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Our presentation is based on



 
       
 

 

   

Md. Ekram Hossain

ID. 2008-3-70-031
Kohinoor Bannya
ID. 2008-3-70-015
Zarin Tasneem
ID. 2008-3-70-013

PHRM-304
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iephalosporin :
iephalosporins are antibacterial agents which inhibit
bacterial cell wall synthesis.It is the second major group of
ȕ-lactam antibiotics.ȕ-lactam is the ring which inhibit the
synthesis of bacterial cell wall.

Background :
The first cephalosporin was cephalosporin i isolated in
1948 from a fungus obtained from sewer waters on the
island of Sardinia.
Molecular modification of cephalosporin i gave
origin to iephalosporins ;most of them are
semisynthetic substances obtained by reaction of 7-
aminocephalosporanic acid (7-AiA) with appropriate
compounds.
Structure Ö
iephalosporins are beta-lactam compounds in which the
beta-lactam ring is fused to a 6-membered dihydrothiazine
ring, thus forming the cephem nucleus.
!   
Ö
The cephalosporin structure contains two chiral centers (6i
&7i).Thus four optically active forms are possible.The
natural isomer (6R & 7R) has the following Stereochemistry
The iephalosporin skeleton reveals that it can be
derived from the same biosynthetic precursors as
penicillin,ie. iystein & valine.
Structural Porperties & SARs of iephalosporin
Structural Porperties :

ƇThe ȕ-lactam ring is essential.

Ƈ A free carboxyl group is needed at i4.
Ƈ The bicyclic is essential.
Ƈ The stereochemistry of the side groups and the
rings is important.
The places where modification can be made are as follows.
Ƈ The 7-acylamino side chain
Ƈ The 3-acetoxy side chain
Ƈ Substitution at i7
SARs of iephalosporin :
Different cephalosporins are developed by changing
the moieties attached at the 3/7 position of the 7-AiA.
Usually substituent at i-3(R2) modify the
pharmacokinetic properties whereas those at i-7 alter
the antibacterial spectrum

R1 - the substituent at this position effects the ȕ-

lactamase resistance and its activity against Gram
(+)ve & Gram (-)ve.
R2 - the substituents primarily effects the
pharmacokinetics:the oral activity,the extent of metabolism
and the duration of action.Electron withdrawn group
provide resonance structure and this incrase stability of the
structure.

iarboxylic acid group - necessary for activity.This

functional group mimics the carboxylic acid group of
alanine when binding the enzyme active site.
 


   

 

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It generally shows activity against Gram (+)ve bacteria.It

is well-absorbed even in presence of fat.
Effective against :
 Streptococcus
 Methicillin sensitive Staphylococcus aureus
 E. ioli
 Klebsiella
 Proteus mirabilis
 Î 
   

*ot effective against :

Pseudomonas and Enterococcus.
H. Influenzae
M. catarrhalis
Other gram negative ȕ-lactamase organisms
 Î 
   

ilinical uses :
Uncomplicated, community-acquired infections of the
skin and soft tissue and urinary tract.

First generation drugs:

iefadroxil
iephapirin
iefazolin etc.
 !    
Have increased gram-negative activity, but decreased
gram-positive activity. They have improved activity
against common ȕ-lactamase producing respiratory
Pathogens.
Effective against :
 Methicillin sensitive S. aureus
 H. Influenzae
 *. iaterrhalis
 E. ioli
 Klebsiella
 Proteus mirabilis
ilinical uses :
for mixed aerobic/anaerobic infections of the skin and soft
tissues, intra-abdominal, and gynecologic infections, and
surgical prophylaxis.
Indicated second line:
Otitis media
Bronchitis
Sinusitis
 !    

Second generation drugs:

iefaclor
iephalothin
iefoxitin etc.
 v    

 Better resistance to plasmid mediated

ȕ-lactamase activity.
 So they have expanded coverage of gram negative as
compared to 1st and 2nd generation
 ionvenient dosage-once or twice daily
 Expensive
They have variable loss of efficacy against gram positive
coverage especially
- Streptococcus pneumoniae and
- Staphylococcus species
This limits their usefulness in otitis media and respiratory
infections.
They are most useful oral 3rd generation antibiotics.
  # 

How it works?

Inhibits bacterial cell wall synthesis by binding to one or

more of the penicillin-binding proteins (PBPs) which in
turn inhibits the final transpeptidation step of
peptidoglycan synthesis in bacterial cell walls, thus

inhibiting cell wall biosynthesis
 iefotaxime
 ilinical Use:
iefotaxime is used for infections of the respiratory
tracts, bones, joints, urogenital system, meningitis,
and septicemia . It generally has good coverage
against most Gram *egetive Bacteria.
 iefotaxime
  

The methoxyimino moiety confers stability to ȕ- ȕ-lactamase
enzymes produced by many Gram-Gram-negetive bacteria. Such
stability to ȕ-
ȕ-lactamases increases the activity of cefotaxime
against otherwise resistant Gram-
Gram-negative organisms.
 iefotaxime
Side effects
 Allergic reactions (rash; hives; itching; difficulty
breathing)
 *ausea or vomiting; stomach pain/cramps; unusual
bruising or bleeding; unusual tiredness; vaginal
irritation or discharge.
 Î    

