Penicillins

·        Chemistry.

·        Mechanisms of action.

·        Pharmacokinetics.

·        Adverse reactions.

·        Spectrum of antimicrobial activity.

Chemistry

1.    All penicillins share the basic nucleus – 6 aminopenicillanic acid which is made up of:

a.       Thiazolidine ring.

b.       Beta-lactam ring.

2.    The penicillin nucleus is the main structural requirement for biological activity.

3.    The side chain (R) determines many of the antibacterial and pharmacological characteristics of a particular type of penicillin.

Mechanism of action

1.    Act on growing bacterial cell wall therefore metabolically inactive cells are unaffected.

2.    Bind to penicillin-binding proteins (PBP) blocking final step in cell wall synthesis by inhibiting transpeptidation.

3.       Incapable of withstanding the osmotic gradient between its interior and its environment the cell swells and rupture.

4.       Bacterial resistance:

a.       Some bacteria produce beta-lactamases which break open the beta lactam bond and destroy activity of the drug.

b.       Other bacteria are resistant because they lack specific receptors for penicillin or they are impermeable to the drug.

Pharmacokinetics

1.       Absorption:

a.       Oral: penicillin V, aminopenicillins, isoxazolylpenicllins.

b.       Parenterl: penicillin G, carboxypenicillins, ureidopenicillins, piperazine penicillins.

2.       Distribution:

a.       Widely distributed throughout the body.

b.    Do not enter CSF unless meninges are inflamed.

c.       Plasma half-life: < 2h.

3.       Metabolism: minimally metabolized in the liver except for nafcillin which is metabolized mainly in the liver.

4.       Excretion:

a.    Most are excreted unchanged in the urine except for nafcillin.

b.       Excretion through the kidneys is rapid and can be blocked by probenecid.

c.       Small amounts are excreted via the biliary tract.

Adverse reactions:

1.    High therapeutic index compared to other antimicrobials.

2.       Hypersensitivity (1 – 10%):

a.       Anaphylaxis (0.015 – 0.04%).

b.       Rash.

c.       Fever.

d.       Vasculitis.

e.       Serum sickness: fever, skin rash, arthritis and lymphadenopathy.

f.       Interstitial nephritis: rare, methicillin implicated most frequently.

3.       Parenteral infusion of large doses: lethargy, confusion, myoclonic jerks, convulsions.

4.       Decreased platelet aggregation: carbenicillin and ticarcillin.

5.       Diarrhea: ampicillin.

6.       Suprainfection: secondary to changes of bacterial flora, seen more often with the use of broad spectrum penicillins.

7.       Anaemia and neutropenia: uncommon.

Spectrum of antimicrobial activity

Narrow spectrum Penicillins

1.       Benzylpenicillin:

a.       Destroyed by gastric acid and is unsuitable for oral use.

b.    Used when high plasma concentration is required.

2.       Benzylpenicillin is used in infections caused by:

3.       Benzylpenicillin is active against:

a.       Gram-positive cocci.

b.       Gram-negative cocci.

c.       Gram-positive bacilli.

d.       Anaerobes excluding bacteroids spp.

e.       Spirochaetes

4.       Benzylpenicillin has little activity against Gram-negative bacilli and enterobacteriaeae.

5.       Phenoxymethylpenicillin (Penicillin V):

a.       Resistant to gastric acid and can be given orally.

b.    Less active than benzylpenicillin against Neisseria spp.

c.    Not suitable for use in gonorrhoea and meningococcal meningitis.

d.       Useful against streptococcii and staphylococcus aureus.

e.    All oral penicillins are best given on an empty stomach to avoid absorption delay caused by food.

Broad spectrum penicillins

1.       Spectrum of activity:

a.       Activity of these semi-synthetic penicillins extends beyond Gram-positive and Gram-negative cocci which are susceptible to benzylpenicillin and includes many Gram-negative bacilli.

b.    They do not resist beta-lactamases.

c.    Less active than benzylpenicillin against Gram-positive cocci, but more active than the beta-lactamase-resistant penicllins.

d.       Useful activity against Enterococcus faecalis and many strains of Haemophilus influenazae.

2.       Ampicillin:

a.       Acid-stable and is moderately well absorbed when swallowed.

b.    Half-life: 1h.

c.    1/3 of a dose appears unchanged in the urine.

d.    Drug is concentrated in the bile.

e.    May cause diarrhoea.

f.       Cause a macular rash.

3.       Pivampicillin and bacampicillin:

a.       Esters of ampicillin.

b.    De-esterified in the gut mucosa or liver to release ampicillin into the systemic circulation.

c.       Better absorbed than ampicillin and give higher blood concentrations.

d.    Less affected by food in the gut and causes less diarrhea.

4.       Amoxycillin:

a.    Half-life: 1h.

b.       Diarrhoea is less frequent than with ampicillin.

c.    For oral use, amoxycillin is preferred as it has greater bioavailability and less adverse effects.

d.    Co-amoxiclav (Augmentin): in which clavlanic acid, a beta-lactamese inhibitor is added, is used for respiratory or urinary tract infections due to beta-lactamase producing organisms.

e.       These include most strains of Staphylococcus aureus, many strains of Escherichia coli and Haemophilus influenzae.

f.       Cholestatic jaundice with use of co-amoxiclav.

5.       Carboxypenicillins:

a.       Same antibacterial spectrum as ampicillin but have the additional capacity against Pseudomonas aeruginosa and indole positive Proteus spp.

b.       Ticarcillin is 4x more active against Pseudomonas aeruginosa than carbenicillin.

c.    Both carbenicillin and ticarcillin are given as disodium salts; this source of sodium should be borne in mind when treating patients with impaired cardiac or renal function.

d.       Carboxypenicillins inactivate aminoglycosides if both drugs are given in the same syringe or i.v. infusion system.

6.       Ureidopenicillins:

a.       Adapted from ampicillin with a side-chain derived from urea.

b.       Higher efficacy against Pseudomonas aeruginosa than carboxypenicillins.

c.       Degraded by beta-lactamases.

d.    Must be given parenterally and are eliminated in the urine.