Broad-spectrum penicillins (beta-lactamase inhibitor combinations): amoxicillin+clavulanate and piperacillin+tazobactam
The beta-lactamase enzyme inhibitors, clavulanate and tazobactam, have little inherent antibacterial activity; they inhibit the beta-lactamase enzymes produced by Staphylococcus aureus, Bacteroides fragilis and Haemophilus influenzae, and some of the beta-lactamase enzymes produced by Escherichia coli and Klebsiella species. They are used in combination with amoxicillin (clavulanate) or piperacillin (tazobactam) to significantly broaden the spectrum of activity of these antibiotics.
Amoxicillin+clavulanate and piperacillin+tazobactam should be reserved for infections caused by bacteria that produce beta-lactamase enzymes. Additional treatment for anaerobic bacteria (eg metronidazole) is usually not required with these combinations.
Piperacillin is only available in combination with tazobactam. Piperacillin is the only penicillin in Australia that has activity against Pseudomonas aeruginosa. For directed therapy of pseudomonal infections, piperacillin+tazobactam should be dosed at 6-hourly intervals unless the patient has kidney impairment (for information about dosage adjustment, see piperallicin+tazobactam). Administration over 3 hours is preferred to ensure adequate drug exposure for pseudomonal infections; when this is not possible (eg the patient is receiving other drugs via the same line), administration over 30 minutes may be used.
In these guidelines, piperacillin+tazobactam administered by prolonged infusion is recommended for patients who have septic shock or who require intensive care support to ensure adequate drug exposure. A recent meta-analysis1 observed a reduction in mortality with the use of piperacillin+tazobactam administered as a loading dose followed by a continuous infusion when compared with dosing piperacillin+tazobactam intermittentlyAbdul-Aziz, 2024. It is the consensus opinion of the Antibiotic expert group that although high-quality clinical evidence to support this practice in children is lacking, this recommendation is still relevant to children.
Although there is limited clinical evidence to support the commonly used dose of oral amoxicillin+clavulanate (875+125 mg orally, 12-hourly) for some indications, it is widely used in practice without notable clinical failures. However, this dose may not be adequate to treat some pathogens, including Haemophilus influenzae and Enterobacterales. In these guidelines, amoxicillin+clavulanate 875+125 mg orally, 8-hourly is recommended for serious infections that are suspected or confirmed to be caused by Enterobacterales or Haemophilus influenzae when adequate source control has not been achieved or intravenous to oral switch occurs early.
Intravenous amoxicillin+clavulanate is recommended for a limited number of infections in these guidelines. At the time of writing, there is limited clinical evidence to determine the optimal dosage regimen of intravenous amoxicillin+clavulanate:
- For adults and children who weigh 40 kg or more, amoxicillin+clavulanate 1+0.2 g intravenously, 6-hourly or 2+0.2 g intravenously 8-hourly can be used; pharmacokinetic/pharmacodynamic modelling suggest that both regimens reach similar target attainment. The choice of regimen is influenced by patient factors (eg impaired kidney and liver function) and drug availability.
- For children who weigh less than 40 kg, there are few data to determine intravenous amoxicillin+clavulanate dosing. In these guidelines, the recommendations reflect the dosages commonly used in Australian clinical practice, with a consideration of pharmacokinetic and pharmacodynamic principles.