Impact of Rapid Pathogen Identification From Blood Cultures (RABbIT) (RABbIT)

Impact of Rapid Pathogen Identification From Blood Cultures (RABbIT - Rapid Blood Culture Intervention Trial)

Septic shock carries high mortality, which may be exacerbated by inappropriate initial therapy. Inappropriate therapy may result from unanticipated antimicrobial resistance. Conversely, positive blood cultures may result from contamination, leading to unnecessary therapy and procedures and possibly prolonged hospitalization. Clinicians may also resort to broad spectrum antimicrobials and be hesitant to de-escalate while awaiting susceptibility results.

The investigators hypothesize that rapid identification of pathogens and antimicrobial resistance will ameliorate the above problems and improve time to optimal therapy, avoid unnecessary therapy and ultimately improve patient outcomes. While there are a number of in-vitro and uncontrolled clinical studies, there is a paucity of well-designed clinical trials objectively examining the real-world clinical and health-economic impact of such technology. To date only one randomised trial has been performed in the US (ClinicalTrials.gov NCT01898208), at a setting with low endemic rates of antimicrobial resistance. This is a companion study to NCT01898208. The investigators aim to study the clinical impact and cost-effectiveness of a strategy for rapid pathogen and resistance detection in a setting with a moderate to high levels of antimicrobial resistance.

Study Overview

• Status: Unknown
• Conditions: Sepsis; Fungemia; Bacteremia; Blood Stream Infection
• Intervention / Treatment: Device: Filmarray Blood Culture ID (BCID) panel; Device: Rosco Diagnostica ESBL/carbapenemase screen kit

Detailed Description

Hypothesis:

1. Rapid pathogen identification from blood cultures, including early identification of resistance (via specific genetic markers or phenotypic tests), will allow timelier initiation of appropriate antibiotic therapy and improved patient outcomes
2. Rapid organism identification from blood cultures will allow timelier initiation of effective and optimal antibiotic therapy; minimizing the use of unnecessary antibiotics, including combination therapy

Devices to be studied for this proposed study:

1. BCID panel (Biofire Diagnostics Inc., bioMerieux) : The BCID panel is an FDA-approved nucleic acid amplification test (based on nested polymerase chain reaction) which detects Gram positive, Gram negative, the major Candida species and antimicrobial resistance markers (mecA for methicillin resistance, van A/B for vancomycin resistance, blaKPC for Klebsiella pneumoniae carbapenemase (KPC)) directly from positive blood cultures in < 1 - 1.5 hours
2. Rosco Diagnostica extended-spectrum beta-lactamase (ESBL) and carbapenemase screen kit (Rosco Diagnostica): These kits are CE-marked (Approved in the European Union) rapid chromogenic tests for ESBL/ carbapenemase detection from both blood cultures and cultured bacterial colonies.

• Study Type: Interventional
• Enrollment (Anticipated): 832
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore
    • Tan Tock Seng Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age > 21 years and above to 103 years
2. Blood culture flagged positive on automated instrument, with Gram positive, Gram negative bacteria or Yeast on Gram staining (including polymicrobial blood cultures)
3. Ability to provide informed consent or ability to obtain informed consent from legal guardian/representative (verbal and written)

Exclusion Criteria:

1. Patients whose blood cultures turn positive, but have no organism seen on Gram stain.
2. Patients who have been previously enrolled.
3. Patients who withdraw their consent (verbal or written).
4. Patients with any positive blood culture in the preceding 7 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rapid diagnostic arm; Standard Tan Tock Seng Hospital (TTSH) practices (bacterial culture and susceptibility testing) AND FilmArray Blood Culture ID (BCID) Panel test AND Rosco Diagnostica ESBL and carbapenemase screen will be performed. The Interventions to be administered are the rapid diagnostic tests: FilmArray Blood Culture ID (BCID) Panel test AND Rosco Diagnostica ESBL and carbapenemase screen. Subjects will be recruited 8am-3pm daily, weekdays only. Results of the BCID and Rosco test will be communicated to the managing physicians by phone in real-time.	Device: Filmarray Blood Culture ID (BCID) panel; The BCID panel is an FDA-approved nucleic acid amplification test (based on nested polymerase chain reaction) which detects Gram positive, Gram negative, the major Candida species and antimicrobial resistance markers (mecA for methicillin resistance, van A/B for vancomycin resistance, blaKPC for KPC carbapenemase) directly from positive blood cultures in < 1 - 1.5 hours; Other Names: BCID; Device: Rosco Diagnostica ESBL/carbapenemase screen kit; These kits are CE-marked (Approved in the European Union) rapid chromogenic tests for extended-spectrum beta-lactamase / carbapenemase detection from both blood cultures and cultured bacterial colonies.
No Intervention: Standard of care (control); Standard Tan Tock Seng Hospital (TTSH) practices (bacterial culture and susceptibility testing) will be used. FilmArray BCID and Rosco Diagnostica ESBL and carbapenemase screen will NOT be performed. Subjects will be recruited 8am-3pm daily, weekdays only.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from positive blood culture result to effective/optimal antibiotics	An effective antibiotic is defined as an antibiotic regimen to which the bacterial/fungal isolate is susceptible (or predicted to be susceptible for Candida, per speciation).An optimal antibiotic is defined as an antibiotic regimen to which the bacterial/fungal isolate is susceptible/predicted to be susceptible, which is the most narrow spectrum and targeted, as recommended by institutional guidelines. This will be considered as the time from the positive Gram stain to first effective and the first optimal antibiotic.	Approximately 14 days after positive blood culture

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical outcome (Infection related mortality)	Infection-related at 30-day, 90-days and 1-year	1 year
Clinical outcome (All-cause related mortality)	All cause mortality at 30-day, 90-days and 1-year mortality	1 year
Clinical outcome (Quality of life)	Quality of life at enrolment, 90-days and at 1 year, as measured by the tools EQ-5D-5L QoL/SF-12	1 year
Time from positive blood culture result to bacterial identification		Approximately 3 days
Duration of hospitalization (days)		Participants were followed for the duration of hospital stay, approximately 28 days
Duration of bacteremia/fungemia (days)		Patient-dependent variable, estimated up to 7 days
Time to isolation precautions	Time taken for implementation of appropriate infection control measures (isolation precautions) as appropriate for pathogen detected	Estimated up to 5 days
Antibiotic-associated adverse events	This included all adverse events that occurred within 2 weeks following enrollment and were documented in the medical record.	Approximately 14 days after positive blood culture
Antimicrobial utilization (hours/days of therapy)	Difference between the date and time of the antibiotic start order (or Gram stain-positive blood culture, if antibiotics were started prior to the positive culture result) and the date and time of the antibiotic stop order. Shorter duration of broad spectrum antibiotics and longer duration of narrow-spectrum antibiotics were considered favorable outcomes.	Approximately 4 days after enrollment
Mean Total Hospitalization Costs Per Subject	These will be calculated based on actual billable patient costs (without government subventions/subsidies) following 7 days after the positive blood culture episode and for the duration of hospitalization, up to an estimated 24 weeks.	Approximately 7 days after positive blood culture for up to an estimated 24 weeks
Mean Laboratory Costs Per Subject	These will be calculated based on actual billable laboratory costs (without government subventions/subsidies) following 7 days after the positive blood culture episode and for the duration of hospitalization, up to an estimated 24 weeks.	Approximately 7 days after positive blood culture for up to an estimated 24 week
Mean Antimicrobials Costs Per Subject	These will be calculated based on actual billable antimicrobial costs (without government subventions/subsidies) following 7 days after the positive blood culture episode and for the duration of hospitalization, up to an estimated 24 weeks.	Approximately 7 days after positive blood culture and for duration of entire hospitalization
Cost-effectiveness analysis	Incremental cost-effectiveness ratios will be determined by dividing the difference between the average costs of treating a patient in the after phase (C1) and the average cost in the before phase (C0) by the difference between average health outcomes (QALYs) gained in the after phase (O1) and those gained in the before phase (O0). The incremental cost-effectiveness ratio is calculated by the following equation: (C1 - C0)/(O1 - O0). Incremental cost-effectiveness ratios using quality adjusted/sepsis adjusted life years gained as the health outcome of interest will then be determined, based on the method of Jones et al Crit Care Med. 2011 June ; 39(6): 1306-1312.	Up to 1 year after enrolment and using a 'modeled horizon' based on sepsis-adjusted life expectancies
Time on effective/optimal antibiotics within first 96 hours of positive blood culture	An effective antibiotic is defined as an antibiotic regimen to which the bacterial/fungal isolate is susceptible (or predicted to be susceptible for Candida, per speciation).An optimal antibiotic is defined as an antibiotic regimen to which the bacterial/fungal isolate is susceptible/predicted to be susceptible, which is the most narrow spectrum and targeted, as recommended by institutional guidelines. This will be considered in the 96-hour time frame from the positive Gram stain.	First 96 hours after blood culture turns positive