 

 Fourth generation cephalosporins are extended spectrum

agents with similar activity against gram-positive
organisms. They also have a greater resistance to beta-
lactamases than the third generation cephalosporins. Many
can cross blood brain barrier and are effective in
meningitis. E.g cefepime,
cefepime, cefpirome,
cefpirome, cefaclidine,
cefaclidine,
cefozoporan
 Zwitterion structure can easily penetrate the outer cell
membrane porins.
porins.
 Enhanced stability against beta-
beta-lactamase .
 i
iefepime was developed in early 1990s. It was marketed in
1994 . It is effective in treating both Gram-
Gram-positive and
Gram--negative organisms.,
Gram
 i
 ilinical Use:
It is used to treat complicated episodes of urinary
tract infections, skin infections, and intra-
intra-abdominal
infections. It is also often used as an Empiric
Therapy for Febrile *eutropenic Patients. The
effectiveness of iefepime over other antibacterial
drugs lies in its great activity against susceptible
bacteria.
 iefepime
Side effects:
This medication may cause headache, nausea,dizziness,vaginal
yeast infection.
Adverse effects:
Mental/mood changes, vomiting, severe stomach cramps,
watery or bloody diarrhoea,
diarrhoea, fever or unusual weakness, muscle
twitching (myoclonus
(myoclonus),
), unusual bleeding or bruising, yellowing
of the eyes
  
 

Mechanism of action: inhibit transpeptidases (PBPs)

responsible for cell wall synthesis. Transpeptidase
enzyme is one of the penicillin binding proteins that
normally reside in the bacterial inner membrane and
perform construction ,repair and housekeeping functions
maintaining the cell wall function and play a vital role in
cell growth and division.
iephalosporin antibiotics bind to penicillin binding
proteins (PBPs) to bacteria and inhibit the formation of
cell well
  
 
Time-dependent, bactericidal activity versus most
pathogens.
Spectrum of activity determined by:
Affinity for target PBPs
Ability to penetrate through porins in the gram-
negative cell wall.
Stability to beta-lactamase degradation
Mechanism of action
 | 

 

 Broad spectrum of activity

 Stability to Î-lactamase
 Oral and parenteral preparations
 Widely accepted
 Treats µday to day¶ as well as
µserious infections¶
 High safety profile
 
 $ 

In general, %
    

 
have
    $   
  
 $    and
less gram-negative activity, while    
 
, with a few exceptions, have    
  $  $  and less gram-positive activity. The
only fourth generation agent has both gram-positive
and gram-negative activity.
 !
Î


An enzyme called Î-lactamase is present in many

different types of bacteria, which serves to 'break' the
beta lactam ring, which effectively nullifies the
antibiotic's effectiveness.But iephalosporins show
quiet stability to Î-lactamase.
 2
   
   

iephlosporins are prepared as the oral and parenteral

preparation for the $   of the consumers.
 | 
  & 
  

As it is convenient for the consumers and show less

side effects so it is accepted and has safety profile.
   
 

 

 Emerging resistance patterns

 Side effects

 III & IV generation cephalosporins

were available only as parenteral
formulations

 Pharmacoeconomics
Emerging resistance patterns :
Sometime the bacteria produces a lot of Beta-lactamase
enzye which destory the activity of the ȕ-lactam ring by
opening the ring.

Three important in medicine which are used in the

resistance :
ilavulanic acid
Sulbactam
Tazobactam
Side effects :
Serious, adverse reactions to the cephalosporins are
uncommon. As with most antibiotics, the full
spectrum of hypersensitivity reactions may occur,
including rashes, fever, eosinophilia, serum sickness
and anaphylaxis
The incidence of immediate-type allergic reactions to
the cephalosporins is increased among patients
known to be allergic to penicillins
 
 ' 
 
Adults (Age 13 years & older)
 Upper respiratory tract infections :100 mg bid for
5-10 days
 Acute exacerbation of chronic bronchitis :200 mg
bid for 10 days
 Acute community acquired pneumonia :200 mg
bid for 14 days
 Uncomplicated gonorrhoea: 200 mg single dose
 Uncomplicated urinary tract infections:100 mg
bid for 7 days
Adults (Age 13 years & older)
 Skin & skin structure infections : 400 mg bid for 7-
14 days

ihildren (Age 5 months to 12 years)

 Acute otitis media : 10 mg/kg (max 100 mg/dose)
OD or 5mg/kg (max 200 mg/dose) bid for 10 days
 Pharyngitis and /or tonsillitis : 5 mg/kg/dose
(max100 mg/dose) bid for 5-10 days
  
      

 
  
   

—  Show less activity against Gram (+)ve
much,but very much against Gram (-)
ve bacteria.
΢ Show little stability to the Î-lactamase
enzyme.
 

 Pyelonephritis, iAP, SBP, meningitis
  Used to treat meningitis.
Show activity against both Gram (+)ve
& Gram (-) ve bacteria
Show strong stability to the Î-
lactamase enzyme.
*osocomial infections including
pneumonia, sepsis, febrile neutropenia
sporin places in therapy
Used to treat meningitis

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