Uncomplicated Gram-Negative Bacteremia in Adults

How is uncomplicated gram-negative bacteremia defined?

Generally, consider infections that meet ALL FOUR of the following criteria as uncomplicated gram-negative bacteremia:¹

• Criteria 1: bacteremia secondary to one of the following types of infections:¹
  • urinary tract
  • intra-abdominal or biliary
  • catheter-related
  • pneumonia WITHOUT structural lung disease, empyema/abscess, or cystic fibrosis
  • skin and soft tissue
• Criteria 2: source control (See row “What is the role of source control?”) (See exceptions in row “Which infections are more likely to be considered complicated?”)¹
• Criteria 3: patients WITHOUT immunocompromise and risk for an opportunistic infection^1,a,b
• Criteria 4: clinical improvement within 72 hours of receiving appropriate antibiotic treatment (e.g., afebrile, hemodynamic stability)¹

Which infections are more likely to be considered complicated?

• Some infections may be considered complicated, regardless of source control. Examples of complicated infections even with source control may include:¹
  • bone and joint
  • central nervous system (CNS)
  • endovascular (e.g., endocarditis, infected pacemaker, septic thrombophlebitis)

What is the role of source control?

• Source control consists of the following:¹
  • removal of infected hardware, catheters, or devices
  • drainage of infected fluid collections (e.g., abscess)
  • assurance of no residual or metastatic sites of infection (as appropriate) via methods such as imaging

Which IV antibiotics are usually recommended for uncomplicated gram-negative bacteremia?

• To guide IV antibiotic choice, consider C&S results, MICs, infection source, patient-specifics (e.g., renal function, allergies) in addition to following available facility protocols. Examples of IV antibiotics and dosing used to treat gram-negative bacteremia based on the causative pathogen include:^2,5,6,15,16
  • E. coli or Klebsiella: ceftriaxone 2 g IV every 24 hours. See our Beta-Lactam Allergy: FAQs, for options in patients with penicillin allergies.
    • ESBL-producing pathogens (often resistant to ceftriaxone): ertapenem 1 g IV every 24 hours
  • Pseudomonas aeruginosa (extended infusions given over about four hours): cefepime 2 g IV every eight hours, piperacillin/tazobactam 4.5 g IV every eight hours, or meropenem 1 g IV every eight hours
  • Other less common pathogens (e.g., Citrobacter, Enterobacter cloacae, Serratia marcescens): cefepime extended infusion 2 g IV every 8 to 12 hours (if susceptible to ceftriaxone and ceftazidime)

What is an appropriate duration of treatment for uncomplicated gram-negative bacteremia?

• Use seven days of antibiotics for most patients with uncomplicated gram-negative bacteremia.^3,4,7
• Clinical outcomes and microbiological cure seem similar whether using seven days of antibiotics or 14 days of antibiotics to treat uncomplicated gram-negative bacteremia [Evidence Level A-1].^1,3,4,14
  • Consider day one as the first day of effective therapy (e.g., the first day of antibiotics with coverage of the identified pathogen).¹
    • However, even with antibiotics that cover the pathogen, if patients do not improve until source control is achieved, day one should be the day source control is achieved.¹
  • Most data are in infections due to Enterobacterales (e.g., Escherichia coli, Klebsiella [including ESBL-producing pathogens]), but there are some data supporting seven days of antibiotics for uncomplicated gram-negative bacteremia due to Pseudomonas.^1,14
• Reducing antibiotic treatment duration for uncomplicated gram-negative bacteremia may be an important antimicrobial stewardship intervention.¹⁴ Some evidence suggests shorter antibiotics courses may reduce the emergence of multidrug-resistant gram-negative bacteria.⁷

When are oral antibiotics appropriate to treat uncomplicated gram-negative bacteremia?

• Transitioning to oral antibiotics can reduce unnecessary IV lines and potential complications and may be associated with a reduced length of stay for patients with uncomplicated gram-negative bacteremia.¹³
• It may be appropriate to transition to oral antibiotics in patients with uncomplicated gram-negative bacteremia if the following criteria are met:^1,6
  • Improving clinically on IV antibiotics. (Note that if a patient is initially started on oral therapy and is improving clinically, oral therapy can be continued.)
  • Confirmed source of the infection.
  • C&S indicates sensitivity to available oral antibiotics.
  • Patient has an intact, functional gastrointestinal tract (e.g., able to tolerate oral intake, no concern for absorption issues).

Which oral antibiotics may be appropriate to treat uncomplicated gram-negative bacteremia?

• To guide oral antibiotic choice, consider C&S results, infection source, patient-specifics, and possible adverse effects.
• Preferred oral antibiotics for uncomplicated gram-negative bacteremia usually include:^1,6,8,9
  • Fluoroquinolones(e.g., ciprofloxacin 750 mg PO bid, levofloxacin 750 mg PO once daily)^1,11
    • May reduce chance of infection recurrence compared to beta-lactams.⁸
    • Gram-negative coverage usually outweighs possible risks associated with fluoroquinolones due to the short duration of therapy.
  • TMP/SMX (e.g., 2 double strength tablets PO BID or 8 to10 mg/kg/day [TMP] PO divided in 2 or 3 doses.
    • Consider which patients may NOT be appropriate for treatment with TMP/SMX (e.g., first trimester of pregnancy, CrCl <15 mL/min) and possible side effects, such as hyperkalemia.⁵
• Oral beta-lactams are usually NOT considered first-line oral step-down therapy due to lower bioavailability and potential for inadequate serum concentrations relative to the MIC and necessary dosing frequency.^1,9,11,12
  • However, data are growing to support oral beta lactam use to complete antibiotic treatment in some cases of gram-negative bacteremia (e.g., gram-negative bacteremia from urinary source).^9,10
  • If considering use of an oral beta-lactam, consult an infectious disease specialist or work with the antibiotic stewardship team to ensure appropriate choice and dose. Specific considerations may include bioavailability, source of infection, identified pathogen, MIC (if available or possibly surrogate MIC if necessary).¹²
    • High beta-lactam doses may be necessary (e.g., cephalexin PO 1,000 mg every 6 hours, amoxicillin/clavulanate 875/125 mg PO every 8 hours).^6,12,15
  • Due to concerns about meeting pharmacokinetic targets for gram-negative infections., the following beta-lactams should NOT be routinely recommended as oral step-down therapy for uncomplicated gram-negative bacteremia: cefadroxil, cefpodoxime, cefprozil, cefuroxime, and cefdinir.^1,12

What is the role for repeat blood cultures in uncomplicated gram-negative bacteremia?

• Repeat blood cultures are not needed to confirm successful treatment in most cases of uncomplicated gram-negative bacteremia.¹
• Repeat blood cultures may be helpful in patients:¹
  • who are NOT responding clinically within 72 hours of starting antibiotics.
  • when there is concern for an endovascular infection (e.g., endocarditis).
  • with limited or no source control.