Antibiotics 1: Penicillins and Cephalosporins

Classes of antibiotics
1. Bactericidal vs. Bacteriostatic
  1. Bactericidal
    1. Kill bacteria
    2. No bacteria left when drug is removed
    3. Penicillins
    4. Cephalosporins
    5. Fluoroquinolones
    6. Aminoglycosides
    7. Metronidazole
    8. Sulphonamides + trimethoprim (Potentiated sulphonamides)
  2. Bacteriostatic
    1. Slow bacterial growth
    2. Sulphonamides
    3. Trimethaprim
    4. Tetracyclines
    5. Chloramphenicol
    6. Linomycin
  3. Concentration dependent (static/cidal)
    1. Erythromycin
    2. (Macrolides)
    3. Low conc = static
    4. High conc = cidal
    5. Tend to use low concs (static effect) in practice
2. Time vs. Concentration Dependence
  1. Time Dependent
    1. Work slowly
    2. Plasma levels should be above minimum inhibitory concentration (MIC) for as long as possible in each 24 hour period
    3. Penicillins
    4. Cephalosporins
  2. Concentration Dependent
    1. Peak concentration determines how effective the drug will be
    2. Aminoglycosides
    3. Fluoroquinolones
    4. Metronidazole
    5. The greater the concentration, the greater the effect
      1. Whilst still limiting side effects
3. Spectrum of activity
  1. What bacteria are the drug effective against?
β-lactam antibiotics
1. 3 carbons, 1 nitrogen forming ring which is important for the activity of the drug
2. Antibacterial activity
  1. Ability to bind to transpeptidases
    1. Mutations reduce effectiveness
  2. Drug access to transpeptidase
    1. In gram –ve bacteria LPS can hinder drug passage
  3. Stability against β-lactamase activity
    1. e.g. penicillinase – break down β-lactam drugs
3. β-lactamase
  1. Diverse group of enzymes
  2. Specific to the bacteria
  3. Staphylococcal β-lactamase = penicillinase
  4. Breaking of the β-lactam ring means rigidity is lost
    1. Drug is unable to bind to the transpeptidase, is thus no longer effective
4. Clavulanic acid
  1. β-lactamase inhibitor
  2. No antibacterial effect alone
  3. Several products containing amoxicillin and clavulanic acid licensed for veterinary use in cats, dogs and cattle
    1. e.g. synulox – 1:1 mix of amoxicillin and clavulanic acid
Penicillins
1. Pharmacokinetics
  1. Oral availability – varies depending on acid stability
  2. Widely distributed – but do not cross blood brain barrier
  3. Eliminated by kidney
Cephalosporins
1. Pharmacokinetics
  1. Some can be orally administered, most parenterally
  2. Widely distributed – some cross blood brain barrier (most don’t)
  3. Eliminated by kidney
Carbapenems and Monobactams
1. Tend not to be licensed for vet use
Antibacterial Agent Targets
1. Biochemical reactions
  1. Class I
    1. Not unique to bacteria
    2. Non-lethal
    3. Poor targets
  2. Class II
    1. Better targets e.g. folate synthesis
      1. Different enzyme pathway c.f. host
        Allows specificity
  3. Class III
    1. Important targets
    2. Bacteria specific reactions
      1. Fewer side effects
      2. Products are specific to bacteria e.g. peptidoglycan
2. Bacterial cell wall
  1. Peptidoglycan (aka murein) synthesis
    1. Cytoplasm
      1. Membrane
        Extra-membrane
        Formation of linear peptidoglycan polymer
        Cross-linking of the linear units to form a complex lattice structure
        Attachment of NAMA and NAG to a lipid carrier
      2. Synthesis of NAMA and NAG
      3. Building a pentapeptide chain on NAMA (5 - one is lost in latter stages)
  2. Inhibitors of peptidoglycan synthesis (tends to affect final step)
    1. β-lactams: penicillins, cephalosporins
    2. Glycopeptides: vancomycin
    3. Cycloserine
    4. Bacitracin
  3. Gram +ve vs. -ve
    1. Gram +ve
      1. Thick cell wall (50% peptidoglycan)
      2. No outer membrane
    2. Gram -ve
      1. Thin cell wall (5% peptidoglycan)
      2. An outer membrane (obstructs antibacterial entry)
        Restricted, delayed access to the peptidoglycan - so the drugs are less effective
  4. Peptidoglycan structure
    1. NAMA = N-acetylmuramic acid
    2. NAG = N-acetyglucosamine – amino sugars
    3. Tetrapeptide side chains are comprised of 4 amino acids
      1. 5 glycine residues link the tetrapeptide side chains
        Peptide cross links are formed between the glycine chains
        Main site of action of penicillins and cephalosporins
Adverse reactions and contraindications
1. Wide therapeutic ratio
  1. Mammalian cells lack a cell wall
    1. Can give high doses with minimal toxic effect
2. Hypersensitivity
  1. Almost immediate
  2. Usually mild
  3. Can be fatal
    1. Anaphylaxis
3. Gastrointestinal superinfection
  1. Death of susceptible gut flora allows proliferation of non-susceptible bacteria
Mycobacteria
1. TB in cattle not treatable – animals must be destroyed
2. Treatment in cats
  1. A fluoroquinolone (inhibits DNA gyrase)
  2. + clarithromycin (a macrolide, inhibits protein synthesis)
  3. + rifampicin (inhibits RNA synthesis)
3. Can get in pets (mostly cats)
  1. Small no. of cases per year
4. Arbinosyl transferase – addition of arabinose units
5. Fatty acid synthase 1 and 2 – mycolic acid
6. Prolonged treatment needed - not easy to kill

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Antibiotics 1: Penicillins and Cephalosporins

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