Like imipenem, meropenem is not active orally. It is provided as a sterile lyophilized powder to be made up in normal saline or 5% dextrose solution for parenteral administration. Approximately 70% to 80% of unchanged meropenem is excreted in the urine following intravenous or intramuscular administration. The remainder is the inactive metabolite formed by hydrolytic cleavage of the jS-lactam ring. The lower incidence of nephrotoxicity of meropenem (compared with imipenem) has been correlated with its greater stability to DHP-I and the absence of the DHP-I inhibitor cilastatin in the preparation. Meropenem appears to be less epileptogenic than imipenem when the two agents are used in the treatment of bacterial meningitis.
Biapenem is a newer second-generation carbapenem with chemical and microbiological properties similar to those of meropenem.67 Thus, it has broad-spectrum antibacterial activity that includes most aerobic Gram-negative and Grampositive bacteria and anaerobes. Biapenem is stable to DHP-I67 and resistant to most ^-lactamases.68 It is claimed to be less susceptible to metallo-^-lactamases than either imipenem or meropenem. It is not active orally.
o CEPHALOSPORINS Historical Background
The cephalosporins are 3-lactam antibiotics isolated from Cephalosporium spp. or prepared semisynthetically. Most of the antibiotics introduced since 1965 have been semisynthetic cephalosporins. Interest in Cephalosporium fungi began in 1945 with Giuseppe Brotzu's discovery that cultures of C. acremonium inhibited the growth of a wide variety of Gram-positive and Gram-negative bacteria. Abraham and Newton68a in Oxford, having been supplied cultures of the fungus in 1948, isolated three principal antibiotic components: cephalosporin Pl, a steroid with minimal antibacterial activity; cephalosporin N, later discovered to be identical with synnematin N (a penicillin derivative now called penicillin N that had earlier been isolated from C. salmosynnematum); and cephalosporin C.
The structure of penicillin N was discovered to be d-(4-amino-4-carboxybutyl)penicillanic acid. The amino acid side chain confers more activity against Gram-negative bacteria, particularly Salmonella spp., but less activity against Gram-positive organisms than penicillin G. It has been used successfully in clinical trials for the treatment of typhoid fever but was never released as an approved drug.
Cephalosporin C turned out to be a close congener of penicillin N, containing a dihydrothiazine ring instead of the thiazolidine ring of the penicillins. Despite the observation that cephalosporin C was resistant to S. aureus ^-lactamase, early interest in it was not great because its antibacterial potency was inferior to that of penicillin N and other penicillins. The discovery that the a-aminoadipoyl side chain could be removed to efficiently produce 7-aminocephalospo-ranic acid (7-ACA),69,70 however, prompted investigations that led to semisynthetic cephalosporins of medicinal value. The relationship of 7-ACA and its acyl derivatives to 6-APA and the semisynthetic penicillins is obvious. Woodward et al.71 have prepared both cephalosporin C and the clinically useful cephalothin by an elegant synthetic procedure, but the commercially available drugs are obtained from 7-ACA as semisynthetic products.
The chemical nomenclature of the cephalosporins is slightly more complex than even that of the penicillins because of the presence of a double bond in the dihydroth-iazine ring. The fused ring system is designated by Chemical Abstracts as 5-thia-1-azabicyclo[4.2.0]oct-2-ene. In this system, cephalothin is 3-(acetoxymethyl)-7-[2-(thienylacetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. A simplification that retains some of the systematic nature of the Chemical Abstracts procedure names the saturated bicyclic ring system with the lac-tam carbonyl oxygen cepham (cf., penam for penicillins). According to this system, all commercially available cephalosporins and cephamycins are named 3-cephems (or A3-cephems) to designate the position of the double bond. (Interestingly, all known 2-cephems are inactive, presumably because the 3-lactam lacks the necessary ring strain to react sufficiently.) The trivialized forms of nomenclature of the type that have been applied to the penicillins are not consistently applicable to the naming of cephalosporins because of variations in the substituent at the 3-position. Thus, although some cephalosporins are named as derivatives of cephalosporanic acids, this practice applies only to the derivatives that have a 3-acetoxymethyl group.
