What is the treatment for carbapenem-resistant Enterobacteriaceae (CRE) infections?

Treatment for Carbapenem-Resistant Enterobacteriaceae (CRE) Infections

Ceftazidime-avibactam 2.5g IV every 8 hours is the recommended first-line treatment for carbapenem-resistant Enterobacteriaceae (CRE) infections, with the specific regimen tailored to the infection site and susceptibility testing results. 1, 2

First-Line Treatment Options

Based on Infection Site:

1. Bloodstream Infections (BSI):

   • Ceftazidime-avibactam-based therapy 1
   • Polymyxin-based combination therapy with carbapenem 1
   • Treatment duration: 10-14 days 2

2. Complicated Urinary Tract Infections (cUTI):

   • Ceftazidime-avibactam 2.5g IV q8h 1
   • Meropenem-vaborbactam 4g IV q8h or imipenem-cilastatin-relebactam 1.25g IV q6h 1
   • Plazomicin 15 mg/kg IV q12h as an alternative 1
   • Single-dose aminoglycoside for simple cystitis 1
   • Treatment duration: 7-14 days 2

3. Complicated Intra-abdominal Infections (cIAI):

   • Ceftazidime-avibactam 2.5g IV q8h plus metronidazole 1
   • Tigecycline 100mg IV loading dose then 50mg IV q12h or eravacycline 1mg/kg IV q12h 1
   • Treatment duration: 5-14 days 2

4. Pneumonia:

   • Colistin (polymyxin E) with or without carbapenems 1
   • Consider adjunctive inhaled colistin for pneumonia 1
   • Treatment duration: 7-14 days 2

Combination Therapy Approaches

1. Aminoglycoside-containing combinations:

   • Recommended for CRE infections when susceptible 1
   • May improve cure rates and reduce mortality 1
   • Monitor renal function closely and avoid other nephrotoxic drugs 1
   • Perform therapeutic drug monitoring (TDM) when available 1

2. Fosfomycin-containing combinations:

   • Recommended when CRE isolate is susceptible to fosfomycin or synergistic effect is demonstrated 1
   • Avoid in patients with hypernatremia, cardiac or renal insufficiency 1

3. Ceftazidime-avibactam combinations:

   • Combination with aztreonam shows synergistic activity against metallo-β-lactamase producers 3
   • Combination with meropenem may be effective against highly resistant strains 3

Special Considerations

1. Prolonged infusion of β-lactams:

   • Recommended for pathogens with high MICs 1
   • High-dose extended-infusion meropenem (2g IV q8h as 3-hour infusion) when appropriate 2

2. Therapeutic Drug Monitoring (TDM):

   • Strongly recommended for polymyxins, aminoglycosides, and carbapenems 1, 2
   • Particularly important in:
     • Drugs with narrow therapeutic index
     • Patients with organ dysfunction
     • Difficult-to-reach infection sites
     • Severe infections like BSI and sepsis 1

3. Infectious Disease Consultation:

   • Highly recommended for management of CRE infections 1

Resistance Mechanisms and Treatment Selection

CRE may produce different carbapenemases that affect treatment choices:

• KPC producers: Ceftazidime-avibactam, meropenem-vaborbactam effective 4, 5
• NDM producers (metallo-β-lactamases): Consider ceftazidime-avibactam plus aztreonam 3, 5
• OXA-48 producers: Ceftazidime-avibactam effective 4, 5

Monitoring Response

• Assess clinical response within 48-72 hours of initiating therapy 2
• If no improvement after 72 hours, consider source control issues 2
• Adjust therapy based on susceptibility testing results 1

Pitfalls and Caveats

1. Avoid tigecycline monotherapy for CRE pneumonia due to poor outcomes 1

2. Resistance development is a concern with newer agents; use combination therapy for severe infections 4

3. Susceptibility testing is crucial before initiating therapy, as resistance patterns vary widely 1

4. Polymyxins (colistin) have significant nephrotoxicity; monitor renal function closely 2

5. Double carbapenem therapy (often ertapenem plus another carbapenem) may be considered for KPC-producing Enterobacteriaceae when other options are limited 6

By following this structured approach based on infection site, susceptibility patterns, and patient factors, clinicians can optimize treatment outcomes for these challenging infections.