Penicillins, broad-spectrum

Key examples

• Amoxicillin
• Co-amoxiclav

 

Common indications

1. Empirical treatment of pneumonia, which may be caused by Gram-positive (e.g. Streptococcus pneumoniae) or Gram-negative pathogens (e.g. Haemophilus influenzae).
2. Empirical treatment of urinary tract infection (most commonly caused by Escherichia coli). Trimethoprim and nitrofurantoin are alternatives.
3. As part of combination treatment (as co-amoxiclav) for hospital-acquired infection or intra-abdominal sepsis, which may be caused by Gram-negative and anaerobic pathogens or antibiotic-resistant organisms.
4. As part of combination treatment for H. pylori-associated peptic ulcers.

 

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. For amoxicillin, addition of an amino group to the side chain increases activity against aerobic Gram-negative bacteria, making this a ‘broad-spectrum’ antibiotic. Addition of the β-lactamase inhibitor clavulanic acid (creating co-amoxiclav) increases the spectrum of antimicrobial activity further to include β-lactamase-producing bacteria (e.g. Staphylococcus aureus, Gram-negative anaerobes).

 

Important adverse effects

• Gastrointestinal upset such as nausea and diarrhoea are common. Less frequently, antibiotic-associated colitis occurs when broad-spectrum antibiotics kill normal gut flora, allowing overgrowth of toxin-producing Clostridium difficile. This is debilitating and can be complicated by colonic perforation and/or death. Penicillin allergy affects 1–10 of people. This usually presents as a skin rash 7–10 days after first 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 features including hypotension, bronchospasm and angiooedema. Cholestatic jaundice is a rare adverse effect of co-amoxiclav.

 

Warnings

• Broad-spectrum penicillins should be used with caution in people at risk of C. difficile infection, particularly those in hospital and the elderly. 
• The main contraindication to the use of broad-spectrum penicillins 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. 
• The dose of broad-spectrum penicillins should be reduced in patients with severe renal impairment (risk of crystalluria).

 

Important interactions

• Penicillins reduce renal excretion of methotrexate, increasing the risk of toxicity. 
• Broad-spectrum penicillins can enhance the anticoagulant effect of warfarin by killing normal gut flora that synthesise vitamin K.