Dwi

 Indria  Anggraini1,  Rovina  Ruslami2

1Dept.  P harmacology   Faculty   of  Medicine,  Lampung  University;  
2Dept.  P harmacology   Faculty   of  Medicine,  Padjajaran  University
Overview
 INTRODUCTION:
M.O  is  classified  as  gram  (+)  or  (-­‐)  ≈ gram  staining
BUT:  not  that  simple;  difference  in  structure  of  cell  wall

Gram  (+)
• Relatively  simple  structure
• 50%  peptidoglycan,  40%  acidic  polymer  (highly  polar)  and  10%  protein&  
polysaccharides

Gram  (-­‐)
• Much  more  complex
• Periplasmic space
• Peptidoglycan layer
• Outer  membrane
• Complex  polysaccharide
• Periplasmic space
• contain  enzymes  &  other  component

• Peptidoglycan layer
• forming  5%  of  cell  wall

• Outer  membrane
• contain  protein  molecules  and  lipoprotein  that  linked  to  
peptidoglycan

• Complex  polysaccharide  
• ≠ in  different  strains,  determine  antigenicity of  m.o
• endotoxins à inflamm reactions,  fever,  etc
• porins à hydrophylic A.M  can  move  freely
• Difficulty  to  penetrate  complex  outer  layer  à
reasons  why  some  A.M  are  less  effective  
against  gram  (-­‐)  m.o  than  against  gram  (+)

• LPS  of  cell  wall  is  a  major  barrier  to  penetration  for:
• penicillin  G
• methicillin
• vancomycin
• rifampicin
Inhibitor of cell wall synthesis

• Beta  Lactam  (  =  BL  )  AM:  

-­‐ Penicillins  
-­‐ Cephalosporins
-­‐ Carbapenems  
-­‐ Monobactams  
• Others  →  Glycopeptides  
 Thiazolidine ring

B-­‐lactam ring
•B-­lactam  ring
•Thiazolidine  ring  

•B-­lactam  ring
•Thiazolidine  ring  – susbtituent  
are  added  in  R1,  2  or  3

•B-­lactam  ring  only

•B-­lactam  ring
• Thiazolidine  ring:  
S  was  replaced  by  C
PENICILLIN:
1928:  Alexander  Flemming  
Staph  +  penicillium  à growth  of  staph  was  inhibited

Extraction  of  the  substance

1941:  Tested  to  pts  with  septicemia

5  days  à improved  well

Now…it’s  widely  used,  very  effective
BUT..destroyed  by  B-­‐lactamase  &  amidase
• inhibit  synthesis  of  cell  wall  peptidoglycan
• bind  to  P-­BP  of  bacteria  à inhibit  transpeptidase
• inactivation  of  an  inhibitor  autolytic enzymes  in  cell  
wall  à lysis of  bacterium
1. Natural  penicillin:   Pen-­G  and  Pen-­V
2. Anti  satph penicillin
>  Stable  to  penicillinase

3. Extended  spectrum  penicillin

>  ampicillin,   amoxillin
>  (+)  B-­lactamase inhibitor  (clavulanic acid  or  sulbactam)

4. Anti  pseudomonas   penicillin

5. Penicillin   +  AMG
>  has  synergitic effect
Broader  spectra
1. Natural  à have  no  peptidoglycan or  cell  wall  that  
impermiable to  the  drugs
2. Acquired  (by  plasmid)
a. Produce  B-­lactamase à destroy  the  drug
b. ↓ permeability  to  drug  à D  can’t  reach  P-­BP
c. Altered  P-­BP
1. A  ≈ to  gastric  acid  and  severity  of  infections
• p.o,  iv,  im,  i.t,  depot  (PP-­‐G,  BP-­‐G)
• Empty  stomach  (ampi),  amox (J)
2. D:  
• Cross  PBB  à BUT  non-­‐teratogenic
• Do  not  Cross  BBB  à Except  in  inflammed
meningens
3. M  &  E
• Through  kidney  (tubular  secretion)
1. Are  given  p.o unless  severe  infection
2. Uses  include:
• Bacterial  meningitis
• Bone  &  joint  infection
• Skin  &  soft  tissue  infection
• URTI,  UTI  (including  GO),  Endocarditis,  etc
3. Empirical,  emerge  of  drug  resistance  !!
Cephalosporins

Penicillin  – Cephalosporin:
• ≈ chemically,  m.o.a,  &  toxicity
• >  stable  to  B-­‐lactamase
• broader  spectrum  of  activity
Cephalosporin  classification:
• 4  generation  (~  spectrum  AM  activity)
• against  gr(+) also  against  gr(-­‐)
 1st 2nd 3rd 4th

Cephadroxil Cefuroxime Cefotaxime Cefepime

Cephalexin Cefoxitin Ceftazidime
Cephazolin Ceftriaxone
Cefepime
Cefoperazone

better  activity  against  gr  (+) • improved  activity  against  gr  (+)
• more  resistant  to  B-­lactamase
Cephalosporins
Cephalosporins

1. A  ≈ most  of  all  must  be  given  iv  (poor  oral  absorption)
• p.o:  cefalexin,  cefuroxime
2. D:  
• Cross  BBB  à for  3rd generation
3. M  &  E
• Through  kidney  (tubular  secretion)
• Ceftriaxone &  cefoperazone à bile
Other  B-­‐lactam AM

• Imipenem,  meropenem,  ertapenem

• Very  broad  spectrum  (aerobic  (gr (+),  (-­‐),anaerobic)  
• Resistant  to  B-­‐lactamase
• PK:  iv,  renal  excretions
• AEs:  nausea,  vomit,  diarrhea
Other  B-­‐lactam AM

• Has  only  B-­‐lactam ring  (exp:  aztreonam)

• Narrow  spectrum  (gr (-­‐)  à can’t  for  empirical  th/
• Resistant  to  B-­‐lactamase
• PK:  iv  and  im,  renal  excretions
• AEs:  non  toxic,  little  cross-­‐sensitivity   allergic
(alternative  for  pts  who  allergic  to  penicillin)
Other  inhibitor  of  Cell  wall  synthesis

• A  glycopeptide,  effective  for  MRSA

• BUT  now:  emerging  of  resistance  to  Vancomycin
• M.O.A:  inhibit  synthesis  of  phospholipids
• A.M  spectrum:  serious  infection  only
• Allergic  to  B-­‐lactam;,  AB-­‐associated  collitis (p.o)
• PK:  slow  iv  ;  renal  excretion
• AEs  is  a  serious  problem  (fever,  phlebitis,  hearing  
loss,  shock,  redman syndrome)  à slow  infusion
Other  inhibitor  of  Cell  wall  synthesis

• Very  toxic  for  systemic

• So..only  to  topical  application
• Effective  for  gram  (+)  m.o