Download Cephalosphorins

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Cephalosporins
• are B-Lactam antibiotics isolated from Cephalosporium
spp.
• inhibit wide variety of gram(+) and gram(-) bacteria
• Abraham and Newton, the suppliers of fungi cultures
isolated three principal antibiotic components:
 Cephalosporin PI- a steroid with minimal antibacterial property
 Cephalosporin N - Identical with synnematin N ( also called penicillin N
 Cephalosporin C -Resistant to S. aureus B-lactamase; antibacterial
property is inferior to penicillin N.
Cephalosporins
•
Cephalosporin N or Penicillin N
- the amino acid in the chain confers more activity against
gram(-) bacteria particularly Salmonella spp.
- less active against gram(+) organism
- contains thiazolidine ring
NH2
O
H
HO
H
S
NH
CH3
N
O
CH3
O
O
OH
Cephalosporins
•
Cephalosporin C
- congener of Penicillin N
- contains dihydrothiazide ring
NH2
O
H
HO
H
NH
S
O
N
O
O
OH
CH3
O
O
Nomenclature of Cephalosporins
Chemical Abstracts
> fused ring is named 5-thia, 1-azabicyclo[4.2.0]oct-2-ene
> CEPHALOTHIN (is an antibiotic of the cephalosporin class. It is related to the
penicillin drugs in how it kills bacteria, but cephalosporins have a much broader range of
is 3-(acetoxymethyl)-7-[2(thienylacetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene2-carboxylic acid.
> saturated bicyclic ring system is named as cepham
> all cephalosporins and cefamycins are named as 3-cephems,
to designate the position of the double bond in the structure.
activity against bacteria than penicillins.
Degradation of Cephalosporins
SOLV OL YS I S
S
S
R1 – CONH – CH – CH
l
l
CO ------ N
CH2
R – CONH – CH – CH
CH2
solvolysis
l
l
l
l
C
CO ------ N
C
C
CH2 - - - R2
C
CH2OH
l
l
CO2H
CO2H
(Strong acidic solution)
Desacetylcephalosporin
Cephalosporin
S
R – CONH – CH – CH
l
l
CO ------ N
Desacetylcephalosporin
Lactone
( In active form)
CH2
l
C
C
CH2
C ---- O
O
Lactonize
Degradation of Cephalosporins
B –LACTAMASE
HYDROLYSIS OF
S
Hydrolysis
of the ß-lactamase
R1 – CONH – CH – CH
l
l
CO ------ N
R1 – CONH – CH – CH
l
l
CO2H NH
CH2
l
C
C
CH2 - - - R2
l
CO2H
Cephalosporin
S
CH2
l
C
C
CH2 - - - R2
l
CO2H
Cephalosporoic acid
S
R1 – CONH – CH – CH
l
l
CO2H N
CH2
l
C
C
CH2
l
CO2H
Anhydrodesacetylphalosporoic acid
Degradation of Cephalosporins
ACYLASES
Cephalosporin
Aminocephalosporanic acid
Desactyl-7Aminocephalosporanic
acid Lactone
CEPHALOSPORIN STRUCTURE
increases the acid
stability of the betalactam ring.
O
ll
R1 – C - NH --R2
O
OR3
Spectrum of Activity
CEPHALOSPORINS
> are considered broad-spectrum antibiotics with
similar activities to that of ampicillin.
> more resistant to the inactivation by the beta-lactamases,
particularly those produced by gram(+) bacteria.
> exhibit potent activity against most species of Klebsiella
Different potencies are due to:
1. Different bacterial strains
2. Characteristics of individual bacterial species
3. Resistance to the inactivation of the beta-lactamases
4. Permeability of the bacterial cell
5. Intrinsic activity against bacterial enzymes involved
in cell wall synthesis and cross linking.
