1. β-LACTAM ANTIBIOTICS

2. Introduction β-Lactam antibiotics:
Most widely produced and used antibacterial drugs in the world.
Have a common β-Lactam ring structure.

3. HISTORY
1928- Alexander Fleming discovers penicillin is isolated and tested penicillin mass produced by fermentation 1950’s- 6-APA and semi-synthetic penicillins are developed. 1960’s to today- novel β-lactams/ β-lactamase inhibitors

4. BETA-LACTAM ANTIBIOTICS
(inhibitors of cell wall synthesis)
Their structure contains a beta-lactam ring.
The major subdivisions are:
Penicillins
(B) Cephalosporins
(c) Carbapenems
(e.g. meropenem, imipenem)
(d) Monobactams
(e.g. aztreonam)
(e) Beta-lactamase Inhibitors
(e.g. clavulanic acid, sulbactam).

5. SUMMARY OF ANTIMICROBIAL AGENTS AFFECTING CELL WALL SYNTHESIS
INHIBITORS OF CELL
WALL SYNTHESIS
b-LASTAMASE
INHIBITORS
b-LASTAMASE
ANTIBIOTIC
OTHER
ANTIBIOTIC
Clavulanic acid
Sulbactam
Tazobactam
Bacitracin
Vancomycin
PENICILLINS
CEPHALOSPORINS
CARBAPENEMS
MONOBACTAMS
Imipenem/cilastatin
Meropenem*
Ertapenem
Amoxicillin
Ampicillin
Cloxacillin
Dicloxacillin
Indanyl carbenicillin
Methicillin
Nafcillin
Oxacillin
Penicillin G
Penicillin V
Piperacillin
Ticarcillin
Aztreonam
1st GENERATION
2nd GENERATION
3rd GENERATION
4th GENERATION
Cefadroxil
Cefazolin
Cephalexin
Cephalothin
Cefaclor
Cefamandole
Cefprozil
Cefuroxime
Cefotetan
Cefoxitin
Cefdinir
Cefixime
Cefoperazone
Cefotaxime
Ceftazidime
Ceftibuten
Ceftizoxime
Ceftriaxone
Cefepime
(according to Lippincott´s Pharmacology, 2009)

6. PENICILLINS
A. FLEMING
(1881–1955)
Penicillin G
P. notatum
(1929)

7. Originally obtained from the fungus Penicillium notatum
PENICILLIN
Originally obtained from the fungus Penicillium notatum
Present source:- a high yielding mutant of P. chrysogenum

8. CHEMICAL PROPERTIES The compound consists of 2 basic structures:
1 Thiazolidine Ring (A)
2.Beta-Lactam Ring (B)
Penicillin G (PnG) having a benzyl side chain at R (benzyl penicillin) is the original penicillin used clinically.
Amidase : Split off the side chain of natural penicillin to produce 6-aminopenicillanic acid.
Other side chains can then be attached to it resulting in different semisynthetic penicillins.
At the carboxyl group attached to the thiazolidine ring, salt formation occurs with Na+ and K+.
These salts are more stable than the parent acid.
Sod. PnG is highly water soluble.
It is stable in the dry state, but solution deteriorates rapidly at room temperature, though it remains stable at 4°C for 3 days.
Therefore, PnG solutions are always prepared freshly.
PnG is also thermolabile and acid labile.

9. MECHANISM OF β LACTAM
Interfere with the synthesis of bacterial cell wall.
The bacteria synthesize UDP-N-acetylmuramic acid (NAM) pentapeptide and UDP-N-acetyl glucosamine(NAG).
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 neighbouring strands.
This cross linking provides stability and rigidity to the cell wall.

10. TRANSPEPTIDASE- PBP
Transpeptidases enzyme is for establishment of cross linkages between peptide chains of the neighbouring strands
These enzymes and related proteins constitute the penicillin binding proteins (PBPs) which have been located in the bacterial cell membrane.
Each organism has several PBPs and differ in their affinity towards different β -lactam antibiotics.

11. β -lactam antibiotic binding to PBPs results in:
MECHANISM OF ACTION
β -lactam antibiotic binding to PBPs results in:
Inhibition of transpeptidase:
Transpeptidase catalyzes the cross-linking of the pentaglycine bridge with the fourth residue (D-Ala) of the pentapeptide.
The fifth reside (also D-Ala) is released during this reaction.
Structural irregularities:
Binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects.

12. 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 and bacterial lysis.
Bactericidal action.
Rapid cell wall synthesis occurs when the organisms are actively multiplying; β –lactam antibiotics are more lethal in this phase.

