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

NCT07820501 | Not Yet Recruiting DMC

• 2 other identifiers: ROAD-RCTGrant Number 2039566
• Study Type: interventional
• Target: 610
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Hospital-acquired Pneumonia (HAP); Ventilator-Associated Pneumonia (VAP); Critical Illness; Nosocomial Respiratory Infection

Keywords

Hospital-Acquired Pneumonia; Ventilator-Associated Pneumonia; Nosocomial Respiratory Infection; Intensive Care Unit; Mechanical Ventilation; Antimicrobial Resistance; Therapeutic Drug Monitoring; Drug Dose Optimization; Randomized Controlled Trial; Precision Dosing

Outcome Measures

Primary Outcomes (1)

• Clinical cure

  Clinical cure at Day 14 following initiation of study beta-lactam antimicrobial therapy. Clinical cure is defined as completion of the antimicrobial treatment course without recommencement of antimicrobial therapy for the same infectious episode within 48 hours of cessation, cessation of therapy not being due to palliative care, and survival for at least 48 hours after completion of the antimicrobial course.

  Day 14

Secondary Outcomes (8)

• Time to Clinical Cure

  Up to Day 14

• All-cause mortality

  28 days

• Emergence of antibiotic resistance

  Day 14

• Incremental Cost-Utility Ratio

  Day 28

• Treatment emergent adverse events

  Day 14

Study Arms (2)

Arm 1: Resistance-Optimised Precision Dosing

EXPERIMENTAL

Participants will receive piperacillin/tazobactam or meropenem using resistance-optimised precision dosing guided by model-informed precision dosing (MIPD). Dosing recommendations will be based on patient clinical characteristics and therapeutic drug monitoring results to achieve predefined antibiotic exposure targets associated with suppression of antimicrobial resistance. Dosing will be reviewed and adjusted throughout treatment according to MIPD recommendations until cessation of study antibiotic therapy, intensive care unit discharge, or Day 14, whichever occurs first.

Behavioral: Resistance-Optimised Precision Dosing

Arm 2: Standard Care Dosing

ACTIVE COMPARATOR

Participants will receive piperacillin/tazobactam or meropenem dosed according to routine clinical practice at the participating site. The initial choice of antibiotic, dose, infusion duration, dosing interval, and any subsequent dose adjustments will be determined by the treating clinical team in accordance with local standard care. Therapeutic drug monitoring may be performed if it is part of routine clinical practice at the study site. Treatment will continue until antibiotic cessation, intensive care unit discharge, or Day 14 after initiation of study antibiotic therapy, whichever occurs first.

Behavioral: Standard Care Dosing

Interventions

Resistance-Optimised Precision Dosing BEHAVIORAL

Participants assigned to the intervention group will receive piperacillin/tazobactam or meropenem using resistance-optimised precision dosing guided by model-informed precision dosing (MIPD). Dosing recommendations will be based on patient clinical characteristics and therapeutic drug monitoring results and are intended to achieve antibiotic exposure targets associated with suppression of antimicrobial resistance while remaining within established safety limits. Dosing will be reviewed and adjusted during treatment using MIPD recommendations.

Arm 1: Resistance-Optimised Precision Dosing

Standard Care Dosing BEHAVIORAL

Participants assigned to the standard care group will receive piperacillin/tazobactam or meropenem according to routine clinical practice at the participating site. Antibiotic dose, infusion duration, dosing interval, and dose adjustments will be determined by the treating clinical team. Therapeutic drug monitoring may be performed if it is part of usual care at the study site.

Arm 2: Standard Care Dosing

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The University of Queensland: lead
• Queensland Health: collaborator
• Medical Research Future Fund: collaborator

Related Publications (1)

• Roberts JA, Heffernan AJ, Chai MG, et al. 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. CMI Communications. 2025;2:105051.

  RESULT

MeSH Terms

Conditions

Healthcare-Associated Pneumonia; Pneumonia, Ventilator-Associated; Critical Illness

Condition Hierarchy (Ancestors)

Cross Infection; Infections; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Aaron Heffernan

CONTACT

+610411588291; Aaron.Heffernan@health.qld.gov.au

Joyce Alvarenga

CONTACT

+61733465045; road-rct@uq.edu.au

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomized in a parallel-group design to receive either resistance-optimised precision dosing guided by MIPD or standard care antibiotic dosing. Participants will remain in their assigned group for the duration of the study intervention.

Study Record Dates

• First Submitted: August 16, 2026
• First Posted: September 15, 2026
• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): September 1, 2029
• Last Updated: September 15, 2026

Record last verified: 2026-08