3. • Inside bacterial cell is much concentration of
ions and metabolites
• It is required for cells to function normally :
• to generate energy
• Synthesize macromolecules
• grow and divide
• It cause high osmotic pressure
4. Antibiotics
affecting cell wall
Source
Therapeutic application
Penicillin
Pencillium chrysogenum
Pencillin notatum
Gram +ve coccal infections, syphilis,
gonorrhoea, meningo coccal
meningitis
Cephalosporin
Cephalosporium spp
Allergic to penicillin
Cycloserine
Streptomyces
TB caused by resistance bacilli
Bacitracin
Bacillus licheniformis
Sterilization of gut before surgery,
topical application
Vancomycin
Streptomyces orientalis
Staphylococcal infection resistant to
other drugs
Fofsomycin
Active against +Ve, G-ve.
6. Fosfomycin
Cytoplasm
X
X
sugar
Inactivating the enzyme
Pyruvyl transferase enzyme
Inhibits formation of UDP-M
called a "Park nucleotide"
Cycloserine
Amino acid
UDP-M pentapeptide
X
X
alanine (ala) analog
inhibits conversion L-ala to D-ala
inhibits formation of D-ala-D-ala
6
13. Vancomycin
Cell wall
Vancomycin ( binds to D-alanyl-D- alanine protion
of terminal end of peptidoglycan pentapeptide
Makes transglycolase enzyme ineffectual
cause inhibition of elongation
15. Beta lactams
•inhibit penicillin binding proteins(Transpeptidase)
Cell wall
•stop cross-linking
•Activate autolysin enzyme
There functions are diverse: catalyze the
transpeptidase reaction, maintain shape, forms
septums during division, Inhibit autolytic
enzymes.
Penicillin binding protein
16. BETA LACTAM ANTIBIOTICS
• Clinically useful families of beta-lactam
compounds include the
– Penicillins,
– Cephalosporins,
– Monobactams
– Carbapenems
17. History
• The penicillins were the first antibiotics discovered as natural
products from the mold Penicillium.
• In 1928, Sir Alexander Fleming, professor of bacteriology at St.
Mary's Hospital in London, was culturing Staphylococcus aureus.
• He noticed zones of inhibition where mold spores were growing.
• He named the mold Penicillium rubrum.
• It was determined that a secretion of the mold was effective against
Gram-positive bacteria.
18. CHEMISTRY AND PROPERTIES
• 1-THIOZOLIDINE RING
• 2-BETA LACTAM RING
O
S
C
NH CH
CH
2
O
C
CH3
C
CH3
1
N
•Beta lactamase
• Gastric acid
CH
COOH
•Penicillanic acid
19. • The penicillin nucleus itself is the chief
structural requirement for biological activity;
• Metabolic transformation or chemical
alteration of this portion of the molecule
causes loss of all significant antibacterial
activity
22. Pharmacokinetics
Oral administration of Penicillin G:
• Acid labile –destroyed by gastric acid
• About one-third of an orally administered dose of penicillin G is
absorbed from the intestinal tract under favorable conditions.
• Gastric juice at pH 2 rapidly destroys the antibiotic.
Parenteral Administration of Penicillin G:
• From im site absorption is rapid and complete
• Peak plasma levels attained in 30min
23. Pharmacokinetics
•
Cont…
Penicillin G is distributed widely throughout the body, but the concentrations
in various fluids and tissues differ widely.
•
Approximately 60% of the penicillin G in plasma is reversibly bound to
albumin.
•
Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and
intestine
•
Cerebrospinal Fluid. Penicillin does not readily enter the CSF when the
meninges are normal. However, when the meninges are acutely inflamed,
penicillin penetrates into the CSF more easily.
•
Little metabolized because rapid excretion
24. Pharmacokinetics
Cont…
• The half-time for elimination is about 30 minutes in normal
adults (upto 10 hours in renal failure) .
• Approximately 10% of the drug is eliminated by glomerular
filtration and 90% by tubular secretion.
• While probenecid markedly decreases the tubular secretion
of the penicillins,
25. Preparations and dose
• Benzylpenicillin (sodium and potassium salts)
• Repository preparations:
• Insoluble salts, only im injection never iv injection
– Procaine penicillin
– Benzathine penicillin
26. Unitage of Penicillin
1 U OF CRYSTALLINE SOD. BENZYL PENICILLIN
=0.6 µg OF THE STANDARD PREPARATION
1GM =1.6 MILLION UNITS
1 MU = 0.6 GM
27. Resistance mechansims
• Produce β lactamase (penicillinase)
– destroys antibiotic
• modified penicillin binding proteins
– don’t bind antibiotic
• modified porins
– no internalization of antibiotic
27
28. Adverse effects
• Hypersensitivity Reactions. Hypersensitivity reactions are most
common adverse effects noted with the penicillins, and these
agents probably are the most common cause of drug allergy.
• The basis of which is the fact that degradation products of
penicillin combine with host protein and become antigenic.
(Penicilloic acid)
29. Adverse effects
Cont…
• In approximate order of decreasing frequency, manifestations
of allergy to penicillins include maculopapular rash, urticarial
rash, fever, bronchospasm, vasculitis, serum sickness,
exfoliative dermatitis, Stevens-Johnson syndrome, and
anaphylaxis
• The overall incidence of such reactions to the penicillins varies
from 0.7% to 10% in different studies.
30. Adverse effects
• Very high doses of penicillin G can cause
seizures in kidney failure.
