Authors: W E WICK, W S BONIECE

Two new antibiotics, structurally related to cephalothin, have been given the generic names cephaloglycin and cephaloridine. Cephaloglycin is the dipolar ion of 7-(d-alpha-aminophenylacetamido)-cephalosporanic acid. Cephaloridine is 7-[alpha-(2-thiophene)acetamido]-3-(1-pyridylmethyl)-3-cephem-4-carboxylic acid betaine. These new compounds were evaluated simultaneously. The broad spectrum of activity observed in vitro and in vivo with both antibiotics, the good oral absorption obtained with cephaloglycin, and the stability of cephaloridine are emphasized. The data suggest that both antibiotics merit clinical trial in humans.

Topics: Alcaligenes; Anti-Bacterial Agents; Bacillus subtilis; Blood Chemical Analysis; Cephaloglycin; Cephaloridine; Cephalothin; Chemical Phenomena; Chemistry; Chromatography; Clostridium tetani; Corynebacterium diphtheriae; Drug Resistance; Drug Resistance, Microbial; Enterobacter; Enterobacteriaceae; Escherichia coli; Haemophilus; In Vitro Techniques; Klebsiella; Mice; Neisseria gonorrhoeae; Neisseria meningitidis; Pharmacology; Proteus; Pseudomonas; Pseudomonas aeruginosa; Research; Salmonella; Shigella; Staphylococcus; Streptococcus; Streptococcus pneumoniae; Toxicology

PubMed: 14325888
DOI: 10.1128/am.13.2.248-253.1965

Comparative Study

Authors: B M Tune, D Fravert, C Y Hsu...

Cephaloridine and cephaloglycin are the two most nephrotoxic cephalosporins released for human use. Cephaloridine has been shown to produce both oxidative and mitochondrial respiratory injury in renal cortex in patterns of dose (or concentration) and time that are consistent with pathogenicity. Cephaloglycin also produces respiratory toxicity, and recent studies have provided evidence that this injury results from an inactivation of mitochondrial anionic substrate transporters. The abilities of cephaloglycin to produce oxidative changes and cephaloridine to block mitochondrial substrate uptake have not been examined yet. We therefore compared these two cephalosporins with one another and with cephalexin, which is not nephrotoxic, in the production of the following: (1) several components of oxidative stress or damage [depletion of reduced glutathione (GSH) and production of oxidized glutathione (GSSG) in renal cortex, inhibition of glutathione reductase in vitro, and production of the lipid peroxidation products malondialdehyde (MDA) and conjugated dienes (CDs) in renal cortex]; and (2) renal cortical mitochondrial toxicity [to both respiration with, and the transport of, succinate]. Cephaloridine depleted GSH and elevated GSSG in renal cortex, inhibited glutathione reductase, and increased both MDA in whole cortex and CDs in cortical microsomes and mitochondria. While cephaloglycin depleted GSH at least as much as did cephaloridine, it produced one-fifth as much GSSG and had little or no effect on glutathione reductase activity or on cortical MDA or microsomal CDs; cephaloglycin caused a transient small increase of mitochondrial CDs. Cephalexin produced no oxidative changes except for a slight increase of mitochondrial CDs comparable to that produced by cephaloglycin. Both cephaloridine and cephaloglycin, but not cephalexin, decreased the unidirectional uptake of, and respiration with, succinate in cortical mitochondria. We conclude that cephaloridine and cephaloglycin are both toxic to mitochondrial substrate uptake and respiration, but differ significantly in their generation of products of oxidation.

Topics: Animals; Cephaloglycin; Cephaloridine; Female; Glutathione; Glutathione Reductase; Kidney; Lipid Peroxidation; Mitochondria; Oxygen Consumption; Rabbits

PubMed: 2930580
DOI: 10.1016/0006-2952(89)90233-5

Authors: J Haginaka, T Nakagawa, T Uno...

Metabolism and pharmacokinetics of cephaloglycin in man were investigated. High performance liquid chromatographic and gas chromatographic-mass spectrometric analyses of metabolites excreted in human urine following oral administration of cephaloglycin revealed that cephaloglycin was biotransformed in two pathways i.e. elimination of 3-acetyl group and hydrolysis of side chain amide linkage. The former yielded deacetylcephaloglycin, a part of which further underwent lactonization to deacetylcephaloglycin lactone, and the latter led to benzoyl formic acid via phenylglycine. The urinary excretion amounts of these metabolites and intact cephaloglycin were determined by a reversed phase ion pair high performance liquid chromatography. The average total excretion amounts at infinite time accounted for 0.50% of the administered dose for intact cephaloglycin, 17.09% for deacetylcephaloglycin, 0.35% for deacetylcephaloglycin lactone, and 0.86% for benzoyl formic acid. The excretion of phenylglycine was less than 0.2%, its chromatographic peak being too small to allow accurate determination. The rate constants for absorption, metabolism, and urinary excretion were estimated by the moment analysis of the excretion rate-time curves.

