BALANCE+ Vanguard Phase

BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections

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.

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.

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 EXCLUSION CRITERIA

(A) DE-ESCALATION VS. NO DE-ESCALATION DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform

Exclusion Criteria

1. receiving an empiric antibiotic regimen at the time of blood culture finalization to which the GN pathogen(s) are not sensitive

2. carbapenem-resistance (so that patients will not need to remain on reserve-use agents)

3. no de-escalation option due to any or all of

   i. resistance ii. allergies iii. medical contraindications iv. drug-interaction risk v. other relevant reason

4. patients with a suspected or proven polymicrobial source of infection

(B) BETA-LACTAM VS. NON-BETA-LACTAM ORAL/ENTERAL TREATMENT DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform
2. initially treated with intravenous antibiotics, but clinical team transitioning patient to oral/enteral antibiotic within 7 days of starting treatment

Exclusion Criteria

1. enrolled in an arm of another BALANCE+ platform domain which limits the use of oral/enteral therapy

   - no-de-escalation arm

2. no non-beta-lactam options due to any or all of

   i. resistance ii. allergies iii. medical contraindications iv. drug-interaction risk v. other relevant reason

3. no beta-lactam options due to any or all of

   i. resistance ii. allergies iii. medical contraindications iv. drug-drug interaction risk v. other relevant reason

(C) CENTRAL VASCULAR CATHETER REPLACEMENT DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform
2. has an indwelling central vascular catheter that was already in place within the 48-hour period before the onset of bloodstream infection (i.e. is not a new catheter placed within 48 hours of the onset of infection)

Exclusion Criteria

1. patient has no ongoing need for a central vascular catheter

2. patient has definite indication for central vascular catheter removal

   1. ongoing septic shock with definite/probable line source
   2. concomitant S. aureus bacteremia
   3. concomitant candidemia
   4. local suppurative signs (severe redness, warmth, pain, swelling or fluctuance/collection) necessitating catheter removal, or other clinical evidence of infected line (e.g. imaging/echocardiographic findings)
   5. definite alternative source of GN BSI

(D) LOW-RISK AmpC DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform

2. positive blood culture with GN bacterium, of the following species

   1. Serratia spp.
   2. Morganella spp.
   3. Providencia spp.
   4. Proteus spp. other than P.mirabilis
   5. organism is sensitive to ceftriaxone

Exclusion Criteria

1. severe allergy to beta-lactams (eg, type 4 hypersensitivity reaction or DRESS)
2. baseline phenotypic resistance to ceftriaxone

(E) FOLLOW UP BLOOD CULTURE DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform

Exclusion Criteria

1. patient already discharged home prior to day 4

2. definite indication for repeat blood culture testing

   1. concomitant Staph. aureus bacteremia
   2. concomitant Candidemia
   3. clinical suspicion for infective endocarditis (e.g., presence of prosthetic valve, implantable cardiac device)