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With Infectious Disease Consultation Within 72 Hours of Enrollment		Approximately within 72 hours of positive blood culture
Time to First Appropriate De-escalation or First Appropriate Escalation of Antibiotics	De-escalation included discontinuation of 1 or more antibiotics and/or switching from a broad- to a narrow spectrum antibiotic. Escalation included initiation of 1 or more antibiotics and/or switching from a narrow- to a broad-spectrum antibiotic	Positive Gram stain, 96 hours after enrollment
Percent of Contaminated Blood Cultures Not Treated or Treated for Less Than 24 Hours	Contaminated blood cultures were defined as growth of organisms such as coagulase-negative staphylococci from a single blood culture set when greater than or equal to 2 blood culture sets were collected, except among subjects suspected to have true bacteremia associated with central venous catheters or devices.	Within 24 hours after positive blood culture
Length of Entire Hospitalization (Days)		Participants are followed for the duration of hospital stay, approximately 15 days
Length of Intensive Care Unit Stay (days)		Within 14 days of positive blood culture until ICU discharge, up to an estimated 24 weeks.
Percentage of Patients Who Acquired Clostridium Difficile Within 30 Days After Enrollment		Approximately 30 days after positive blood culture
Percentage of Patients Who Acquired Multidrug-resistant organisms Within 30 Days After Enrollment	Multidrug-resistant organisms included vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, extended-spectrum cephalosporin-resistant Enterobacteriaceae, and Pseudomonas aeruginosa and Acinetobacter species resistant to greater than or equal to 3 antibiotic classes.	Approximately 30 days after positive blood culture

Collaborators and Investigators

• Sponsor: Tan Tock Seng Hospital
• Collaborators: Mayo Clinic
• Investigators: Principal Investigator: Shawn Vasoo, MD, Tan Tock Seng Hospital; Principal Investigator: Partha P De, MD, Tan Tock Seng Hospital; Principal Investigator: Christine B Teng, MSc, National University of Singapore/Tan Tock Seng Hospital

Publications and helpful links

General Publications

• Ong SWX, Hon PY, Wee SSH, Chia JWZ, Mendis S, Izharuddin E, Lin RJ, Chia PY, Sim RCS, Chen MI, Chow A, Yoong J, Lye DC, Teng CB, Tambyah PA, Banerjee R, Patel R, De PP, Vasoo S. Accuracy of a Rapid Multiplex Polymerase Chain Reaction Plus a Chromogenic Phenotypic Test Algorithm for Detection of Extended-Spectrum beta-Lactamase and Carbapenemase-Producing Gram-Negative Bacilli in Positive Blood Culture Bottles. Clin Infect Dis. 2022 May 30;74(10):1850-1854. doi: 10.1093/cid/ciab848.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2017
• Primary Completion (Actual): July 2, 2019
• Study Completion (Anticipated): July 2, 2020

Study Registration Dates

• First Submitted: March 29, 2016
• First Submitted That Met QC Criteria: April 14, 2016
• First Posted (Estimate): April 19, 2016

Study Record Updates

• Last Update Posted (Actual): September 10, 2019
• Last Update Submitted That Met QC Criteria: September 9, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections; Sepsis; Bacteremia; Fungemia
• Other Study ID Numbers: 2015/00255

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes