Penicillin is a true antibiotic, developed as it was out of the Penicillium fungi. It was first discovered by the Scottish physician, Alexander Fleming, in 1928 (but clinically used from 1942) – with the pharmacology of penicillin branching out even further. Today, for example, penicillin refers to a family of drugs including penicillin G, penicillin V, amoxicillin, flucloxacillin, and tarcillin. Each class, indeed each drug, is effective against particular strains of bacteria – with some effective against Staphylococci and Streptococci, whereas others are primarily used for their antipseudomonal activity.

Here, we take a quick glance at the pharmacology of penicillin – first by understanding their common mechanism of action, before going on to discuss classes of penicillin, their spectrum of activity, resistance, pharmacokinetics, and – finally – their unwanted effects.

Mechanism of action

Penicillin is a beta-lactam antibiotic. As such, it binds to penicillin-binding proteins to inhibit synthesis of peptidoglycan – the backbone of the cell wall. By crippling the integrity of this wall, penicillin drugs compromise the integrity of the bacterial cell. Among these penicillin-binding proteins are transpeptidases – essential for the cell wall cross-linkage. The activity of penicillin is determined by its structure. All penicillin drugs have a thiazolidine ring connected to a B-lactam ring – this combined structure itself attached to a side-chain. It’s invariably this side-chain that determined the activity of each penicillin.

Structure of Penicillins

Spectrum of activity

The first penicillin – that discovered in 1928 – was penicillin G, also known as benzylpenicillin. Along with penicillin V, these two drugs are active against many aerobic Gram-positive bacteria, a limited spectrum of Gram-negative bacteria, and many anaerobic microorganisms. Recall that Gram-positive organisms include staphylococci, streptococci, and bacilli (Corynebacterium, Clostridium, Listeria, Bacillus). This contrasts with Gram-negative organisms such as E. coli, Salmonella, Pseudomonas, Neisseria, Klebsiella, and Proteus strains.

Both penicillin G (benzylpenicillin) and penicillin V (phenoxymethylpenicillin) are only effective in the absence of beta-lactamases – enzymes that break down the beta-lactam ring, rendering void the antibacterial activity of the penicillin drug. Phenoxymethylpenicillin is also less active against Gram-negative bacteria than benzylpenicillin. The pharmacology of penicillin invariably depends, however, on the penicillin’s specific chemical structures.

For example, adding an acyl side-chain to the beta-lactam ring prevents access from beta-lactamases – precisely what was synthesised in the form of flucloxacillin. However, flucloxacillin is less active than benzylpenicillin against bacteria that do not produce beta-lactamase. As a consequence, flucloxacillin is mostly used to treat beta-lactamase-producing staphylococci – strains which are commonly isolated in the hospital environment (narrow spectrum penicillin).

Penicillins

Flucloxacillin is therefore mostly used in the treatment of the following infections:

  • Skin infections (Wounds, abscesses, boils)
  • Respiratory infections (tonsillitis, pneumonia, sinusitis)
  • Other (endocarditis, osteomyelitis, meningitis, septicaemia, enteritis)

Turning to ampicillin and amoxicillin we find the aminopenicillins. These drugs have, in contrast to flucloxacillin, extended-spectrum activity – including many Gram-negative bacilli. Despite this advantage, they are less effective against Gram-positive cocci when compared to benzylpenicillin. Both ampicillin and amoxicillin are inactivated by beta-lactamases.

The ureidopenicillins (eg. piperacillin) and amidinopenicillins (eg. pivmecillinam) are also extended-spectrum in effect. Piperacillin is active against Pseudomonas aeruginosa, and pivmecillinam is mostly effective against Gram-negative bacteria. Carboxypenicillins – such as ticarcillin – are seldom used nowadays, but they have activity against Pseudomonas and Proteus species, as well as activity against Bacteroides fragilis.

Beta-lactamase, as we have gathered, is an enzyme that breaks down the vital beta-lactam ring of penicillin antibiotics. Inhibitors of beta-lactamase have been developed – such as clavulanic acid – which serve to protect the beta-lactam ring from fatal degradation. Clavulanic acid itself has no antibacterial activity. Other inhibitors of beta-lactam are also used, such as tazobactam – commonly used alongside piperacillin in the treatment of nosocomial pneumonia caused by Pseudomonas aeruginosa.

Bacterial resistance

The pharmacology of penicillin is also associated with resistance. Resistance typically occurs through the generation of beta-lactamases – enzymes that hydrolyse the beta-lactam ring. There isn’t just one type of beta-lactamase enzyme, but rather hundreds of types – often differing due to the presence of different metalloenzymes.

Pharmacokinetics

Here are just some of the points one should consider about the pharmacokinetics of penicillins:

  • Only 1/3 of orally administered benzylpenicillin is absorbed – the remainder is destroyed by stomach acid. As a result, benzylpenicillin administration is restricted to IM and IV routes.
  • Penicillin V is more acid stable than benzylpenicillin and is notably better absorbed in the gut, too. For this reason, phenoxymethylpenicillin is available for oral administration.
  • Penicillins are rapidly eliminated by the kidney and half-lives are short. Penicillin V and penicillin G have half-lives of around 1 hour.
  • Flucloxacillin and amoxicillin are almost completely (and rapidly) absorbed from the gut. This contrasts with ampicillin which is incompletely absorbed. These three drugs flucloxacillin, amoxicillin, and ampicillin, can be administered IM and IV, as well as orally.
  • Pivmecillinam is a prodrug, hydrolysed in the body to the active substance mecillinam. Piperacillin is administered via the intravenous route in combination with the beta-lactamase inhibitor, tazobactam.

Unwanted effects

Penicillins are generally well tolerated drugs. Though 10 percent of people claim to have an allergy to penicillin, only 0.03 percent suffer from serious allergies. Penicillins may be associated with the following unwanted effects:

  • Hypersensitivity reactions (1-10% of patients)
  • Nausea, vomiting
  • Aminopenicillins (such as amoxicillin) can produce a maculopapular rash in patients with glandular fever.
  • Prolonged high doses can cause reversible neutropenia and eosinophilia.
  • Diarrhoea
  • Cholestatic jaundice – particularly with flucloxacillin.

That’s about it for the pharmacology of penicillin. If you possess any worthwhile knowledge about this drug class, feel free to add your contribution to the comments section below. If you think you know it all about penicillin, why not take our penicillin quiz today.

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