Penicillins, penicillinase-resistant

Key Examples

• Flucloxacillin

 

Common indications

Staphylococcal infection, including:

1. Skin and soft tissue infections such as cellulitis (in combination with benzylpenicillin for more severe infection).
2. Osteomyelitis and septic arthritis.
3. Other infections, including endocarditis.

 

Mechanisms of action

• Penicillins inhibit the enzymes responsible for cross-linking peptidoglycans in bacterial cell walls. This weakens cell walls, preventing them from maintaining an osmotic gradient. Uncontrolled entry of water into bacteria causes cell swelling, lysis and death.
• Penicillins contain a β-lactam ring, which is responsible for their antimicrobial activity. Side chains attached to the β-lactam ring can be modified to make semi-synthetic penicillins. The nature of the side chain determines the antimicrobial spectrum and other properties of the drug.
• For flucloxacillin, an acyl side chain protects the β-lactam ring from β-lactamases, which are enzymes made by bacteria to deactivate penicillin. This makes flucloxacillin effective against β-lactamase producing staphylococci. Meticillin-resistant Staphylococcus aureus (MRSA) resists the actions of flucloxacillin by reducing penicillin binding affinity.

 

Important adverse effects

• Minor gastrointestinal upset is common. Penicillin allergy affects 1–10 of people. This usually presents as a skin rash 7–10 days after first exposure or 1–2 days after repeat exposure (delayed IgG-mediated reaction). Less commonly, an immediate (minutes to hours) life-threatening IgE-mediated anaphylactic reaction occurs with some or all of hypotension, bronchial and laryngeal spasm/oedema and angioedema. Liver toxicity, including cholestasis and hepatitis, is a rare but serious adverse effect which can occur even after treatment has been completed. Central nervous system toxicity (for example convulsions, coma) can occur with high doses of penicillin or where severe renal impairment delays excretion.

 

Warnings

• Flucloxacillin can generally be used safely in most situations, although a dose reduction is required for patients with renal failure. The main contraindication to flucloxacillin use is a history of penicillin allergy. Note that allergy to one type of penicillin implies allergy to all types as it is due to a reaction to the basic penicillin structure. Flucloxacillin is also contraindicated in patients with prior flucloxacillin-related hepatotoxicity.

 

Important interactions

• Penicillins reduce renal excretion of methotrexate, increasing the risk of toxicity.