Resistance-Optimised Antimicrobial Dosing in Critically Ill Patients, a Randomised Controlled Trial

Overview

Critically ill people who need a breathing machine often develop hospital-acquired lung infections. These infections are commonly treated with the antibiotics piperacillin/tazobactam or meropenem. However, standard antibiotic doses may not always provide the right drug levels to fully treat the infection or help prevent antibiotic resistance. The purpose of this study is to determine whether a resistance-optimized antibiotic dosing approach improves recovery compared with standard antibiotic dosing in critically ill adults with hospital-acquired respiratory infections. Participants will be randomly assigned to 1 of 2 groups: Resistance-optimized precision dosing - guided by therapeutic drug monitoring and dosing software. Standard care - antibiotic dosing used at the participating hospital. All participants will receive treatment with either piperacillin/tazobactam or meropenem as determined by their treating clinical team. The study will compare whether the precision dosing approach leads to better clinical recovery, reduces the development of antibiotic-resistant bacteria, and is safe for participants. Approximately 610 mechanically ventilated adults will be enrolled from intensive care units in multiple countries. Participants will be followed for up to 28 days after starting study antibiotic treatment.

Critically ill adults who require mechanical ventilation commonly develop hospital-acquired respiratory infections. These infections are frequently treated with the beta-lactam antibiotics piperacillin/tazobactam or meropenem. Standard antibiotic dosing may not always achieve drug levels that provide the best balance between treating infection and reducing the development of antibiotic resistance. The Resistance-Optimised Antimicrobial Dosing in Critically Ill Patients Randomized Controlled Trial (ROAD-RCT) is a multicentre, international, investigator-initiated, open-label, randomized, parallel-group superiority trial. The study aims to determine whether resistance-optimised precision dosing improves clinical cure compared with standard care dosing in mechanically ventilated critically ill adults with hospital-acquired respiratory infections. A total of approximately 610 participants will be enrolled and randomized in a 1:1 ratio to one of two treatment strategies: Resistance-optimised precision dosing guided by model-informed precision dosing (MIPD). Standard care antibiotic dosing according to local clinical practice. Participants will receive treatment with either piperacillin/tazobactam or meropenem as prescribed by their treating clinical team. In the intervention group, dosing recommendations will be supported by therapeutic drug monitoring (TDM), patient clinical information, and dosing software to help achieve antibiotic exposure targets associated with suppression of antimicrobial resistance while remaining within accepted safety limits. Participants assigned to standard care will receive antibiotic dosing determined by their treating clinicians. The primary outcome is clinical cure at Day 14 after initiation of study antibiotic therapy. Secondary outcomes include time to clinical cure, mortality, treatment-related adverse events, duration of organ support therapies, emergence of antibiotic resistance, acquisition of new resistant microorganisms, hospital and intensive care unit length of stay, quality of life, and health-economic outcomes. Participants will be followed for up to 28 days after initiation of study antibiotic treatment. The study hypothesis is that resistance-optimised precision dosing will improve clinical cure while reducing the emergence of antimicrobial resistance compared with standard care dosing. The results of this study will provide evidence about the effectiveness, safety, feasibility, and potential scalability of precision antibiotic dosing strategies in critically ill patients with hospital-acquired respiratory infections.