Transcript Second-generation cephalosporins

Cephalosporins
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.
NH2
O
H
O
NH
OH
O
7
H
6
5
S
O
CH3
4
N
1
HO
3
2
O
Cephalosporin C
NH2
7
O
O
6
N
1
HO
5
S
O
CH3
4
3
O
2
O
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 (7α-H) and cephamycins (7α-OCH3):
O
O
H
R
NH
O
7
6
N
1
HO
OCH 3
5
S
4
3
R
NH
X
O
2
O
Cephalosporins
7
6
N
1
5
S
4
3
X
2
HO
O
Cephamycin
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
Cephalothin
Cephapirin
Cefazolin
Cephalexin*
Cephradine*
Cefadroxil
Cefamandole
Cefuroxime
Cefonicid
Ceforanide
Cefaclor*
Cefoxitin
Cefotetan
Cefprozil*
Cepuroxime axetil*
Cefmetazole
Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
Cefoperazone
Cefixime*
Cefpodoxime
proxetil*
Ceftibuten*
Cefdinir*
Cefepime
Cefpirome
Cefclidin
* Oral agents
Structure activity relationship

SAR of oral cephalosporin 1st and 2nd generation
 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
O
S
CH2
C
NH
S
N
O
Cephalothin
CH2OCCH3
C
O
O
OH
* Cefazolin
O
S
N
N
CH2
C
NH
N
Cefazolin
N
N
N
O
CH3
CH2S
S
C
O
OH
* Cefazolin
O
S
N
N
CH2
C
NH
N
O
Cefazolin
N
N
N
CH3
CH2S
S
C
O
OH
*Cephalexin
O
S
CH
C
NH2
NH
N
O
CH3
C
Cephalexin
O
OH
* Cephradine
O
S
CH
C
NH
N
NH2
O
CH3
C
O
Cephradine
OH
* Cefadroxil
O
S
HO
CH
C
NH2
NH
N
O
CH3
C
Cefadroxil
O
OH
Second generation:
* Cefamandole
O
S
CH
C
NH
OH
N
N
N
O
N
CH2S
Cefamandole
N
C
O
OH
CH3
* Cefoxitin
O
OCH 3
S
CH2
C
NH
S
N
O
CH2OCNH2
Cefoxitin
C
O
OH
O
* Cefaclor
O
S
C
CH
NH
N
NH2
Cl
O
Cefachlor
C
O
OH
* Cefuroxime
O
S
C
C
NH
NOCH3
O
O
O
N
CH2OCNH2
Cefuroxime
C
O
OH
* Cefuroxime axetil
O
S
C
C
NH
NOCH3
O
O
O
N
CH2OCNH2
O
Cefuroxime axetil
C
O
O
CHOCCH3
CH3
* Cefonicid
O
S
CH
C
OH
NH
N
N
N
O
N
CH2S
Cefonicid
N
C
O
OH
CH2SO3H
* Cefotetan
O
H2N
O
C
C
C
HO
CH3O
S
S
C
S
NH
N
N
N
O
N
CH2S
O
N
C
O
OH
CH3
Cefotetan
* Ceforanide
O
S
CH2
C
CH2NH2
NH
N
N
N
O
N
CH2S
Ceforanide
N
C
O
OH
CH2CO2H
* Cefmetazole
O
NCCH2SCH2
C
CH3O
S
NH
N
N
N
O
N
CH2S
Cefmetazole
N
C
O
OH
CH3
Third generation:
*Cefotaxime
S
H2N
O
S
N
C
NH
NOCH 3
O
C
O
N
CH2OCCH 3
Cefotaxime
C
O
OH
*Ceftizoxime
O
S
S
C
H2N
C
NH
N
NOCH3
N
O
H
Ceftizoxime
C
O
OH
*Ceftriaxone
O
S
CH3
S
C
H2N
C
N
O
N
NOCH3
CH2S
O
Ceftriaxone
C
O
OH
*Cefixime
O
S
S
C
C
NH
N
N
NOCH2CO2H
Cefixime
OH
N
NH
N
H2N
N
CH=CH 2
O
C
O
OH
*Cefpodoxime proxetil
O
S
S
C
H2N
C
NH
N
NOCH3
N
CH2OCH3
O
Cefpodoxime proxetil
O
C
O
O
CHOCOCH(CH3)2
CH3
Third generation cephalosporins with good activity against
Pseudomonas:
O
S
*1-Cefoperazone
S
C
H2N
C
NH
N
NH
C
O
N
O
N
O
CH2S
O
C
O
OH
Cefoperazone
C2H5
*2-Ceftazidime
O
S
S
C
H2N
C
NH
N
+
N
N
N
O
CH2
O
C
CH3
C
CH3
CO2H
O
OH
Ceftazidime
N
N
N
N
N
CH3
Fourth Generation Cephalosporins:
* Cefpirome
O
H
H
N
S
C
H2N
S
C
HN
3
N
N
OCH 3
+N
O
CO2
Cefpirome
* Cefepime
O
H
H
N
S
C
H2N
S
C
HN
H3C
N+
N
N
OCH 3
Cefepime
O
CO2
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-5thiotetrazole 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.
Third generation cephalosporins (Cont.)
• 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.
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