在研广谱头孢菌素类抗生素的新进展

目前头孢菌素类药物的研究热点在于寻找对耐药革兰阳性致病菌敏感,尤其是对耐甲氧西林金黄色葡萄球菌(MRSA)敏感的头孢菌素类化合物及对高活性化合物进行结构修饰,改善其药学性质.本文先就2008年上市的抗MRSA广谱新药ceftobiprole进行介绍,再将近十余年研发中的广谱头孢菌素类抗生素的新进展做一简要综述,其中ceftaroline和FR264205(CXA-101)是较有前景的候选药物,ceftaroline新药上市申请(NDA)有望于2010年获准.     

Synthesis and biological activity of some broad-spectrum N-acylphenyglycine cephalosporins.

The synthesis and the in vitro and in vivo antibacterial activities of a series of N-acylated phenylglycine cephalosporins are described. These compounds exhibit activity against a broad spectrum of gram-positive and gram-negative bacteria including some strains of Pseudomonas aeruginosa, a bacterial species normally insensitive to the cephalosporin antibiotics. The cephalosporins were prepared by acylation of cephaloglycin or its 3-tetrazolylthiomethyl analogue. In several cases, the acylations produced mixtures of diastereomeric cephalosporins, the components of which, when separated, showed different levels of antibiotic activity. Optimum activity was obtained when the acyl moiety on the phenylglycine nitrogen contained an oxygen atom centrally located between the amide carbonyl and a carboxyl substituent, preferably in a three- or five-membered ring. Replacement of acetoxymethyl by (1-methyl-1H-tetrazol-5-yl)thiomethyl at the 3 position resulted in overall improvement in activity both in vitro and in vivo. Against a group of P. aeruginosa strains, the best compounds of this series showed activity on the order of carbenicillin.     

Characterization of a plasmid coding for resistance to broad-spectrum cephalosporins in Salmonella typhimurium

Five strains of Salmonella typhimurium isolated from faeces of infants hospitalized at Trousseau Hospital in Paris have been found to be resistant to third-generation cephalosporins. This resistance is by a transferable plasmid-mediated mechanism. The beta-lactamase gene which encodes for an enzyme similar to SHV-2 has been cloned into plasmid pBR322 and expressed in Escherichia coli RR1.     

New cephalosporins and 7 alpha-methoxy cephalosporins. Chemistry and biological activities

The synthesis and the in vitro activity of a number of cephalosporins and 7 alpha-methoxy cephalosporins having 7-acyl substituents derived from 1-methyl-4 (or 5)-nitro-1H-imidazolyl-thioacetic acids are described. The microbiological profile is influenced by the position of both the nitro group and the side-chain sulfur atom on the 1-methyl imidazole, and by the nature of the 3-substituent.     

New cephalosporins in development pipelines

One of the most commercially successful classes of human antibacterials is the cephalosporins, intially introduced in the 1960s, commanding a major market share worldwide. The cephalosporins have evolved slowly, keeping intact the 7R-amino-cephalosporanic acid nucleus, while changing substituents mostly at the C-7 and C-3 positions to develop both oral and parenteral cephalosporins with a wide range of antibacterial activities. With success and wide usage, however, comes resistance, and the current generation of cephalosporins, evolving from the third and fourth generation, are barely keeping one step ahead of β-lactamase and cephalosporinase enzymes that hydrolyse the cephalosporins. More than two dozen oral and parenteral cephalosporins are in development, many seeking a niche position to gain a foothold in a mature therapy area. Key advantages such as β-lactamase and cephalosporinase resistance, coverage of S. pneumoniae, P. aeruginosa or enterococci, reduced side effects, or pharmaco-economic advantage, may distinguish the successful new cephalosporins from the ‘me-too’; cephalosporins.     

New prospects for research on cephalosporins

The present paper reviews the newly-developed cephalosporins and considers their potential for filling the gaps left by earlier cephalosporins in terms of of spectrum of activity, pharmacokinetic parameters, development of resistance and tolerability. Research on narrow-spectrum cephalosporins, directed specifically against enterobacteria and Pseudomonas, on cephalosporins with a low inoculum effect and on oral cephalosporins is discussed. The chemical substitutions responsible for enhancing or reducing the activity of cephalosporins against various bacteria, for altering pharmacokinetic behaviour and for producing unwanted side-effects are described.     

New cephalosporins with 7-acyl groups derived from beta-ketoacids. I. 7-(beta-Ketoacylamino)cephalosporins.

The synthesis and antimicrobial profile of a series of 7-(beta-ketoacylamino)cephalosporins (1) bearing an acetoxymethyl or a heterocyclichiomethyl group at the 3-position are described. Of this series, 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-7-(3-oxobutyrylamino)ceph-3-em-4-carboxylic acid (11) showed moderate antibacterial activities in in vitro and in vivo tests.     

Emerging cephalosporins

Several cephalosporins are in clinical development as broad-spectrum agents with potent activity against multi-resistant staphylococci as well as the Gram-positive and Gram-negative bacteria normally susceptible to advanced generation cephalsoporins. These agents represent a novel activity for the class and challenge a dogma that β-lactams do not have clinically useful activity against multi-resistant staphylococci. The most advanced of these agents, ceftobiprole, is approaching registration and, if approved, will present physicians with a new paradigm in treatment of serious infections by multi-resistant organisms.     