Topics: Adult; Biotransformation; Cephaloglycin; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans; Kinetics; Male

PubMed: 7380734
DOI: 10.7164/antibiotics.33.236

Authors: J M Applestein, E B Crosby, W D Johnson...

Serum and urine concentrations of cephaloglycin (an orally absorbed derivative of cephalosporin C) were determined in normal volunteers and in patients. The in vitro activity of cephaloglycin was also studied. All strains of group A streptococci (Streptococcus pyogenes) and Diplococcus pneumoniae were inhibited by 0.4 mug of cephaloglycin per ml. Eighty per cent of the Staphylococcus aureus strains and about 50% of the Escherichia coli and Proteus mirabilis strains were inhibited by 1.6 mug of cephaloglycin per ml. Klebsiella-Aerobacter species were more resistant to cephaloglycin and 12.5 mug per ml was required to inhibit 70% of these strains. When single doses of 250, 500, or 1,000 mg of cephaloglycin were administered to fasting volunteers, a peak serum concentration of at least 0.5 mug per ml was achieved. A full breakfast did not interfere with absorption of cephaloglycin. Probenecid enhanced both the peak serum concentration and the duration of antibiotic activity in the serum. Serum concentrations of cephaloglycin were even higher in patients who were receiving repeated doses. The peak serum concentrations of cephaloglycin in all volunteers and patients were adequate to inhibit all strains of group A streptococci and D. pneumoniae. Many of the peak serum concentrations were adequate to inhibit some strains of S. aureus, E. coli, and P. mirabilis. Urine levels of cephaloglycin were high enough in all volunteers and patients to inhibit more than 90% of the E. coli and P. mirabilis strains and over 70% of the strains of Klebsiella-Aerobacter.

Topics: Bacteria; Cephalosporins; Enterobacter; Escherichia coli; Humans; Klebsiella; Probenecid; Proteus; Staphylococcus; Streptococcus pneumoniae; Streptococcus pyogenes; Urinary Tract Infections

PubMed: 4385749
DOI: 10.1128/am.16.7.1006-1010.1968

Authors: P Braun, J R Tillotson, C Wilcox...

A large number of recently isolated bacterial pathogens were tested for susceptibility to cephalexin and cephaloglycin by the replica inoculating method. Strains of group A hemolytic streptococci, viridans (alpha and gamma) streptococci, pneumococci, gonococci, meningococci, and penicillin G-sensitive Staphylococcus aureus were all moderately to highly susceptible to both of these cephalosporin analogues, nearly all of the strains being two to eight (median four) times more susceptible to cephaloglycin than to cephalexin. The penicillin G-resistant, penicillinase-producing strains of S. aureus varied in their susceptibility; many were moderately resistant to both analogues, particularly to cephalexin. Strains of enterococci, Haemophilus influenzae, and most of the common gram-negative bacilli were moderately to highly resistant. Reducing the size of the inoculum had variable effects on inhibition by these drugs, depending on the species or strain. The activity of cephalexin was very little affected by pH of the medium within the clinical range or by incubation at 37 C in broth for up to 24 hr. In contrast, cephaloglycin in broth deteriorated rapidly at 37 C, and its activity was markedly reduced in alkaline medium. Both cephalexin and cephaloglycin were rapidly absorbed and excreted into the urine after single oral doses of 500 mg. Much higher levels were achieved and sustained with the former. Absorption of both analogues was delayed when taken with food, and the levels in the serum were significantly higher and better sustained when probenecid was also given. Very high concentrations of cephalexin were excreted into the urine during the first 4 hr, and the levels were still high in the 4- to 8-hr collection. The concentrations of cephaloglycin in the urine at these times were much lower. An average of 80 to 93% of the dose of cephalexin and 25 to 30% of the cephaloglycin were accounted for as active drug in the urine collected in 8 hr. Both analogues were well tolerated.

Topics: Adult; Cephalosporins; Enterobacteriaceae; Escherichia coli; Haemophilus influenzae; Humans; In Vitro Techniques; Klebsiella; Neisseria gonorrhoeae; Neisseria meningitidis; Penicillin Resistance; Proteus; Pseudomonas aeruginosa; Serratia marcescens; Staphylococcus; Streptococcus; Streptococcus pneumoniae

PubMed: 4387222
DOI: 10.1128/am.16.11.1684-1694.1968

Authors: H R Sullivan, R E Billings, R E McMahon...

