Trends in the development of beta-lactam antibiotics

In many ways it is ironic that the first description of a beta-lactamase occurred in 1940 with an enzyme isolated from Escherichia coli since in recent years there has been a major interest in Gram-negative species and the development of agents to overcome the hydrolytic action of beta-lactamases of Gram-negative species. There have been four distinctly different approaches to the development of new beta-lactam antibiotics. These have been the search for inhibitors of beta-lactamases and agents such as clavulanic acid and sulbactam are examples of compounds which by virtue of Kcat function act as suicide inhibitors and make old antibiotics new. There has been the modification of the penicillin and cephem nucleus to increase beta-lactamase stability or failing that to improve the ability of the compounds to pass through the cell wall and increase affinity for critical beta-lactam receptors, i.e. penicillin-binding proteins. There has been the development of carbapenem type of agents such as imipenem which would have broad activity including aerobic, anaerobic, Gram-positive and Gram-negative species. There has been the discovery of the monobactam agents of which aztreonam is an example of a compound with great beta-lactamase stability but with activity limited to Gram-negative aerobic species. Bacterial resistance has indeed been the major factor that has modified use of beta-lactams and influenced the development of the aforementioned types of drugs. The widespread presence of beta-lactamases in common pathogens such as Haemophilus influenzae, Neisseria gonorrhoeae, Escherichia coli, Klebsiella sp., Pseudomonas aeruginosa, and Bacteroides fragilis has made it necessary to have beta-lactamase stable compounds for initial therapy of infection. It is possible to analyze structure-activity relations of beta-lactam compounds to determine changes which will be most advantageous in light of known and expected resistance patterns. But the increased realization in recent years of the importance of the pharmacokinetics of beta-lactam drugs has made it essential that the development of new compounds be based on an integration of microbiological and pharmacokinetic parameters. Interest in the prevention of resistant flora has also affected the development of new drugs since it is increasingly appreciated that alteration of intestinal flora contributes to selection of drug resistant microorganisms. Finally, new toxicities or adverse effects associated with the use of certain new agents has modified the development of certain compounds.