The renal mitochondrial toxicity of beta-lactam antibiotics: in vitro effects of cephaloglycin and imipenem. (1/9)

The nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin, and imipenem produce irreversible injury to renal mitochondrial anionic substrate uptake and respiration after 1 to 2 h of in vivo exposure. Toxicity during in vitro exposure is nearly identical but is immediate in onset and is reversed by the mitochondria being washed or the substrate concentrations being increased. A model of injury that accounts for these findings proposes that the beta-lactams fit carriers for mitochondrial substrate uptake, causing inhibition that is initially reversible and becomes irreversible as the antibiotics acylate the transporters. These studies were designed to create an environment of prolonged in vitro exposure, first, to determine whether toxicity becomes irreversible with time and, second, to study the molecular properties of toxicity. Respiration with and the uptake of succinate and ADP were measured in rabbit renal cortical mitochondria exposed for 2 to 6 h to 300 to 3,000 micrograms of cephalexin (nontoxic) or cephaloglycin or imipenem (nephrotoxic) per mL and then washed to remove the antibiotic. In vitro cephalexin reduced respiration only slightly and was therefore not studied further. Cephaloglycin and imipenem irreversibly reduced both respiration and succinate uptake. ADP uptake was unaffected by cephaloglycin and was slightly reduced by imipenem. Finally, cilastatin, which prevents the tubular necrosis produced by imipenem in vivo, reduced its mitochondrial toxicity in vitro. It is concluded that the pattern of in vitro injury of the nephrotoxic beta-lactams to mitochondrial substrate uptake and respiration evolves in a time-dependent and concentration-dependent manner, consistent with the proposed model of acylation and inactivation of substrate transporters, and that the protective action of cilastatin against imipenem occurs at least partly at a subcellular level.  (+info)

Enhancement of fluorescence development of end products by use of a fluorescence developer solution in a rapid and sensitive fluorescent spot test for specific detection of microbial beta-lactamases. (2/9)

A fluorescent spot test method for specific detection of microbial beta-lactamases as previously published (K. C. S. Chen, J. S. Knapp, and K. K. Holmes, J. Clin. Microbiol. 19:818-825, 1984) was improved by the use of a fluorescence developer solution. The fluorescence developer solution used in this study consisted of 0.78 M sodium tartrate buffer containing 12% formaldehyde at a final pH of 4.5. An addition of 1 volume of fluorescence developer solution to 5 volumes of ampicillin or cephalex substrate solution incubated with beta-lactamase-producing organisms, followed by heating the mixture at 45 degrees C for 10 min resulted in enhancement of fluorescence of the end products of beta-lactamase activity. This provides a more sensitive assay for microbial beta-lactamases and offers the potential for direct detection of beta-lactamases in clinical specimens.  (+info)

Inhibition of beta-lactam antibiotics at two different times in the cell cycle of Streptococcus faecium ATCC 9790. (3/9)

Treatment of Streptococcus faecium ATCC 9790 with sublytic concentrations of beta-lactam antibiotics revealed two different division blocks in the cell division cycle. One block, induced by N-formimidoyl thienamycin and methicillin, occurred before the completion of chromosome replication, whereas the other, induced by cefoxitin and cephalothin, took place later in the cycle. In addition, these antibiotics gave rise to distinct morphological forms; the antibiotics acting at the earlier block point produced mainly "dumbbells," whereas those affecting the later time formed "lemons." When used in combination N-formimidoyl thienamycin and cefoxitin exerted synergistic killing on this strain. These data suggest that beta-lactam antibiotics have at least two sites of action in S. faecium.  (+info)

Acidic degredation of cephaloglycin and high performance liquid chromatographic determination of deacetylcephaloglycin in human urine. (4/9)

In order to provide fundamental knowledge about the determination of deacetylcephaloglycin excreted in human urine as an active metabolite of cephaloglycin, the degradation of cephaloglycin in acidic media has been investigated with varying reaction temperature between 30 degrees and 50 degrees C and pH between 1.2 and 2.8. The degradation pathway observed under these conditions was the elimination of the 3-acetyl group yielding deacetylcephaloglycin followed by formation of deacetylcephaloglycin lactone. Estimation of first order rate constants revealed that deacetylation is the rate-determining step for the degradation of cephaloglycin to the lactone. It is found from the kinetic results that reproducible assays of deacetylcephaloglycin excreted in urine can be achieved by a quantitative conversion to deacetylcephaloglycin lactone in a medium of pH 1.4 at 37 degrees C for 2 hours, followed by a reversed-phase ion-pair high-performance liquid chromatography. The utility of the present method is demonstrated by determining the time course of urinary excretion of deacetylcephaloglycin after oral administration of cephaloglycin capsule.  (+info)

Differential antibiotic excretion in unilateral structural pyelonephritis. (5/9)

Differential antibiotic excretion studies in eight patients with unilateral structural pyelonephritis showed that in all instances there was impairment in antibiotic excretion on the affected side compared with the normal kidney. Both peak and mean urinary concentrations were decreased on the structurally abnormal side. The degree of defect in antibiotic concentration was proportional to the amount of unilateral medullary damage, as measured by differential renal function studies. While the antibiotic concentrations achieved had an inconsistent relationship to cure in three patients with proven unilateral infections, the striking decreases in urinary antibiotic levels may argue against oral penicillin-G treatment of unilateral pyelonephritis in which there is renal parenchymal damage.  (+info)

Chromatographic analysis and pharmacokinetic investigation of cephaloglycin and its metabolites in man. (6/9)

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.  (+info)

Fluorimetric assay of cephradine, cephalexin and cephaloglycin. (7/9)

1 A simple, rapid and reproducible fluorimetric assay for cephradine, cephalexin and cephaloglycin is described. 2 The method involves addition of formaldehyde which catalyses the formation of fluorescent derivatives. 3 The structural similarities between the side chains of these antibiotics and their identical excitation and emission spectra suggest that they may be forming similar fluorescent derivatives.  (+info)

In vitro activities of five oral cephalosporins against aerobic pathogenic bacteria. (8/9)

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.  (+info)

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