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Antibiotic Groups - β-lactams

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"عسى أن تكون علما ينتفع به"
groups of antibiotics
Beta lactam ring
Beta lactamase resistant antibiotics

Publicado en: Educación

Antibiotic Groups - β-lactams

  1. 1. Antibiotic Groups β-Lactams
  2. 2. Members  Amoxicillin  Ampicillin  Benzylpennicillin  Cloxacillin  Dicloxacillin  Calvulanic acid  Ceftazolin  Cefoperazone  Ceftaquin  Ceftiofur  Fefuroxime  Cephalexin
  3. 3. History  In 1929, Fleming cultured Penicillium notatum which produced an antibacterial substance.  A decade later, the subsequent purification of penicillin and its use by Florey, Chain, and others lead to successfully treating infections in human patients.  In 1945, Fleming, Florey, and Chain were jointly awarded the Nobel Prize in Physiology or Medicine for this work.
  4. 4. Mechanism of Action  They act by disrupting peptidoglycan synthesis in actively multiplying bacteria. 1. β-Lactams bind to proteins in the cell membrane [penicillin- binding proteins (PBPs)] – These proteins are enzymes that catalyze cross-linkages between the peptide chains on the N-acetylmuramic acid-N-acetylglucosamine backbone of the peptidoglycan molecule. 2. Lack of cross-linkages results in the formation of a weak cell wall and can lead to lysis of growing cells.
  5. 5. Spectrum  Bactericidal  Gram positive  The differences in susceptibility of Gram-positive and Gram negative bacteria to β-lactams are due to: – The larger amount of peptidoglycan in the cell wall of gram positive. – The differences in PBPs (Penicillin Binding protein) between organisms. – It is difficult for some β-lactams to penetrate the outer lipopolysaccharide layer of the Gram-negative cell wall.
  6. 6. Resistance  Gram-positive bacterial resistance to β-lactams is due to: 1. The action of β-lactamase enzymes that break the β-lactam ring. 2. Modification of PBPs. Resulting in reduced binding affinity of the β-lactam for the peptide chain.  Gram-negative bacteria are naturally resistant to some of the β-lactams because the β-lactam cannot penetrate the outer lipopolysaccharide membrane of the cell wall.
  7. 7. Pharmacokinetics  Antimicrobial activity is usually time dependent. – β-Lactams have a slower kill rate than do fluoroquinolones and aminoglycosides, and killing activity starts after a lag phase.  The β-lactams are wholly ionized in plasma.  They have relatively small volumes of distribution.  They have a short half-live.  They do not cross biological membranes well but are widely distributed in extracellular fluids.  Elimination is generally through the kidneys.
  8. 8. β-Lactams Development 1. Penicillin development 1. Benzylpenicillin (penicillin G) 2. Phenoxymethylpenicillin (penicillin V) 3. Anti-staphylococcal penicillins 4. The extended or broad-spectrum penicillins 5. Anti-pseudomonal penicillins 6. β-lactamase resistant penicillins (Gram-negative) 2. Cephalosporin development 1. First generation cephalosporins 2. Second generation cephalosporins 3. Third generation cephalosporins 4. Fourth generation cephalosporins
  9. 9. Cont. … 1. Penicillin development  Penicillins are characterized by their 6-aminopenicillanic acid (6-APA) core. – This is a thiazolidone ring linked to a β-lactam ring and a side chain at position C6, which allows them to be distinguished from one another. – Penicillins can be separated into six groups on the basis of their activity.
  10. 10. Cont. … a) Benzylpenicillin (penicillin G)  The first β-lactam purified for clinical use from Penicillium cultures.  Clinical limitations were soon recognized due to: 1. Instability in the presence of gastric acids 2. susceptibility to β-lactamase enzymes 3. Ineffectiveness against many Gram-negative organisms. 4. It also has a short terminal half-life of around 30–60 min.  Benzylpenicillin is still the best antibiotic to use against most Gram-positive organisms (except resistant staphylococci and enterococci) and some Gram-negative bacteria.
  11. 11. Cont. …  It is administered by deep intramuscular injection as procaine penicillin, where procaine provides a depot effect as a result of slow absorption.
  12. 12. Cont. … b) Phenoxymethylpenicillin (penicillin V)  The first modification to the 6-APA core was acylation to produce phenoxymethylpenicillin (penicillin V), which is more acid-stable and active orally.
