gnosts.and Ivtanagenment of Infectious I)iscases i CHAPTER 20 Cephalosporins COO- DAVID R. ANDES A WILLIAM A. CRAIG FIGURE 20-1 . Basic cephalosporin nucleus . Although the discovery of the cephalosporin antibiotic class was re- duced by gram-negative anaerobic and aerobic bacteria ." These com. ported in 1945, it took nearly two decades for this class to achieve pounds, however, have lower affinity for the penicillin-binding protein clinical utility. Giuseppe Brotzu is widely credited for discovery of the (PBP) target in gram-positive bacteria .' The cephamycin group is broad-spectrum inhibitory effects of sewage outflow in Sardinia, structurally related to the cephalosporins but originated as a metabo . Italy.' Professor Brotzu subsequently isolated the mold Cephalosporin lite from Streptomyces lactamdurans .b The basic building block of the B acremonium (now Acremonium chrysogenum) and demonstrated an- cephamycin group is cephamycin C . Hydrolysis of cephamycin C, timicrobial activity of culture filtrates against both gram-positive and however, produces the 7-ACA nucleus. gram-negative bacteria . He also demonstrated the in vivo activity of Many modifications of the acyl side chain have been undertaken . these culture filtrates in both animal infection models and several pa- The first compounds resulting from addition of a thienyl ring or a tients. The filtrate was used both locally by injection into skin ab- tetrazole structure at R1 included the first-generation cephalosporins, scesses and systemically for the therapy of brucella and typhoid fever . A decade after the initial discovery', the cephalosporin substances C were isolated and identified as fermentation products of the mold .' Investigators at Oxford, including Florey and Abraham, systematically Cefazolin studied the physical, chemical, and structural characteristics of N=N` S cephalosporins as they had those of the penicillin class a decade ear- N-CH2-C-HN N-N lier. Three substances, cephalosporins P, N, and C, were identified . S J_Cl~ Each of the products possessed antimicrobial activity. However, only CH2-S__~1 cephalosporin C demonstrated activity against both gram-negative and NmC-CH2 -positive bacteria . In addition, it had advantageous stability in the pres- A COOH ence of acid and penicillinases .2 Cephalosporin C became the founda- tion of subsequent drug development . - The first cephalosporin, cephalothin, was introduced for clinical use 0 in 1964 . There are more than 20 cephalosporin antibiotics in use today . J-CH2-C-HN S The cephalosporin class is among the most widely prescribed antimi- CH2-O-C-CH3 crobial classes because of its broad spectrum of activity, low toxicity, 11 B ease of administration, and favorable pharmacokinetic profile . COOH FlGUR G, Cefa< CHEMISTRY Cephapirin 0 Most of the available cephalosporins are semisynthetic derivatives of N S-CH2-C-HN . The basic structure of the cephem nucleus includes a 11 cephalosporin C \\ / II - 3-lactam ring fused to a six-member sulfur-containing dihydrothiazine 0 CH,-O-C CK cephalot stitution ring (Fig. 20-1). The cephem nucleus is chemically distinct from the C oral absi penicillin nucleus, which in contrast contains a five-member thiazoli- COOH clor, cef dine ring . Basic structure numbering of the cephalosporin ring system Cephradine . The starting lated on, begins within the dihydrothiazine ring at the sulfur moiety enhance material utilized as the nucleus for current cephalosporin development D CH-C-HN pivoxyl is 7-aminocephalosporanic acid (7-ACA) . Attempts to alter the physio- CH3 are curr chemical and biologic properties of the cephalosporins by chemical side The chain modifications were based upon similar success with structural velopm, .' changes at the 6-aminopenicillanic acid side chain of penicillin COOH are due Chemical modifications of the basic cephem structure by substitution of Cefadroxil changes constituents at positions 1, 3, and 7 have led to the various cephalosporin group tt E CH-C-HN compounds in use today.°s Alterations in positions C7 and C3 are also HO chain a commonly referred to as RI and R2, respectively. In general, changes at CH3 of impT RI affect the microbial spectrum of activity. These modifications often the q-c affect the stability of the compound to enzymatic destruction by (3-lac- COOH The se . tamases or the affinity of the compound for the drug target . Modification Cephalexin additio at R2 often alters the pharmacology of the compound . Changes in the ring at R2 constituent may influence the ability of the compound to reach cer- CH-C-HN tain infection sites such as the central nervous system or may simply F many CH prolong the elimination half-life of the drug . 