Gram-negative Bacteremia
Conditions
Brief summary
The goal of the BALANCE+ clinical trial is to transform random care to randomized care for patients with Gram negative bloodstream infections to inform best treatment approaches and optimize outcomes. BALANCE+, a perpetual platform trial, will efficiently answer multiple questions that are important for hospitalized patients with Gram negative bloodstream infections.
Detailed description
Bloodstream infections (BSIs) are common and lethal, ranking among the top 7 causes of death, with 600,000 cases and 90,000 deaths per year in North America, and 1.2 Million cases and 150,000 deaths per year in Europe. Despite being a leading cause of death worldwide, bloodstream infections remain understudied. Treatment approaches are complicated by rising rates of antimicrobial resistance and declining new drug development. BALANCE+ provides a platform upon which to answer multiple pressing cross-cutting questions for patients with Gram negative bloodstream infections, including the concept of de-escalating antibiotic spectrum, optimal transition to oral antibiotics, and the role for routine follow up blood culture testing. The trial will also include a syndrome-specific question of whether to remove or retain a central vascular catheter, and a pathogen-specific question of whether cephalosporins are sufficient for patients with low-risk AmpC organisms. As each question is answered, optimal therapies will be adopted into usual care, and new questions will be introduced into the platform of the trial. The evidence generated by BALANCE+ will improve cure for this vulnerable patient population.
Interventions
No de-escalation group: continue to receive the same antibiotic that was started initially (as long as it is confirmed to be effective based on the blood culture sensitivity result) De-escalation group: switched to narrower spectrum antibiotic.
Beta-lactam antibiotic: This can be ciprofloxacin, moxifloxacin, levofloxacin or trimethoprim-sulfamethoxazole. Non beta-lactam antibiotic: This can be, but not limited to, amoxicillin, amoxicillin-clavulanate, cephalexin, cefadroxil, or cefixime.
Central vascular catheter replacement: the catheter will be changed by the treating team as soon as possible and within a maximum of 72 hours from blood culture finalization Central vascular catheter retention: the catheter will not be changed and will be retained until it is no longer needed.
Cephalosporin (ceftriaxone) at standard doses Carbapenem (like Meropenem, Ertapenem etc) at standard doses
Routine follow-up blood culture: routine repeat blood collection 4 days from the index blood collection with positive bacteria. No follow-up blood culture: no routine repeat blood collection 4 days from the index blood collection with positive bacteria
Sponsors
Canadian Institutes of Health Research (CIHR)
Sunnybrook Health Sciences Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Intervention model description
72 in the overall platform AND at least 12 in each domain.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
PLATFORM INCLUSION CRITERIA 1. admitted to a participating hospital 2. positive blood culture with Gram negative (GN) bacterium PLATFORM
Exclusion criteria
1. patient's goals of care are for palliation with no active treatment 2. moribund patient, not expected to survive \> 72 hours DOMAIN SPECIFIC INCLUSION AND
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Follow-up blood culture domain | 90 days | * Ordinal DOOR outcome: (dead at 90 days) \< (alive at 90 days with reinfection and readmission) \< (alive at 90 days with reinfection or readmission) \< (alive at 90 days with neither reinfection nor readmission) * No tie-breaker |
| Recruitment rate (co-primary outcomes of BALANCE+ vanguard phase) | 1 year | Recruitment rate will be measured as the number of patients randomized to each study domain, overall, and by individual participating site. Investigators will target a minimum overall recruitment rate of 1 patient/site/month in the de-escalation domain, beta-lactam versus non-beta-lactam stepdown domain, and FUBC domain; and 0.25 patients/site/month in the line replacement domain. |
| Protocol adherence (co-primary outcomes of BALANCE+ vanguard phase) | 1 year | Protocol adherence will be calculated differently depending on the domain, but in each case will require adherence to the specific intervention arm and complete follow-up for the primary outcome. Investigators will target ≥90% adherence in each arm of each domain. |
| De-escalation versus no de-escalation domain | 90 days | * Patient-centered, ordinal Desirability of Outcome Ranking (DOOR) outcome: (dead at 90 days) \< (alive at 90 days with reinfection and readmission) \< (alive at 90 days with reinfection or readmission) \< (alive at 90 days with neither reinfection nor readmission) * Tie-breaker within ordinal levels: new antimicrobial resistance (AMR) colonization or infection from routine cultures |
| Oral beta-lactam versus non beta-lactam domain | 90 days | * Ordinal DOOR outcome: (dead at 90 days) \< (alive at 90 days with reinfection and readmission) \< (alive at 90 days with reinfection or readmission) \< (alive at 90 days with neither reinfection nor readmission) * Tie-breaker within ordinal levels: new AMR colonization or infection from routine cultures |
| Central vascular catheter retention versus replacement domain | 90 days | * Ordinal DOOR outcome: (dead at 90 days) \< (alive at 90 days with reinfection and readmission) \< (alive at 90 days with reinfection or readmission) \< (alive at 90 days with neither reinfection nor readmission) * No tie-breaker |
| Low-risk AmpC domain | 90 days | * Ordinal DOOR outcome: (dead at 90 days) \< (alive at 90 days with reinfection and readmission) \< (alive at 90 days with reinfection or readmission) \< (alive at 90 days with neither reinfection nor readmission) * Tie-breaker within ordinal levels: new AMR colonization or infection from routine cultures |
Secondary
| Measure | Time frame |
|---|---|
| 90-day mortality | 90 days |
| 90-day reinfection | 90 days |
| 90-day all cause readmission | 90 days |
| 90-day AMR colonization/infection | 90 days |
| 90-day Clostridioides difficile infection (CDI) | 90 days |
| 30-day mortality | 30 days |
| 60-day mortality | 60 days |
Countries
Canada
Outcome results
None listed