Evaluating treatment strategies 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 culture finalization 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 transitioning patient 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 of oral/enteral therapy:
   * no-de-escalation arm (patients in the no de-escalation arm cannot be randomized into this domain unless they are ready for discharge home, in which case de-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 culture finalization
3. Central vascular catheter replacement domain

   Inclusion Criteria
   * included in BALANCE+ platform
   * 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
   * 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 o concomitant S. aureus bacteremia

     * concomitant candidemia
   * 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)
4. Low-risk AmpC domain

   Inclusion Criteria
   * included in BALANCE+ platform
   * positive blood culture with GN bacterium, of the following species: i. Serratia spp. ii Morganella spp. iii Providencia spp. iv Proteus spp. other than P.mirabilis
   * organism is susceptible to ceftriaxone

   Exclusion Criteria

   \- severe allergy to beta-lactams (e.g., type 4 hypersensitivity reaction or DRESS)
   * 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 o concomitant S. aureus bacteremia o concomitant Candidemia o clinical suspicion for infective endocarditis
6. 4 day versus 7-day antibiotic duration

   Inclusion Criteria • improving clinical trajectory, based on meeting all of these criteria by the 4th calendar day of adequate antibiotics:

   o temperature 35.0ºC-37.9ºC

   o not on vasopressors

   o FiO2 ≤ 50%

   Exclusion Criteria

   • Has not undergone successful source control (if required) before completing 4th calendar day of adequate antibiotics

   • Neutropenia (\<0.5 × 10⁹/L)
   * solid organ or bone marrow transplantation
   * suspected or documented deep-seated infection requiring prolonged antibiotics