21 William A. Craig and David R. Andes

Although the discovery of the class was Modifications at R2 often alter the pharmacology of the compound. reported in 1945, it took almost 2 decades for this class to achieve Changes in the R2 constituent may influence the ability of the com- clinical utility. Giuseppe Brotzu is widely credited for discovery of the pound to reach certain infection sites, such as the central nervous broad-spectrum inhibitory effects of sewage outflow in Sardinia, Italy.1 system, or may simply prolong the elimination half-life of the drug. Professor Brotzu subsequently isolated the mold Cephalosporin acre- The predominant changes at R1 (position C7) include the addition monium (now Acremonium chrysogenum) and demonstrated antimi- of an acyl side chain and the substitution of the hydrogen with crobial activity of culture filtrates against both gram-positive and a methoxy group.5 The R1 methoxy substitution led to the develop- gram-negative bacteria. He also demonstrated the in vivo activity of ment of the cephamycin group of compounds, including cefoxitin, these culture filtrates in animal infection models and in several patients. cefmetazole, and cefotetan. This alteration enhanced resistance The filtrate was administered both locally by injection into skin to β-lactamase produced by gram-negative anaerobic and aerobic abscesses and systemically for the treatment of brucellosis and typhoid bacteria.5,6 However, these compounds have lower affinity for the fever. -binding protein (PBP) target in gram-positive bacteria.7 The A decade after the initial discovery, the cephalosporin substances cephamycin group is structurally related to the cephalosporins but were isolated and identified as fermentation products of the mold.2 originated as a metabolite from Streptomyces lactamdurans.6 The basic Investigators at Oxford, including Florey and Abraham, systematically building block of the cephamycin group is cephamycin C. Hydrolysis studied the physical, chemical, and structural characteristics of cepha- of cephamycin C produces the 7-ACA nucleus. losporins, as they had for the penicillin class a decade earlier. Three Many modifications of the acyl side chain have been undertaken. substances—cephalosporin P, N, and C—were identified. Each of the The first compounds resulting from addition of a thienyl ring ora products possessed antimicrobial activity but only cephalosporin C tetrazole structure at R1 included the first-generation cephalosporins— demonstrated activity against both gram-negative and gram-positive cephalothin, , and cefazolin (Fig. 21-2). The simple sub- bacteria. In addition, it had advantageous stability in the presence of stitution of an aminobenzyl group in the C7 position is important for acid and penicillinases.2 Cephalosporin C became the foundation of oral absorption of the cephalosporins.5 Cephalexin, cephradine, cefa- subsequent drug development. clor, cefprozil, and loracarbef all have this structure or a closely related The first cephalosporin pharmaceutical, cephalothin, was intro- one (Fig. 21-3). Absorption of later-generation cephalosporins is duced for clinical use in 1964. There are more than 20 cephalosporin enhanced by the production of ester formulations. Axetil, proxetil, or in use today (17 in the United States). The cephalosporin pivoxil esters of cefuroxime, cefpodoxime, and cefditoren are currently class is among the most widely prescribed antimicrobial classes because available. of its broad spectrum of activity, low toxicity, ease of administration, Most of the chemical modifications in cephalosporin development and favorable pharmacokinetic profile. that have resulted in changes in microbiologic spectrum are alterations CHEMISTRY Most of the available cephalosporins are semisynthetic derivatives of Cefazolin cephalosporin C. The basic structure of the cephem nucleus includes NN S C N N a β-lactam ring fused to a six-member sulfur-containing dihydrothi- N CH2 HN azine ring (Fig. 21-1). The cephem nucleus is chemically distinct from N S CH O N CH2 3 the penicillin nucleus, which contains a five-member thiazolidine ring. O S Basic structure numbering of the cephalosporin ring system begins within the dihydrothiazine ring at the sulfur moiety. The starting mate- A COOH rial used as the nucleus for current cephalosporin development is Cephalothin 7-aminocephalosporanic acid (7-ACA). Attempts to alter the physio- S O CH2 C HN chemical and biologic properties of the cephalosporins by chemical S N CH O C CH side chain modifications were based on successes with similar struc- O 2 3 tural changes at the 6-aminopenicillanic acid side chain of penicillin.3 O Chemical modifications of the basic cephem structure by substitution B COOH of constituents at positions C1, C3, and C7 led to the various cephalo- 4,5 Cefadroxil sporin compounds in use today. Alterations in position C7 and C3 S are also commonly referred to as R1 and R2, respectively. In general, HO CH C HN changes at R1 affect the microbial spectrum of activity. These modifica- N CH O 3 tions often have an impact on the stability of the compound to enzy- NH matic destruction by β-lactamases or on its affinity for the drug target. 2 O C COOH Cephalexin 1 S CH C HN 7 S R C HN 1 N CH O 3 3 R NH O N 2 2 O O D COOH - COO FIGURE 21-2 First-generation cephalosporins. A, Cefazolin. B, FIGURE 21-1 Basic cephalosporin nucleus. Cephalothin. C, Cefadroxil. D, Cephalexin. 278