptibility studies of these complexes were also carried out showing their paramagnetic behavior. From the infra red studies and elemental analysis of the complexes, it has been shown that the drug molecule serves as a bidentate ligand coordinating through both its carboxylate at C-3 and beta-lactam nitrogen and the metal having a square planar or octahedral geometry. To evaluate the changes in microbiological activity of cephradine after complexation, antibacterial studies were carried out by observing the changes in MIC (minimum inhibitory concentration) of the complexes and compared with the parent drug by measuring the zone of inhibition of complexes and compared with the parent cephalosporin against both Gram-positive and Gram-negative organisms. For MIC observation, serial dilution method was employed and zone series were determined by disk diffusion method. Our investigations reveal that formation of complexes results in decrease in antibacterial activity of cephradine and MIC values are increased.

The inhibitory effects of five angiotensin-converting enzyme (ACE) inhibitors on the uptake of an aminocephalosporin antibiotic, cefroxadine, by rabbit small intestinal brush-border membrane vesicles were examined in the presence of an inward H+ gradient. Dixon plot analysis showed that all these ACE inhibitors inhibited the uptake of cefroxadine, which is transported by a H+/oligopeptide transporter in the membrane, in the order of enalapril

Effects of angiotensin-converting enzyme (ACE) inhibitors, captopril, enalapril maleate and quinapril, on the uptake of aminocephalosporin antibiotic, cefroxadine, by rabbit small intestinal brush border membrane vesicles were examined. These ACE inhibitors significantly inhibited the uptake of cefroxadine, which is transported by H+/dipeptide transporter in the membrane, in the order of captopril < enalapril < quinapril in the presence of an inward H+ gradient. Inhibitory effect of quinapril was more marked than that of aminocephalosporin cephradine, while in the absence of an inward H+ gradient inhibition by these ACE inhibitors was much less. Dixon plot analysis showed that the inhibition by enalapril and quinapril in the presence of an inward H+ gradient occurred in a competitive manner and estimated inhibition constants of these two drugs to be 5.3 mM and 0.46 mM, respectively. These results suggested the strong affinity of these ACE inhibitors, especially quinapril, on the H+/dipeptide transporter.

Characteristics of transport of an oral aminocephalosporin, cefroxadine, in rabbit small intestinal brush border membrane vesicles were examined. Uptake rate of cefroxadine was saturable in the presence of an inward H+ gradient, and kinetic parameters were similar to those of cephradine. However, the uptake rate was almost linear with the concentration in the absence of an inward H+ gradient up to 5 mM. Overshoot phenomenon was observed in the presence of an inward H+ gradient at 37 degrees C, but it disappeared with decrease of temperature. The Arrhenius plot of uptake rate constant showed a break point at approximately 30 degrees C. Cefroxadine uptake was optimum in the vicinity of pH 5.5 at 37 degrees C, but the dependence on extravesicular pH disappeared at 15 degrees C. The uptake of cefroxadine in the presence of an inward H+ gradient was markedly inhibited by other aminocephalosporins such as cephalexin, but the inhibition was only slight in the absence of an inward H+ gradient. Alkyl alcohols such as n-hexyl alcohol also inhibited H(+)-coupled uptake of cefroxadine at the concentration range at which the alcohols increased the membrane fluidity, and overshoot phenomenon diminished, suggesting that H(+)-coupled transport of cefroxadine is sensitive to the alcohol-induced increase in membrane fluidity. On the other hand, the alcohols rather stimulated its uptake in the absence of an H+ gradient.

The antibacterial effects of subminimal inhibitory concentrations (sub-MICs) of antibiotics were studied in two animal models. In mice, the oral cephalosporin CGP 9000 was effective in 11 of 20 different gram-negative infections and cephalexin was effective in one of these infections, both at 50% effective doses (ED(50)) that produced peak concentrations of drug in plasms equal to one-half to one-sixteenth the minimal inhibitory concentration (MIC) for the infecting organism. In gram-positive infections, both antibiotics were effective only at concentrations above the MIC. In rabbits, sub-MICs of cephaloridine, ampicillin, and gantamicin were maintained for 6-10 hr by intravenous infusion. At steady-state concentrations equal to one half to one-eighth the MIC, the beta-lactam antibiotics caused elongation and filamentation, and gentamicin caused enlargement, of Proteus mirabilis, Escherichia coli, and Salmonella typhimurium in peritoneal exudate; the number of viable cells of each of these bacteria was temporarily reduced. In infections with E. coli and P. mirabilis, sub-MIC's of beta-lactam antibiotics and of gentamicin prolonged the survival rates for infected animals beyond those for control animals. Rabbits infected with S. typhimurium and treated with ampicillin at a concentration of one-third the MIC Tended to die sooner than did control animals.

The pharmacokinetic parameters of cefroxadin and cephalexin were compared after simultaneous oral administration of the two cephalosporins to 21 subjects. The influence of the dose, the formulation, and food intake on these parameters was investigated. Both drugs were equally well absorbed from all of the tested formulations; identical percentages of the dose were recovered in the urine in all cases. The elimination half-life of cefroxadin and, consequently, the area under the plasma concentration-time curve were about 10% less than those of cephalexin. Plasma concentrations and cumulative excretion curves of the two drugs were almost superimposable. Food intake had the same effect on both drugs; absorption was slowed, but the amounts absorbed were almost the same as those in fasted subjects.

Cefroxadine (GCP-9000; CXD), 7 beta[D-2-amino-2-(1,4-cyclohexadienyl)-acetamido]-3-methoxy-ceph-3-em-carboxylic acid, is a new orally active cephalosporin derivative. The spectrum of antibacterial activity of CXD is identical with that of cephalexin (CEX), but CXD was twofold more effective than CEX against Escherichia coli and Klebsiella pneumoniae, CXD was as stable to penicillinase as CEX, but it was hydrolyzed by cephalosporinase, with a relative rate of hydrolysis similar to that of CEX. The affinities of CXD and CEX to penicillin-binding proteins of E. coli were estimated; the affinity of CXD to penicillin-binding protein 1Bs was higher than that of CEX. Consistent with this, CXD had more intensive lytic activity than CEX. In vivo antibacterial activities of CXD and CEX were compared using systemic infections of mice with E. coli and K. pneumoniae; CXD was consistently more active than CEX.