Introduction to Penicillins Pharmacology

Penicillin was discovered in 1928 by the Scottish microbiologist, Alexander Fleming, though it wasn’t until 1942 that these medicines were used publicly. The class has since gone on to become one of the most widely used antibacterial drug classes.

The onset of bacterial resistance has dampened their therapeutic potential, though they remain widely used in the clinical setting.

There are many different penicillin classes:

  • Natural penicillins – benzylpenicillin, phenoxymethylpenicillin
  • Beta-lactamase resistant penicillins – flucloxacillin, nafcillin, dicloxacillin
  • Antipseudomonal penicillins – piperacillin with tazobactam, carbenicillin
  • Broad-spectrum penicillins – amoxicillin, ampicillin, co-amoxiclav,

Below, we go through each of these classes in turn – identifying their indications and spectrum of activity. Later, we review penicillins pharmacology in more detail – focussing on their mechanism of action, side effect profiles and drug interactions.

NATURAL PENICILLINS

Benzylpenicillin and phenoxymethylpenicillin are used in the treatment of the following infections:

  • Streptococcal infections – pneumonia, tonsillitis, endocarditis and skin and soft tissue infections
  • Tetanus
  • Meningitis, septicemia
  • Cellulitis

There are two long-acting forms of benzylpenicillin – benzathine benzylpenicillin and procaine benzylpenicillin; long-acting forms that are administered via the intramuscular route.

BETA-LACTAMASE RESISTANT

Flucloxacillin is a prominent example.

As a narrow-spectrum antibacterial drug, flucloxacillin is used to treat Gram-positive infections such as:

  • Chest, ear, nose and throat infections
  • Skin and soft tissue infections
  • Endocarditis
  • Osteomyelitis

Flucloxacillin may also be used to prevent infections developing during surgery.

ANTIPSEUDOMONAL PENICILLINS

Piperacillin is a broad-spectrum agent used to treat serious, hospital-acquired infections.

The antipseudomonal activity of piperacillin derives from its chemical structure. Unlike many other penicillins, piperacillin (and other ureidopenicillins) have a polar side chain incorporated into the molecule; a side chain that can penetrate Gram-negative organisms, including Pseudomonas aeruginosa.

Infections treated by piperacillin with tazobactam (beta-lactamase inhibitor) include:

  • Skin and soft tissue infections
  • Respiratory tract infections
  • Intra-abdominal sepsis
  • Urinary tract infections

Piperacillin cannot be absorbed orally. It is administered via the IV or IM route.

BROAD-SPECTRUM PENICILLINS

Broad-spectrum penicillins include amoxicillin and ampicillin. Their indications include:

  • Respiratory infections – bronchitis, pharyngitis
  • Pneumonia – whether caused by Gram-positive or Gram-negative organisms
  • Urinary tract infections – alternative medicines include trimethoprim and nitrofurantoin
  • Hospital-acquired infections
  • Endocarditis
  • Combination treatment of Helicobacter pylori infections
  • Otitis media

With these indications in mind, let’s now turn to penicillins pharmacology – how the drugs work to exert their therapeutic effects.

Mechanism of action

Penicillins have a common mode of action.

Peptidoglycan cross-links form the backbone of the bacterial cell wall. This wall constantly undergoes remodelling, keeping the integrity of the bacterial cell in shape.

Beta-lactam antibacterials destroy the cell wall by compromising peptidoglycan cross-links.

That’s where the beta-lactam ring comes in.

The four-membered ring binds to the enzyme DD-transpeptidase; the enzyme needed to catalyse cross-link formation. As a result, the integrity of the cell wall becomes compromised which, in the end, causes the bacterial cell to wither away and die.

As we learned, penicillins come with different spectrums of activity. Some, such as flucloxacillin, are narrow-spectrum drugs whereas others, such as piperacillin, have activity against Pseudomonas aeruginosa. These differences relate to the ancillary structures and R-groups attached to the compound.

  • In the case of piperacillin, a polar side-chain assists in the penetration of P. aeruginosa.
  • For amoxicillin, the addition of an amino group increases activity against aerobic Gram-negative organisms.

The relationship between structure and activity is very important.

Beta-lactamase inhibitors

Beta-lactamase is an enzyme that breaks down the beta-lactam ring.

Many penicillins are susceptible to beta-lactamase, rendering redundant the drug’s antibacterial potential. However, several inhibitors of beta-lactamase have since been developed – compounds that combat this widespread form of bacterial resistance.

They have little to no antibacterial activity themselves, but they prevent degradation of the beta-lactam ring and, to that end, contribute to a wider antibacterial effect.

Use of beta-lactamase inhibitors is important for Gram-negative infections. That’s because most resistance from Gram-positive organisms comes from variations in penicillin-binding proteins.

Examples include:

  • Clavulanic acid – usually combined with amoxicillin and ticarcillin
  • Sulbactam – usually combined with ampicillin
  • Tazobactam – usually combined with piperacillin

Side effects

Penicillins are broadly associated with the following side effects:

  • Gastrointestinal effects – nausea, diarrhea etc.
  • Antibiotic-associated colitis due to Clostridium difficile infection
  • Skin rash – symptoms of penicillin allergy
  • Cholestatic jaundice – rare, linked to amoxicillin-clavulanic acid / flucloxacillin

Generally, though, penicillins are well-tolerated drugs.

Clinical considerations

When we talk about the clinical pharmacology of penicillins, we need to think about the following factors:

  • That dose reductions are necessary in patients with renal impairment.
  • That penicillins should be avoided where there is a history of penicillin allergy. Note that though 10 percent of people are commonly considered “allergic”, the true figure is much, much less.
  • That penicillins reduce the elimination of methotrexate, increasing the potential risk of toxicity.
  • That penicillins – particularly antipseudomonal penicillins and broad-spectrum penicillins increase the anticoagulant effect of warfarin by laying waste to colonic flora that otherwise produces vitamin K.
  • That broad-spectrum penicillins increase the risk of difficile infection, particularly in patients who are at risk – the elderly, or in patients who are immunocompromised.

Penicillins remain an important class of medicines. They are used to treat mild to serious bacterial infections and have, for over 70 years, added considerable value to the clinician’s toolkit.

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