Bacteremia, Blood Stream Infection, Fungemia, Sepsis
Conditions
Brief summary
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.
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.
Interventions
DEVICEFilmarray 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
DEVICERosco 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.
Sponsors
Mayo Clinic
Tan Tock Seng Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
21 Years to 103 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time from positive blood culture result to effective/optimal antibiotics | Approximately 14 days after 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 as the time from the positive Gram stain to first effective and the first optimal antibiotic. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of hospitalization (days) | Participants were followed for the duration of hospital stay, approximately 28 days | — |
| Antibiotic-associated adverse events | Approximately 14 days after positive blood culture | This included all adverse events that occurred within 2 weeks following enrollment and were documented in the medical record. |
| Antimicrobial utilization (hours/days of therapy) | Approximately 4 days after enrollment | 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. |
| Mean Total Hospitalization Costs Per Subject | Approximately 7 days after positive blood culture for up to an estimated 24 weeks | 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. |
| Mean Laboratory Costs Per Subject | Approximately 7 days after positive blood culture for up to an estimated 24 week | 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. |
| Mean Antimicrobials Costs Per Subject | Approximately 7 days after positive blood culture and for duration of entire hospitalization | 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. |
| Cost-effectiveness analysis | Up to 1 year after enrolment and using a 'modeled horizon' based on sepsis-adjusted life expectancies | 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. |
| Time on effective/optimal antibiotics within first 96 hours of positive blood culture | First 96 hours after blood culture turns positive | 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. |
| Clinical outcome (Infection related mortality) | 1 year | Infection-related at 30-day, 90-days and 1-year |
| Clinical outcome (All-cause related mortality) | 1 year | All cause mortality at 30-day, 90-days and 1-year mortality |
| Clinical outcome (Quality of life) | 1 year | Quality of life at enrolment, 90-days and at 1 year, as measured by the tools EQ-5D-5L QoL/SF-12 |
| Time from positive blood culture result to bacterial identification | Approximately 3 days | — |
| Duration of bacteremia/fungemia (days) | Patient-dependent variable, estimated up to 7 days | — |
| Time to isolation precautions | Estimated up to 5 days | Time taken for implementation of appropriate infection control measures (isolation precautions) as appropriate for pathogen detected |
Other
| Measure | Time frame | Description |
|---|---|---|
| Length of Entire Hospitalization (Days) | Participants are followed for the duration of hospital stay, approximately 15 days | — |
| Percentage of Subjects With Infectious Disease Consultation Within 72 Hours of Enrollment | Approximately within 72 hours of positive blood culture | — |
| 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 | Approximately 30 days after positive blood culture | 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. |
| Time to First Appropriate De-escalation or First Appropriate Escalation of Antibiotics | Positive Gram stain, 96 hours after enrollment | 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 |
| Percent of Contaminated Blood Cultures Not Treated or Treated for Less Than 24 Hours | Within 24 hours after positive blood culture | 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. |
Countries
Singapore
Outcome results
None listed