Antibiotics 1: Penicillins and Cephalosporins

Antibiotics 1: Penicillins and Cephalosporins

1. Classes of antibiotics

   • Bactericidal vs. Bacteriostatic
     • Bactericidal
       • Kill bacteria
       • No bacteria left when drug is removed
       • Penicillins
       • Cephalosporins
       • Fluoroquinolones
       • Aminoglycosides
       • Metronidazole
       • Sulphonamides + trimethoprim (Potentiated sulphonamides)
     • Bacteriostatic
       • Slow bacterial growth
       • Sulphonamides
       • Trimethaprim
       • Tetracyclines
       • Chloramphenicol
       • Linomycin
     • Concentration dependent (static/cidal)
       • Erythromycin
       • (Macrolides)
       • Low conc = static
       • High conc = cidal
       • Tend to use low concs (static effect) in practice
   • Time vs. Concentration Dependence
     • Time Dependent
       • Work slowly
       • Plasma levels should be above minimum inhibitory concentration (MIC) for as long as possible in each 24 hour period
       • Penicillins
       • Cephalosporins
     • Concentration Dependent
       • Peak concentration determines how effective the drug will be
       • Aminoglycosides
       • Fluoroquinolones
       • Metronidazole
       • The greater the concentration, the greater the effect
         • Whilst still limiting side effects
   • Spectrum of activity
     • What bacteria are the drug effective against?

2. β-lactam antibiotics

   • 3 carbons, 1 nitrogen forming ring which is important for the activity of the drug
   • Antibacterial activity
     • Ability to bind to transpeptidases
       • Mutations reduce effectiveness
     • Drug access to transpeptidase
       • In gram –ve bacteria LPS can hinder drug passage
     • Stability against β-lactamase activity
       • e.g. penicillinase – break down β-lactam drugs
   • β-lactamase
     • Diverse group of enzymes
     • Specific to the bacteria
     • Staphylococcal β-lactamase = penicillinase
     • Breaking of the β-lactam ring means rigidity is lost
       • Drug is unable to bind to the transpeptidase, is thus no longer effective
   • Clavulanic acid
     • β-lactamase inhibitor
     • No antibacterial effect alone
     • Several products containing amoxicillin and clavulanic acid licensed for veterinary use in cats, dogs and cattle
       • e.g. synulox – 1:1 mix of amoxicillin and clavulanic acid

3. Penicillins

   • Pharmacokinetics
     • Oral availability – varies depending on acid stability
     • Widely distributed – but do not cross blood brain barrier
     • Eliminated by kidney

4. Cephalosporins

   • Pharmacokinetics
     • Some can be orally administered, most parenterally
     • Widely distributed – some cross blood brain barrier (most don’t)
     • Eliminated by kidney

5. Carbapenems and Monobactams

   • Tend not to be licensed for vet use

6. Antibacterial Agent Targets

   • Biochemical reactions
     • Class I
       • Not unique to bacteria
       • Non-lethal
       • Poor targets
     • Class II
       • Better targets e.g. folate synthesis
         • Different enzyme pathway c.f. host
           • Allows specificity
     • Class III
       • Important targets
       • Bacteria specific reactions
         • Fewer side effects
         • Products are specific to bacteria e.g. peptidoglycan
   • Bacterial cell wall
     • Peptidoglycan (aka murein) synthesis
       • Cytoplasm
         • 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
         • Synthesis of NAMA and NAG
         • Building a pentapeptide chain on NAMA (5 - one is lost in latter stages)
     • Inhibitors of peptidoglycan synthesis (tends to affect final step)
       • β-lactams: penicillins, cephalosporins
       • Glycopeptides: vancomycin
       • Cycloserine
       • Bacitracin
     • Gram +ve vs. -ve
       • Gram +ve
         • Thick cell wall (50% peptidoglycan)
         • No outer membrane
       • Gram -ve
         • Thin cell wall (5% peptidoglycan)
         • An outer membrane (obstructs antibacterial entry)
           • Restricted, delayed access to the peptidoglycan - so the drugs are less effective
     • Peptidoglycan structure
       • NAMA = N-acetylmuramic acid
       • NAG = N-acetyglucosamine – amino sugars
       • Tetrapeptide side chains are comprised of 4 amino acids
         • 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

7. Adverse reactions and contraindications

   • Wide therapeutic ratio
     • Mammalian cells lack a cell wall
       • Can give high doses with minimal toxic effect
   • Hypersensitivity
     • Almost immediate
     • Usually mild
     • Can be fatal
       • Anaphylaxis
   • Gastrointestinal superinfection
     • Death of susceptible gut flora allows proliferation of non-susceptible bacteria

8. Mycobacteria

   • TB in cattle not treatable – animals must be destroyed
   • Treatment in cats
     • A fluoroquinolone (inhibits DNA gyrase)
     • + clarithromycin (a macrolide, inhibits protein synthesis)
     • + rifampicin (inhibits RNA synthesis)
   • Can get in pets (mostly cats)
     • Small no. of cases per year
   • Arbinosyl transferase – addition of arabinose units
   • Fatty acid synthase 1 and 2 – mycolic acid
   • Prolonged treatment needed - not easy to kill

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