CEPHALOSPORINS
Cephalosporin compounds were first isolated from cultures of Cephalosporium
acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu. He noticed that these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever. Researchers at the Sir William Dunn School of Pathology at the University of Oxford isolated Cephalosporin C, which had stability to B-lactamases but was not sufficiently potent for clinical use. The cephalosporin nucleus, 7-Aminocephalosporanic acid (7-ACA), was derived from Cephalosporin C and proved to be analogous to the penicillin nucleus 6-Amino penicillanic acid. Modification of the 7-ACA side-chains resulted in the development of useful antibiotic agents and the first agent
Cephalothin was launched by Eli Lilly in 1964.
Mode of Action: Cephalosporins are bactericidal and have the same mode of action as other B-lactam antibiotics (such as Penicillins). Cephalosporins disrupt the synthesis of the peptodoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity, especially in Gram-positive organisms. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as
penicillin binding proteins.
Clinical Uses: Cephalosporins are indicated for the prophylaxis and treatment of bacterial infections caused by susceptible organisms. First-generation cephalosporins are predominantly active against Gram-positive bacteria and successive generations have
increased activity against Gram-negative bacteria.
CHEMISTRY;
The nomenclature of cephalosporin is more complex than penicillins because of the presence of a double bond in dihydrothiazine ring.Basic nucleus is made up of 7-Amino cephalosporanic acid(7-ACA).
Semi synthetic modification of the basic 7-ACA nucleus has resulted from acylation of the 7-amino group with different acids or nucleophilic substitution or reduction of the acetoxyl group.
The semi synthetic Cephalosporins has got the following advantages over natural Cephalosporins.
- Increased acid stability
- Better oral absorption
- Broad antimicrobial spectrum
- Increased activity against resistant microorganisms
- Decreased allerginicity
- Increased tolerance
BASED ON GENERATIONS
a) First Generation: eg. Cefacetrile, Cefalexin, Cefadroxil, Cefaloglycin, Cephalothin
Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazaflur Cefazedone. Cefazolin, Cefradine, Cefroxadine,
Ceftezole.
b) Second Generation: eg. Cefonicid, Cefprozil, Cefuroxime, Cefuzonam, Cefaclor,
Cefamandole, Ceforanide, Cefotiam, Carbacephems, Loracarbef, Cephamycins, Cefbuperazone, Cefmetazole, Cefminox, Cefotetan, Cefoxitin.
Generation: eg. Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpodoxime. Cefteram, Ceftibuten, Ceftiofur, Ceftiolene, Ceftizoxime, Ceftriaxone, Ceftazidime, Cefpiramide, Cefsulodin.
d) Fourth Generation: eg. Cefclidine, Cefepime, Cefluprenam, Cefoselis, Cefozopran,
Cefpirome, Cefquinome.
Yet to be Classified: eg. Cefaclomezine, Cefaloram, Cefaparole, Cefcanel,Cefedrolor,Cefempidone,Cefetrizole,Cefivitril,Cefmatilen, Cefmepidium, Cefovecin, Cefoxazole Cefrotil, Cefsumide, Ceftioxide, Ceftobiprole,
Cefuracetime.
II. Based on Route of Administration
a) Oral Cephalosporins: eg. Cephalexin, Cephadrine, Cefadroxil, Cefachlor,
Cefprozil, Loracarbef, Cefuroxine auetil, Cefpodoxime proxetil, Cefixime.
b) Parenteral Cephalosporins: eg. Cephalothin, Caphapirin, Cefazolin,
Cefamandole, Cefonicid, Cefornaide, Cefuroxime, Cefotaxime, Ceftizoxime,
Ceftrixone, Ceftazidime, Cefoperazone.
STRUCTURE OF CEPHALOSPORINS
- The cephalosporins are derivatives of 7-aminocephalosporanic acid and are closely related in structure to penicillin. 7-aminocephalosporinic acid (7-ACA) is used as
precursor for many semisynthetic cephalosporins.
- The cis-stereochemistry at positions 6 and 7 are important.
They are relatively stable in dilute acid and are highly resistant to penicillinase. They have a ß-lactam ring which is vital for activity. Bicyclic ring system, fused B lactam and dihydrothiazine ring form a bicyclic system which is important for activity.
The acylamino side chain may be altered. Other groups may be substituted for the acetoxy group which may or may not serve as good leaving group. The nature of the leaving group is important for activity.
Better leaving group tend to give Cephalosporin C analogues with better activity. First-Generation Cephalosporins: Activity is comparably lower than penicillins
but possess a broad spectrum of activity. Greater activity for Gram-positive organisms than Gram-negative organisms. The methyl group in Cephalexin is a poor leaving group (less active), but improves absorption. Cephalothin has an acetoxy as a leaving group and 1-(Thiophen-2-yl) propan-2-one in its acylamino side chain. Despite being a good leaving group, the acetoxy moiety is susceptible to enzyme catalysed hydrolysis. Cephaloglycin's acylamino side chain is same as Ampicillin's. Cephaloridine has pyridinium as a leaving group.
Second-Generation Cephalosporins: Have increased activity against Gram negative bacteria, but some have decreased Gram-positive activity. Many can cross the blood-brain barrier. Cefuroxime is also an example of an oximino cephalosporin. The presence of the imino methoxy group appears to increase stability against certain B-lactamases.
Third-Generation Cephalosporins: Even better activity against Gram-negative bacteria. Some compounds have the same problem of decreased Gram-positive activity as the previous generation.Improved beta-lactomase resistance and many can also cross blood-brain barrier.
Fourth-Generation Cephalosporins: Better Gram-ve bacteria activity, beta-lactomase resistance and many can also cross the blood brain barrier .Gram positive activity similar to the 1 st generation .The fourth generation compound exists az zwitterion.They are also used against pseudomonad aeruginosa.
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