Guideline for the Management of Gram negative Bloodstream Infections in Immunocompetent Adults

Criteria & Principles

General Guidance

• Recommendations below are intended as a general guideline for management of GN-BSI to provide favorable clinical outcomes while minimizing unintended consequences. Patient-specific factors should influence decisions on agent, duration, and transition to oral therapy.
• These criteria do not apply to immunocompromised hosts [e.g., solid organ transplant recipients, hematopoietic stem cell transplant recipients, patients actively receiving chemotherapy, expected prolonged neutropenia with absolute neutrophil count < 500 cells/mL, recent CD4 count < 200 cells/mL, chronic high dose corticosteroids (equivalent to prednisone ≥ 20 mg/day), or immunomodulatory therapy]
• See Figure 1 summarizing key steps in decision-making through diagnostic and therapeutic management of GN-BSI.

Step 1: Evaluate clinical factors indicating complicated versus uncomplicated GN-BSI (Table 1). Determine the need for course control intervention and/or ID consult.

Step 2: Select empiric antibiotic(s) and, if indicated, document blood culture clearance.

1. Empiric Therapy
   1. Individual patient factors including severity of presentation (e.g., septic shock), previous antibiotic exposure, and previous culture data should be reviewed and utilized to guide empiric therapy.
   2. In patients with suspected intra-abdominal source or mixed soft tissue infection, metronidazole should be added to ceftriaxone, cefepime, aztreonam, or ciprofloxacin for anaerobic coverage. Piperacillin/tazobactam provides adequate coverage for obligate anaerobes as monotherapy.
   3. Empiric antibiotic therapy recommendations based on initial speciation from rapid diagnostics can be found on the Rapid Diagnostics page of CustomID.
   4. Clinical pharmacists may dose adjust (increase or decrease) antibiotics based on patient renal function. Full policy guidance and renal dosing adjustments can be found on the Adult Renal Dose Adjustment Policy page of CustomID.
2. Repeat Blood cultures: Repeat blood cultures to document clearance are recommended ONLY if at least ONE of the following are true:
   1. Complicated GN-BSI (see Table 1)
   2. Patient does NOT have appropriate clinical response within 72 hours of starting antibiotics (e.g., afebrile, hemodynamically stable, resolving leukocytosis)
   3. Endovascular infection or endocarditis
   4. Limited or no source control
   5. Hemodialysis
   6. Indwelling intravascular device, including cardiac devices
   7. Delayed appropriate antibiotic therapy, defined as > 24 hours from when initial blood culture was drawn

Step 3: Tailor antibiotic therapy and/or switch to an appropriately dosed oral agent based on susceptibility data and clinical response.

1. Targeted Therapy: Adjust antibiotics based on antimicrobial susceptibility results to a narrow spectrum agent (Table 2) UNLESS the pathogen is known to have the following drug resistance patterns:
   1. Extended-spectrum Beta-lactamase (ESBL)-producing: Enterobacterales that are intermediate or resistant to ceftriaxone are considered ESBL-producing and should be treated with a carbapenem (meropenem or ertapenem with ID consult approval).
   2. AmpC-producing: Patients with uncomplicated GN-BSI from ampC pathogens Enterobacter cloaecae, Klebsiella (Enterobacter) aerogenes, or Citrobacter freundii can be treated with cefepime when cefepime-susceptible and not cefepime-resistant or susceptible dose-dependent. Due to the risk of inducible beta-lactamase production, ceftriaxone and piperacillin/tazobactam are NOT recommended for GN-BSI with these organisms, even if reported as susceptible.

          

           *Addition of metronidazole required for anaerobic coverage

           See the Adult Renal Dose Adjustment Policy page for renal dose adjustments.

2. Transition to Oral Therapy Considerations​
   1. Source control achieved
   2. Patient clinically improved on effective intravenous antibiotics within 48-72 hours (e.g., afebrile, leukocytosis improving)
   3. Patient has an intact and functional gastrointestinal tract
   4. Culture data demonstrates susceptibility to an appropriate oral antibiotic (Table 3)
      
      1. Preferred oral agents are fluoroquinolones or trimethoprim/sulfamethoxazole (TMP/SMX) due to greater clinical data and optimal pharmacokinetics.
      2. Patients who cannot use fluoroquinolones or TMP/SMX due to contraindications or organism susceptibility patterns may receive appropriately dosed oral beta-lactam alternatives (Table 3). Switch to oral beta-lactams should occur after multiple days of initial IV therapy, and ideally include non-obese patients with uncomplicated GN-BSI from UTI source.
   5. Patients with GN-BSI due to ESBL- or ampC-producing pathogens can be transitioned to oral fluoroquinolones or TMP/SMX if they fulfill all other criteria above.

           NOTE: The following oral agents should NOT be used for GN-BSI:

• Cefadroxil, cefpodoxime, or cefdinir due to unfavorable pharmacokinetics and/or spectrum of activity
• Agents with limited systemic absorption or low serum levels (e.g., fosfomycin, nitrofurantoin, doxycycline)

Table 3: Suggested Oral Antibiotic Therapy (consult pharmacy for patient-specific dosing recommendations and for patients with obesity)

See the Adult Renal Dose Adjustment Policy page for renal dose adjustments.

Step 4: Determine appropriate duration of therapy based on antibiotic agent, infection source, and route.

1. Duration of Therapy: 7 days of active therapy for uncomplicated GN-BSI
   1. Uncomplicated GN-BSI should be treated with a 7-day total course of effective IV, oral fluoroquinolone, or SMX/TMP.
   2. If using appropriately dosed oral beta-lactam alternatives, a longer duration of therapy may be considered based on indication and patient-specific factors.
   3. For uncomplicated GN-BSI, day 1 is the first day of therapy on an antibiotic to which the pathogen was susceptible. For patients requiring source control interventions, day 1 is the day of source control or first day of effective therapy, whichever came last.
   4. For patients with complicated GN-BSI, longer durations may be warranted, in agreement with existing indication-specific guidelines, documented blood clearance, and/or ID recommendations.
   5. In patients requiring outpatient parenteral antibiotic therapy, please consult ID to determine the treatment plan prior to the day of discharge.