How do you treat patients with Carbapenem-Resistant Enterobacteriaceae (CRE) positive infections?

Treatment of Carbapenem-Resistant Enterobacteriaceae (CRE) Infections

For patients with CRE infections, treatment should be based on the specific infection site, with newer β-lactam/β-lactamase inhibitor combinations (ceftazidime-avibactam or meropenem-vaborbactam) as the preferred agents for severe infections when active in vitro. 1

Treatment Algorithm Based on Infection Site

Bloodstream Infections (BSI)

1. First-line options:

   • Ceftazidime-avibactam 2.5g IV q8h (infused over 3h) 1
   • Meropenem-vaborbactam 4g IV q8h 1
   • Imipenem-cilastatin-relebactam 1.25g IV q6h 1

2. Alternative options (if newer agents unavailable or resistant):

   • Polymyxin-based combination therapy:
     • Colistin 5mg CBA/kg IV loading dose, then 2.5mg CBA (1.5 CrCl + 30) IV q12h plus
     • Tigecycline 100mg IV loading dose, then 50mg IV q12h OR
     • Meropenem 1g IV q8h by extended infusion (if MIC ≤8 mg/L) 1

Complicated Urinary Tract Infections (cUTI)

1. First-line options:

   • Ceftazidime-avibactam 2.5g IV q8h 1, 2
   • Meropenem-vaborbactam 4g IV q8h 1
   • Imipenem-cilastatin-relebactam 1.25g IV q6h 1
   • Plazomicin 15mg/kg IV q12h 1, 2

2. Alternative options:

   • Aminoglycosides (if susceptible):
     • Gentamicin 5-7mg/kg/day IV once daily 1
     • Amikacin 15mg/kg/day IV once daily 1, 2

3. For simple cystitis due to CRE:

   • Single-dose aminoglycoside 1

Complicated Intra-abdominal Infections (cIAI)

1. First-line options:

   • Ceftazidime-avibactam 2.5g IV q8h plus metronidazole 500mg IV q6h 1
   • Tigecycline 100mg IV loading dose, then 50mg IV q12h 1
   • Eravacycline 1mg/kg IV q12h 1

2. Alternative options:

   • Polymyxin-based combinations (as above) 1

Pneumonia

1. First-line options:

   • Ceftazidime-avibactam or meropenem-vaborbactam (if active in vitro) 1

2. If only tigecycline is an option:

   • Use high-dose tigecycline (not as monotherapy) 1

Treatment Duration

• Bloodstream infections: 7-14 days 1
• Complicated UTI: 5-7 days 1
• Complicated intra-abdominal infections: 5-7 days 1

Combination vs. Monotherapy Recommendations

1. For newer agents (when susceptible):

   • Ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol can be used as monotherapy 1

2. For severe infections with limited options:

   • Use combination therapy with two in vitro active drugs 1
   • For metallo-β-lactamase producers: Consider aztreonam plus ceftazidime-avibactam 1

3. For non-severe infections:

   • Monotherapy with an active agent based on susceptibility testing is appropriate 1

Important Clinical Considerations

• Infectious disease consultation is highly recommended for management of CRE infections 1

• Antimicrobial susceptibility testing is crucial for guiding treatment selection 1

• Avoid tigecycline monotherapy for bloodstream infections and pneumonia 1

• Carbapenem-based combinations should generally be avoided unless the meropenem MIC is ≤8 mg/L, where high-dose extended-infusion meropenem may be part of combination therapy 1

• Prolonged infusion of β-lactams is recommended for pathogens with high MICs 1

• Treatment outcomes are significantly better with newer agents like ceftazidime-avibactam compared to colistin (hospital mortality 9% vs 32%) 3

Pitfalls and Caveats

• CRE infections have high mortality rates, especially with inappropriate empirical therapy 1

• Resistance mechanisms vary (KPC, NDM, OXA-48), affecting treatment options 4

• Tigecycline achieves low serum and urinary concentrations, limiting its use for bloodstream and urinary tract infections 1

• Colistin has significant nephrotoxicity and neurotoxicity risks 5

• Resistance to newer agents can develop during treatment, requiring close monitoring 1

• Combination therapy selection should be guided by susceptibility testing results 1

By following this treatment algorithm based on infection site and severity, clinicians can optimize outcomes for patients with these challenging multidrug-resistant infections.