13. Nontoxic to human:-
The peptidoglycan cell wall is unique to bacteria.
No such substance is synthesized by higher animals.
Higher susceptibility of the gram-positive bacteria:-
In gram-positive bacteria:
The cell wall is almost entirely made of peptidoglycan
In gram-negative bacteria:
It consists of alternating layers of lipoprotein and peptidoglycan.

14. Cross linking

15. BACTERIA RESISTANCE Three main mechanism:-
Produce β-lactamase after contact with β-lactam antibiotics.
β-lactamase can inactivate ß-lactam antibiotics through rupture the ß- lactam ring.
Different microorganisms produce a number of distinct β-lactamase.
(2) Many bacterial can alter PBPs with decreased affinity for ß-lactam antibiotics.
This can result in failure of antibiotics binding to active sites.

16. (3) The concentration of antibiotics in target site is too low because of lacking of porin protein.
This permeability block is particularly seen in resistance gram-negative bacteria that possess a complex outer layer.
Increased active antibiotics efflux which reduce the drug in bacteria is the other reason for low concentration in target site.

17. PENICILLINS I. Natural penicillins Benzylpenicillin (Penicillin G)
Instable in water solution.

18. STRUCTURE
Benzyl penicillin (Pen G)
R =
Phenoxymethyl penicillin (Pen V)
Acyl side
chain
6-Aminopenicillanic acid
(6-APA)
Acyl side
chain
Thiazolidine
ring
6-Aminopenicillanic acid
(6-APA)
Acyl side
chain
Thiazolidine
ring
b-Lactam
6-Aminopenicillanic acid
(6-APA)
Acyl side
chain
Side chain varies depending on carboxylic acid present in fermentation medium
Penicillin G
Penicillin V
(first orally active penicillin)

19. NATURAL PENICILLINS PHARMACOKINETICS ANTIBACTERIAL SPECTRUM:
Benzylpenicillin (Penicillin G)
Instable in water solution.
Great antibacterial activity.
ANTIBACTERIAL SPECTRUM:
Gram-positive cocci:
Streptococcus pyogenes, non-β- lactamase producing staphylococcus aureus, sensitive streptococcus pneumoniae, aerobic Gram positive cocci.
Gram-positive bacilli:
Corynebacterium Diphtheriae; Bacillus Anthracis; Anaerobic Clostridium Tetani; Clostridium Perfringens; Clostridium Botulinum; Actinomyces.
Gram-negative cocci:
Nesseria meningitides; Neisseria gonorrhoeae.
Spirochetes:
Treponema pallidum; leptospira spp.; borrelia burgdorferi.
PHARMACOKINETICS
Acid labile
Poor oral absorption.
Absorption of sod. PnG from i.m. site is rapid
Peak plasma level in 30 min.
Distributed extracellularly.
Reaches most body fluids, but penetration in serous cavities and CSF is poor.
60% is plasma protein bound.
Very rapid renal excretion.
Plasma t ½ - 30 min.

20. ADVERSE REACTIONS 1. Hypersensitivity Major problem -1-10%
Frequently:- Rash, itching, urticaria and fever.
less common:- Wheezing, angioneurotic edema ( Rapid swelling of the dermis), serum sickness (an allergic reaction to an injection of serum) and exfoliative dermatitis (scaling of the skin).
Anaphylaxis (an acute allergic reaction to an antigen) is rare but fatal.
All topical preparations of penicillin have been banned.

21. 2.Local irritancy and direct toxicity
Pain at i.m. injection site, nausea on oral ingestion and thrombophlebitis (inflammation of the wall of a vein with associated thrombosis) of injected vein.
Toxicity to the brain
Mental confusion, muscular twitchings (local, involuntary muscle contraction and relaxation) , convulsions (a sudden, violent, irregular movement of the body) and coma in patients with renal insufficiency.
Bleeding
With high doses
Due to interference with platelet function.
Intrathecal injection of PnG:
No longer recommended
Because of arachnoiditis (chronic pain caused by inflammation in the spinal canal) and degenerative changes in spinal cord.
I.V. injection of procaine penicillin:-
Produces CNS stimulation, hallucinations and convulsions due to procaine.

22. 3. Jarisch-Herxheimer reaction : (An increase in the symptoms of a spirochetal disease)
Produce shivering, fever, myalgia (pain in a muscle) , exacerbation of lesions, even vascular collapse.
Due to release of spirochetal lytic products.
4.Superinfections :
Rare with PnG
Because of its narrow spectrum.

