Betalactam antibiotics

This presentation discusses pharmacology of beta lactum antibiotics

1. BETALACTAM ANTIBIOTICS
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2. Beta lactam antibiotics
•Similar chemical structure
•High efficacy & low toxicity
•Frequently prescribed
•Cell wall synthesis inhibitors
•Penicillin
•Cephalosporin
•Carbapenem- Faropenem- orally effective
•Monobactam
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3. Beta- Lactam Antibiotics:
The antibiotics which contain beta lactam ring are
beta lactam antibiotics.
•Penicillins
•Cephalosporins
•Monobactams
•Carbapenems
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4. Chemistry:
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5. The Penicillins
History:
•Sir Alexander Fleming discovered Penicillin in 1928 from
Penicillium notatum.
•Penicillin is now obtained from the fungus Penicillium
Chrysogenum for therapeutic use.
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6. Chemistry:
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7. • Bactericidal drugs.
•Inhibits the cell wall synthesis.
•Rapid action on growing & multiplying bacteria

Mechanism of action of Penicillin
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8. Beta-lactam antibiotics mechanism of action
Bind Penicillin binding proteins
Bactericidal Effect
Inhibit cross-linking of Peptidoglycan
Cell-Wall deficient bacteria
Undergo lysis
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9. NAM
D-Ala
DA
L-Lys
DA
D-Glu
NAG
NAM
D-Ala
DA
L-Lys
DA
D-Glu
NAG__
Transpeptidase
Bacteriophenol lipid
Peptide link
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11. •More effective for gram positive bacteria
•In gram positive bacteria thick peptidoglycan layer is
easily accessible to beta lactam antibiotics.
•In gram negative bacteria thin peptidoglycan layer present
between outer layer and cytoplasmic membrane
•Outer layer is lipoplysaccharide, it consists of porin
channels.
•Only Hydrophilic Penicillins can diffuse through Porin
channels.
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12. Mechanism of bacterial resistance to Penicillins
1. Modification of PBP in cell membrane.
high-molecular-weight PBPs that has decreased affinity for the
antibiotic. Eg: Streptococcus pneumoniae
2 ) Inability of the agent to penetrate to its site of action.
In gram –ve bacteria contain porins in outer membrane –
impermeable to antibiotics

3) Active efflux pumps
E. coli & N. gonorrhoea
4) β – lactamases Produced by Gram +ve &–ve bacteria
Inactivate Betalactam antibiotics by opening the betalactam
ring.


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13. Classification of Penicillins
1)Penicillin G & its esters
Penicillin G (Benzyl Penicillin)
Procaine Penicillin G, Benzathine Penicillin G
2) Acid resistant Penicillin
Phenoxymethylpenicillin (Penicillin V)
Phenoxyethylpenicillin
3) Penicllinase- resistant Penicillins
a) Acid labile: Methicillin, Nafcillin,
b) Acid resistant: cloxacillin, dicloxacillin, Flucloxacillin
4) Penicillins effective against gm +ve & some gm –ve
bacteria
Ampicillin, Amoxycillin, Talampicillin, Pivampicillin
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14. 5) Extended spectrum penicillins
a) Carboxypenicillins:
Carbenicillin, Ticarcillin
b) Ureidopenicillins:
Piperacillin, Mezlocillin, Azlocillin
c) Amidopenicillins:
Mecillinam, Pivmecillinam
6) Penicillins with β – lactamase inhibitors
Amoxycillin – clavulanic acid (Augmetin)
Ampicillin - Sulbactam
Piperacillin - Tazobactam
Anti
Pseudomonial
Penicillins
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15. BenzylPenicillin
•P-G also known as natural penicillin, Benzyl penicillin,
aqueous crystalline penicillin
•Activity of P-G is defined in Units. 1 mg of P-G = 1600 units
•1 g of P-G = 1.6 million unit or mega unit (Mu).
Antibacterial spectrum;
gram positive cocci: Streptococci, staphylococci,
gram –ve cocci: Nisseria
Gram +ve bacilli: Bacillus anthracis, Corynebacterium
diphtheriae, clostridium sp

