EaRly impAct theraPy With Ceftazidime-avibactam Via rapID Diagnostics (RAPID)

National University of Singapore

Status and phase: Enrolling; Phase 4

Conditions: Ventilator Associated Pneumonia; Healthcare Associated Infection; Carbapenem-Resistant Enterobacteriaceae Infection; Blood Stream Infections; Hospital-acquired Pneumonia

Treatments: Diagnostic Test: Rapid Diagnostics

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT05979545

ADVANCE-ID 22-002

20535 (Other Identifier)

23-0135 (Other Grant/Funding Number)

225457/Z/22/Z (Other Grant/Funding Number)

Details and patient eligibility

About

RAPID is an investigator initiated Phase 4, multinational, multicentre, open-label, randomised controlled superiority trial evaluating the clinical impact of rapid microbiological diagnostics combined with antimicrobial stewardship and early targeted antibiotic therapy compared with standard-of-care diagnostics and antibiotics.

Hospitalised adult patients with bloodstream infections, hospital-acquired pneumonia or ventilator-associated pneumonia are randomised in a 1:1 ratio to the intervention or control arm.

The main analysis population comprises patients with infections caused by Pseudomonas aeruginosa or carbapenem-resistant Enterobacterales. A secondary analysis population includes patients with infections caused by other specified multidrug-resistant Gram-negative organisms.

Patients will be randomised to either a control or intervention arm. Patients randomised to the intervention arm will have relevant specimens analysed by rapid microbiological diagnostics and will have early availability of ceftazidime-avibactam if appropriate. Patients randomised to the control arm, will have samples analysed by clinical microbiology laboratories using standard of care diagnostics. Antibiotics will be available to these patients as per usual institutional practice.

The primary outcome is a composite of all-cause mortality or absence of improvement in Sequential Organ Failure Assessment (SOFA) score at Day 14 following the index culture.

Full description

The RAPID trial integrates rapid molecular diagnostics with locally adapted antimicrobial stewardship guidelines to facilitate timely identification of Gram-negative pathogens, detection of antimicrobial resistance genes and appropriate antibiotic selection.

In the intervention arm, positive blood cultures will undergo testing using the BioFire Blood Culture Identification 2 (BCID2) Panel, while respiratory specimens from patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) will be tested using the BioFire FilmArray Pneumonia Panel or Pneumonia Plus Panel. Rapid diagnostic testing will be initiated within four hours of Gram-negative bacilli being observed on Gram stain, alongside conventional microbiological testing. Clinicians will receive guidance on interpreting resistance gene results and selecting antibiotics according to locally adapted antimicrobial stewardship protocols. Ceftazidime-avibactam will be available for patients with Pseudomonas aeruginosa or Enterobacterales with detected carbapenemase genes, subject to predefined eligibility criteria and local regulatory approval. Antibiotic treatment may subsequently be modified based on conventional susceptibility testing and clinical judgement.

In the control arm, microbiological investigations and antibiotic treatment will follow standard institutional practices, with antibiotic selection determined by the treating clinicians.

Study population assignment will be based on conventional microbiological identification and antimicrobial susceptibility testing in both arms. The main analysis population will comprise patients with bloodstream infections, HAP or VAP caused by Pseudomonas aeruginosa or carbapenem-resistant Enterobacterales. The secondary analysis population will include patients with infections caused by ceftriaxone/cefotaxime/ceftazidime-resistant Enterobacterales, carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex or Stenotrophomonas maltophilia. Patients in the secondary population will receive antibiotics according to locally adapted antimicrobial stewardship guidelines rather than protocol-directed ceftazidime-avibactam.

Participants will be followed for 60 days following the index culture, with assessments of clinical outcomes, mortality, antibiotic utilisation, microbiological outcomes, antimicrobial resistance and functional status. Repeat microbiological cultures will be performed to assess bacterial persistence, and initial bacterial isolates will undergo antimicrobial susceptibility testing and whole-genome sequencing at a central laboratory.

Enrollment: 1,526 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Adult patients aged 18 years or older (21 years or older in Singapore) who meet at least one of the following criteria:

   • At risk of developing bloodstream infection, hospital-acquired pneumonia (HAP), or ventilator-associated pneumonia (VAP) due to Pseudomonas aeruginosa or carbapenem-resistant Enterobacterales; OR
   • Blood culture bottles showing Gram-negative bacilli on Gram stain; OR
   • Suspected HAP or VAP with respiratory specimens showing Gram-negative bacteria on Gram stain.

2. For randomisation, all of the following criteria must be fulfilled:

   • Written informed consent obtained from the participant or their authorised representative.
   • An appropriate blood or respiratory specimen received by the participating microbiology laboratory, with Gram-negative bacilli detected on Gram stain.
   • Patients with HAP or VAP must fulfil the US Centers for Disease Control and Prevention National Healthcare Safety Network (CDC NHSN) criteria.
   • No exclusion criteria are met.

Exclusion criteria

1. Refractory shock or comorbid condition such that the patient is not expected to survive more than 48 hours.
2. Suspected catheter-related bloodstream infection where the implicated vascular catheter cannot be removed.
3. Treatment is not intended to cure the infection.
4. Infection requiring prolonged antibiotic treatment (more than two weeks).
5. Incarceration in a correctional facility.
6. Previous enrolment in the RAPID trial within the preceding 60 days.
7. Patients younger than 18 years (younger than 21 years in Singapore).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,526 participants in 2 patient groups

Intervention

Active Comparator group

Description:

Rapid microbiological diagnostics using the BioFire BCID2 Panel for bloodstream infections or BioFire FilmArray Pneumonia/Pneumonia Plus Panel for respiratory infections, combined with locally adapted antimicrobial stewardship and early targeted antibiotic therapy. Samples from patients randomised to the intervention arm will undergo the BioFire FilmArray systems. Patients will be then administered with the study drug, ceftazidime-avibactam when Pseudomonas aeruginosa or carbapenemase producing Enterobacterales detected. Appropriate antibiotic must be administered according to predefined antibiotic stewardship guidelines within 24 hours of the Gram stain being performed on the index specimen.

Treatment:

Diagnostic Test: Rapid Diagnostics

Control

No Intervention group

Description:

Standard-of-care microbiological diagnostics and antibiotic treatment according to local clinical practice and treating physician discretion. Patients randomised to the control arm, will have samples analysed by clinical microbiology laboratories using standard of care diagnostics. Antibiotics treatment will be administered as per usual institutional practice from hospital supplies.