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Introduction
The cephalosporins are -Lactam antibiotics that are closely related both structurally and functionally to the penicillins. Mechanism of action, mechanism of resistance and some other properties of cephalosporins are identical to penicillins) Cephalosporins are one of the most widely used antibiotics and are equal in importance to penicillin.
In 1948
Abraham and his colleagues have been supplied cultures of the fungus and was isolated three principal antibiotic components:
- Cephalosporin P, (a steroid antibiotic that resembles fusidic acid) with minimal antibacterial activity. - Cephalosporin N, later discovered to be identical with synnematin N (a penicillin derivative now called penicillin N) - Cephalosporin C.
Penicillin N (Cephalosporin N)
*Most of the antibiotics introduced since 1965 have been semisynthetic cephalosporins.
HO
HO
Cephalosporin C
7- aminocephalosporinic acid
*Compounds containing 7-aminocephalosporanic acid are: - Relatively stable in dilute acid. - Highly resistant to penicillinase, regardless of the nature of their side chains and their affinity for the enzyme.
This compound has been modified by the addition of different side chains to create a whole family of cephalosporin antibiotics.
Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.
Cephalosporins (7-H) and cephamycins (7-OCH3):
O H R NH O 7 6 N 1 5 S 4 3 2 O X R
O OCH3 NH O 7 6 N 1 5 S 4 3 2 O X
HO
HO
Cephalosporins
Cephamycin
Most natural cephalosporin and cephamycin are not used clinically for side effects, but semi-synthetic products are used.
Mechanism of action
- Alteration of binding site. - Decrease permeability. - Production of lactamase enzymes (enzymatic inactivation).
Classification of cephalosporins Cephalosporins have been classified as first, second, third and fourth generation largely on the basis of bacterial susceptibility patterns and resistance to - lactamases:
First generation Second generation Third generation Fourth generation
Cefamandole Cefuroxime Cefonicid Ceforanide Cefaclor* Cefoxitin Cefotetan Cefprozil* Cepuroxime axetil* Cefmetazole
Cefotaxime Ceftizoxime Ceftriaxone Ceftazidime Cefoperazone Cefixime* Cefpodoxime proxetil* Ceftibuten* Cefdinir*
* Oral agents
Classification of cephalosporins
* Cefazolin
O N N N Cefazolin O C O OH CH2 S C NH N CH2S S N N CH3
* Cefazolin
O N N N Cefazolin O C O OH CH2 S C NH N CH2S S N N CH3
*Cephalexin
O S CH NH2 C NH N O C Cephalexin O OH CH3
* Cephradine
O S CH NH2 C NH N O C Cephradine O OH CH3
* Cefadroxil
O S
HO
CH NH2
NH N O C O CH3 OH
Cefadroxil
Second generation:
* Cefamandole
O S CH OH Cefamandole O C NH N O C OH CH2S N CH3 N N N
* Cefoxitin
O CH2 S O Cefoxitin O C OH C NH N CH2OCNH2 O OCH3 S
* Cefaclor
O S CH NH2 Cefachlor O C NH N O C OH Cl
* Cefuroxime
O S C O NOCH3 Cefuroxime O O C OH C NH N CH2OCNH2 O
* Cefuroxime axetil
O S C O NOCH3 O C O O CHOCCH 3 CH3 C NH N CH2OCNH2 O O
Cefuroxime axetil
* Cefonicid
O S CH OH Cefonicid O C NH N O C OH CH2S N CH2SO3H N N N
* Cefotetan
O H2N C C HO C O O Cefotetan S O C OH O S C NH N CH2S N CH3 N N N CH3O
* Ceforanide
O S CH2 CH2NH2 Ceforanide O C NH N O C OH CH2S N CH2CO2H N N N
* Cefmetazole
O NCCH2SCH2 C NH N O Cefmetazole O C OH CH2S N CH3 N N N CH3O
Third generation:
*Cefotaxime
S H2N N O S C C NH O N CH2OCCH3 C O OH O
NOCH3 Cefotaxime
*Ceftizoxime
S H2N N NOCH3 Ceftizoxime O O C OH C O S C NH N H
*Ceftriaxone
S H2N N NOCH3 Ceftriaxone O O C OH C O S C NH N CH2S N O CH3 N N OH
*Cefixime
S H2N N NOCH2CO2H Cefixime O C O OH C O S C NH N CH=CH2
*Cefpodoxime proxetil
S H2N N NOCH3 Cefpodoxime proxetil O O C O C O S C NH N CH2OCH3 O CHOCOCH(CH 3)2 CH3
N C2H5
*2-Ceftazidime
S H2N N N O CH3 C CH3 O C CO2H O OH Ceftazidime C O S C NH N CH2 + N
+ N
* Cefepime
O N H2N S C N OCH3 Cefepime O CO2 C HN N H H S H3 C N+
Pharmacokinetics
1- Administration:
All cephalosporins except cefadroxil, cephalexin, cephradine, cefaclor, cefuroxime axetil, cefdinir, cefixime and ceftibuten must be administered intravenously because of their poor oral absorption.
2- Distribution: - All of cephalosporins distribute very well into body fluids. However, several cephalosporins penetrate into CSF in sufficient concentration to be useful for the treatment of meningitis. These include: Cefuroxime (2nd gen.), ceftriaxone, cefotaxime and ceftizoxime (3rd gen.).
3- Fate: - Elimination occurs through tubular secretion and/or glomerular filtration. Cefoperazone are excreted through the bile and are frequently used in patients with renal insufficiency.
Adverse reactions
The most common adverse reactions are:
4- Nephrotoxicity.
Therapeutic uses
- When Gm +ve bacteria is involved a 1st generation agents is preferable. - When the pathogen is gm ve and the infection is serious parentral use of a 3rd generation agent is recommended.
First generation cephalosporins are: Excellent agents for skin and soft tissue infections due to S. aureus and S. Pyogenes. A single dose of cefazolin just before surgery is the preferred as prophylaxis
Second-generation cephalosporins
The second generation agents have inferior activity against penicillin-resistant S. pneumoniae compared to either the 3rd generation agents or ampicillin and therefore should not be used for treatment of meningitis or pneumonia.
In case where Gm -ve bacteria and anaerobes are involved such as intraabdominal infections, pelvic inflammatory disease and diabetic foot infection, cefoxitin and cefotetan have been shown to be effective. For colorectal surgery where prophylaxis for intestinal anaerobes is desired, cefoxitin or cefotetan (2nd generation) are preferred.
Third generation cephalosporins Third generation cephalosporins have been considered to be the drugs of choice for serious infections caused by: Klebsiella, Enterobacter, Proteus, Haemophilus species. Ceftriaxone is now the drug of choice for all form of gonorrhea. Cefotaxime or ceftriaxone (as part of a 3-drug combination with vancomycin and ampicillin) are used for the initial treatment of meningitis in nonimmunocompromised adults and children older than 3 months.