Emerging cephalosporins

Several cephalosporins are in clinical development as broad-spectrum agents with potent activity against multi-resistant staphylococci as well as the Gram-positive and Gram-negative bacteria normally susceptible to advanced generation cephalsoporins. These agents represent a novel activity for the class and challenge a dogma that beta-lactams do not have clinically useful activity against multi-resistant staphylococci. The most advanced of these agents, ceftobiprole, is approaching registration and, if approved, will present physicians with a new paradigm in treatment of serious infections by multi-resistant organisms.     

New broad-spectrum cephalosporins with anti-pseudomonal activity. I. Synthesis and antibacterial activity of 7 beta-[D-2-[(4-hydroxy-1,5-naphthyridine-3-carbonylamino)- and (4-hydroxypyridine-3-carbonylamino)]-2-(4-hydoxyphenyl)acetamido] cephalosporins

The synthesis and the antibacterial activity of 7 beta-[D-2-[(4-hydroxy-1,5-naphthyridine-3-carbonylamino)- and (4-hydroxypyridine-3-carbonylamino)]-2-(4-hydroxyphenyl)acetamido]-cephalosporins with various substituents at the 3-position in the cephem nucleus are described. These compounds exhibited strong antibacterial activities against a variety of Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa and Enterobacter aerogenes, which are insensitive to cefazolin and cefmetazole. The compounds (3e, 4e) having a 1-methyl-1H-tetrazolylthiomethyl group at the 3-position appeared to show the best activity in each series. The 4-hydroxypyridine-3-carbonylamino derivative 4e gave higher peak serum concentrations and urinary recovery rates than those of the 4-hydroxy-1,5-naphthyridine derivative 3e when administered subcutaneously to mice and intramuscularly to rats.     

Novel oral cephalosporins

The therapeutic use of oral cephalosporins to treat infectious diseases continues to challenge clinicians; many attempts have been made over recent years to improve the efficacy and spectrum of these anti-infectives. Many oral cephalosporins are in development and include cefdinir, cefprozil, cefetamet pivoxil, cefcapene pivoxil, cefcanel daloxate hydrochloride in Phase II trials, S-1090 in Phase III trials and the novel compounds E1100, E1101 and BRL-57347. Differences between these drugs are sometimes subtle and the improvement over existing compounds modest, although recent cephalosporins have shown greater activity against Gram-negative bacterial infections. A better knowledge of the pharmacodynamic and pharmacokinetic interrelationships of existing oral cephalosporins is demanded for a more rational use of these compounds and to avoid the subsequent development of resistance. Perhaps with such an approach, the perceived need for new cephalosporins will diminish.     

Novel oral cephalosporins

The therapeutic use of oral cephalosporins to treat infectious diseases continues to challenge clinicians; many attempts have been made over recent years to improve the efficacy and spectrum of these anti-infectives. Many oral cephalosporins are in development and include cefdinir, cefprozil, cefetamet pivoxil, cefcapene pivoxil, cefcanel daloxate hydrochloride in Phase II trials, S-1090 in Phase III trials and the novel compounds E1100, E1101 and BRL-57347. Differences between these drugs are sometimes subtle and the improvement over existing compounds modest, although recent cephalosporins have shown greater activity against Gram-negative bacterial infections. A better knowledge of the pharmacodynamic and pharmacokinetic interrelationships of existing oral cephalosporins is demanded for a more rational use of these compounds and to avoid the subsequent development of resistance. Perhaps with such an approach, the perceived need for new cephalosporins will diminish.     

Penicillins and cephalosporins

Penicillins and cephalosporins belong to the most prescribed antibiotics. Despite the relatively extended knowledge of these drugs, the qualitative and quantitative analysis of the compounds still gives rise to many problems. These difficulties are due to the chemical instability of the common -lactam nucleus, the minor differences in chemical structures between the analogues, and the complex and relatively fast degradation of the compounds in aqueous solutions. In this review a compilation of the physicochemical properties, the degradation routes and methods for analysis of these substances in biological and other matrices is presented.     

Esters of cephalosporins part IX. New method of isolation of cefetamet pivoxil

A new method of isolation of cefetamet pivoxil, which results in higher purity and higher yield than according to the known methods, was worked out. The new method depends on ability to the adsorption on acidic active carbon of total amount of this antibiotic together with only a small amount of impurities. During two-step elution all impurities were washed out in the first step and in the next step pure cefetamet pivoxil was eluated by another solvent.     

Erythrocyte binding of cephalosporins

A rapid sample preparation and HPLC technique was used to study the erythrocyte binding properties of six cephalosporins at therapeutic concentrations. The negligible red blood cell partition coefficients indicated that only small amounts of the cephalosporins were taken up by the blood cells at all drug concentrations. Thus, plasma concentrations were about twice as high as the respective blood concentrations. Blood/plasma ratios solely depended on the haematocrit and were independent of the extent of protein binding.