Download Beta – Lactam Antibiotics

Beta – Lactam Antibiotics
Prof. R. K. Dixit
Pharmacology and Therapeutics
K. G. M. U. Lucknow
[email protected]
Objectives
After completion of this lecture you will be able to
understand
– What are betalactam antimicrobials
– Mechanism of action
– Types of Penicillin, Uses, ADRs
– Classification of Cephalosporin, Uses, ADRs
– Members of Carbapenem and Monobactam, Uses, ADRs
•Have Beta-lactam ring
•Important groups are (PCcM) Paracetamol
Penicillins
Cephalosporins
Carbapenems
Monobactams
Broken by Amidase enzyme
Active material
Raw material for other
penicillin
Broken by Betalactamase enzyme
Inactive
Responsible for
hypersensitivity
Active material
Raw material for other
penicillin
Inactive (Major Determinant)
Responsible for
hypersensitivity
Penicillin
Cephalosporins
Carbapenem
Monobactam
Beta Lactamase inhibitor (Claulanic acid and Sulbactam)
Suicide Inhibitors
Beta Lactamase
Penicillin
•First antibiotic to be used clinically in 1941
•One of the least toxic antibiotic even today
•Obtained from
Penicillium notatum (Early)
Penicillium chrysogenum (Now, Better Yield)
•Scientists- Fleming – Chain – Florey
•Original Penicillin –
•Penicillin G, Benzyl Penicillin ( R is Benzyl (CH2C6H5) )
Chemistry
•Penicillin nucleus consists of
•Thiazolidine ring (Ring A)•Sulphur containing with COOH (Carboxyl group),
•Beta lactam ring (Ring B) – (Broken by Betalactamase)
•Side chain is attached at position – 6- (NHCOR)
•Side chains attached through amide linkage. (Broken by
Amidase)
• Beta Lactam ring is broken by –
• Penicillinase (Beta Lactamase), and by gastric acid.
• Resultant Product is Penicilloic acid with
• No anti-bacterial activity but
• Acts as antigenic determinant (Major determinant)
• Penicillins are available as
• Na+ or K+ salts .
• Amine salts such as Procaine and Benzathine Penicillin.
Natural Penicillin –
-Broken down by Amidase = (Removes Side Chain)
•Penicillin – side chain =
•6- Amino-Penicillanic acid (6-APA)
•Active moiety
•Has intact Betalactam ring (B)
•With NH2 group at position 6 joined to
thiazolidine ring.
•Large amount of 6-APA are produced from
culture of P. chrysogenum. (Fungal Amidase
hydrolyze side chain at position-6.)
•6-APA is basic raw material
•Different types of penicillin are obtained by attaching
different groups at position -6.
•6-APA + other side chains =
•Different types of semi synthetic Penicillins (Different
Pk and Pd)
•Sodium or Potassium salts
•More stable (Stability decreases after making solution)
•Natural Penicillin is
•Benzyl penicillin or Penicillin G (PnG) and
it is
•Thermo and Acid labile
Penicillin Units
•One unit of Sodium Benzyl Penicillin = 0.6µg
Or
•One mega unit = 0.6 gram
Or
•One gram = 1.6 million units
MOA
•Bacteria are unique
•Don’t have osmotic regulating mechanism
•Cell wall controls osmotic changes.
•Cell wall is composed of
•Peptidoglycans
•Cross linked by peptide chains.
•NAM – NAG ( N-acetyl muramic acid and N- acetyl glucosamine)
•Cross linked by a Pentaglycine cross bridge
(Extending from the L-lysine residue of one peptide chain to the Dalanine residue of another peptide chain).
• Cross bridging is transpeptidation reaction.
• Transpeptidase and related proteins (Penicillin
Binding Proteins) are used for making cross
linkage.
• Cross linking provides stability, strength.
