3. 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.
4. • 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.
5. • 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.
6. • Penicillin N (Cephalosporin N)
*Most of the antibiotics introduced since 1965 have been
semisynthetic cephalosporins.
7. • 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
S
NH
H H
O
HO O
O
CH3OO
OH
NH2 O
Cephalosporin C
N
S
O
HO O
O
CH3ONH2
7- aminocephalosporinic acid
1
2
3
4
5
6
7
5
4
3
2
1
67
8. This compound has been modified by the addition of different
side chains to create a whole family of cephalosporin antibiotics.
9. • Most cephalosporins are produced semisynthetically by the chemical
attachment of side chains to 7-aminocephalosporanic acid.
• Cephalosporins (7α-H) and cephamycins (7α-OCH3):
Cephalosporins
1
2
3
4
5
6
N
S
O
HO O
X
NH
H
R
O
7
Cephamycin
1
2
3
4
5
6
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.
11. The mechanism of resisTance of m.o
- Alteration of binding site.
- Decrease permeability.
- Production of β–lactamase enzymes (enzymatic inactivation).
12. 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
13. SAR of oral cephalosporin 1st
and 2nd
generation
rucTure acTiviTy relaTionship
SAR of 3rd generation oral and parentral:
1- β-lactam ring responsible for action.
2- β-lactamase stability.
3- Potency and spectrum.
26. Third generation cephalosporins with good activity against
Pseudomonas:
*1-Cefoperazone
N
S
O
NH
C
CH2S
C
O
O OH
Cefoperazone
C
S
N
H2N
NH
C
N
N
O
O
O
C2H5
N
N
N
N
CH3
*2-Ceftazidime
N
S
O
NH
C
C
O
O OH
Ceftazidime
C
S
N
H2N
N
O
C CO2HCH3
CH3
N
CH2
+
27. Fourth Generation Cephalosporins:
* Cefpirome
NN
S
HN
O
H H
CO2
CC
N
S
H2N
N
O
-
OCH3
Cefpirome
+3
N
S
HN
O
H H
CO2
N
CC
N
S
H2N
N
O
-
OCH3
Cefepime
H3C
+
* Cefepime
28. 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.).
29. 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.
30. 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.
31. 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
32. 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.
33. 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.
34. • 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.)
35. 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