Antipseudomonal Cephalosporins
cefotaxime
Ceftriaxone
Ceftriaxone
Cefoperazone
Moxalactam
ceftazidime
contain the polar
functionalities such as
(carboxy and Nacylureido)
Adverse Reactions and Drug Interactions
> non-toxic compound and exhibit selective toxicity towards bacteria
> Allergy and hypersensitivity are most common reactions
cefamandole, cefotetan, cefmetazole, moxalactam, cefoperazone have
higher incidence of hypoprothrombinemia
>poor nutritional status, debilitation, GIT surgery, hepatic disease or renal
failure may lead to severe bleeding
>vitamin K supplement is given to high risk patients undergoing
cephalosporin therapy
>react with alcohol due to the accumulation of acetaldehyde
Classification of Cephalosporin
1. First generation Cephalosporins
 are moderate spectrum agents, with a spectrum of
activity or treatable range of bacteria that includes
penicillinase-producing, methicillin-susceptible
staphylococci and streptococci
They also have activity against some Escherichia
coli, Klebsiella pneumoniae and Proteus mirabilis,
but have no activity against Bacteroides fragilis,
enterococci, methicillin-resistant staphylococci,
Pseudomonas, Acinetobacter, Enterobacter, indolepositive Proteus, or Serratia.
Classification of Cephalosporin
Cefaclor
1. First generation Cephalosporins
Cefprosil
Loracarbef
Cefazolin
Cephradine
Cephalexin
Cefadroxil
Cefoxitin Na
Cefoperazone
Cefuroxime Na
Cefixime
Cefotetan
Disodium
Classification of Cephalosporin
2. Second generation Cephalosporins
> have a greater Gram-negative
spectrum while retaining some activity
against Gram-positive cocci. They are
also more resistant to beta-lactamase.
Cefaclor
(Ceclor, Distaclor, Keflor, Raniclor)
Cefonicid (Monocid)
Cefprozil (cefproxil; Cefzil)
Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym)
Cefuzonam
Classification of Cephalosporin
2. Second generation Cephalosporins
> with antianaerobe activity
Cefmetazole
Cefoxitin
Cefotetan
> The following cephems are also sometimes
grouped with second-generation cephalosporins:
A. Carbacephems:
- loracarbef (Lorabid)
B. Cephamycins:
- cefbuperazone, cefmetazole
(Zefazone), cefminox, cefotetan
(Cefotan), cefoxitin (Mefoxin)
Classification of Cephalosporin
3. Third generation Cephalosporins
Third-generation cephalosporins have a broad spectrum of
activity and further increased activity against Gram-negative
organisms.
 They may be particularly useful in treating hospital-acquired
infections, although increasing levels of extended-spectrum
beta-lactamases are reducing the clinical utility of this class of
antibiotics.
 They are also able to penetrate the CNS, making them useful
against meningitis caused by pneumococci, meningococci, H.
influenzae, and susceptible E. coli, Klebsiella, and penicillinresistant N. gonorrhoeae.
Classification of Cephalosporin
3. Third generation Cephalosporins
Cefcapene
Cefdaloxime
Cefdinir (Omnicef, Cefdiel)
Cefditoren
Cefetamet
Cefpodoxime (Vantin,)
Cefteram
Ceftibuten (Cedax)
Ceftiofur
Cefixime (Suprax)
Cefmenoxime
Cefodizime
Cefotaxime (Claforan)
Cefpimizole
Ceftiolene
Ceftizoxime (Cefizox)
Ceftriaxone (Rocephin)
Classification of Cephalosporin
4. Fourth generation Cephalosporins
Fourth-generation cephalosporins
are extended-spectrum agents with
similar activity against Gram-positive
organisms as first-generation
cephalosporins.
Cefozopran
Cefpirome (Cefrom)
Cefquinome
They also have a greater resistance
to beta-lactamases than the thirdgeneration cephalosporins.
Cefclidine
Cefepime (Maxipime)
Cefluprenam
Cefoselis
 Many can cross the blood-brain
barrier and are effective in meningitis.
They are also used against
Pseudomonas aeruginosa.
Classification of Cephalosporin
5. Fifth generation Cephalosporins
Ceftobiprole has been described as "fifth generation" though
acceptance for this terminology is not universal.
Ceftobiprole (and the soluble prodrug medocaril) are on the
FDA fast-track.
Ceftobiprole has powerful antipseudomonal characteristics
and appears to be less susceptible to development of
resistance.
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