What is the treatment approach for Carbapenem-Resistant Enterobacteriaceae (CRE) infections in an intensive care unit (ICU)?

Treatment of CRE Infections in the Intensive Care Unit

For severe CRE infections in the ICU, use meropenem-vaborbactam or ceftazidime-avibactam as monotherapy if the organism is susceptible in vitro; for metallo-β-lactamase (MBL) producers or organisms resistant to these newer agents, use cefiderocol or aztreonam plus ceftazidime-avibactam combination therapy. 1

First-Line Treatment Algorithm for Severe CRE Infections

Step 1: Identify Resistance Mechanism and Susceptibility Pattern

• Obtain antimicrobial susceptibility testing immediately to guide antibiotic selection, as genotypic characterization of resistance mechanisms is critical for treatment decisions 1
• Determine if the organism produces KPC, OXA-48, or metallo-β-lactamases (NDM, VIM), as this fundamentally changes treatment approach 2

Step 2: Select Initial Therapy Based on Resistance Profile

For KPC or OXA-48 producers (non-MBL):

• Use ceftazidime-avibactam 2.5 g IV every 8 hours infused over 3 hours as first-line monotherapy 1, 3
• Alternative: meropenem-vaborbactam 4 g IV every 8 hours 1
• Do NOT add combination therapy if the organism is susceptible to these agents, as combination therapy with newer β-lactam/β-lactamase inhibitors shows no mortality benefit and increases toxicity risk 1

For MBL producers (NDM, VIM) or organisms resistant to ceftazidime-avibactam and meropenem-vaborbactam:

• Use cefiderocol as monotherapy for severe infections 1
• Alternative: aztreonam plus ceftazidime-avibactam combination therapy (aztreonam is stable against MBLs, and ceftazidime-avibactam protects aztreonam from other β-lactamases) 1

Step 3: When Newer Agents Are Unavailable or Organism Is Pan-Resistant

For organisms susceptible only to older agents (polymyxins, aminoglycosides, tigecycline, fosfomycin):

• Use combination therapy with more than one in vitro active drug for severe infections 1
• Polymyxin-based combination therapy is recommended, with the companion drug selected based on susceptibility testing 1
• Evidence supports combination therapy particularly for high-risk patients (INCREMENT score 8-15), where two or more active antibiotics reduced 30-day mortality (adjusted HR 0.56,95% CI 0.34-0.91) 1

Avoid these regimens:

• Do NOT use carbapenem-based combination therapy unless meropenem MIC ≤8 mg/L, where high-dose extended-infusion meropenem (6 g/day over 3-hour infusions) may be added to polymyxin 1
• Do NOT use tigecycline for bloodstream infections or hospital-acquired/ventilator-associated pneumonia due to poor outcomes; if absolutely necessary for pneumonia, use high-dose tigecycline (100 mg loading, then 50 mg IV every 12 hours) 1

Site-Specific Treatment Considerations

Bloodstream Infections (BSI)

• Ceftazidime-avibactam 2.5 g IV every 8 hours is recommended for CRE-BSI 1
• Polymyxin-based combination therapy is an alternative when newer agents are unavailable 1
• Combination therapy should be based on susceptibility testing results 1

Complicated Intra-Abdominal Infections (cIAI)

• Ceftazidime-avibactam 2.5 g IV every 8 hours plus metronidazole for CRE cIAI 1, 3
• Alternative: Tigecycline 100 mg IV loading dose then 50 mg IV every 12 hours 1
• Alternative: Polymyxin-based combination therapy with companion drug based on susceptibility 1

Complicated Urinary Tract Infections (cUTI)

• Ceftazidime-avibactam 2.5 g IV every 8 hours 1, 3
• Meropenem-vaborbactam 4 g IV every 8 hours 1
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours 1
• Plazomicin 15 mg/kg IV every 12 hours 1
• For simple cystitis: single-dose aminoglycoside 1

Pneumonia (HAP/VAP)

• Use the same agents as for severe infections above, but avoid tigecycline monotherapy due to poor lung penetration and outcomes 1
• If tigecycline must be used, employ high-dose regimens 1

Critical Pitfalls to Avoid

• Never use monotherapy with polymyxins, tigecycline, or aminoglycosides for severe CRE infections when these are the only active agents—always use combination therapy with at least two in vitro active drugs 1, 4, 5
• Do not add unnecessary combination therapy to newer β-lactam/β-lactamase inhibitors (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol) when the organism is susceptible, as this provides no benefit and increases toxicity 1
• Avoid carbapenem monotherapy or standard-dose carbapenems for documented CRE infections unless using high-dose extended-infusion regimens with MIC ≤8 mg/L as part of combination therapy 1
• Do not use ceftriaxone or other third-generation cephalosporins for CRE, as they are completely ineffective 6

Special Considerations for ICU Patients

• Pharmacokinetic/pharmacodynamic optimization is critical in critically ill patients due to altered volume of distribution, renal function, and drug clearance 7
• For polymyxin-based regimens, loading doses are essential in the ICU setting to achieve therapeutic levels rapidly 7
• Source control is mandatory—no antibiotic regimen will succeed without adequate drainage of abscesses, removal of infected devices, or surgical intervention when indicated 4, 5
• Monitor for emergence of resistance during therapy, particularly with ceftazidime-avibactam monotherapy, where resistance can develop during treatment 4