3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.1. Scrap
                  3.1.1.4. Antibiotics
                      3.1.1.4.1. Beta-lactam
 3.1.1.4.1.1. Penicillin 

Penicillin

[PHW2

All drugs in this class have a fused beta-lactam/thiazolidine ring

Classes

  • Narrow spectrum
    * e.g. benzylpenicillin
  • Narrow spectrum penicillin resistant to staphylococcal beta-lactamase
    * e.g. flucloxacillin
  • Moderate spectrum penicillin
    * e.g. amoxycillin, ampicillin
  • Broad spectrum penicillin
    * e.g. amoxycillin with clavulanic acid
  • Broad spectrum with anti-pseudomonal activities
    * e.g. piperacillin

Pharmacodynamics

Actions

  • Bactericidal action by inhibition of bacterial cell wall synthesis

Mechanism of action

  1. Intact beta-lactam ring binds to various proteins including
    * Transpeptidase and carboxypeptidase
  2. Binding prevents cross-linkage of peptidoglycan, and weakens the cell walls
  3. Effects of this weakening varies according to the species

 

Effects on Gram-positive cocci

  • Possesses a thick peptidoglycan cell wall
  • When exposed to beta-lactam
    --> Growth continues normally but reduced peptidoglycan cross-linkage
    --> Cell wall weakened
    --> Eventually lysis

NB:

  • However, extinction is not achieved even when the bacteria are sensitive, because some cells remain dormant (the persistors) until the antibiotics is removed
  • Synergy is achieved with certain antibiotics (e.g. gentamicin) and extinction becomes possible

Effects on Gram-negative bacilli

  • Possesses thinner peptidoglycan wall which is surrounded by lipopolysaccharide-lipoprotein envelope
  • Exposure to beta-lactam causes weakening of cell wall
    --> bacteria becomes spherical due to osmosis
    --> When placed in hypo-osmolar environment, lysis occurs
  • However, bacilli like Haemophilus Influenzae have low intracellular osmolality
    --> Rarely becomes osmotically challenged enough for lysis to occur

Resistance

  • Penicillin can be rendered ineffective by beta-lactamase, which hydrolyses the beta-lactam ring
  • Several varieties exist
  • Gram-positive type and Gram-negative type are fundamentally different
  • Gram-negative beta-lactamase is encoded on bacterial chromosomes and plasmids, which may be disseminated
    * i.e. basis of acquired resistance

Side-effects

  • Hypersensitivity
  • Diarrhoea

 

Hypersensitivity

  • Allergy to penicillin occurs in up to 10% of population
  • Anaphylaxis occurs in 0.01%
  • Cross-reactivity between penicillin, cephalosporins, and carbapenem occurs in 5 to 10%
  • Reactions include urticaria, anaphylaxis, and interstitial nephritis

 

Diarrhoea

  • Common during oral therapy
  • Ampicillin is associated with a low risk of pseudomembranous colitus (0.3 - 0.7%)

 

Pharmacokinetics

Absorption

  • Intestinal absorption is variable
  • Some are available only in parenteral preparations

Distribution

Protein-binding = Variable
* Ampicillin = 20%
* Flucloxacillin = 93%

Metabolism

Up to 20% metabolised

 

Elimination

  • Half-life = short
    * Benzylpencillin = 30 min
    * Ampicillin = 2 hours
  • 60% - 90% excreted unchanged in urine
    * Mainly by renal tubular secretion
  • 10% excreted in bile

Specific examples

Benzylpenicillin (Penicillin G)

  • Inactivated by gastric acid
  • Must be given parenterally
  • Active against a wide-range of Gram-positive pathogens, Gram-negative cocci and occasional Gram-negative bacilli
  • Streptococci and Neisseria are extremely sensitivity
  • H. influenzae, staphylococci, and pseudomonas are resistant

Flucloxacillin

  • Semi-synthetic
  • Well absorbed from gut, but should be given IV for serious infection
  • Less active against Gram-positive cocci than benzylpencillin, but is effective against beta-lactamase positive staphylococci
  • May cause cholestatic jaundice several weeks after the end of a treatment course

Ampicillin

  • Effective against the same range of organisms as benzylpenicillin (but slightly less active)
  • Also has some activity against H. influenzae, Salmonella, Escherichia Coli, and E. faecalis
  • Ampicillin produces a maculopapular rash in
    * 10% of all patients
    * 95% of patients with infectious mononucleosis

Amoxycillin

  • Amoxycillin has same spectrum as ampicillin
  • Better bioavailability and bactericidal to susceptible Gram-negative organism at lower concentration

Clavulanic acid

  • Clavulanic acid irreversibly inhibits a large range of beta-lactamases
  • Combination of amoxycillin reduces the minimum inhibitory concentration (MIC) against H. influenzae, E coli, Klebsiella, and Staphylococcus aureus 8 - 64 fold

Ticarcillin

  • Broad spectrum (lower activity than benzylpencillin)
  • Particularly indicated for use against pseudomonas
  • Often combined with clavulanic acid
  • Synergistic action against pseudomonas when combined with aminoglycosides
  • Causes platelet dysfunction at high doses

Clinical

Special considerations

Haemodialysis

  • Pencillin dose adjustment is unnecessary except for benzylpenicillin (the dose of which should be reduced by 30%)