What is the recommended treatment for patients infected with Carbapenem-resistant Enterobacteriaceae (CRE)?

Treatment of Carbapenem-Resistant Enterobacteriaceae (CRE) Infections

For severe CRE infections, use meropenem-vaborbactam or ceftazidime-avibactam as first-line monotherapy if the organism is susceptible in vitro. 1

Treatment Algorithm by Infection Severity and Resistance Mechanism

Severe Infections (BSI, HAP/VAP, Septic Shock)

KPC-producing CRE:

• First-line: Ceftazidime-avibactam 2.5 g IV q8h OR meropenem-vaborbactam 4 g IV q8h 1
• For pneumonia specifically, consider meropenem-vaborbactam as preferred choice due to superior lung penetration (63-65% ELF concentrations, consistently exceeding MIC90) 1
• Alternatives: Imipenem-relebactam or cefiderocol (limited clinical data) 1
• Do NOT use combination therapy with these newer agents unless resistance develops 1

OXA-48-producing CRE:

• First-line: Ceftazidime-avibactam 2.5 g IV q8h 1

Metallo-β-lactamase (MBL)-producing CRE:

• First-line: Ceftazidime-avibactam 2.5 g IV q8h PLUS aztreonam (combination therapy required) 1
• Alternative: Cefiderocol (conditional recommendation, lower quality evidence) 1

Pan-resistant CRE (susceptible only to polymyxins/aminoglycosides/tigecycline):

• Use polymyxin-based combination therapy with more than one active agent in vitro 1
• Avoid carbapenem-based combinations unless meropenem MIC ≤8 mg/L, where high-dose extended-infusion meropenem may be used as part of combination 1

Non-Severe Infections

Complicated Urinary Tract Infections (cUTI):

• Preferred: Ceftazidime-avibactam 2.5 g IV q8h 1
• Alternatives: Meropenem-vaborbactam 4 g IV q8h OR imipenem-cilastatin-relebactam 1.25 g IV q6h 1
• For simple cystitis: Single-dose aminoglycoside 1
• Alternative for cUTI: Plazomicin 15 mg/kg IV q12h or aminoglycosides for short duration 1

Complicated Intra-abdominal Infections (cIAI):

• Ceftazidime-avibactam 2.5 g IV q8h PLUS metronidazole 1
• Alternatives: Tigecycline 100 mg IV loading then 50 mg IV q12h OR eravacycline 1 mg/kg IV q12h 1
• Polymyxin-based combination therapy based on susceptibility testing 1

Low-risk, non-severe infections:

• Use older antibiotics active in vitro on individual basis according to source of infection 1
• For cUTI: aminoglycosides (including plazomicin) preferred over tigecycline 1

Critical Prescribing Considerations

Tigecycline restrictions:

• Do NOT use for bloodstream infections or HAP/VAP 1
• If necessary for pneumonia, use high-dose tigecycline only 1

Infectious disease consultation:

• Strongly recommended for all MDRO infections 1

Prolonged infusion strategy:

• Use extended infusions of β-lactams for pathogens with high MIC 1

Antibiotic stewardship:

• Reserve new β-lactam/β-lactamase inhibitor combinations for CRE; avoid using them for third-generation cephalosporin-resistant Enterobacterales that remain carbapenem-susceptible 1

Common Pitfalls to Avoid

• Do not combine ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol with other antibiotics for susceptible CRE (strong recommendation against combination) 1
• Avoid tigecycline monotherapy for bloodstream infections due to suboptimal serum concentrations 1
• Do not use carbapenem-based combinations for CRE unless specific MIC criteria met (meropenem MIC ≤8 mg/L) 1
• Be aware of ceftazidime-avibactam resistance emergence (0-12.8% in KPC producers); consider meropenem-vaborbactam if KPC variants (D179Y) suspected 1
• Monitor for meropenem-vaborbactam adverse effects including seizures (especially with CNS disorders or renal impairment), rhabdomyolysis, and thrombocytopenia 2