What is the preferred treatment for Ventilator-Associated Pneumonia (VAP) caused by carbapenem-resistant Enterobacteriaceae (CRE): high-dose meropenem with colistin or ceftazidime (Ceftazidime)/avibactam with aztreonam?

Treatment of VAP Caused by CRE: Ceftazidime-Avibactam Plus Aztreonam is Superior

For ventilator-associated pneumonia caused by carbapenem-resistant Enterobacteriaceae, ceftazidime-avibactam combined with aztreonam is the preferred treatment over high-dose meropenem with colistin, particularly when metallo-β-lactamase production is confirmed or suspected. This recommendation is based on significantly lower 30-day mortality (19.2% vs 44%) and superior clinical outcomes compared to colistin-based regimens 1.

Carbapenemase Type Determines Optimal Therapy

The critical first step is identifying the carbapenemase mechanism whenever possible before treatment initiation 1:

For MBL-Producing CRE (NDM, VIM, IMP)

• Ceftazidime-avibactam 2.5g IV q8h (infused over 2 hours) PLUS aztreonam is the strongly recommended regimen 1
• This combination achieves 30-day mortality of 19.2% versus 44% with alternative therapies including colistin-based regimens 1
• The mechanistic rationale: aztreonam is not hydrolyzed by metallo-β-lactamases, while avibactam protects aztreonam from co-produced ESBLs and AmpC enzymes 1, 2
• ESCMID provides a conditional recommendation with moderate-quality evidence for this combination in severe MBL-producing CRE infections 1

For KPC or OXA-48-Producing CRE (Non-MBL)

• Ceftazidime-avibactam 2.5g IV q8h as monotherapy is preferred 1
• Nearly 100% of KPC-producing and OXA-48-producing CRE strains are susceptible to ceftazidime-avibactam 1
• Combination therapy is NOT recommended when the organism is susceptible to ceftazidime-avibactam alone 1

Why High-Dose Meropenem Plus Colistin is Inferior

• Colistin-based regimens showed the highest mortality rates in comparative studies of MBL-producing CRE infections 1
• Meropenem-colistin combinations demonstrated only 25% synergism, 15.4% additive effect, and 59.6% indifference in vitro against carbapenem-resistant K. pneumoniae VAP isolates 3
• Carbapenem-based combination therapy should be avoided for CRE infections unless meropenem MIC is ≤8 mg/L, and even then only if newer β-lactam/β-lactamase inhibitors are unavailable 1
• Colistin versus ceftazidime-avibactam studies show adjusted 30-day mortality of 32% versus 9%, respectively (difference 23%, P=0.001) 4

Practical Implementation Algorithm

Step 1: Obtain carbapenemase genotyping or phenotypic testing immediately 1

Step 2: Initiate empiric therapy based on local epidemiology:

• If MBL prevalence >20% in your institution: Start ceftazidime-avibactam 2.5g IV q8h PLUS aztreonam 1
• If predominantly KPC/OXA-48: Start ceftazidime-avibactam 2.5g IV q8h alone 1

Step 3: De-escalate once carbapenemase type confirmed:

• If KPC or OXA-48 confirmed: Discontinue aztreonam, continue ceftazidime-avibactam monotherapy 1
• If MBL confirmed: Continue both agents 1

Step 4: Treatment duration is 7-14 days for VAP 5

Critical Pitfalls to Avoid

• Never use aztreonam monotherapy for MBL-producing organisms—it will fail due to co-produced ESBLs and AmpC enzymes 2, 6
• Monitor for resistance emergence: 3.8-10.4% of patients develop ceftazidime-avibactam resistance during treatment; obtain repeat cultures if clinical deterioration occurs within 48-72 hours 6
• Do not add polymyxins or fosfomycin to the ceftazidime-avibactam/aztreonam combination—the dual β-lactam regimen alone demonstrates superior outcomes 6
• Avoid tigecycline for VAP—it is specifically not recommended for pneumonia due to inadequate lung penetration 1

Alternative Option: Cefiderocol

• Cefiderocol may be considered as an alternative with conditional recommendation and low-quality evidence 1
• Clinical cure rates of 75% (12/16) in MBL-producing CRE subgroup from CREDIBLE-CR trial 1
• 96% of carbapenem-resistant K. pneumoniae VAP isolates were sensitive to cefiderocol in recent studies 3
• However, concerns exist regarding high MIC values and risk of treatment-emergent resistance 1

Resistance Patterns Requiring Awareness

• High rates of resistance to ceftazidime-avibactam (79%) have been reported in some VAP cohorts with NDM-producing organisms 3
• Bla NDM is the most prevalent carbapenemase gene (50%), followed by bla OXA-48 (36.5%), then bla KPC (11.5%) in VAP isolates 3
• All carbapenem-resistant K. pneumoniae VAP isolates in recent studies were resistant to ceftolozane-tazobactam 3