What is the drug of choice for treating Carbapenemase-producing Escherichia coli (E. coli)?

Treatment of Carbapenemase-Producing E. coli

For carbapenemase-producing E. coli, ceftazidime-avibactam 2.5 g IV every 8 hours (infused over 2-3 hours) is the drug of choice for KPC and OXA-48 producers, while metallo-β-lactamase (MBL) producers require mandatory combination therapy with ceftazidime-avibactam PLUS aztreonam. 1, 2

Treatment Algorithm Based on Carbapenemase Type

For KPC-Producing E. coli (Most Common)

• First-line: Ceftazidime-avibactam 2.5 g IV every 8 hours infused over 2-3 hours 1, 2
• Alternative options include:
  • Meropenem-vaborbactam 4 g IV every 8 hours 1, 2
  • Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours 2

The evidence supporting ceftazidime-avibactam is robust: observational studies show 182 fewer deaths per 1000 patients treated compared to traditional therapies (RR 0.55,95% CI 0.42-0.72), with 307 fewer treatment failures and significantly lower acute kidney injury rates 1. Clinical and microbiological cure rates reached 70-76% for E. coli specifically 3.

For OXA-48-Like Producing E. coli

• Ceftazidime-avibactam 2.5 g IV every 8 hours remains the preferred agent 1, 2
• Avibactam effectively inhibits OXA-48 carbapenemases, with genotypic testing confirming activity in 97.2% of isolates carrying these enzymes 3

For Metallo-β-Lactamase (MBL) Producers (NDM, VIM, IMP)

• Mandatory combination: Ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam 1, 2, 4
• This combination is critical because:
  • Aztreonam is not hydrolyzed by MBLs but is inactivated by co-produced ESBLs 4
  • Ceftazidime-avibactam protects aztreonam from ESBL degradation 1
  • Combination therapy showed significantly lower 30-day mortality (19.2% vs 44%) compared to other regimens 1, 4

Critical pitfall: Never use ceftazidime-avibactam monotherapy for MBL producers—avibactam has no activity against Class B metallo-β-lactamases 2

When Newer Agents Are Unavailable

If ceftazidime-avibactam or other novel β-lactam/β-lactamase inhibitors are not available:

High-Dose Carbapenem Combination Therapy

• High-dose meropenem 6 g/day via 3-hour infusion PLUS polymyxin for KPC producers when meropenem MIC ≤16 mg/L 1
• This strategy showed association with lower 14-day mortality in retrospective cohorts, though evidence certainty is low 1

Double-Carbapenem Regimen

• Ertapenem PLUS meropenem may be considered for KPC producers with high carbapenem MICs 1, 5
• Rationale: ertapenem's higher affinity for carbapenemases may "consume" the enzyme, allowing meropenem activity 1
• Clinical effectiveness maintained even with MEM MICs of 256-512 μg/mL in observational data 5
• Evidence remains insufficient and requires careful patient selection 1

Traditional Combination Therapy

• Polymyxin-based combinations (colistin or polymyxin B) plus at least one other active agent 1
• For severe sepsis/septic shock: combination therapy reduces mortality (35.7% vs 55.5%) compared to monotherapy 2
• Other potential combination partners: tigecycline, aminoglycosides, fosfomycin 6, 7

Combination Therapy Considerations

Monotherapy with newer agents is generally preferred for most infections, reserving combination therapy for specific high-risk scenarios: 2

• Severe sepsis or septic shock at presentation 2
• Pneumonia or other deep-seated infections 1
• Patients with INCREMENT score 8-15 (high mortality risk) 1
• When using polymyxins or tigecycline as primary agents 1

Moderate-certainty evidence supports that treatment with more than one in vitro active antibiotic improves outcomes in high-risk patients 1.

Dosing and Administration Optimization

• Prolonged infusion (3 hours) of ceftazidime-avibactam is independently associated with 30-day survival 1
• Ensure appropriate renal dose adjustments for all agents 2
• For imipenem-cilastatin-relebactam, dose reduction required based on creatinine clearance 2

Treatment Duration by Infection Type

• Bloodstream infections: 7-14 days based on clinical response 2
• Respiratory tract infections: typically 7 days for uncomplicated cases 2
• Complicated urinary tract infections: 5-21 days depending on severity 3

Critical Pitfalls to Avoid

• Never use first or second-generation cephalosporins against E. coli with carbapenemases due to intrinsic resistance mechanisms 2
• Avoid third-generation cephalosporins as monotherapy—high likelihood of resistance development during therapy 2
• Do not use tigecycline monotherapy for bloodstream infections—use newer β-lactam/β-lactamase inhibitors or combination therapy 2
• Avoid piperacillin-tazobactam for carbapenem-resistant strains, particularly with high inoculum infections 1

Carbapenem-Sparing Strategies

In settings with high carbapenem resistance rates, reserve novel β-lactams for patients with documented CRE colonization or upon rapid molecular identification of carbapenemase genes 1. This targeted approach preserves these critical agents and prevents further resistance development 1.

Rapid Diagnostic Testing

Strongly recommend rapid molecular testing to identify specific carbapenemase types before initiating therapy, as time from culture collection to active antibiotic therapy directly influences mortality in critically ill patients 1. Knowledge of the molecular mechanism (KPC vs OXA-48 vs MBL) is crucial because each requires different treatment strategies 1.