0 and 2( The predominant changes at RI (position 7) include the addition of H2 Puoft an acyl side chain and the substitution of the hydrogen with a methoxy COOH group .' This RI methoxy substitution led to the development of the FIGURE 20-2. First-generation cephalosporins. A, Cefaz4 cephamycin group of compounds, such as cefoxitin, cefmetazole, and B, Cephalothin . C, Cephapirin. D, Cephradine . E, Cefadro cefotetan . This alteration enhanced resistance to (3-lactamase pro- F, Cephalexin . Cefotetan 0 Cefamandole I OCH3 S II 2 __1 N-N 1 CH-C- N I'll II CH-C-N N-N HO-C~~S CH2-S-~ N I I N CH2-S II OH N 0 COON CH3 E COOH CH3 Cefoxitin Cefonicid 0 I OCH3 ese corn. CH2 - C-N 0 g protein II I N-N group is CH-C-N I I CH2-0-C-NH2 metabo- CH2 -S N F ck of the OH k COOH nycin C, COOH CH2SO3H Cefaclor dertaken . Cefuroxime ring or a CH-C-HN osporins, II I 0 -C- N I II CI II NH2 O CH2-O-C-NH2 N COON I OCH3 COON Cefprozil CH3 -N HO CH-C- HN Cefmetazole I 1 11 CH=CH J_CH3 II I OCH3 H NH2 0 5 N-N N-C-CH2-S -CH2- C-N COON CH2-S-~, N HO O/f Loracarbef D C=O CH3 CH-C-HN I II I H NH2 O CI COOH FIGURE 20-3 . Second-generation cephalosporins . A, Cefamandole . B, Cefonicid . C, Cefuroxime . D, Cefmetazole . E, Cefotetan . F, Cefoxitin . G, Cefaclor. H, Cefprozil . I, Loracarbef. 0 II -C-C cephalothin, cephaloridine, and cefazolin (Fig . 20-2). The simple sub- reduces activity against staphylococci . Two other modifications that stitution of an aminobenzyl group in the 7 position is important for have resulted in compounds with increased activity against P aerugi- oral absorption of the cephalosporins .5 Cephalexin, cephradine, cefa- nosa are an ureido-2,3-dioxopiperazine group and a carboxyl group on clor, cefprozil, and loracarbef all have this structure or a closely re- the a-carbon with cefoperazone and moxalactam, respectively .' These lated one (Fig . 20-3). Absorption of later generation cephalosporins is changes are similar to those with piperacillin and carbenicillin. enhanced by the production of ester formulations . Axetil, proxetil, or Numerous modifications at R2 or the 3 position have also played a pivoxyl esters of cefuroxime, ceftamet, cefpodoxime, and cefditoren significant role in the development of the current cephalosporins . An 3 are currently available. acetoxy side chain is present in cephalothin, cephapirin, and cefo- The majority of the chemical modifications in cephalosporin de- taxime.5 Cephalosporins with this structure can be metabolized in both velopment, which have resulted in changes in microbiologic spectrum, the serum and liver to a less active desacetyl derivative . Such drugs are due to alterations at the a-carbon of the acyl side chain .' These also tend to have a short half-life . A chloride substitution at R2 en- changes have ranged from the relatively simple addition of a hydroxyl hanced the gram-negative spectrum of activity and led to the develop- group to the addition of large synthetic moieties . Each of the acyl side ment of cefaclor, an early second-generation cephalosporin. The chain alterations has led to enhanced gram-negative potency because unique pharmacology of ceftriaxone results from an R2 modification . 3 of improved (3-lactamase stability. The addition of a hydroxyl group at Substitution of a heterocyclic thiomethyl group at the 3 position in- the 01-carbon led to the second-generation cephalosporin cefamandole . creases its biliary secretion and remarkably prolongs the elimination The second-generation cephalosporin cefuroxime resulted from the half-life of the compound because of protein binding .'," The addition addition of a methoxyimino group in the a position along with a furyl of positively charged quaternary ammonium moieties in the 3 position nng at the P-acyl side chain . Addition of a 2-aminothiazol group to the contributed to the development of the fourth-generation cephalo- 7- Q-acyl side chain and a methoxyimino group to the a-carbon led to sporins cefepime and cefpirome .9 The chemical modification produces 3 many of the third- and fourth-generation cephalosporins (Figs . 20-4 a zwitterion, which enhances the ability of the compound to penetrate and 20-5)."9 Cefotaxime, ceftizoxime, ceftriaxone, cefepime, cef- the outer membrane of gram-negative organisms . Not all modifica- p>rome, and cefpodoxime all have a similar structure at the 7 position . tions have led to desired effects . The placement of a thiomethyl tetra- CeftaZidime ;efazolin . differs from these drugs by replacing the methoxyimino zole ring (MTT) at the R2 position not only enhanced antibacterial efadroxil- group with a dimethylacetic acid moiety attached to the imino group .' activity but also resulted in two important adverse effects that have s alteration enhances activity against Pseudomonas aeruginosa but limited use of these compounds ."," Cefamandole, cefotetan, and