details of cephalosporin and their classification
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CephalosporinsCephalosporins
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Introduction
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The cephalosporins are β-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.
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• The cephalosporins are isolated from: - Cephalosprium species - Prepared semisynthetically.
• In 1945
Giuseppe Brotzu`s discovered that cultures of Cephalosporium acremonium inhibited the growth of a wide variety of Gram-positive and Gram-negative bacteria.
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• 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.
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• Penicillin N (Cephalosporin N)
*Most of the antibiotics introduced since 1965 have been semisynthetic cephalosporins.
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• Cephalosporin C can be hydrolyzed by acid to 7-aminocephalosporanic 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.
N
SNH
H H
O
HO O
O
CH3OO
OH
NH2 O
Cephalosporin C
N
S
O
HO O
O
CH3ONH2
7- aminocephalosporinic acid
12
3
4
56
7
5
4
3
21
67
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This compound has been modified by the addition of different side chains to create a whole family of cephalosporin antibiotics.
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• Most cephalosporins are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.
• Cephalosporins (7α-H) and cephamycins (7α-OCH3):
Cephalosporins
12
3
4
56
N
S
O
HO O
X
NH
H
R
O
7
Cephamycin
12
3
4
56
N
S
O
HO O
X
NH
OCH3
R
O
7
Most natural cephalosporin and cephamycin are not used clinically for side effects, but semi-synthetic products are used.
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Mechanism of action
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The mechanism of resistance of m.o
- Alteration of binding site. - Decrease permeability. - Production of β–lactamase enzymes (enzymatic inactivation).
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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 β- lactamases:
First generation Second generation Third generation Fourth generation
CephalothinCephapirinCefazolinCephalexin*Cephradine*Cefadroxil
CefamandoleCefuroximeCefonicidCeforanideCefaclor*CefoxitinCefotetanCefprozil*Cepuroxime axetil*Cefmetazole
CefotaximeCeftizoximeCeftriaxoneCeftazidimeCefoperazone Cefixime*Cefpodoxime proxetil*Ceftibuten*Cefdinir*
CefepimeCefpiromeCefclidin
* Oral agents
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SAR of oral cephalosporin 1st and 2nd generation
Structure activity relationship
SAR of 3rd generation oral and parentral:
1- β-lactam ring responsible for action.
2- β-lactamase stability. 3- Potency and spectrum.
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Classification of cephalosporins
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First generation :
*Cephalothin
N
S
O
NH
C
CH2OCCH3
C
O
O OH
Cephalothin
CH2S
O
* Cefazolin
N
S
O
NH
C
CCH2
O
O OH
Cefazolin
NN
N NN
SCH3CH2S
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* Cefazolin
N
S
O
NH
C
CCH2
O
O OH
Cefazolin
NN
N NN
SCH3CH2S
*Cephalexin
N
S
O
NH
CH3
C
CCH
O
O OH
NH2
Cephalexin
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* Cephradine
N
S
O
NH
CH3
C
CCH
O
O OH
NH2
Cephradine
* Cefadroxil
N
S
O
NH
CH3
C
CCH
O
O OH
HO
NH2
Cefadroxil
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Second generation: * Cefamandole
N
S
O
NH
C
C
O
O OH
Cefamandole
N
NN
NCH2S
CH3
CH
OH
* Cefoxitin
N
SOCH3
O
NH
C
CH2OCNH2
CCH2
S
O
OO OH
Cefoxitin
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* Cefaclor
N
S
O
NH
Cl
C
CCH
O
O OH
NH2
Cefachlor
* Cefuroxime
N
S
O
NH
C
CH2OCNH2
C
O
O OH
Cefuroxime
C
NOCH3
OO
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* Cefuroxime axetil
N
S
O
NH
C
CH2OCNH2
C
O
OCefuroxime axetil
C
NOCH3
OO
O CHOCCH3
O
CH3
* Cefonicid
N
S
O
NH
C
C
O
O OH
Cefonicid
N
NN
NCH2S
CH2SO3H
CH
OH
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* Cefotetan
N
S
O
NH
C
CH3O
C
O
O OHCefotetan
NN
NN
CH2S
CH3
S
S
C
C
C
O
O
H2N
HO
* Ceforanide
N
S
O
NH
C
C
O
O OH
Ceforanide
N
NN
NCH2S
CH2CO2H
CH2
CH2NH2
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* Cefmetazole
N
S
O
NH
C
CH3O
C
O
O OH
Cefmetazole
NCCH2SCH2
NN
NN
CH2S
CH3
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Third generation:
*Cefotaxime
N
S
CH2OCCH3
C
O
NH
OHO
OCC
O
NOCH3
S
NH2N
Cefotaxime
*Ceftizoxime
N
S
O
NH
C
H
C
O
O OH
Ceftizoxime
C
NOCH3
S
NH2N
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N
S
O
NH
C
C
O
O OH
Ceftriaxone
C
NOCH3
S
NH2N N
N
N OH
CH2S O
CH3
*Ceftriaxone
*Cefixime
N
SNH
C
CH=CH2O
CC
S
NH2N
O
O OH
Cefixime
NOCH2CO2H
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*Cefpodoxime proxetil
N
SNH
CH2OCH3
C
O
C
O
O
NOCH3
Cefpodoxime proxetil
S
NH2N C
O CHOCOCH(CH3)2
O
CH3
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Third generation cephalosporins with good activity against Pseudomonas:
*1-CefoperazoneN
S
O
NH
C
CH2S
C
O
O OHCefoperazone
C
S
NH2N
NH
C
N
N
O
O
O
C2H5
N
NN
N
CH3
*2-Ceftazidime
N
S
O
NH
C
C
O
O OHCeftazidime
C
S
NH2N
NO
C CO2HCH3
CH3
NCH2
+
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Fourth Generation Cephalosporins:
* Cefpirome
NN
SHN
O
H H
CO2
CCN
S
H2N
N
O
-OCH3
Cefpirome
+3
N
SHN
O
H H
CO2
N
CCN
S
H2N
N
O
-OCH3
Cefepime
H3C
+
* Cefepime
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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.).
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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.
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Adverse reactions
The most common adverse reactions are:
1- Allergic and hypersensitivity reactions
2- A disulfiram-like effect 3-Bleeding: - Bleeding can occur with cefamandole, cefotetan, cefmetazole moxalactam and cefoperazone (containing an N-methyl-5- thiotetrazole moiety at the 3 position) b/c of antivitamin K effects, administration of the vitamin corrects the problem.
4- Nephrotoxicity.
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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
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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.
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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.
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• Ceftazidime + aminoglycoside is the drug of choice for Pseudomonas meningitis.
• The antimicrobial spectrum of cefotaxime and ceftriaxone is excellent for the treatment of community acquired pneumonia, i.e. that caused by pneumococci, H. influenzae, S. aureus.
Third generation cephalosporins (Cont.)
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The fourth generation
• The fourth generation are indicated for the empirical treatment of nosocomial infections where antibiotic resistance due to extended spectrum β-lactamases are anticipated. e.g. cefepime has superior activity against nosocomial isolates of Enterobacter, Citrobacter compared to ceftazidime and piperacillin