spirochetes, actinomycetes,listeria monocytogenes, Borrelia
burgodorferi, Treponema pallidum is extremely sensitive
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16. Kinetic of Penicillin-G
•Acid labile; also food interferes absorption
•i.m., i.v routes
•Peak concentration in 30min (t½ 30min)
•Duration: 4-6h
•Plasma albumin binding (65%)
•Well distributed (penetrate csf in infection)
• Excretion by secretion (90%) by gf (10%)
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17. KINETICS:
•Acid labile, orally not effective
•Route: IM or IV
•Distribution: widely distributed
•Penicillin normally doesn’t cross BBB but in meningeal
inflammation it crosses.
•urinary excretion occurs by tubular secretion.
Penicillin + Probenecid
•Probenecid competes for renal tubular secretion and there by
prolongs the duration of action of Penicillin
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18. Repository Penicillins:
These are relatively insoluble in water & release slowly when
injected.
•Procaine Penicillin IM 24hours
•Fortified procaine penicillin
•Benzathine Penicillin Deep IM 7-10days
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19. Adverse Reactions
•Penicilins are highly safe drugs with a high therapeutic Index.
Minor Reactions:
Oral – nausea & vomiting
IM – local pain erythema & induration.
IV (benzylpenicillin) – thrombophlebitis
IV (Procaine benzylpenicillin) – anxiety, mental disturbances,
paraesthesia & seizures due to procaine.
-intrathecal route: cause arachnoiditis, convulsions &
encephalopathy
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20. Hypersensitivity reactions
–Skin rash
–Urticaria
– Fever
–Dermatitis
–Bronchospasm
–Angioedema
–Joint pain
–Serum sickness
–Anaphylactic shock
–Jerisch Herxheimer reaction (due to release of endotoxin of
spirochaetes)
Seizure on high dose
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21. Anaphylaxis :
Symptoms of anaphylaxis usually begin within a few
minutes after penicillin administration, irrespective of route
of administration.
•It is characterized by
acute cardiovascular collapse
bronchospasm & Hypotension
angioedema (larynx)
Adrenaline: drug of choice - IM
Dopamine- infusion
Antihistamines
synthetic Glucocorticoids maintenance after controlling the
severity
Note: Concentrated adrenaline by IV produces cardiac
arrhythmias. Slow diluted IV adrenaline does not cause.

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22. Skin tests:
1)Scratch method:
Scratch the skin through a drop of solution containing 10,000
units of benzyl penicillin per ml.
Central wheal due to local edema (not diffuse erythema)
occurs after 15 min is positive reaction.
2) Another skin test –
administration of 0.05 ml of Penicilloyl-polylysine
intradermally.
-Observation - +ve inflammatory response,
-Combination of these 2 tests will predict virtually all
reactions to Penicillin.
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23. USES OF PENICILLINS:
Prophylaxis:
1. Rheumatic fever:
2. Bacterial endocarditis:
3. Agranulocytosis
Treatment:
1) Streptococcal infections:
Pharyngitis, Otitis media, Scarlet fever,
Rheumatic fever, Subacute bacterial endocarditis
2) Pneumococcal infections:
Pneumococcal pneumonia and
meningitis, Pericarditis, Empyema
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24. 3) Meningococcal infection

4) Syphilis ,
5)lyme disease, listeriosis
6) Leptospirosis

7) Diphtheria
8) Tetanus and gas gangrene
9) Anthrax
10) Actinomycosis
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25. Semisynthetic Penicillins
•Major drawbacks of benzylpenicillin are
-Inactivated by gastric juice
-Short duration of action
-Poor penetration into CSF
-Narrow spectrum of activity
-Development of resistant organisms.
-Possibility of anaphylaxis.
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26. Oral Penicillin: Phenoxy methyl penicillin (Penicillin V)
Penicillinase (β – lactamase) resistant penicillins:
Methicillin, Cloxacillin, Dicloxacillin, Flucloxacillin
•Nafcillin excreted through bile and preferred in renal failure
patients.
•Methicillin and nafcillin : parenteral route
•Interstitial nephritis: Nafcillin
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27. Penicillins effective against gram positive and negative
bacteria:

Ampicillin, Amoxicillin, talampicillin, pivampicillin
Talampicillin and pivampicillin are prodrugs
Failure of oral contraceptives with Ampicillin due to
inhibition of colonic flora, so it interfere with deconjugation &
enterohepatic circulation of contraceptives.
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28. AMPICILLIN AMOXICILLIN
Incompletely absorbed from the gut Completely absorbed
Better bioavailability
Food affects absorption Food does not affects the absorption
Alters the gut flora and more incidence of
diarrhea and super infection
Minimal alteration of the gut flora so less
incidence of diarrhea and super infection
Concentrated in bile Concentrated in respiratory secretions
and sputum
More active against shigella and H.
influenzae
Less active against shigella and H.
influenzae.
More active against H.pylori
Preferred route by IM/IV except in GIT
infection (oral)
Preferred used by oral route
Short duration of action
(4times a day)
Rash is common
Longer duration of action
3 times a day
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29. Therapeutic Uses:
•Urinary tract infections:
•Upper Respiratory tract infections:
•Gonorrhea
•Bacillary dysentery
•Typhoid
•Cholecystitis
•Periodontitis
•Meningitis
•Sub acute bacterial endocarditis
•Septicemias : along with Gentamicin

