Resistance Optimised Antibiotic Dosing (The ROAD Study): Is dosing of meropenem and piperacillin-tazobactam optimised to prevent the emergence of antibiotic resistance safe and feasible in the ICU? A pilot study

<h2>Abstract</h2><h3>Background</h3> Pre-clinical data suggest that resistance to beta-lactam antibiotics can be suppressed with higher than conventional antibiotic exposures. The objective of this study was to assess the safety, tolerability, and feasibility, of piperacillin/tazobactam and meropenem dosing regimens that were optimised to suppress the emergence of bacterial resistance among critically ill patients. <h3>Methods</h3> This was a prospective, open-labelled clinical trial conducted in a tertiary referral intensive care unit. Critically ill adults receiving either piperacillin/tazobactam or meropenem were eligible for inclusion. Following enrolment, doses were adjusted using Bayesian dosing software and therapeutic drug monitoring to achieve a beta-lactam trough concentration to MIC ratio (C_min/MIC) ≥4. The primary endpoint was any potential beta-lactam exposure-related adverse events including neurotoxicity, nephrotoxicity and hepatotoxicity. Feasibility was described as the proportion of patients achieving target beta-lactam exposures. <h3>Results</h3> Twenty-five patients were enrolled (mean age 56.6 years [SD 17.32], 14 piperacillin/tazobactam and 11 meropenem). Twenty-three patients (92 %) achieved the target drug exposure. In 56 % of patients (<i>n</i> = 14), the dosing intervention was a change to a continuous infusion with 36 % of patients (<i>n</i> = 9) also receiving an increased daily dose. Median (range) maximum meropenem and piperacillin/tazobactam doses were 6 ([3 ]– [12]) g/day and 22.5 ([9]– [27]) g/day respectively. Five patients developed ‘at risk' acute kidney injury, whilst one patient developed kidney ‘failure'. One patient developed hepatotoxicity. No adverse events were assessed to be caused by the study antibiotic. Resistance emergence was identified in one patient. <h3>Conclusion</h3> Beta-lactam antibiotic doses that are optimised to suppress resistance emergence in critically ill patients appear to be safe, tolerable and feasible. Further evaluation via randomised controlled trials is required.