Critical Illness, Hospital-acquired Pneumonia (HAP), Nosocomial Respiratory Infection, Ventilator-Associated Pneumonia (VAP)
Conditions
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
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.
Detailed description
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.
Interventions
BEHAVIORALResistance-Optimised Precision Dosing
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.
BEHAVIORALStandard Care Dosing
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.
Sponsors
The University of Queensland
Queensland Health
Medical Research Future Fund
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The patient is ≥ 18 years of age. 2. 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. 3. The patient is intubated and mechanically ventilated. 4. 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. 5. 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. 6. Piperacillin/tazobactam or meropenem have been commenced in an ICU that participates in ROAD-RCT. 7. The patient has an appropriate arterial or venous access for blood sampling.
Exclusion criteria
1. The patient is known or suspected to be pregnant. 2. The patient has a known allergy to piperacillin/tazobactam or meropenem. 3. The patient has a community-acquired respiratory infection or chemical pneumonitis in the context of bronchoaspiration. 4. The patient has received piperacillin/tazobactam or meropenem for more than 48 h. 5. 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. 6. 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). 7. The patient's death is deemed imminent and inevitable. 8. The patient has previously been enrolled in ROAD-RCT. 9. The patient is or has been enrolled in another antimicrobial clinical trial that may interfere with the intervention as determined by the study investigators. 10. 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. 11. There is a prior known or likely reason that the patient would not consent if they were able to be asked.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical cure | Day 14 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Cure | Up to Day 14 | Time in hours from initiation of study antibiotic therapy to clinical cure. |
| All-cause mortality | 28 days | Any death documented within time frame |
| Emergence of antibiotic resistance | Day 14 | 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. |
| Incremental Cost-Utility Ratio | Day 28 | Incremental Cost-Utility Ratio incorporating the Quality adjusted life years based on the EQ-5D-5L questionnaire, with costs converted using purchasing power parity. |
| Treatment emergent adverse events | Day 14 | Any adverse event attributed to the study drug per protocol definitions. |
| C. difficile diarrhoea | Day 14 | Diagnosis of C. difficile diarrhoea |
| Duration of artificial organ support | Day 14 | Duration of mechanical ventilation, renal replacement therapy, extracorporeal membrane oxygenation, and duration of vasopressor therapy. |
| Intensive Care Unit Length of Stay | Day 28 | Duration of ICU admission |
Contacts
CONTACTAaron Heffernan
CONTACTJoyce Alvarenga
Outcome results
None listed