Recent Developments in the Field of Cephem Antibiotics

Dürckheimer, Walter; Adam, Friedhelm; Fischer, G.; Kirrstetter, R. G. H.

doi:10.1016/b978-0-12-013317-8.50006-x

Cited by 32 publications

(17 citation statements)

References 378 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The introduction of a methoxyimino-aminothiazolyl moiety in the acyl side chain of cephalosporins brought about significant enhancement of activity, extension of the antibacterial spectrum-especially against gram-negative bacteria-and high resistance to inactivation by P-lactamases (3,9). The introduction of polar C-3'-substituents into a cephem nucleus improves the activity of the aminothiazolyl cephalosporins, especially against staphylococci and P. aeruginosa, without loss of activity against members of the Enterobacteriaceae.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 111V), a new broad-spectrum cephalosporin

Limbert¹,

Isert²,

Klesel³

et al. 1991

Antimicrob Agents Chemother

107

View full text Add to dashboard Cite

Cefquinome is a new injectable aminothiazolyl cephalosporin derivative. It is stable against chromosomally and plasmid-encoded I8-lactamases and has a broad antibacterial spectrum. Staphylococcus aureus, streptococci, Pseudomonas aeruginosa, and members of the family Enterobacteriaceae (Escherichia coli, Salmonella spp., Klebsiella spp., Enterobacter spp., Citrobacter spp., and Serratia marcescens) are inhibited at low concentrations. Cefquinome is also active against many strains of methicillin-resistant staphylococci and enterococci. Its in vitro activity against gram-negative anaerobes is very limited. The high in vitro activity of cefquinome is reflected by its high in vivo efficacy against experimental septicemia due to different gram-positive and gram-negative bacteria. We studied the pharmacokinetic properties of cefquinome in mice, dogs, pigs, and calves. After single parenteral administrations, cefquinome displayed high peak levels, declining with half-lives of about 0.5, 0.9, 1.2, and 1.3 h, respectively. The areas under the concentration-time curve determined for dogs and mice showed linear correlations to the given doses. In dogs the urinary recovery was more than 70% within 24 h of dosing.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Cefotaxime was the first representative of this group of cephalosporins (11). During our efforts to find new derivatives with even broader antibacterial spectra or better pharmacokinetics, a series of polar cephalosporins was synthesized (3). From these compounds, cefpirome was selected to be developed for use in human medicine (6,13).…”

mentioning

confidence: 99%

Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 111V), a new broad-spectrum cephalosporin

Limbert¹,

Isert²,

Klesel³

et al. 1991

Antimicrob Agents Chemother

107

View full text Add to dashboard Cite

show abstract

“…Cefquinome (CFQ) is a fourth‐generation cephalosporin developed exclusively for use in animals (CVMP, ). It has high antimicrobial activity against a broad spectrum of gram‐negative and gram‐positive bacteria in connection with the introduction of a aminothiazolyl methoxyimino moiety into the acyl side chain, which make CFQ resistant to inactivation by chromosomally and plasmid‐encoded β‐lactamases (CVMP, ; Durckheimer, Adam, Fischer, & Kirrstetter, ; Limbert et al., ). It has been approved for treatment of respiratory tract diseases in cattle, pigs and horses, acute mastitis and foot rot in cattle, calf and foal septicemia and metritis‐mastitis‐agalactia syndrome in sows (CVMP , , ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep

