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%)