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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 PICephalosporin NCephalosporin C

- a steroid with minimal antibacterial property

- Identical with synnematin N ( also called penicillin N

-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

SNH

H H

N

HO

NH2

O

OO

CH3

CH3

OHO

Cephalosporins

• Cephalosporin C- congener of Penicillin N

- contains dihydrothiazide ring

NH

H H

N

HO

NH2

O

OO

CH3

OH

O

O

O

S

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

activity against bacteria than penicillins. is 3-(acetoxymethyl)-7-[2-(thienylacetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-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.

Degradation of Cephalosporins

S

R1 – CONH – CH – CH CH2

l l l CO ------ N C C CH2 - - - R2

l CO2H

=

(Strong acidic solution)

solvolysis

S

R – CONH – CH – CH CH2

l l l CO ------ N C C CH2OH l CO2H

=

CephalosporinDesacetylcephalosporin

S

R – CONH – CH – CH CH2

l l l CO ------ N C C CH2

C ---- O

O

==

DesacetylcephalosporinLactone

( In active form)

Lactonize

S O L V O L Y S I S

S

R1 – CONH – CH – CH CH2

l l l CO ------ N C C CH2 - - - R2

l CO2H

=

Cephalosporin

Hydrolysis of the ß-lactamase

S

R1 – CONH – CH – CH CH2

l l l CO2H NH C C CH2 - - - R2

l CO2H

=

Cephalosporoic acid S

R1 – CONH – CH – CH CH2

l l l CO2H N C

C CH2 l CO2H

=

Anhydrodesacetylphalosporoic acid

Degradation of CephalosporinsH Y D R O L Y S I S O F B – L A C T A M A S E

Degradation of CephalosporinsA C Y L A S E S

Cephalosporin Aminocephalosporanic acid Desactyl-7-Aminocephalosporanic

acid Lactone

CEPHALOSPORIN STRUCTURE

R2

OR3O =

O llR1 – C - NH ---

=

increases the acid stability of the beta-lactam ring.

Spectrum of Activity

> 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

CEPHALOSPORINS

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

Moxalactam

Cefoperazone Ceftriaxonecefotaxime

ceftazidime

Ceftriaxone

contain the polar functionalities such as

(carboxy and N-acylureido)

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, indole-positive Proteus, or Serratia.

Classification of Cephalosporin

1. First generation Cephalosporins

CefazolinLoracarbef

Cephalexin

Cefoperazone

Cefotetan Disodium

Cefoxitin Na

Cefaclor

Cefprosil

Cefadroxil

Cephradine

Cefuroxime Na

Cefixime

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 penicillin- resistant N. gonorrhoeae.

Classification of Cephalosporin

3. Third generation Cephalosporins

Cefcapene Cefdaloxime Cefdinir (Omnicef, Cefdiel) Cefditoren Cefetamet

Cefixime (Suprax) Cefmenoxime Cefodizime Cefotaxime (Claforan) Cefpimizole

Cefpodoxime (Vantin,) Cefteram Ceftibuten (Cedax) Ceftiofur

Ceftiolene Ceftizoxime (Cefizox) Ceftriaxone (Rocephin)

Classification of Cephalosporin

4. Fourth generation CephalosporinsFourth-generation cephalosporins are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. They also have a greater resistance to beta-lactamases than the third-generation cephalosporins.

Many can cross the blood-brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa.

Cefclidine Cefepime (Maxipime)

Cefluprenam Cefoselis

Cefozopran Cefpirome (Cefrom)

Cefquinome

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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