Çorum

et al. 2019

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

The purpose of this study was to determine the pharmacokinetics of cefquinome (CFQ) following single and repeated subcutaneous (SC) administrations in sheep. Six clinically healthy, 1.5 ± 0.2 years sheep were used for the study. In pharmacokinetic study, the crossover design in three periods was performed. The withdrawal interval between the study periods was 15 days. In first period, CFQ (Cobactan, 2.5%) was administered by an intravenous (IV) bolus (3 sheep) and SC (3 sheep) injections at 2.5 mg/kg dose. In second period, the treatment administration was repeated via the opposite administration route. In third period, CFQ was administrated subcutaneously to each sheep (n = 6) at a dose of 2.5 mg/kg q. 24 hr for 5 days. Plasma concentrations of CFQ were measured using the HPLC‐UV method. Pharmacokinetic parameters were calculated using non‐compartmental methods. The elimination half‐life and mean residence time of CFQ after the single SC administration were longer than IV administration (p < 0.05). Bioavailability (F%) of CFQ following the single SC administration was 123.51 ± 11.54%. The area under the curve (AUC0‐∞) and peak concentration following repeated doses (last dose) were higher than those observed after the first dose (p < 0.05). CFQ accumulated after repeated SC doses. CFQ can be given via SC at a dose of 2.5 mg/kg every 24 hr for the treatment of infections caused by susceptible pathogens, which minimum inhibitory concentration is ≤1.0 μg/ml in sheep.

show abstract

“…Cephalosporins are ␤-lactam antibiotics, and cephalosporinases are the bacterial resistance enzymes that hydrolyze and, therefore, inactivate these antibiotics. The cephalosporinase enzyme is well characterized biochemically and structurally (21,22), and the synthesis of cephem compounds is established (23). We chose to incorporate Mtx and Dex at the C3Ј and C7 positions, respectively, of the cephem core.…”

Section: Resultsmentioning

confidence: 99%

Chemical complementation: A reaction-independent genetic assay for enzyme catalysis

Baker

Bleczinski

Lin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

102

View full text Add to dashboard Cite

A high-throughput assay for enzyme activity has been developed that is reaction independent. In this assay, a small-molecule yeast three-hybrid system is used to link enzyme catalysis to transcription of a reporter gene in vivo. Here we demonstrate the feasibility of this approach by using a well-studied enzyme-catalyzed reaction, cephalosporin hydrolysis by the Enterobacter cloacae P99 cephalosporinase (␤-lactam hydrolase, EC 3.5.2.6). We show that the three-hybrid system can be used to read out cephalosporinase activity in vivo as a change in the level of transcription of a lacZ reporter gene and that the wild-type cephalosporinase can be isolated from a pool of inactive mutants by using a lacZ screen. The assay has been designed so that it can be applied to different chemical reactions without changing the components of the threehybrid system. A reaction-independent high-throughput assay for protein function should be a powerful tool for protein engineering and enzymology, drug discovery, and proteomics. E nzymes are able to catalyze a broad range of chemical transformations not only with impressive rate enhancements but also with both regio-and stereoselectivity and so are attractive candidates as practical alternatives to traditional smallmolecule catalysts. With applications as diverse as chemical synthesis, reagents for commercial products and biomedical research, and even therapeutics, there is a great demand for enzymes with both improved activity and novel catalytic function (1, 2). In theory, the properties of an enzyme can be altered by rational design; however, rational design is greatly hindered in practice by the complexity of protein function. With advances in molecular biology the possibility has arisen that an enzyme with the desired catalytic property can instead be isolated from a large pool of protein variants. Recently directed evolution has been used successfully to modify the substrate (3) or cofactor specificity (4) of an existing enzyme. These experiments, however, are limited to reactions that are inherently screenable or selectable, reactions where the substrate is a peptide (5, 6) or the product is fluorescent (4) or an essential metabolite (3,7,8). What are needed now to realize the power of directed evolution experiments are screening and selection strategies that are general, strategies that do not limit the chemistry and that can readily be adapted to a new target reaction.Early success with assays based on binding to transition-state analogs and suicide substrates convinced researchers that it should be possible to engineer proteins to catalyze a broad range of reactions (9), but it was difficult to translate binding events into read-outs for enhanced catalytic activity. Recently, attention has turned to direct selections for catalytic activity. While strategies ranging from in vitro fluorescence assays to physically linking the enzyme to its substrate have all recently been reported (10-15), a general solution to this problem is yet to emerge.In vivo complementation, in which a...

show abstract

Recent Developments in the Field of Cephem Antibiotics

Cited by 32 publications

References 378 publications

Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 111V), a new broad-spectrum cephalosporin

Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 111V), a new broad-spectrum cephalosporin

Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep

Chemical complementation: A reaction-independent genetic assay for enzyme catalysis

Contact Info

Product

Resources

About