m





m

p The cephalosporins are ñ-Lactam antibiotics that are
closely related both structurally and functionally to the
penicillins.

p ×echanism of action, mechanism of resistance and

some other properties of cephalosporins are identical
to penicillins)

p Cephalosporins are one of the most widely used

antibiotics and are equal in importance to penicillin.
? The cephalosporins are isolated from:
- m


species
- Prepared semisynthetically.

? In 1945
½iuseppe Brotzu`s discovered that cultures
of m



 
inhibited
the growth of a wide variety of ½ram-positive
and ½ram-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 G ephalosporin N)

*Most of the antibiotics introduced since 1965 have been

semisynthetic cephalosporins.
? Cephalosporin C can be hydrolyzed by acid to 7-aminocephalosporanic
acid.

Ê
 



  
 Ê
 
    

Ê
  

 
Ê  Ê 
  
 


 
 

   
  

*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.
? ×ost cephalosporins are produced semisynthetically by the chemical
attachment of side chains to 7-aminocephalosporanic acid.
? Cephalosporins (7Į-H) and cephamycins (7Į-OCH3):

 

 
 
   
 Ê
  Ê

Ê   
 Ê 
  
 

 
 


  
 

×ost natural cephalosporin and cephamycin are not used

clinically for side effects, but semi-synthetic products are used.
Mechanism of action

  m    
 m  

- Alteration of binding site.

- Decrease permeability.

- Production of ȕ±lactamase enzymes (enzymatic inactivation).

 mm
  m

 

Cephalosporins have been classified as first, second, third and

fourth generation largely on the basis of bacterial susceptibility
patterns and resistance to ȕ- lactamases:
Π            Π   

  !  
 ! # ! 
   ! # !"# !  
! "
 !  !  #  !
 

# $ !   ! " 
  $ ! 
 $ !  " 
! #
!# !#$
! !  #
! "
$ #
$
 # #
$ !%  $
! "
 !   $
* §ral agents

m
 m

  
 

ÿ ÕAR of oral cephalosporin 1st and 2nd generation

ÿ ÕAR of 3rd generation oral and parentral:

a- ȕ-lactam ring responsible for action.

2- ȕ-lactamase stability.

3- Potency and spectrum.

lassification of cephalosporins
Œirst generation :

* ephalothin



  Ê

Ê

  




 

* efazolin

Ê
Ê 
  Ê

Ê Ê Ê
Ê
 
 

! "


 

* efazolin


Ê
Ê   Ê
Ê Ê Ê
Ê

 
! "






* ephalexin

  Ê
Ê
Ê



#


* ephradine



 Ê

Ê
Ê
  


   

* efadroxil


 
 Ê

Ê
Ê
  


!  #
 

Õecond generation:

* efamandole



 Ê

Ê Ê
Ê

 
 Ê
Ê
!  
 
 



* efoxitin
 



  Ê

Ê
 
Ê

!#


 

* efaclor



 Ê

Ê
Ê
  

! 
 
 

* efuroxime


  Ê


Ê
 Ê
 
Ê

! # 
 

* efuroxime axetil


  Ê



Ê
 Ê
 
Ê


!   

  






* efonicid



 Ê

Ê Ê
Ê

 
 Ê
Ê
!  
 

 

* efotetan


 Ê   

  Ê

Ê Ê

  Ê
 
 Ê
 Ê

 


! 

* eforanide



  Ê

Ê Ê
Ê

Ê
  
 Ê
Ê
!  
 



* efmetazole



Ê   Ê
Ê Ê
Ê

 Ê
Ê
! "
 


 
hird generation:

* efotaxime


Ê Ê   Ê


Ê
Ê
 



! 

 

* eftizoxime


Ê   Ê

Ê
Ê
 Ê


!"  
 

* eftriaxone



 Ê 


Ê   Ê
Ê
Ê
Ê
 Ê
 
 Ê 
!   
 

* efixime


 Ê   Ê

Ê
Ê
Ê



&

!  

 

* efpodoxime proxetil

 Ê   Ê
Ê
Ê
Ê
 



!  # #






 '


hird generation cephalosporins with good activity against
Pseudomonas:


*1- efoperazone Ê   Ê
Ê Ê Ê
Ê Ê

 Ê
Ê




 

Ê !  " 

Ê

  

*2- eftazidime

 Ê   Ê
Ê (
Ê Ê Ê





  



! " 

Œourth Generation ephalosporins:

* efpirome




Ê

Ê  
Ê

Ê 3 +Ê
Ê

 

!  

* efepime





Ê

Ê  
Ê
 

Ê Ê Ê


 

! 
 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- Œate:

- 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

he 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.
 herapeutic uses

- When ½m +ve bacteria is involved a ast generation agents is

preferable.
- When the pathogen is gm ±ve and the infection is serious
parentral use of a 3rd generation agent is recommended.

Œirst generation cephalosporins are:

? Excellent agents for skin and soft tissue infections due to

Õ    and Õ  .
? A single dose of cefazolin just before surgery is the preferred
as prophylaxis
Õecond-generation cephalosporins

? The second generation agents have inferior activity against

penicillin-resistant Õ 

  compared to either the 3rd
generation agents or ampicillin and therefore should not be
used for treatment of meningitis or pneumonia.

? n case where ½m -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.
hird generation cephalosporins

? Third generation cephalosporins have been considered to be

the drugs of choice for serious infections caused by:
Î  , Enterobacter,  , 

 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.
hird generation cephalosporins G ont.)

? Ceftazidime + aminoglycoside is the drug of choice for

 
 meningitis.

? The antimicrobial spectrum of cefotaxime and ceftriaxone is

excellent for the treatment of community acquired pneumonia,
i.e. that caused by

,     , Õ   .
he fourth generation

? The fourth generation are indicated for the empirical treatment

of nosocomial infections where antibiotic resistance due to
extended spectrum ȕ-lactamases are anticipated.

e.g. cefepime has superior activity against nosocomial

isolates of Enterobacter, Citrobacter compared to
ceftazidime and piperacillin