What are the recommended antibiotic regimens for treating vancomycin‑resistant Enterococcus (VRE) infections in adults, including options for uncomplicated urinary tract infection, bacteremia, endocarditis, and intra‑abdominal infections?

Treatment for Vancomycin-Resistant Enterococcus (VRE) Infections

For serious VRE infections including bacteremia, pneumonia, and complicated intra-abdominal infections, linezolid 600 mg IV or PO every 12 hours is the first-line therapy, achieving clinical cure in approximately 81% of patients and microbiological cure in 86%. 1, 2

Site-Specific Treatment Algorithm

Uncomplicated VRE Cystitis (Lower UTI)

First-line oral therapy:

• Fosfomycin 3 g PO as a single dose is the preferred agent, achieving high urinary concentrations that reliably eradicate VRE 1, 2, 3
• Nitrofurantoin 100 mg PO every 6 hours for 5–7 days is an equally effective alternative 4, 1, 3
• High-dose ampicillin (18–30 g IV daily in divided doses) or amoxicillin 500 mg PO/IV every 8 hours can overcome even ampicillin-resistant VRE due to urinary concentrations exceeding the MIC 4, 1, 3

Treatment duration: 3–7 days for uncomplicated cystitis 1

Complicated VRE UTI or Pyelonephritis

• Linezolid 600 mg IV or PO every 12 hours for 5–7 days is the preferred systemic agent 1, 2
• High-dose daptomycin 8–12 mg/kg IV daily can be considered, particularly when bacteremia is suspected or confirmed 1, 3

Critical pitfall to avoid: Tigecycline should never be used for VRE UTI or any suspected upper tract infection due to poor urinary and serum concentrations despite its large volume of distribution 1, 2

VRE Bacteremia

Preferred regimens:

• High-dose daptomycin ≥9 mg/kg/day (optimally 10–12 mg/kg/day) is associated with significantly lower mortality (adjusted OR 0.26,95% CI 0.09–0.74) compared to standard dosing 1, 2
• Linezolid 600 mg IV or PO every 12 hours is an equally acceptable first-line option with 30-day mortality comparable to daptomycin 1, 2

Combination therapy consideration:

• When daptomycin MIC is ≤2 mg/L, adding a β-lactam (ampicillin 2 g IV q4–6h, ceftaroline, or meropenem) to daptomycin reduces 30-day mortality by approximately 77% 1

Duration:

• 10–14 days for uncomplicated bacteremia (no metastatic focus, no device-related infection) 1
• 4–6 weeks for persistent bacteremia (>72 hours), endocarditis, or metastatic infection 1

Essential action: If blood cultures remain positive after 72 hours of appropriate therapy, perform transesophageal echocardiography to rule out endocarditis and investigate for undrained abscesses or device-related infection 1

VRE Endocarditis

• Minimum 6 weeks of combination antimicrobial therapy is mandatory 1, 2
• Cardiac surgery consultation is required, as surgery combined with combination antibiotic therapy improves survival outcomes 4, 1
• High-dose daptomycin (10–12 mg/kg/day) plus a β-lactam is the preferred regimen given the need for bactericidal activity 1

Key consideration: Vancomycin-resistant E. faecium endocarditis is associated with higher mortality and longer bacteremia duration compared to vancomycin-resistant E. faecalis 4

VRE Pneumonia

• Linezolid 600 mg IV every 12 hours for a minimum of 7 days is the recommended agent due to excellent lung penetration 1, 2

VRE Complicated Intra-Abdominal Infections

When bacteremia is absent:

• Linezolid 600 mg IV every 12 hours for 5–7 days (guided by clinical response and source control adequacy) 1, 2
• Tigecycline 100 mg IV loading dose, then 50 mg IV every 12 hours is an acceptable alternative for intra-abdominal infections without bacteremia 4, 1

Critical error to avoid: Never use tigecycline when bacteremia is present or suspected, as poor serum concentrations lead to high treatment failure rates 1, 2

Essential Pre-Treatment Considerations

Before initiating anti-VRE therapy:

• Differentiate VRE colonization from true infection, as unnecessary treatment drives resistance and increases costs 4, 1, 2
• Obtain susceptibility testing, since approximately 60% of E. faecium are vancomycin-resistant with variable ampicillin susceptibility 1, 2
• Remove central venous catheters or other foreign bodies and ensure adequate surgical drainage of closed-space infections 1, 2

Safety Monitoring Requirements

For linezolid:

• Monitor for serotonin syndrome symptoms every 4–6 hours during the first 72 hours, especially in patients on SSRIs, SNRIs, tricyclic antidepressants, or bupropion 1, 2
• Monitor for thrombocytopenia in patients receiving >14–21 days of therapy 5

For high-dose daptomycin:

• Monitor creatine kinase (CK) levels, though meta-analyses show no significantly increased risk of CK elevation with high-dose regimens 1, 2
• Monitor for rhabdomyolysis, neuropathy, and eosinophilic pneumonia 1

Agents to Avoid

• Ceftaroline has poor activity against enterococcus and should not be used empirically for VRE 4, 2
• Tigecycline for bacteremia or suspected upper tract infection due to inadequate serum concentrations 1, 2
• Standard-dose daptomycin (6 mg/kg) is insufficient for VRE bacteremia; doses of 10–12 mg/kg are required 1

High-Risk Populations

For profoundly immunosuppressed patients (transplant recipients, ECMO):

• Extend therapy to 4–6 weeks analogous to other immunocompromised hosts 1
• High-dose daptomycin (10–12 mg/kg IV once daily) is preferred as first-line for critically ill patients 1