Beta lactam antibiotics (penicillins)

6th semester pharmacology (anti-microbial agents)

1. BETA LACTAM ANTIBIOTICS
PENICILLINS
Done by
ABSHA BASHEER

2. PENICILLINS
•Penicillin was the first antibiotic to be used clinically in
1941
• Less toxic drug of its kind
•Obtained from fungus Penicillium notatum but
presently obtained from P. chrysogenum
•Penicillin consists of fused thiazolidine and β-lactam
ring

3. Mechanism of action

4. • β-lactam antibiotics interfere with bacterial cell wall synthesis.
•The bacteria synthesize UDP-N-acetylmuramic acid pentapeptidea
nd UDP-N-acetyl glucosamine.
• The peptidoglycan residues are linked together forming long strands
and UDP is split off.
• The final step is cleavage of the terminal D-alanine of the peptide
chains by transpeptidases; the energy so released is utilized for
establishment of cross linkages between peptide chains of the
neighboring strands.

5. • This cross linking provides stability and rigidity to the
cell wall.
• The β-lactam antibiotics inhibit the transpeptidases so
that cross linking does not take place.
•When susceptible bacteria divide in the presence of a β-
lactam antibiotic—cell wall deficient (CWD) forms are
produced.
•Because the interior of the bacterium is hyperosmotic, the
CWD forms swell and burst → bacterial lysis occurs.

6. Antibacterial spectrum
• PnG is a narrow spectrum antibiotic
• Activity is limited primarily to gram-positive bacteria, few
gram negative ones and anaerobes.
• Cocci:
– Gram negative cocci—Neisseria gonorrhoeae and N.
meningitidis
–Gram positive cocci; Streptococci
• Bacilli: Gram-positive bacilli—majority of B. anthracis,
Corynebacterium diphtheriae

7. Bacterial resistance
•Many bacteria are inherently insensitive to PnG because in them the target
enzymes & PBPs are located deeper under lipoprotein barrier
• Primary mechanism of acquired resistance is production of penicillinase
• Narrow spectrum β-lactamase
• Gram-positive penicillinase producers large quantity
•Gram-negative produces small quantity located inbetween the lipoprotein
and peptidoglycan layers
•Staphylococcal penicillinase is inducible and methicillin is an important
inducer
•Alteration in porin channel (gram-negative bacteria)

8. Pharmacokinetics
• Penicillin G is acid labile, therefore destroyed by gastric acid.
• Peak plasma level is attained in 30 min.
• It is distributed mainly extracellularly;
• It is little metabolized
• Rapid excretion, about 10% by glomerular filtration and the
rest by tubular secretion. The plasma t½ of PnG in healthy
adult is 30 min.
•Tubular secretion of PnG can be blocked by Probenecid

9. Adverse effects
• Local irritancy and direct toxicity
• Hypersensitivity
•Superinfections
•Jarisch-Herxheimer reaction

10. Uses
•Streptococcal infections
• Pneumococcal infections
• Meningococcal infections
•Gonorrhoea
•Syphilis
• Diphtheria
•Prophylactic uses
–Rheumatic fever
–Bacterial endocarditis

11. Semisynthetic penicillin
•Semisynthetic penicillins are produced by chemically combining specific
side chains (in place of benzyl side chain of PnG) Or by incorporating
specific precursors in the mould cultures.
• The aim of producing semisynthetic penicillins has been to overcome the
shortcomings of PnG
• Poor oral efficacy
• Susceptibility to penicillinase
• Narrow spectrum of activity
• Hypersensitivity reactions
•β-lactamase inhibitors have been developed augment the antibacterial
activity

13. Acid-resistant alternative to penicillin-g
• It differs from PnG only in that it is acid stable.
• Oral absorption is better;
• Peak blood level is reached in 1 hour
• Plasma t½ is 30–60 min.
•Used in less serious infections like streptococcal
pharyngitis, sinusitis, otitis media,

14. Penicillinase-resistant penicillins
•These congeners have side chains that protect
the β-lactam ring from attack by
staphylococcal penicillinase.
•This also partially protects the bacteria from
the βlactam ring
•Non-penicillinase producing organisms are
much less sensitive to these drugs than to
PnG.

15. Extended spectrum penicillins
•These semisynthetic penicillins are active against a variety of
gramnegative bacilli as well
• Aminopenicillins
• Ampicillin
• It is active against all organisms sensitive to PnG.
• In addition, many gram-negative bacilli, e.g. H. influenzae, E.
coli, Proteus, Salmonella Shigella and Helicobacter pylori are
inhibited.

16. Pharmacokinetics
• Ampicillin is not degraded by gastric acid; oral absorption is
incomplete but adequate. Food interferes with absorption.
• Distributed extracellularly
• Not metabolized
• Partly excreted in bile & reabsorbed (enterohepatic circulation)
• However, primary channel of excretion is kidney, but tubular
secretion is slower than for PnG
• Plasma t½ is 1 hr.

17. Uses
•Urinary tract infections
•Respiratory tract infections
•Meningitis
•Gonorrhoea
•Typhoid fever
•Subacute bacterial endocarditis
•H. pylori

18. Adverse effects
• Diarrhoea is frequent after oral administration. It is incompletely absorbed,
causes alteration of bacterial flora
• Rashes especially in patients with AIDSor lymphatic leukaemia
• Patients with a history of immediate type of hypersensitivity to PnG should
not be given Ampicillin as well.
• Drug interaction
• Hydrocortisone inactivates Ampicillin if mixed in i.v. solution
• By inhibiting colonic flora, it may interfere with deconjugation and
enterohepatic cycling of oral contraceptives → failure of OC
• Probenecid retards renal excretion of Ampicillin

19. Beta-lactamase inhibitors
•β-lactamases inactivate β-lactam antibiotics by
opening the βlactam ring.
• Different β-lactamases differ in their substrate
affinities.
• Three inhibitors of this enzyme clavulanic acid,
sulbactam and tazobactam are available for
clinical use.

20. CLAVULANIC ACID
• Obtained from Streptomyces clavuligerus
• It has a β-lactam ring but no antibacterial activity of its own.
• It inhibits a wide variety of β-lactamases (but not class I
cephalosporinase.
• Clavulanic acid is a ‗progressive‘ inhibitor
•It gets inactivated after binding to the enzyme.
• It permeates the outer layers of the cell wall of gram-negative
bacteria and inhibits the periplasmically located β-lactamase.

21. • Pharmacokinetics
• Clavulanic acid has rapid oral absorption & BAB 60%
Its elimination t½ of 1 hr
• Tissue distribution matches with Amoxicillin
• Combination is called coamoxiclav.
•Eliminated mainly by glomerular filtration and its
excretion is not affected by Probenecid.
• Amoxicillin is primarily excreted unchanged by tubular
secretion.

22. •Uses
•Skin and soft tissue infections
• Gonorrhoea
• Adverse effects
•Same as for Amoxicillin
• But GIT tolerance is poorer—especially in children.
• Other AE are Candida stomatitis/vaginitis and rashes.
• Some cases of hepatic injury reported with the
combination.