Topics: Animals; Anti-Bacterial Agents; Bile; Carbon Isotopes; Chromatography, Paper; Feces; Formates; Injections, Intraperitoneal; Intestinal Absorption; Mandelic Acids; Rats

PubMed: 5768560
DOI: 10.7164/antibiotics.22.27

Comparative Study

Authors: S Shadomy, G Wagner, M Carver...

Cefaclor (Lilly 99638) and cefatrizine (BL-S640, SK&F 70771) are orally absorbed, broad-spectrum semisynthetic cephalosporins. They were compared in vitro with cephalexin, cephaloglycin, and cepharadine against a variety of aerobic pathogenic bacteria by an agar dilution procedure. Cefaclor and cefatrizine were found to be similar or superior to cephalexin, cephaloglycin, and cephradine in terms of activity against gram-positive cocci other than enterococci. Only cefatrizine demonstrated any potentially useful activity against some susceptible isolates of enterococci. Cefaclor and cefatrizine also were highly active, equally or more so than the other oral cephalosporins, against several gram-negative species including Escherichia coli, Enterobacter aerogenes, and Klebsiella pneumoniae. None of the cephalosporins were particularly active against Enterobacter cloacae. Both cefaclor and cefatrizine were active against Proteus mirabilis; cefatrizine was uniquely active against indolepositive Proteus species.

Topics: Aerobiosis; Bacteria; Cefatrizine; Cephalexin; Cephaloglycin; Cephalosporins; Cephradine; Drug Resistance, Microbial; In Vitro Techniques; Microbial Sensitivity Tests

PubMed: 921258
DOI: 10.1128/AAC.12.5.609

Review

Authors: L P Garrod

Topics: Ampicillin; Carbenicillin; Cephalexin; Cephaloglycin; Cephaloridine; Cephalosporins; Cephalothin; Cloxacillin; Dicloxacillin; Halogens; Humans; Methicillin; Oxacillin; Penicillin G; Penicillin V; Penicillinase; Penicillins; Phenyl Ethers

PubMed: 4211871
DOI: 10.1136/bmj.3.5923.96

Comparative Study

Authors: B M Tune, C Y Hsu, D Fravert...

Three beta-lactams, desacetylcephaloglycin, ampicillin, and loracarbef, were studied to test a hypothesis derived from retrospective analysis of previously studied cephalosporins: that beta-lactam nephrotoxicity develops in approximate proportion to tubular cell antibiotic concentrations and lactam ring reactivities. Concentrations of each beta-lactam (and insulin) in rabbit renal cortex and serum were measured at the end of 0.5-hr infusions of 100 mg antibiotic/kg body weight and 0.5 to 0.67 hr later. Total cortical AUCs (total areas under the curve of concentration and time in renal cortex) and transported cortical AUCs (total minus insulin-space beta lactam) were calculated from these measurements. Reactivities, determined by the rate constants of lactam-ring opening at pH 10, were taken from the literature. Nephrotoxicity was quantified by grades of proximal tubular cell necrosis and by serum creatinine concentrations 2 days after infusion of 100-1500 mg/kg of the antibiotics. Desacetylcephaloglycin was slightly less nephrotoxic than cephaloglycin; the AUCs reactivities, and toxicities of these two cephalosporins fit the proposed model, particularly when allowance is made for hepatic and renal deacetylation of cephaloglycin. The very low AUCs, limited reactivity, and absence of nephrotoxicity of ampicillin also fit the model. Loracarbef had a transported AUC less than three times, and reactivity one-thirtieth, those of cefaclor, respectively. Although only at 1500 mg/kg, loracarbef was significantly more nephrotic than cefaclor. If the relativity of loracarbef with its targeted bacterial proteins, which is essentially the same as that of cefaclor, is considered instead of the base hydrolysis rate constant, than loracarbef also fits the model. By the same analysis, the comparatively high in vitro stability of other carbacephems, although pharmaceutically convenient, may not limit their nephrotoxicity.

Topics: Acylation; Ampicillin; Animals; Anti-Bacterial Agents; Biological Transport; Cephaloglycin; Cephalosporins; Half-Life; Infusions, Intravenous; Kidney; Kidney Cortex; Penicillins; Rabbits; Structure-Activity Relationship; Tissue Distribution

PubMed: 8619902
DOI: 10.1016/0006-2952(95)02237-6

Authors: M M Hoehn, C T Pugh

Thin-layer and paper chromatographic systems were used to detect and determine the concentration of cephaloglycin and its biologically active metabolites in serum and urine. Data are presented on the procedures, solvent systems, and specific techniques used in this evaluation.

Topics: Biological Assay; Cephalosporins; Chromatography, Paper; Chromatography, Thin Layer; Sarcina

PubMed: 5675503
DOI: 10.1128/am.16.8.1132-1133.1968