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30. •Include
carboxypenicillins,
ureidopenicillins,
amidinopenicillins
•
Extended Spectrum Penicillins
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31. •Antipseudomonal Penicillins:

Carboxypenicillins:
Carbenicillin, Ticarcillin
Ureidopenicillins:
Piperacillin, Mezlocillin, Azlocillin
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32. •Effective Proteus, Pseudomonas aeruginosa, klebsiella
•Less effective for gram +ve organisms
•They inactivate Aminoglycosides so should not be used in
same syringe
•Acid labile, Susceptible to Penicillinases
•Carbenicillin Causes CCF ( sodium retention) and bleeding

(abnormal platelet aggregation)
•
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33. Beta - Lactamase inhibitors:
•A beta-lactamase inhibitor is a drug given in conjunction with
a beta-lactam antibiotic.
•It inhibits activity of beta-lactamase that causes resistance of
beta-lactam antibiotics to bacteria.
• progressive inhibition ( first reversible and then irreversible)
Clavulanic acid
Sulbactam
Tazobactam
•It widens antibacterial spectrum of Penicillins
Clavulanic acid + Amoxicillin/ticarcillin
Sulbactam + Ampicillin
Tazobactam + Piperacillin
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34. Ampicillin/amoxicillin + Cloxacillin
Is it rationale
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35. CEPHALOSPORINS
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36. Source: cephalosporium acremonium
Betalactam ring and dihydrothiazine ring
Mechanism of action:
Resistance:
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38. FIRST GENERATION CEPHALOSPORINS:
Oral: Parenteral:
Cephalexin Cefazolin
Cefadroxil Cephalothin
Cephradine
Gram positive organisms
Anaerobes except B.fragilis
Susceptible to beta lactamases
Used in surgical prophylaxis
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39. SECOND GENERATION :
Parenteral Oral
Cefuroxime Cefaclor
Cefoxitin Cefuroxime axetil
•These are more active against gram negative
organisms
•Some are active against anaerobes, but not for P.
aeruginosa
•Partly resistant to betalactamases
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40. Third generation
Parenteral Oral
Cefotaxime Cefixime
Ceftizoxime Cefpodoxime proxetil
Ceftriaxone Cefdinir
Cefoperazone Ceftibuten
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41. •More activity against gram negative bacteria
• Pseudomonas.
•All are highly resistant to β-lactamases from gram negative
bacteria
•They are less active on gram positive cocci and anaerobes
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42. Forth generation
Parenteral
Cefepime
Cefpirome
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43. ADVERSE EFFECTS OF CEPHALOSPORINS
1. Hypersensitivity reactions:
2. Nephrotoxicity
3. Diarrhea:
due to alteration of gut ecology or irritative effect is
more common with oral cephradine and parenteral
cefoperazone

4. Bleeding: due to hypoprothrombinemia
with cephalosporins having a methylthiotetrazole or
cefoperazone, cefotetan, and cefamandole.
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44. 5. Pain at injection site
6. Neutropenia and thrombocytopenia
7. A disulfiram like interaction with alcohol has been reported
with cefoperazone
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45. USES:
1.As alternatives to PnG; particularly in allergic patients .
1.Respiratory, urinary and soft tissue infections caused by
gram negative organisms, especially Klebsiella, Proteus,
Enterobacter, Serratia
3. Surgical prophylaxis
4. Gonorrhoea : Ceftriaxone 250mg single dose
5. Meningitis
Ceftazidime + Gentamicin is the most effective therapy for
Pseudomonas meningitis
6. Typhoid
7. Nosocomial infections
8. Mixed aerobic and anaerobic infections
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46. MONOBACTAMS
Monocyclic Beta lactums ring
Resistant to beta lactamase
AZTREONAM:
•IV. Every 8 hours. 1-2 g.
•Effective for gram negative aerobic bacteria
•Pseudomonas, e.coli, H.influenzae
•ADRs: Rash
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47. CARBAPENEMS
•Betalactam + penem ring
•Highly resistant to beta-lactamases
IMEPENEM:
Imepenam + Cilastatin (inhibitor of renal dehydro peptidase)
Reserved for hospital acquired infection, AIDS, cancer etc –
given by i.v.
Seizure at high dose, nausea, vomiting diarrhoea.
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49. Carbapenems
Meropenem
No need for cilastatin; not hydrolysed by renal
dehydropeptidase.
No seizures
Ertapenem
Faropenem
Orally effective
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50. 1.Revision
2.Symptoms in anaphylactic shock
3.Treatment for anaphylactic shock
4.Betalactamase inhibitors
5.Differences between ampicillin and amoxicillin
6.Orally given penicillins
7.Antipseudomonial penicillins
8.Third generation cephalosporins
9.Fourth generation cephalosporins
10.Second generation cephalosporins
11. Imepenem + cilastatin
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