Resistance-Optimised Antimicrobial Dosing in Critically Ill Patients, a Randomised Controlled Trial (ROAD-RCT)
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.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Inscripción (Estimado)
Fase
- No aplica
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Aaron Heffernan
- Número de teléfono: +610411588291
- Correo electrónico: Aaron.Heffernan@health.qld.gov.au
Copia de seguridad de contactos de estudio
- Nombre: Joyce Alvarenga
- Número de teléfono: +61733465045
- Correo electrónico: road-rct@uq.edu.au
Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
- Adulto
- Adulto Mayor
Acepta Voluntarios Saludables
Descripción
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.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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Experimental: Arm 1: Resistance-Optimised Precision Dosing
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.
|
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.
|
|
Comparador activo: Arm 2: Standard Care Dosing
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.
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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.
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Clinical cure
Periodo de tiempo: Day 14
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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.
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Day 14
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Time to Clinical Cure
Periodo de tiempo: Up to Day 14
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Time in hours from initiation of study antibiotic therapy to clinical cure.
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Up to Day 14
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All-cause mortality
Periodo de tiempo: 28 days
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Any death documented within time frame
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28 days
|
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Emergence of antibiotic resistance
Periodo de tiempo: Day 14
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Antibiotic resistance emergence is defined as any of the following: emergence of resistance to beta-lactam antimicrobials in the index microorganism from the surveillance and/or clinical samples; acquisition of (a) new beta-lactam antimicrobials-resistant microorganism(s) in the surveillance and/or clinical samples, or the detection of new antimicrobial resistance gene classes (whole genome sequencing and metagenomic evaluation) in the surveillance and/or clinical samples.
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Day 14
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Incremental Cost-Utility Ratio
Periodo de tiempo: Day 28
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Incremental Cost-Utility Ratio incorporating the Quality adjusted life years based on the EQ-5D-5L questionnaire, with costs converted using purchasing power parity.
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Day 28
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Treatment emergent adverse events
Periodo de tiempo: Day 14
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Any adverse event attributed to the study drug per protocol definitions.
|
Day 14
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C. difficile diarrhoea
Periodo de tiempo: Day 14
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Diagnosis of C. difficile diarrhoea
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Day 14
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Duration of artificial organ support
Periodo de tiempo: Day 14
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Duration of mechanical ventilation, renal replacement therapy, extracorporeal membrane oxygenation, and duration of vasopressor therapy.
|
Day 14
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Intensive Care Unit Length of Stay
Periodo de tiempo: Day 28
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Duration of ICU admission
|
Day 28
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Colaboradores e Investigadores
Patrocinador
Publicaciones y enlaces útiles
Publicaciones Generales
- 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.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Procesos Patológicos
- Atributos de la enfermedad
- Infecciones del Tracto Respiratorio
- Infecciones
- Enfermedades de las vías respiratorias
- Enfermedades pulmonares
- Neumonía
- Infección cruzada
- Enfermedad iatrogénica
- Condiciones Patológicas, Signos y Síntomas
- Neumonía asociada a la atención médica
- Enfermedad crítica
- Neumonía asociada a ventilador
Otros números de identificación del estudio
- ROAD-RCT
- Grant Number 2039566 (Otro número de subvención/financiamiento: Australian Medical Research Future Fund (MRFF))
Plan de datos de participantes individuales (IPD)
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Información sobre medicamentos y dispositivos, documentos del estudio
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