• Pain at im injection site
• Nausea on oral ingestion
• Thromboplebitis of injected vein
Cont…
31. Penicillin V
• Orally active
• Used for the treatment of bacteremia and oral
infections
• Higher minimum bactericidal concentration
32. • The major draw backs of benzylpenicillin are:
– Inactivation by gastric acid
– Short duration of action
– Poor penetration into the CSF
– Narrow spectrum of activity
– Susceptibility to Penicillinase
– Development of resistance
– Possibility of anaphylaxis
33. Penicillinase-resistant penicillins
(antistaphylococcal penicillins)
• These congeners have side chains that protect the beta
lactam ring from attack by staphylococcal penicillinase
• Indicated in infections caused by penicillinase producing
staphylococci (drugs of choice, except in MRSA)
– Methicillin, Cloxacillin
– Oxacillin, Nafcillin, Dicloxacillin
34. Extended spectrum penicillins
• Active against a variety of gram-negative bacilli as well
• Can be grouped according to their spectrum of activity
1. Aminopenicillins:
Ampicillins:
• Active against all organisms sensitive to PnG; in addition, many
gram-negative bacilli
36. Extended spectrum penicillins
Cont…
Pharmacokinetics:
• Acid resistant
• Oral absorption is incomplete but adequate
• Primary excretion is kidney, partly enterohepatic circulation occurs
• Plasma half life is 1hr
Uses:
• UTI, RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentery,
Cholisystitis, Subacute bacterial endocarditis and Septicemias
37. Extended spectrum penicillins
Cont…
Adverse effects:
• Diarrhoea
• Rashes
• Hypersensitivity
Interactions:
• Hydrocortisone –inactivates ampicillin if mixed in the iv solution
• OC –failure of oral contraception
• Probenecid –retards renal excretion
38. Extended spectrum penicillins
Cont…
• Bacampicillin –ester prodrug of ampicillin
• Talampicillin, Pivampicillin and Hetacillin are other Prodrugs of
ampicillin
Amoxicillin:
• Close congener of ampicillin but not a prodrug
• Similar to it in all aspects except:
– Better oral absorption
– Higher and sustained blood levels are produced
– Incidence of diarrhoea is lower
– Less effective against Shigella and H. influenzae
40. Extended spectrum penicillins
Cont…
• These are called antipseudomonal penicillins
• Piperacillin is more potent among these
• Carbenicillin is less effective against Salmonella, E. Coli and
enterobacter but not active against Klebshiella and gram-positive
cocci
• Piperacillin has good activity against Klebshiella, and is used mainly
in neutropenic/ immunocompromised patients having serious
gram-negative infections and in burns
41. G+Ve cocci
Staphylococcus (Boils, bone, joint, infections of wounds)
• Non Beta lactamase producing- Pencillin G or V
• Beta lactamase producing – Flucloxacillin
Streptococcus, haemolytic types( Bacterimia, scarlet fever, toxic shock
syndrome) – Pencillin-G or Pencillin V
Enterococcus (endocarditis)- Pencillin G + gentamicin
Pneimococcus (pneumonia) Pencillin G or Pencillin V or ampicillin or
macrolide
42. G –ve cocci
• Morasella catarrhalis(Sinusitis) amoxicillin+clavunic acid
• Neisseria gonorrhoeae (gonorrhoea) amoxicillin+clavunic acid
G+ve rods
• Clostridium (tetanus, gangrene)- Pencillin G
• Listeria monocytogenes (Rarely cause meningitis) Amocillin±aminoglycoside
43. G-ve rods
• Haemophilius influenzae (R.T.I, ear, sinuses, meningitis)
Ampicillin or cefuroxime
• Pasterurella multocida (wound infection, abcess)
Amoxicillin+ calvulanic acid
• H. pylori Metroindazole + amoxicillin+ Ranitidine
Other
• Oropharyngeal infection- Pencillin G
• Rheumatic fever - Prophylactic
45. 2nd line drug for
•
•
•
•
•
•
Corynebacterium (diphtheria)- Macrolide- Pencillin G
UTIextend spectrum pencillins(Amoxicillin)
Shigella (dysentery) – Q -ampicillin
Salmonella (typhoid)- Quinolone- amoxicillin
Whooping cough – Macrolide - Ampicillin
Borella recurrentis (relapsing fever)- Benzylpencillin
46. Beta-lactamase inhibitors
• Clavulanic acid, Sulbactam and
Tazobactam
• They contain beta-lactam ring but
themselves, do not have
significant antibacterial activity
47. Beta-lactamase inhibitors
Clavulanic acid:
•
Obtained from Streptomyces clavuligerus
•
Called a suicide inhibitor
•
Pharmacokinetics matches amoxicillin with which it is used
Sulbactam:
•
Semisynthetic beta-lactamase inhibitor
•
Related chemically as well as in activity to clavulanic acid
•
It is also a progressive inhibitor
•
Combined with ampicillin
Cont…
48. Beta-lactamase inhibitors
Cont…
Tazobactam:
• Similar to Sulbactam
• Pharmacokinetics matches with Piperacillin with which it is used for used
in severe infections like peritonitis, pelvic/urinary/respiratory infections
• However, the combination is not effective against piperacillin-resistant
Pseudomonas
49. Ampicillin
Amoxycillin
Oral incomplete absorption
Oral complete absorption
Food Dec. absorption
No
CSF meningitis
No
Shigella respond
No
Streptococci viridans respond
Respond
Bacilliary desentry responds
No
Gentamicin Synergistic action
No
Dec. OC pills activity
No
Salbactum
Clavulanic acid
250-500mg of QID Equals to
250-500mg TDS
-----
Used in H.Pylori Regimens
