What is the recommended treatment approach for Carbapenem-Resistant Enterobacteriaceae (CRE) infections?

Treatment of Carbapenem-Resistant Enterobacteriaceae (CRE) Infections

For CRE infections, ceftazidime-avibactam 2.5g IV every 8 hours (infused over 3 hours) is the preferred first-line agent when the isolate is susceptible, with meropenem-vaborbactam 4g IV every 8 hours or imipenem-cilastatin-relebactam 1.25g IV every 6 hours as equally effective alternatives. 1

Site-Specific Treatment Algorithms

Bloodstream Infections

• First choice: Ceftazidime-avibactam 2.5g IV every 8 hours infused over 3 hours for 7-14 days 1, 2
• Alternative options: Meropenem-vaborbactam 4g IV every 8 hours OR imipenem-cilastatin-relebactam 1.25g IV every 6 hours 1
• When newer agents unavailable: Polymyxin-based combination therapy with colistin (5mg CBA/kg IV loading dose, then 2.5mg CBA × [1.5 × CrCl + 30] IV every 12 hours) PLUS either tigecycline (100mg IV loading, then 50mg IV every 12 hours) OR meropenem 1g IV every 8 hours by extended infusion 1
• Duration: 7-14 days based on clinical response and source control 1

Complicated Urinary Tract Infections (cUTI)

• First-line agents: Ceftazidime-avibactam 2.5g IV every 8 hours, meropenem-vaborbactam 4g IV every 8 hours, OR imipenem-cilastatin-relebactam 1.25g IV every 6 hours 1
• Alternative for cUTI: Plazomicin 15mg/kg IV every 12 hours 1
• For simple cystitis only: Single-dose aminoglycoside (gentamicin 5-7mg/kg/day IV OR amikacin 15mg/kg/day IV) 1
• Duration: 5-7 days for cUTI 1

Complicated Intra-Abdominal Infections (cIAI)

• Preferred: Ceftazidime-avibactam 2.5g IV every 8 hours PLUS metronidazole 500mg IV every 6 hours 1
• Alternatives: Imipenem-cilastatin-relebactam 1.25g IV every 6 hours OR tigecycline (100mg IV loading, then 50mg IV every 12 hours) OR eravacycline 1mg/kg IV every 12 hours 1
• Salvage therapy: Polymyxin-based combinations as described above 1
• Duration: 5-7 days with adequate source control 1

Hospital-Acquired/Ventilator-Associated Pneumonia

• Treatment duration: 10-14 days 1
• Agent selection: Follow bloodstream infection algorithm above 1

Critical Management Principles

Mandatory Actions

• Obtain infectious disease consultation immediately for all CRE infections 1, 3
• Base all therapy on antimicrobial susceptibility testing results before finalizing treatment 1
• Use prolonged infusion of β-lactams (infuse over 3 hours) for pathogens with high MICs 1
• Perform therapeutic drug monitoring for polymyxins, aminoglycosides, and carbapenems when used 2

Combination Therapy Considerations

• Combination therapy is NOT routinely recommended for CRE infections unless the patient is critically ill or has limited treatment options 1, 4
• When combining agents: Select based on susceptibility testing and consider synergy testing when available 1, 2
• For severe illness with polymyxins: Always use combination therapy (polymyxin + tigecycline OR polymyxin + meropenem) rather than monotherapy 1

Agents to Absolutely Avoid

• Never use tigecycline monotherapy for CRE pneumonia (strong recommendation) 1
• Never use tigecycline for bloodstream infections or CNS infections due to inadequate serum/CSF concentrations 2, 3
• Avoid aminoglycoside monotherapy except for simple cystitis or uncomplicated UTI 1

Resistance Concerns and Monitoring

Ceftazidime-Avibactam Resistance

• Risk factors: Prior ceftazidime-avibactam exposure, which can select for KPC-3 gene mutations 1
• "See-saw effect": Mutant KPC-3 enzymes may restore meropenem susceptibility while developing ceftazidime-avibactam resistance 1
• Consider combination therapy (ceftazidime-avibactam + carbapenem or colistin) for KPC-3 producers in high-risk patients 1

Carbapenemase Type Matters

• KPC and OXA-48 producers: Ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam are effective 1, 4, 5, 6
• Metallo-β-lactamase (MBL) producers: Newer β-lactam/β-lactamase inhibitors are INEFFECTIVE; must use polymyxin-based regimens 5, 7
• Class A and C carbapenemases: All newer agents remain active 1, 4

Common Pitfalls to Avoid

• Do not use carbapenems empirically without susceptibility data, as this drives further resistance 8, 4
• Monitor for nephrotoxicity and ototoxicity when using aminoglycosides or polymyxins, and avoid combining multiple nephrotoxic agents 2, 3
• Adjust all dosing for renal function: Colistin dosing formula is 2.5mg CBA × (1.5 × CrCl + 30) IV every 12 hours after loading dose 1
• Do not underdose β-lactams: Use extended infusions (3 hours) for meropenem when MIC ≥8 mg/L 1