Cephalosporins

Abstract

AbstractThe cephalosporins, a subgroup of β‐lactam antibiotics, consist of a 4‐membered lactam ring fused through the nitrogen and the adjacent tetrahedral carbon atom to a second heterocycle forming a 6‐membered dihydrothiazine ring. Other structural features common to all the cephalosporins are a carboxyl group on the dihydrothiazine ring on the carbon next to the ring nitrogen and a functionalized amino group on C‐7, the carbon of the β‐lactam ring opposite the nitrogen. Cephalosporins, like all β‐lactam antibiotics, exert their antibacterial effect by interfering with the synthesis of the bacterial cell wall. Cephalosporins are widely used for treating bacterial infections. They are highly effective and have low toxicity. Naturally occurring cephalosporins, cephamycins, and the 7‐formamido cephalosporins are deacetoxycephalosporin C (C14H19N3O8S), deacetylcephalosporin C (C14H19N3O7S), cephalosporin C (C16H12N2O5S),O‐carbamoyldeacetylcephalosporin C (C15H19N4O8S), 3′‐methylthiodeacetoxycephalosporin C (F1) (C15H21N3O6S2), 3′‐sulfothiodeacetoxycephalosporin C (F2), (C14H19N3O9S3), C43–219 (C19H28N4O8S2), 7α‐methoxycephalosporin C (C17H23N3O9S), cephamycin C (C16H22N4O9S), cephamycin A (C25H29N3O14S2), cephamycin B (C25H29N3O11S), Takeda C2801X (C25H29N3O12S), SF‐1623 (C15H21N3O10S3), SQ 28, 516 (C36H55N11O15S1), SQ 28, 517 (C36H56N12O14S1), cephabacin F1or chitinovorin A (C26H41N9O11S), cephabacin H1(C25H40N8O10S), and cephabacin M1(C31H50N8O13S), among others. The biosynthesis of cephalosporins and penicillins both start from the amino acids and proceed via δ‐(L‐α‐aminoadipyl)‐L‐cysteinyl‐D‐valine (LLD‐ACV), C14H25N3O6S, often referred to as the Arnstein tripeptide. In theCephalosporiumspecies and theStreptomycesspecies, an epimerase is present that converts isopenicillin N into penicillin N, C14H21N3O6S, which then undergoes a ring expansion to deacetoxycephalosporin C. Using cephalosporin C as a substrate, another dioxygenase catalyzes the incorporation of a 7α‐hydroxy function, hence forming the corresponding 7α‐methoxycephalosporin. Details of these steps are discussed in the literature. Rapid advances in this area have been made possible by the successful cloning and expression of isopenicillin N synthetase (IPNS) and ring expansion‐hydroxylase (REX). Most cephalosporin antibiotics are white, off‐white, tan, or pale yellow solids that are usually amorphous, but can sometimes be obtained crystalline. The cephalosporins do not usually have sharp melting points, but rather decompose upon heating at elevated temperatures. Much of the chemical reactivity of the β‐lactam antibiotics is associated with the β‐lactam moiety. The geometry and the accompanying increased ring strain results in very little, if any, amide‐resonance stabilization leading to a marked increase in chemical reactivity when compared to a normal amide. Fused β‐lactam antibiotics are readily attacked by nucleophiles with resultant ring opening and loss of biological activity. The cephalosporins are more resistant to ring opening than the penicillins. As of 1991, there were approximately fifty different cephalosporins in clinical use or at an advanced stage of evaluation and development. These include oral cephalosporins, eg, cephalexin (C16H17N3O4S); oral cephalosporins‐prodrugs, eg, cefuroximeaxetil (C20H22N4O10S1); cephamycins, eg, cefoxitin (C15H15N3O6); parenteral cephalosporins, eg, cephalothin (C16H16N2O6S2); and oxadethiacephalosporins, eg, moxalactam latamoxef (C20H20N6O8S). The most common classification divides the cephalosporins into three groups or generations. First‐generation cephalosporins are characterized by good gram‐positive activity and modest to weak gram‐negative activity. Third‐generation cephalosporins have an expanded gram‐negative spectrum and are the most active against enteric gram‐negative bacilli. Structure–activity relationships can be inferred by comparison of the antibacterial properties of the clinical agents and related compounds. Different acyl side chains can result in significant changes in the antibacterial activity. The highest activities are observed when the acylamino side chain at C‐7 is a substituted acetic acid. Resistance to the cephalosporins may result from the alteration of target penicillin‐binding sites (PBPs), decreased permeability of the bacterial cell wall and outer membrane, or by inactivation via enzyme‐mediated hydrolysis of the lactam ring. At present all of the cephalosporins are manufactured from one of four β‐lactams, cephalosporin C, penicillin V, penicillin G, and cephamycin C, which are all produced in commercial quantities by fermentation. The cephalosporins are used for treating infectious diseases of bacterial origin in both humans and animals. First‐generation cephalosporins such as cephalothin and cephalexin are the most active against staphylococci and nonenterococcal streptococci. They are especially useful for treating patients who are allergic to the penicillins or who have mixed infections from gram‐positive and gram‐negative bacteria. The first‐generation cephalosporins have been widely used for prophylaxis in cardiovascular, orthopedic, biliary, pelvic, and intraabdominal surgery. Whereas third‐generation cephalosporins do have some coverage against gram‐positive infections, they are not the agents of choice. Most community‐acquired infections are better treated with drugs other than the third‐generation cephalosporins, the treatment of meningitis being an exception. The third‐generation cephalosporins are effective in the treatment of bacteremias, pneumonias, urinary tract infections, intraabdominal infections, and skin and soft tissue infections. The cephalosporins generally cause few side effects with hypersensitivity reactions being the most common. Thrombophlebitis occurs as a result of intravenous administration of all cephalosporins.