Bacteremia, Gram-Negative (GNR-BSI) in Immunocompetent Adults

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.

This guideline does NOT apply to immunocompromised hosts (eg, Solid organ recipients; hematopoietic cell transplant recipients; patients actively receiving chemotherapy; expected prolonged neutropenia with ANC <500 cells/mL; recent CD4 count <200 cells/mL; chronic high dose corticosteroids (prednisone ≥20 mg/day or equivalent) and/or immunomodulatory therapy).

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Management of GN-BSI Guidance Document

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

Table 1. Criteria for Uncomplicated vs Complicated GN-BSI:

SSTI: Skin and soft tissue infection, CNS: central nervous system

Note: Pathogens with limited treatment options (e.g. Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia) including those with multidrug resistance may warrant ID consultation for treatment choice and duration decisions.

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 Custom ID Rapid Diagnostics page.  
   4. Clinical pharmacists may dose adjust (increase or decrease) antibiotics based on patient renal function. Full policy guidance and renal dose adjustments are located on CustomID.
2.  Repeat Blood Cultures: Repeat blood cultures to document clearance ONLY if at least ONE of the following are true:
   1. Complicated GN-BSI (See Table 1)
   2. Patients do NOT have appropriate clinical response within 72 hours of starting antibiotics (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 (>24 hours from when initial blood culture drawn) appropriate antibiotic therapy

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

3. Targeted Therapy: Adjust antibiotics based on antimicrobial susceptibility results to narrow spectrum agent (Table 2) UNLESS pathogen is known to have drug-resistance:  
   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 500 mg IV q6h (0.5 hr) or ertapenem 1 g IV once daily). ID approval is required.
   2. AmpC-producing: Patients with uncomplicated GN-BSI from ampC pathogens Enterobacter cloacae, 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, even if reported as susceptible.

           Table 2: De-escalating Antibiotic Therapy

 ^*See DUH CustomID for renal dose adjustments

^{^}Addition of metronidazole required for anaerobic coverage

4. Transition to Oral Therapy Considerations:
   1. Source control achieved
   2. Patient clinically improved on effective intravenous antibiotics within 48-72h (e.g., afebrile, leukocytosis improving)
   3. Patient has an intact and functional gastrointestinal tract
   4. Culture data demonstrates susceptibility to an appropriately dosed oral antibiotic (Table 3)
   5. Patients with GN-BSI due to ESBL- or AmpC-producing pathogens can be transitioned to oral fluoroquinolones or trimethoprim/sulfamethoxazole if they fulfill all other criteria above.

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

1. Cefdinir due to unfavorable pharmacokinetics and association with worse clinical outcomes.
2. Agents with limited systemic absorption or low serum levels (eg, fosfomycin, nitrofurantoin, doxycycline).

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

¹Patient- and pathogen-specific factors should be considered when selecting an oral transition agent for gram-negative bacteremia

²Alternative oral beta-lactam agents (i.e. cefuroxime 1g q12h, cefpodoxime 400mg q12h, and cefadroxil 1g q12h) are less preferred based on agent bioavailability, ability to achieve adequate serum concentrations, and/or limited clinical data. Use may be considered on a case-by-case basis in discussion with ID/ASET.

³Doses assume normal renal function. See DUH CustomID for renal dose adjustments.

^{^}Cefazolin susceptibility reported on urine culture does NOT predict susceptibility for GN-BSI due to use of different breakpoints. Use the cefazolin susceptibility from blood cultures to determine if oral cephalexin is active.

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

5. 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 and/or oral therapy
   2. 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.
   3. For patients with complicated GN-BSI, longer durations may be warranted, in agreement with existing indication-specific guidelines, documented blood clearance, and/or ID recommendation.
   4. In patients requiring outpatient parenteral antibiotic therapy, please consult ID to determine treatment plan prior to the day of discharge.