23. CLINICAL USES Infection of streptococcus: 2. Pneumococcal infections:
Like pharyngitis, otitis media, scarlet fever (an infectious bacterial disease affecting especially children, and causing fever and a scarlet rash), rheumatic fever (acute fever marked by inflammation and pain in the joints)
2. Pneumococcal infections:
Pneumococcal pneumonia, Pneumococcal meningitis
3. Treatment of meningococcal meningitis.
Treatment of gonococcal infections such as gonococcal urethritis, gonococcal arthritis.
Syphilis
Diphtheria (causing inflammation of the mucous membranes)
Tetanus (a bacterial disease marked by rigidity and spasms of the voluntary muscles) and gas gangrene (localized death and decomposition of body tissue)
For rare infections like anthrax (affecting the skin and lungs), actinomycosis (bacterial disease caused by Actinomyces), trench mouth (painful, bleeding gums, and ulceration), rat bite fever (causes inflammation of the skin and fever)
Prophylactic uses of Rheumatic fever, Bacterial endocarditis, Agranulocytosis ( deficiency of granulocytes in the blood).

24. SEMISYNTHETIC PENICILLINS

25. Disadvantages of penicillin G
1 . Poor oral efficacy. 2. Susceptibility to penicillinase. 3. Narrow spectrum of activity. 4. Hypersensitivity reactions

26. CLASSIFICATION 1 . Acid-resistant alternative to penicillin G
Phenoxymethyl penicillin (Penicillin V).
2. Penicillinase-resistant penicillins:
Methicillin,Cloxacillin.
3. Extended spectrum penicillins:
Aminopenicillins:
Ampicillin, Bacampicillin, Amoxicillin.
(b) Carboxypenicillins:
Carbenicillin, Ticarcillin.
(c) Ureidopenicillins:
Piperacillin, Mezlocillin.
4. Β Lactamase inhibitors:
Clavulanic acid, Sulbactam, Tazobactam

27. 1. ACID-RESISTANT ALTERNATIVE TO PENICILLIN G
Penicillin V (phenoxymethyl penicillin)
ANTIBACTERIAL ACTION:
Similar with penicillin G but lower activity.
PHARMACOKINETICS:
Acid stable.
Oral absorption is better
Peak blood level in 1 hour
Plasma t 1/ min.
CLINICAL USES:
For streptococcal pharyngitis
Sinusitis
Otitis media
Prophylaxis of rheumatic fever
Less serious pneumococcal infections and trench mouth.
ADVERSE REACTION:
Allergic reaction
Gastrointestinal reaction (burning sensation, nausea, vomiting and diarrhea)

28. PENICILLINASE-RESISTANT PENICILLINS
These have side chains that protect the β-lactam ring from attack by staphylococcal penicillinase.
Nonpenicillinase producing organisms are less sensitive.
Methicillin; Dicloxacillin; Cloxacillin and Oxacillin belong to this kind of penicillins.
Antibacterial activity:
Powerful activity on penicillinase producing staphylococci.
Clinic uses:
Infections caused by penicillinase producing staphylococci.

29. CLOXACILLIN METHICILLIN Isoxazolyl side chain
Highly penicillinase resistant
Adverse Effects:
Haematuria (the presence of blood in urine), albuminuria (the presence of albumin in the urine) and nephritis.
It has been replaced by cloxacillin.
CLOXACILLIN
Isoxazolyl side chain
Highly penicillinase as well as acid resistant.
Antibacterial spectrum:
less active against PnG sensitive organisms.
More active than methicillin against penicillinase producing Staph, but not against MRSA.
Pharmacokinetics:
Incompletely absorbed from oral route, especially if taken in empty stomach.
> 90% plasma protein bound.
Elimination by kidney.
Plasma t1/2 - 1 hour.

30. EXTENDED SPECTRUM PENICILLINS
Active against a variety of gram-negative bacilli as well.
They can be grouped according to their spectrum of activity.
Antibacterial activity:
Ampicillin and amoxicillin similar action to penicillin G sensitive bacteria.
Activity to gram-negative bacteria is greater than that for Penicillin G.

31. AMINOPENICILLIN Led by ampicillin
Has an amino substitution in the side chain.
Some are prodrugs and all have quite similar antibacterial spectra.
None is resistant to penicillinase or to other β-lactamases.

