Newer Cephalosporins and “Expanded-Spectrum” Penicillins

The tremendous effort of the past two decades in developing semisynthetic modifica­ tions of existing antibiotics as well as in screening for new natural agents has produced a large number of new products. which suggested some time ago that a point of diminishing returns was being approached ( I ). In recent years the majority of new compounds reaching clinical investigation has resulted from evolution of the technology for semisynthetic modifications of either the 6-aminopeniciIlanic acid (6-APA) or the 7-aminocephalosporanic acid nucleus (2-6). Chemical alterations have been designed specifically to produce more desirable properties such as the following: (a) improved acid stability; (b) broadened microbiological spectrum; (c) improved activity against resistant organisms (by a variety of mechanisms such as improved resistance to enzymatic degradation. inhibition of degrading enzyme pro­ duction. improved intrinsic activity through better steric fit, better cell penetration, etc); (d) improved metabolic or pharmacologic efficiency, such as better oral absorp­ tion. slower excretion. better tissue diffusion; and (e) decreased allergenecity (I). Significant advances have been made toward these goals. Major among these advances has been enhanced resistance to degradation by staphylococcal .8-lactamase, accomplished with the series of semisynthetic penicil­ lins which have seen extensive clinical application begining with methicillin and subsequently including nafcillin and the isoxazolyl series (oxacillin. cloxacillin. dicloxacillin. and most recently under evaluation. flucloxacillin). The microbiology, pharmacology, and clinical applications of these drugs have been reviewed (7-12) and will not be included in this report because there are few new developments in the application of these agents. In addition to high activity against Gram-positive cocci and bacilli, the action of penicillin G also includes moderately high activity against Neisseria, relatively modest activity against Hemophilus, and low-level activity against Enterobac­ teriaceae such as Escherichia coli and Salmonella (see Table 1). However. early