•β-Lactams inhibit Transpeptidase leading to
•Damage of cross linking
•Weakening of cell wall
•Swelling of cell due to Endosmosis
•Bacterial membrane bursts
•Bacterial lysis
•Additional mechanism –
•Activation of autolysing enzymes
(Murein Hydrolase and Autolysins)
•More lethal during active multiplication
Betalactam
Antibiotics
• Bactericidal activity of penicillin is more against Gram
positive. (Difference in organization of cell wall)
• In gram positive
• Thick layer of Peptidoglycans and teichoic acid (a polyol
phosphate polymer) surrounds the membrane.
• Peptidoglycans layer is easily accessible to Beta lactam antibiotics
• In gram negative
• Two membranes are present. (The cytoplasmic membrane and an
outer membrane with thin layer of Peptidoglycans sandwiched
between the two).
• The outer membrane consists of lipopolysaccharides with narrow
porin channels which function as a barrier to permeability of
antibiotics
• Penicillins which are hydrophilic in nature
(Ampicillin and Amoxicillin) can diffuse through
porin channels and show activity against negative.
• Pseudomonas lacks porins due to which even
Ampicillin and amoxicillin can’t act against them.
• Aminoglycosides addition is synergistic
Resistance against Penicillin
•Natural
•Target enzymes and PBPs are deeply located (Lipoprotein barrier in –ve)
•PBPs of organisms have low affinity for penicillin
•Acquired
•Production of Penicillinase (Beta-Lactamase) enzyme, (>300 subtypes).
Common organisms producing Beta-Lactamase are
•Staphylococcus
•Bacillus subtilis
•Gonococci
•E. coli
•Enterococci
•Haemophilus influenza
•Loss or alteration of Porin channels in gram negative
•Modification of penicillin binding proteins (PBPs)- having low affinity .
•Activation of antibiotic efflux mechanism- Some gram negative bacteria
Adverse effects
•General
•Hypersensitivity reactions (including Anaphylaxis)
More with procaine penicillin,
Intradermal Skin sensitivity test
Major Determinant (Penicilloyl moiety in terms of amount) is
responsible for hypersensitivity other than anaphylaxis
Minor determinants( Penicillamine and Penicillenate) are
responsible for anaphylaxis.
The Penicilloyl moiety or major determinant results from reaction of beta-lactam
ring with endogenous proteins. The Beta lactam ring spontaneously opens in the
body forming a hapten-protein complex, the most abundant but not necessarily
most immunogenic.
Hypersensitivity testing
• Super infections (Ampicillin)
• Nephrotoxicity (Methicillin causing interstitial nephritis)
• Increase in Prothrombin time leading to bleeding
• Jarisch -Herxheimer ReactionCommon in secondary syphilis,
Release of Spirochetal lytic products (Heat stable proteins, endotoxins)
Characterized by fever, myalgia, exacerbation of lesions,
Usually occurs within 2 hours of first dose
Treatment- NSAIDs and Corticosteroids
Also in Borelliosis, Leptospirosis, and Brucelosis
 Adolf Jarisch an Austrian and Karl Herxheimer a German dermatologist
Jarisch Herxheimer Reaction
Drug
Interactions
• With Tetracyclines, Chloramphenicol, Erythromycin– Antagonism
• Penicillin with Aminoglycosides– Synergism.
• Penicillin and Aminoglycosides or Penicillin and
hydrocortisone in same syringe –
– Inactivate each other (Pharmaceutical)
• Ampicillin with Allopurinol –
– High incidence of non-urticarial maculopapular rashes
• Penicillin with Probenecid
– Prolongs action of penicillin by decreasing tubular secretion
Uses
•General , Plus
•Rheumatic fever
•SABE (Streptococcal viridans)
•Gonorrhea
•Syphilis1.2 MU of Procaine penicillin for 12 days or
2.4 MU of Benzathine Penicillin
•Leptospirosis (Weil’s Disease)
•Actinomycosis, Listriosis, Lyme Disease, Anthrax, Rat bite
Erysipeloid, Gingivostomatitis
•Diphtheria
•Tetanus
•Gas gangrene (Clostridium pefringens (welchii)
•Prophylaxis•Rheumatic fever, SABE,
•Agranulocytosis
fever,
Thanks