A Platform Trial for Gram Negative Bloodstream Infections

PLATFORM INCLUSION CRITERIA

Platform Inclusion Criteria:

• admitted to a participating hospital

• positive blood culture with Gram negative (GN) bacterium

Platform Exclusion Criteria:

• patient's goals of care are for palliation with no active treatment

• moribund patient, not expected to survive > 72 hours

• previously enrolled in the platform trial

• not eligible for any domain at the time of screening

DOMAIN SPECIFIC INCLUSION AND EXCLUSION CRITERIA

1. De-escalation versus no de-escalation domain Inclusion Criteria

• included in BALANCE+ platform Exclusion Criteria

• receiving an empiric antibiotic regimen at the time of blood culturefinalization to which the GN pathogen(s) are not sensitive

• arbapenem-non-susceptible

• no de-escalation option due to any or all of:

• antimicrobial resistance

• allergies

• medical contraindications

• drug-drug interaction risk

• other relevant reason

• patients with a suspected or proven polymicrobial source of infection

• > 24 hours since index blood culture susceptibility results finalization

2. Beta-lactam versus non-beta-lactam oral/enteral treatment domain Inclusion Criteria

• included in BALANCE+ platform

• initially treated with intravenous antibiotics, but clinical team transitioningpatient to oral/enteral antibiotic within 7 days of starting treatment Exclusion Criteria

• enrolled in an arm of another BALANCE+ platform domain which limits the use oforal/enteral therapy:

• no-de-escalation arm (patients in the no de-escalation arm cannot be randomizedinto this domain unless they are ready for discharge home, in which casede-escalation is allowable to oral agents at discharge)

• no non-beta-lactam options due to any or all of:

• resistance

• allergies

• medical contraindications

• drug-interaction risk

• other relevant reason

• no beta-lactam options due to any or all of:

• resistance

• allergies

• medical contraindications

• drug-interaction risk

• other relevant reason

• pregnancy

• already received >24 hours of oral antibiotics after index blood culturefinalization

3. Central vascular catheter replacement domain Inclusion Criteria

• included in BALANCE+ platform

• has an indwelling central vascular catheter that was already in place withinthe 48-hour period before the onset of bloodstream infection (i.e. is not a newcatheter placed within 48 hours of the onset of infection) Exclusion Criteria

• patient has no ongoing need for a central vascular catheter

• patient has definite indication for central vascular catheter removal

• ongoing septic shock with definite/probable line source

• concomitant S. aureus bacteremia

• concomitant candidemia

• local suppurative signs (severe redness, warmth, pain, swelling orfluctuance/collection) necessitating catheter removal, or other clinicalevidence of infected line (e.g. imaging/echocardiographic findings)

4. Low-risk AmpC domain Inclusion Criteria

• included in BALANCE+ platform

• positive blood culture with GN bacterium, of the following species: i. Serratiaspp. ii Morganella spp. iii Providencia spp. iv Proteus spp. other thanP.mirabilis

• organism is susceptible to ceftriaxone Exclusion Criteria

• severe allergy to beta-lactams (e.g., type 4 hypersensitivity reaction orDRESS)

• baseline phenotypic non-susceptiblity to ceftriaxone

• more than 1 calendar day beyond availability of susceptibility results

5. Follow up blood culture domain

Inclusion Criteria

• included in BALANCE+ platform

Exclusion Criteria

• patient died or discharged from hospital prior to day 4

• blood culture already collected by the treating team at day 4±1

• >5 days since index positive blood culture collection

• definite indication for repeat blood culture testing

• concomitant S. aureus bacteremia

• concomitant Candidemia

• clinical suspicion for infective endocarditis