Is high-dose β-lactam therapy associated with excessive drug toxicity in critically ill patients?

BACKGROUND: beta-lactam antibiotics may necessitate higher than licensed drug doses to achieve therapeutic exposures in critically ill patients. Therapeutic drug monitoring can be used to guide dosing so as to maximise therapeutic effect whilst reducing the likelihood of exposure-related toxicity. METHODS: A retrospective review of critically ill patients identified those that received higher than licensed doses of either meropenem (3-6 g/day) or piperacillin-tazobactam (16 g-2 g/day) (i.e. high-dose group) guided by therapeutic drug monitoring. beta-lactam-associated toxicities were compared with a patient group of similar age, sex, body mass index and admission diagnosis that received licensed doses of either antibiotic. RESULTS: Mean daily doses were more than 40% higher in the high-dose groups for each antibiotic. There were no significant differences between the high-dose and licensed-dose groups in terms of hepatocellular derangement (17.9% vs. 31.8%, P= 0.25 for meropenem and 17.4% vs. 16.0%, P= 0.90 for piperacillin-tazobactam), cholestasis (28.0% vs. 13.6%, P= 0.32 for meropenem and 13.0% vs. 4.0%, P= 0.26 for piperacillin-tazobactam), need for continuous renal replacement therapy (0% vs. 9.1%, P= 0.10 for meropenem and 0% vs. 8.0%, P= 0.16 for piperacillin-tazobactam), seizure incidence (7.1% vs. 4.5%, P= 0.70 for meropenem and nil for either piperacillin-tazobactam group), thrombocytopenia (9.1% vs. 10.7%, P= 0.85 for meropenem and 4.0% vs. 4.3% for piperacillin-tazobactam), or neutropenia (4.5% vs. 3.6%, P= 0.95 for meropenem and 0.0% vs. 4.3% for piperacillin-tazobactam). CONCLUSIONS: Higher than licensed doses of meropenem and piperacillin-tazobactam guided by therapeutic drug monitoring were not associated with additional toxicities. Larger prospective studies are required to confirm the clinical utility of higher than licensed dosing.