  13. 13. Cont. …  This development led to the ability to produce a wide range of semi-synthetic penicillins by adding side chains to the 6-APA core.
  14. 14. Cont. … c) Anti-staphylococcal penicillins  The first group to be developed  Include methicillin  They are resistant to staphylococcal β-lactamases  From this group, cloxacillin is commonly used to treat mastitis in dairy cows.
  15. 15. Cont. … d) The extended or broad-spectrum penicillins  It is the next class of penicillins  Include ampicillin, which is active against Gram-negative bacteria, including Escherichia coli.  They are susceptible to the action of β-lactamases.  Amoxicillin and amoxicillin + clavulanate are widely used in livestock and companion animals to treat Gram-negative infections, particularly those caused by enteric Enterobacteriaceae.
  16. 16. Cont. … e) Anti-pseudomonal penicillins  It is the next development of penicillins  include carbenicillin  They are not commonly used in animals
  17. 17. Cont. … f) β-lactamase resistant penicillins (Gram-negative)  It is the final class of penicillin development.  Include temocillin.
  18. 18. Cont. … Cephalosporins development  Shortly after the development of benzypenicillin, cephalosporin C was isolated from the fungus Cephalosporium acremonium.  Cephalosporins have a 7- aminocephalosporanic acid core that includes the β-lactam ring.
  19. 19. Cont. …  They were of early interest because: 1. They have activity against Gram-negative bacteria. 2. They are less susceptible to the action of β-lactamases.  Over the years, the cephalosporin core molecule was also modified to provide a series of classes (generations) of semi- synthetic cephalosporins with differing activities.
  20. 20. Cont. … a) The first-generation cephalosporins  Cefadroxil (Duricef) – Cephradine (Velocef) – Cephalaxin (Keflex)  They were introduced to treat β-lactamase-resistant staphylococcal infections.  They also demonstrated activity against Gram negative bacteria.  They are no longer used commonly in companion animals but are still used in dry-cow therapies in dairy cows.
  21. 21. Cont. … b) Second-generation cephalosporins  Cefuroxime (Zenacef) – Cefaclor (Ceclor) – Cefprozil (Cefzil)  They are active against both Gram-positive and Gram- negative organisms.  Oral preparations are widely used to treat companion animals.  Products are registered for use in mastitis control in dairy cows.
  22. 22. Cont. … c) Third-generation cephalosporins  Cefotaxime (Claforan) – Ceftriaxone (Rocephen) – Cefoperazone (Cefobid)  They demonstrate reduced activity against Gram-positive bacteria but increased activity against Gram-negative organisms.  Because of their importance in human medicine, these products should be reserved for serious infections where other therapy has failed.  They are used to treat both livestock and companion animals.
  23. 23. Cont. … d) Fourth-generation cephalosporins  Cefipime (Maxipime)  They have increased activity against both Gram-positive and Gram-negative bacteria.  These are reserve drugs in human medicine but in some countries are registered for use in cattle and horses.
  24. 24. Cont. … Other β-lactams with natural origins  This include carbapenems and monobactams.  These classes of β-lactams are not registered for use in food producing animals but are used off-label in companion animals.
  25. 25. Cont. … Carbapenems  Meronem - Tienam  They are resistant to most β-lactamases.  They have a wide range of activity against Gram-positive and Gram-negative bacteria Monobactams  Aztreonam  They are resistant to most β-lactamases  They have a narrow spectrum of activity with good activity against many Gram-negative bacteria.
  26. 26. Safety  β-Lactam antibiotics are largely free of toxic effects, and the margin of safety is substantial.  The major adverse effect is acute anaphylaxis, which is uncommon and associated mostly with penicillins; – Symptoms include urticaria, angioneurotic edema, and fever occur more commonly.  Penicillin-induced immunity-mediated hemolytic anemia in horses has also been reported.
  27. 27. Cont. …  The administration of procaine penicillin has led to: – Pyrexia, lethargy, vomiting, inappetance, and cyanosis in pigs. – Signs of procaine toxicity, including death in horses.  In humans, sensitization and subsequent hypersensitivity reactions to penicillin are relatively common during treatment.  By comparison, adverse reactions attributed to occupational exposure to penicillin or the ingestion of food containing residues of penicillin are now seldom reported.