32. AMPICILLIN ANTIBACTERIAL SPECTRUM:
Active against all organisms sensitive to PnG
In addition, many gram-negative bacilli.
More active than PnG for Strp. viridans and enterococci;
Equally active for pneumococci, gonococci and meningococci; but less active against other gram-positive cocci.
Penicillinase producing Staph. are not affected, as are other gram-negative bacilli, such as Pseudomonas, Klebsiella, indole positive Proteus and anaerobes like Bacteroides fragilis.
Due to developed resistance; usefulness of this antibiotic has decreased considerably.

33. ADVERSE EFFECTS PHARMACOKINETICS Not degraded by gastric acid;
Oral absorption is incomplete.
Food interferes with absorption.
It is partly excreted in bile.
Primary channel of excretion is kidney.
plasma t1/2 - 1 hr.
ADVERSE EFFECTS
Diarrhoea
High incidence (up to 10%) of rashes
Should not be given to hypersensitivity patients.

34. Urinary tract infections Respiratory tract infections Meningitis
Gonorrhoea
Typhoid fever
Bacillary dysentery
Cholecystitis (inflammation of the gall bladder.)
Subacute bacterial endocarditis
Septicaemias and mixed infections
H. pylori
USES

35. AMOXICILLIN Close congener of ampicillin.
Similar to it in all respects.
Except:
• Oral absorption is better
Food does not interfere with absorption
Higher and more sustained blood levels are produced.
• Incidence of diarrhoea is lower.
• It is less active against Shigella and H. influenzae.
Many physicians now prefer it over ampicillin for bronchitis, urinary infections, SABE and gonorrhoea.

36. CARBOXYPENICILLINS
CARBENICILLIN
Spectrum:
Special feature is activity against Pseudomonas aeruginosa and Proteus which are not inhibited by PnG or aminopenicillins.
Less active against Salmonella, E. coli and Enterobacter,
Klebsiella and gram-positive cocci are unaffected.
Kinetics:
Inactive orally ; used as sodium salt
Excreted rapidly in urine
T1/2 -1 hr
Uses:
Serious infections caused by Pseudomonas or Proteus, e.g. burns, urinary tract infection, septicaemia.
But piperacillin is now preferred.

37. UREIDOPENICLLLINS PIPERACILLIN Antipseudomonal penicillin
8 times more active than carbenicillin.
Good activity against Klebsiella
Used mainly in immunocompromised patients having serious gram-negative infections, and in burns.
T 1/2 is 1 hr.

38. BETA-LACTAMASE INHIBITORS
β-lactamases are a family of enzymes
Produced by many gram-positive and gram-negative bacteria
That inactivate β -lactam antibiotics by opening the β -lactam ring.
Different β –lactamases differ in their substrate affinities.
Three inhibitors of this enzyme clavulanic acid, sulbactam and tazobactam.

39. CLAVULANIC ACID ADVERSE EFFECTS USES MECHANISM Same as for amoxicillin
G.I. tolerance is poorer
Candida stomatitis / vaginitis and rashes.
USES
Active against β –lactamase producing resistant Staph. aureus, H. influenzae, gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella and Shigella.
Coamoxiclav is indicated for:-
Skin and soft tissue infections
Intra-abdominal and gynaecological sepsis
Urinary, biliary and respiratory tract infections
Gonorrhoea
Obtained from Streptomyces clavuligerus
Inhibits a wide variety of β- lactamases.
MECHANISM
A 'progressive' inhibitor.
Binding with β -lactamase is reversible initially, but becomes covalent later-inhibition increasing with time. Called a 'suicide' inhibitor.
It gets inactivated after binding to the enzyme.
It permeates the outer layers of the cell wall of gram negative bacteria.
Inhibits the periplasmically located β- lactamase.
Used in combination with amoxicillin as a coamoxiclav.

40. SULBACTAM TAZOBACTAM Similar to sulbactam
Semi synthetic
Related chemically as well as activity to clavulanic acid.
Progressive inhibitor
Highly active against class II to V but poorly active against class I.
Oral absorption inconsistent. Given parenterally.
Combined with ampicillin for use against b-lactamase producing resistant strains.
INDICATIONS :
PPNG gonorrhoea
Mixed aerobic-anaerobic infections
ADVERSE EFFECTS:
Pain at site of injection, thrombophlebitis of injected vein, rash and diarrhoea
TAZOBACTAM
Similar to sulbactam
Pharmacokinetics matches with piperacillin
Combined with piperacillin
USE:-
Peritonitis, pelvic/ urinary/ respiratory infections caused by β - lactamase producing bacilli .
Combination is not active against piperacillin-resistant Pseudomonas.

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