What is the recommended treatment approach for infections caused by drug-resistant Gram-negative bacilli?

Treatment of Drug-Resistant Gram-Negative Bacilli

Combination therapy with polymyxin plus another in vitro active antibiotic is strongly recommended as the preferred treatment approach for severe infections caused by drug-resistant Gram-negative bacilli (DRGNB), particularly for carbapenem-resistant organisms. 1

Classification and Treatment Approach

Carbapenem-Resistant Enterobacterales (CRE)

1. First-line options for severe infections:

   • Meropenem-vaborbactam or ceftazidime-avibactam if active in vitro (conditional recommendation) 1
   • For metallo-β-lactamase producers resistant to other options: cefiderocol (conditional recommendation) 1

2. For non-severe infections:

   • Use older antibiotics that show in vitro activity based on individual susceptibility testing 1
   • For urinary tract infections: aminoglycosides (including plazomicin) preferred over tigecycline 1

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

1. For severe infections:

   • Combination therapy with two in vitro active antibiotics (polymyxin, aminoglycoside, tigecycline, sulbactam combinations) (conditional recommendation) 1, 2
   • Avoid: polymyxin-meropenem or polymyxin-rifampin combinations (strong recommendation against) 1, 2

2. For CRAB with meropenem MIC ≤8 mg/L:

   • Consider high-dose extended-infusion carbapenem as part of combination therapy 1, 2

3. For sulbactam-susceptible CRAB:

   • Ampicillin-sulbactam is conditionally recommended 2

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• Combination therapy with polymyxin plus another active agent 1
• Consider extended-infusion of β-lactams for pathogens with high MICs 1

Specific Antimicrobial Considerations

Polymyxins (Colistin/Polymyxin E)

• Dosing: Pay attention to correct conversion of dosage units 1

  • 1 million U = 80 mg mass CMS = 33 mg colistin base activity (CBA)
  • Polymyxin B sulfate: 1 mg = 10,000 U
  • Colistin sulfate: 1 mg = 22,700 U

• Monitoring:

  • Therapeutic drug monitoring (TDM) strongly recommended 1
  • Close monitoring of renal function due to nephrotoxicity risk 2
  • Avoid combining with other nephrotoxic or ototoxic drugs 1

Tigecycline

• Avoid as monotherapy for CRAB infections (strong recommendation) 2
• Avoid for bloodstream infections and HAP/VAP 1
• If necessary for pneumonia, consider high-dose regimen 1

Cefiderocol

• Avoid for CRAB infections (conditional recommendation against) 2
• Consider for metallo-β-lactamase-producing CRE with limited options 1

Treatment Duration

• Uncomplicated gram-negative bacteremia: 7 days (non-inferior to 14 days) 3
• Complicated urinary tract and intra-abdominal infections: 5-10 days 2
• Ventilator-associated/hospital-acquired pneumonia and complicated bloodstream infections: 10-14 days 2

Antimicrobial Stewardship Considerations

1. Synergy testing:

   • Consider antimicrobial synergy testing to determine in vitro activity and synergistic effects of combinations 1
   • Methods include checkerboard assay, time-killing curve, broth disc elution, and MTS methods 1

2. Therapeutic drug monitoring:

   • Implement TDM for polymyxins, aminoglycosides, and other antibiotics used against DRGNB 1
   • TDM-guided gentamicin treatment associated with shorter hospital stays, lower mortality rates, and reduced nephrotoxicity compared to non-TDM-guided treatment 1

3. Extended infusions:

   • For meropenem, consider extended infusion (3 hours) to optimize pharmacokinetics, especially for pathogens with higher MICs 1, 4

Common Pitfalls and Caveats

1. Resistance development:

   • Resistance to carbapenems may emerge during treatment of P. aeruginosa infections 5
   • Stenotrophomonas maltophilia is typically resistant to both imipenem and meropenem 5

2. Inappropriate empiric therapy:

   • Mortality rates up to 86.1% reported in CRAB-infected patients receiving inappropriate empiric antimicrobial therapy 2
   • The greatest benefit of combination therapy stems from increased likelihood of choosing an effective agent during empiric therapy 6

3. Tigecycline limitations:

   • Low serum concentrations compromise its use in bloodstream infections 7
   • Poor results in ventilator-associated pneumonia studies 7

4. Colistin considerations:

   • Clarification of PK/PD profile and appropriate dosing is urgent 7
   • Development of resistance must be carefully monitored 7

Remember that treatment decisions should be guided by local resistance patterns, and antimicrobial susceptibility testing is essential for optimizing therapy against drug-resistant Gram-negative bacilli.