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.
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 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.
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.
Parallel
Resistance-Optimised Precision Dosing
BehavioralParticipants 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.
Standard Care Dosing
BehavioralParticipants 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.
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.
Time to Clinical Cure
Time in hours from initiation of study antibiotic therapy to clinical cure.
All-cause mortality
Any death documented within time frame
Emergence of antibiotic resistance
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
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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The University of Queensland
Lead sponsor
Queensland Health
Collaborator
Medical Research Future Fund
Collaborator
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