CephalosporinsCephalosporins

Introduction

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.

• 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.

• 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.

• 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

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 (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.

Mechanism of action

The mechanism of resistance of m.o

- Alteration of binding site. - Decrease permeability. - Production of β–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 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

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.

Classification of cephalosporins

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

* 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

* 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

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

* 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

* 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

* 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

* Cefmetazole

N

S

O

NH

C

CH3O

C

O

O OH

Cefmetazole

NCCH2SCH2

NN

NN

CH2S

CH3

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

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

*Cefpodoxime proxetil

N

SNH

CH2OCH3

C

O

C

O

O

NOCH3

Cefpodoxime proxetil

S

NH2N C

O CHOCOCH(CH3)2

O

CH3

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

+

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

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:

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.

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.

• 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.)

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