CEPHALOSPORINS & MECHANISM OF ACTION
Cephalosporins are a group of semisynthetic antibiotics derived from ‘cephalosporin-C’ obtained from a fungus Cephalosporium. Cephalosporins are chemically related to penicillins the nucleus consists of a β-lactam ring fused to a dihydrothiazine ring, (7-aminocephalosporanic acid). By the addition of different side chains at position 7 of the β-lactam ring (altering the spectrum of activity) and at position 3 of dihydrothiazine ring (affecting pharmacokinetics), a large number of semisynthetic compounds have been produced. Cephalosporins have been conventionally divided into 4 generations. This division has a chronological sequence of development, but more importantly, takes into consideration the overall antibacterial spectrum as well as potency.
First generation cephalosporins
- Parenteral – Cephalothin, Cefazolin
- Oral – Cephradine, Cephalexin, Cefadroxil
Second generation cephalosporins
- Parenteral – Cefuroxime, Cefoxitin
- Oral – Cefaclor,Cefuroxime axetil
Third generation cephalosporins
Parenteral – Cefotaxime ,Ceftizoxime,Ceftriaxone ,Ceftazidime ,Cefoperazone
Oral- Cefixime , Cefpodoxime proxetil,Cefdinir,Ceftibuten,Ceftamet pivoxil
Fourth generation cephalosporins
Parenteral – Cefepime ,Cefpirome
All cephalosporins are bactericidal and have the same mechanism of action as penicillin, i.e. inhibition of bacterial cell wall synthesis.
However, they bind to different proteins than those which bind penicillins. This may explain differences in spectrum, potency, and lack of cross-resistance.
Acquired resistance to cephalosporins could have the same basis as for penicillins, i.e.:
- Alteration in target proteins (PBPs) reduces affinity for the antibiotic.
- Impermeability to the antibiotic or its efflux so that it does not reach its site of action.
- Elaboration of β-lactamases which destroy specific cephalosporins (cephalosporinases).
Though the incidence is low, resistance has been developed by some organisms, even against third-generation compounds. Individual cephalosporins differ in their:
(a) Antibacterial spectrum and relative potency against specific organisms.
(b) Susceptibility to β-lactamases elaborated by different organisms.
(c) Pharmacokinetic properties—many have to be injected, some are oral; the majority are not metabolized, and are excreted rapidly by the kidney; have short t½s, and probenecid inhibits their tubular secretion.
(d) Local irritancy on i.m. injection; few cannot be injected i.m.
Mechanism of action
All β-lactam antibiotics interfere with the synthesis of the bacterial cell wall. The bacteria synthesize UDP-N-acetylmuramic acid pentapeptide, called ‘Park nucleotide’ (because Park in 1957 found it to accumulate when susceptible Staphylococcus was grown in the presence of penicillin) and UDP-N-acetyl glucosamine. The peptidoglycan residues are linked together forming long strands and UDP is split off. The final step is the cleavage of
the terminal D-alanine of the peptide chains by transpeptidases; the energy so released is utilized for the establishment of cross-linkages between peptide chains of the neighboring strands This cross-linking provides stability and rigidity to the cell wall.
The β-lactam antibiotics inhibit the transpeptidases so that cross-linking (which maintains the close-knit structure of the cell wall) does not take place. These enzymes and related proteins constitute the penicillin-binding proteins (PBPs) which have been located in the bacterial cell membrane. Each organism has several PBPs and PBPs obtained from different species differ in their affinity towards different β-lactam antibiotics. This fact probably explains their different sensitivity to the various β-lactam antibiotics.
When susceptible bacteria divide in the presence of a β-lactam antibiotic—cell wall deficient (CWD) forms are produced. Because the interior of the bacterium is hyperosmotic, the CWD forms swell and burst → bacterial lysis. This is how β-lactam antibiotics exert bactericidal action. Under certain conditions and in the case of certain organisms, bizarre shaped or filamentous forms, which are incapable of multiplying, result. Grown in hyperosmotic medium, globular ‘giant’ forms or protoplasts are produced. The lytic effect of these antibiotics may also be due to the derepression of some bacterial autolysins which normally function during cell division.
Rapid cell wall synthesis occurs when the organisms are actively multiplying; β-lactam antibiotics are more lethal in this phase.
The peptidoglycan cell wall is unique to bacteria. No such substance is synthesized (particularly, D-alanine is not utilized) by higher animals. This is why penicillin is practically nontoxic to man.
In gram-positive bacteria, the cell wall is almost entirely made of peptidoglycan, which is >50 layers thick and extensively cross-linked, so that it may be regarded as a single giant mucopeptide molecule. In gram-negative bacteria, it consists of alternating layers of lipoprotein and peptidoglycan (each layer is 1–2 molecules thick with
little cross-linking). This may be the reason for the higher susceptibility of the gram-positive bacteria to PnG.
Blood, pus, and tissue fluids do not interfere with the antibacterial action of β-lactam antibiotics.
References: Essentials of Medical Pharmacology, 6th Edition- KD TRIPATHI