What is the recommended treatment for complicated infections caused by multi-drug resistant Gram-negative bacteria according to Infectious Diseases Society of America (IDSA) guidelines?

Treatment of Multi-Drug Resistant Gram-Negative Bacterial Infections According to IDSA Guidelines

For severe infections caused by carbapenem-resistant Enterobacterales (CRE), meropenem-vaborbactam or ceftazidime-avibactam should be used as first-line therapy if the organism is susceptible in vitro. 1

Treatment Recommendations by Pathogen Type

Carbapenem-Resistant Enterobacterales (CRE)

Severe Infections

• First-line options:

  • Meropenem-vaborbactam (conditional recommendation, moderate evidence) 1
  • Ceftazidime-avibactam (conditional recommendation, low evidence) 1
  • Dosing: Ceftazidime-avibactam 2.5g IV q8h 1

• For CRE with metallo-β-lactamases (MBL):

  • Cefiderocol (conditional recommendation, low evidence) 1
  • Ceftazidime-avibactam plus aztreonam combination (conditional recommendation, moderate evidence) 1
    • This combination has shown significant reduction in 30-day mortality (HR 0.37,95% CI 0.13-0.74) in patients with MBL-producing CRE bacteremia 1

• For CRE susceptible only to polymyxins, aminoglycosides, tigecycline or fosfomycin:

  • Combination therapy with at least two in vitro active drugs (conditional recommendation, moderate evidence) 1
  • Avoid carbapenem-based combinations unless meropenem MIC ≤8 mg/L 1

Non-Severe Infections

• Use monotherapy with older antibiotics if active in vitro, selected based on infection site 1
• For complicated UTI: Aminoglycosides (including plazomicin) preferred over tigecycline 1
• Duration: 7-14 days for bloodstream infections, 5-7 days for other infections 1

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

Severe Infections

• First-line option:

  • Ceftolozane-tazobactam if active in vitro (conditional recommendation, very low evidence) 1
  • Insufficient evidence for imipenem-relebactam, cefiderocol, and ceftazidime-avibactam 1

• For CRPA treated with polymyxins, aminoglycosides, or fosfomycin:

  • Combination therapy with two in vitro active drugs (conditional recommendation, very low evidence) 1

Non-Severe Infections

• Use monotherapy with older antibiotics if active in vitro, selected based on infection site 1

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

Severe Infections

• For CRAB susceptible to sulbactam:

  • Ampicillin-sulbactam (conditional recommendation, low evidence) 1

• For CRAB resistant to sulbactam:

  • Polymyxin (colistin) with or without carbapenems for pneumonia (weak recommendation, low evidence) 1
  • Polymyxin-carbapenem combination for bloodstream infections (weak recommendation, low evidence) 1
  • High-dose tigecycline may be considered if active in vitro 1

• Not recommended:

  • Cefiderocol (conditional recommendation against, low evidence) 1
  • Tigecycline monotherapy for pneumonia (strong recommendation against, low evidence) 1
  • Polymyxin-meropenem or polymyxin-rifampin combinations (strong recommendation against, high/moderate evidence) 1

Special Considerations

Combination vs. Monotherapy

• Monotherapy is recommended for:

  • CRE infections treated with ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol (strong recommendation, low evidence) 1
  • Non-severe infections (good practice statement) 1

• Combination therapy is recommended for:

  • MBL-producing CRE (ceftazidime-avibactam plus aztreonam) 1
  • CRE susceptible only to older agents like polymyxins, aminoglycosides, tigecycline, or fosfomycin 1
  • Severe CRPA infections treated with polymyxins, aminoglycosides, or fosfomycin 1

Infection Site-Specific Considerations

• Bloodstream infections:

  • Avoid tigecycline (conditional recommendation, low evidence) 1
  • Longer treatment duration (7-14 days) 1

• Complicated UTI:

  • Aminoglycosides preferred (including plazomicin) 1
  • Shorter treatment duration (5-7 days) 1

• Intra-abdominal infections:

  • Ceftazidime-avibactam plus metronidazole 1
  • Tigecycline or eravacycline can be considered 1

• Pneumonia:

  • High-dose tigecycline if necessary 1
  • Adjunctive inhaled colistin for CRAB pneumonia 1

Clinical Pitfalls and Caveats

1. Resistance development: Development of resistance to ceftazidime-avibactam has been reported in 3.8-10.4% of patients with KPC-producing CRE infections, regardless of monotherapy or combination therapy use 1

2. Nephrotoxicity risk: Polymyxin-based regimens have significantly higher nephrotoxicity compared to newer agents like ceftazidime-avibactam 2

3. MBL detection: Proper identification of MBL-producing organisms is crucial as they require specific treatment approaches (ceftazidime-avibactam plus aztreonam or cefiderocol) 1

4. Dosing considerations: Extended-infusion of meropenem (3 hours) and appropriate renal dose adjustments for ceftazidime-avibactam are associated with improved outcomes 1

5. Mortality impact: Ceftazidime-avibactam-based therapy has been associated with 66-67% reduction in 14-day and 28-day mortality compared to polymyxin-based therapy for CRE infections 2

The evidence supporting these recommendations varies in quality, with most being conditional recommendations based on low or very low quality evidence. The strongest evidence exists for combination therapy approaches in MBL-producing CRE and against certain combinations for CRAB infections.