To date, the more useful semisynthetic modifications of the basic 7-ACA nucleus have resulted from acylations of the 7-amino group with different acids or nucleophilic substitution or reduction of the acetoxyl group. Structure-activity relationships (SARs) among the cephalosporins appear to parallel those among the penicillins insofar as the acyl group is concerned. The presence of an allylic acetoxyl function in the 3-position, however, provides a reactive site at which various 7-acylaminocephalosporanic acid structures can easily be varied by nucleophilic displacement reactions. Reduction of the 3-acetoxymethyl to a 3-methyl substituent to prepare 7-aminodesacetylcephalosporanic acid (7-ADCA)
Penicillin N Cephalosporin C
derivatives can be accomplished by catalytic hydrogénation, but the process currently used for the commercial synthesis of 7-ADCA derivatives involves the rearrangement of the corresponding penicillin sulfoxide.72 Perhaps the most noteworthy development thus far is the discovery that 7-phenyl-glycyl derivatives of 7-ACA and especially 7-ADCA are active orally.
In the preparation of semisynthetic cephalosporins, the following improvements are sought: (a) increased acid stability, (b) improved pharmacokinetic properties, particularly better oral absorption, (c) broadened antimicrobial spectrum, (d) increased activity against resistant microorganisms (as a result of resistance to enzymatic destruction, improved penetration, increased receptor affinity, etc.), (e) decreased allergenicity, and (f) increased tolerance after parenteral administration.
Structures of cephalosporins currently marketed in the United States are shown in Table 8.4.
Cephalosporins experience various hydrolytic degradation reactions whose specific nature depends on the individual structure (Table 8.4).73 Among 7-acylaminocephalospo-ranic acid derivatives, the 3-acetoxylmethyl group is the most reactive site. In addition to its reactivity to nucleophilic displacement reactions, the acetoxyl function of this group readily undergoes solvolysis in strongly acidic solutions to form the desacetylcephalosporin derivatives. The latter lac-tonize to form the desacetylcephalosporin lactones, which are virtually inactive. The 7-acylamino group of some cephalosporins can also be hydrolyzed under enzymatic (acylases) and, possibly, nonenzymatic conditions to give 7-ACA (or 7-ADCA) derivatives. Following hydrolysis or solvolysis of the 3-acetoxymethyl group, 7-ACA also lac-tonizes under acidic conditions (Fig. 8.5).
The reactive functionality common to all cephalosporins is the ^-lactam. Hydrolysis of the ^-lactam of cephalosporins is believed to give initially cephalosporoic acids (in which the
R' group is stable, [e.g., R' = H or S heterocycle]) or possibly anhydrodesacetylcephalosporoic acids (7-ADCA, for the 7-acylaminocephalosporanic acids). It has not been possible to isolate either of these initial hydrolysis products in aqueous systems. Apparently, both types of cephalosporanic acid undergo fragmentation reactions that have not been characterized fully. Studies of the in vivo metabolism74 of orally administered cephalosporins, however, have demonstrated arylacetylglycines and arylacetamidoethanols, which are believed to be formed from the corresponding arylacetyl-aminoacetaldehydes by metabolic oxidation and reduction, respectively. The aldehydes, no doubt, arise from nonenzymatic hydrolysis of the corresponding cephalosporoic acids. No evidence for the intramolecular opening of the ^-lactam ring by the 7-acylamino oxygen to form oxazolones of the penicil-lanic acid type has been found in the cephalosporins. At neutral to alkaline pH, however, intramolecular aminolysis of the ^-lactam ring by the a-amino group in the 7-ADCA derivatives cephaloglycin, cephradine, and cefadroxil occurs, forming diketopiperazine derivatives.75,76 The formation of dimers and, possibly, polymers from 7-ADCA derivatives containing an a-amino group in the acylamino side chain may also occur, especially in concentrated solutions and at alkaline pH values.
The oral activity conferred by the phenylglycyl substituent is attributed to increased acid stability of the lactam ring, resulting from the presence of a protonated amino group on the 7-acylamino portion of the molecule. Carrier-mediated transport of these dipeptide-like, zwitterionic cephalosporins51 is also an important factor in their excellent oral activity. The situation, then, is analogous to that of the a-aminobenzylpenicillins (e.g., ampicillin). Also important for high acid stability (and, therefore, good oral activity) of the cephalosporins is the absence of the leaving group at the 3-position. Thus, despite the presence of the phenylglycyl side chain in its structure, the
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TABLE 8.4 Structure of Cephalosporins
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