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Chapter: Pharmaceutical Microbiology : Antibiotics And Synthetic Antimicrobial Agents: Their Properties And Uses

There are quite a number of similarities between cephalosporins and penicillins, including their early history. In both cases, the academic research was conducted at Oxford University and the American pharmaceutical companies converted that early work into a marketed product.



There are quite a number of similarities between cephalosporins and penicillins, including their early history. In both cases, the academic research was conducted at Oxford University and the American pharmaceutical companies converted that early work into a marketed product. The discovery of the first cephalosporin was made in 1948 in Sardinia, the research was conducted at the William Dunn School of Pathology during the 1950s and the first antibiotics in the class, cephalothin and cephaloridine, became available in the mid 1960s. Since then many cephalosporins have been synthesized, and more than 60 have been marketed in various countries over the last 40 years, although not all of them are still available. As with the penicillins, the policy in this chapter is to consider the general properties of this class of antibiotics and to provide more detail about selected important cephalosporins, rather than provide a comprehensive listing.


Cephalosporins consist of a six-membered dihydrothiazine ring fused to a β-lactam ring (top structure in Figure 11.4). The position of the double bond in Δ3-cephalosporins is important, since Δ2-cephalosporins (double bond between 2 and 3) are not antibacterial, irrespective of the composition of the side chains. The similarity to the basic penicillin structure is immediately apparent, but the crucial difference is that there is much greater scope for structural modification of the cephalosporins because of the presence of two side chains (on carbons 3 and 7) in contrast to the single side chain of penicillins. Again, the fundamental properties of acid stability (and hence oral availability), antimicrobial spectrum, resistance to β-lactamases and pharmacokinetics can all be substantially varied by sidechain modifications. Several of the cephalosporins act as good inducers of β-lactamases.

The many cephalosporins have been classified into ‘g enerations’, although the usefulness of such a classification has been questioned. There is general acceptance of four generations, but ceftobiprole has been claimed as the first member of the fifth. The assignment of cephalosporins into the first four generations has broadly followed the time course of their introduction, but there has been some overlap, so certain drugs that have been classified into one particular generation were marketed in some countries after the earliest ones of the next. The situation is further complicated by the fact that there is not universal agreement on the generation to which some cephalosporins belong; cefaclor, for example, is considered a first-generation antibiotic in Japan, but is regarded as second-generation in most other countries.

The general trends have been for an increase in activity towards Gramnegative species (usually with a corresponding loss of anti-staphylococcal action), and increased resistance to β-lactamase as the development of cephalosporins has progressed through the generations. First-generation drugs are those that have moderate antimicrobial activity and resistance to staphylococcal, but not Gram-negative, β-lactamases. These were originally used primarily as alternative antibiotics for the treatment of staphylococcal infections, and are rarely first-choice therapy. Like the oral penicillins, the oral cephalosporins may disturb the gut flora and give rise to diarrhoea. The possession of good resistance to both staphylococcal and Gram-negative β-lactamases is the principal characteristic distinguishing the second from the first-generation antibiotics, although improved potency, particularly towards H. influenzae and enterobacteria, is also a feature. Yet higher activity towards Gram-negative bacteria is displayed by third generation drugs, to an extent that some of them have little or no value in the treatment of staphylococcal infections. The parenterally administered third generation cephalosporins, e.g. cefotaxime and ceftazidime, are sometimes used in combination with gentamicin or other aminoglycosides with the intention of achieving synergy. The usefulness of the third generation drugs has diminished somewhat since their introduction as a consequence of the spread of strains capable of producing extended-spectrum β-lactamases and it was this deficiency that the fourth-generation cephalosporins were intended to remedy. Cefpirome and cefepime exhibit extremely good enzyme resistance, but otherwise have much the same antibacterial spectrum as ceftazidime and other third-generation molecules.


Structure-activity relationships


The activity of cephalosporins (and other β-lactams) against Gram-positive bacteria depends on antibiotic affinity for penicillin-sensitive enzymes (PSEs) also known as penicillin binding proteins (PBPs). Resistance results from altered PBPs or, more commonly, from β-lactamases. Activity against Gram-negative bacteria depends on penetration of β-lactams through the outer membrane, resistance to β-lactamases found in the periplasmic space and binding to PBPs. (For further information on mechanisms of action and bacterial resistance, see Chapters 12 and 13). Modification of the cephalosporin nucleus (Figure 11.4) at 7α (i.e. R3) by addition of a methoxy group increases β-lactamase stability but decreases activity against Gram-positive bacteria because of reduced affinity for PBPs; molecules possessing a 7α-methoxy group, e.g. cefoxitin, are termed cephamycins.


Side chains containing a 2-aminothiazolyl group at R1, e.g. cefotaxime, ceftriaxone and ceftazidime, yield cephalosporins with enhanced affinity for PBPs of Gram-negative bacteria and streptococci. An iminomethoxy group (-C=N.OCH3) in, for example, cefuroxime, provides β-lactamase stability against common plasmid-mediated β-lactamases. A propylcarboxy group ((CH3)2-C-COOH) as in ceftazidime increases β-lactamase resistance and also provides activity against Ps. aeruginosa, while at the same time reducing β-lactamase induction capabilities. In cephalosporins susceptible to β-lactamases, opening of the β-lactam ring occurs with concomitant loss of the substituent at R2 (except in cefalexin, where R2 represents H; see Figure 11.4). This is followed by fragmentation of the molecule.


The nature of the R2 substituent influences both the pharmacokinetic properties of the molecule and its ability to enter bacterial cells—particularly to cross the outer membrane of Gram-negative bacteria via porins. For good oral absorption: (1) the R2 substituent must be small, non-polar and stable; a methyl group is considered desirable but might decrease antibacterial activity; and (2) the 7-acyl group (R1) must be based on phenylglycine and the amino group must remain unsubstituted. Esterification of the carboxylic acid group at C4 can, as with the penicillins, result in enhanced oral absorption provided that the ester is rapidly hydrolysed by tissue esterases; this is exemplified in both cefuroxime axetil and cefpodoxime proxetil. The possession of a quaternary nitrogen on the side chain at position 3 has two benefits: it reduces the affinity of the cephalosporin for Gram-negative β-lactamases, in other words, makes it more resistant to enzyme attack, and it makes the molecule zwitterionic which increases the rate at which it can pass through the porin channels into the Gram-negative cell.


Side chains of the various cephalosporins, including those most recently developed, are presented in Figure 11.4 and a summary of the properties of these antibiotics in Table 11.3.

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