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

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.

Inclusion criteria

• The patient is ≥ 18 years of age.
• The patient has been admitted to the hospital for ≥ 48 h or was discharged from a hospital within the preceding seven days and is currently admitted to the ICU.
• The patient is intubated and mechanically ventilated.
• The patient is diagnosed with a probable or definitive respiratory infection and exhibits at least one of the following clinical features:

I. New onset or worsening pulmonary symptoms or signs: increase in volume and/or purulence of respiratory secretions, worsening of hypoxaemia requiring an increase in the FiO2 and/or need for acute changes in the ventilator support system to support oxygenation.

II. Radiological findings deemed consistent with a respiratory infection. III. Clinical signs and symptoms of infection: fever > 38 °C, leucocytosis, increase in acute phase reactants such as C-reactive protein or procalcitonin.

• The patient has been commenced on empiric or targeted treatment with piperacillin/tazobactam or meropenem for the management of a respiratory infection, with an expected duration of treatment of > 72 h.
• Piperacillin/tazobactam or meropenem have been commenced in an ICU that participates in ROAD-RCT.
• The patient has an appropriate arterial or venous access for blood sampling.

Exclusion criteria

• The patient is known or suspected to be pregnant.
• The patient has a known allergy to piperacillin/tazobactam or meropenem.
• The patient has a community-acquired respiratory infection or chemical pneumonitis in the context of bronchoaspiration.
• The patient has received piperacillin/tazobactam or meropenem for more than 48 h.
• The antimicrobial dose initiated empirically is > 4 g daily for meropenem and > 18 g daily (16 g piperacillin / 2 g tazobactam) for piperacillin/tazobactam (excluding the loading dose) in patients who are not receiving renal replacement therapy.
• The antimicrobial dose initiated empirically is > 18 g daily (16 g piperacillin / 2 g tazobactam) for piperacillin/tazobactam and > 2 g daily for meropenem in patients receiving renal replacement therapy (Table 1).
• The patient's death is deemed imminent and inevitable.
• The patient has previously been enrolled in ROAD-RCT.
• The patient is or has been enrolled in another antimicrobial clinical trial that may interfere with the intervention as determined by the study investigators.
• The patient has a baseline (at ICU admission or enrolment) positive rectal and/or nasopharyngeal screening swab, or is known to have been colonised within the past 6 months, with any of the following beta-lactam-resistant Gram-negative microorganism(s): carbapenem-resistant Enterobacterales, P. aeruginosa with DTR or carbapenem-resistant A. baumannii complex.
• There is a prior known or likely reason that the patient would not consent if they were able to be asked.