What are the recommended oral and intravenous antibiotics, dosing regimens, and monitoring for vancomycin‑resistant Enterococcus (VRE) infections?

Treatment of Vancomycin-Resistant Enterococcus (VRE) Infections

First-Line Antibiotic Selection

For VRE bacteremia and serious systemic infections, use high-dose daptomycin (≥9 mg/kg IV once daily) as first-line therapy, as it demonstrates superior mortality outcomes compared to standard dosing (6-9 mg/kg), with an adjusted odds ratio of 0.26 (95% CI 0.09-0.74) for 30-day mortality. 1, 2, 3 Linezolid 600 mg IV or PO every 12 hours is an equally acceptable first-line alternative, achieving microbiological cure rates of 86.4% and clinical cure rates of 81.4%. 4, 1, 2

Bacteremia Treatment Algorithm

• Start with high-dose daptomycin 10-12 mg/kg IV once daily for VRE bacteremia, particularly in critically ill patients or those with immunosuppression 2, 3
• Add a β-lactam (ampicillin 2 g IV q4-6h, ceftaroline, or meropenem) to daptomycin when the MIC is ≤2 mg/L, as combination therapy reduces 30-day mortality by approximately 77% 1, 2
• Switch to linezolid 600 mg IV/PO q12h if the patient is on serotonergic medications (SSRIs, SNRIs, tricyclics, bupropion), as daptomycin carries no risk of serotonin syndrome 5, 2
• Avoid daptomycin doses of 6-9 mg/kg, as these standard doses are associated with significantly higher mortality compared to both linezolid and high-dose daptomycin 3

Duration of Therapy for Bacteremia

Clinical Scenario	Treatment Duration
Uncomplicated bacteremia (no metastatic focus, no device)	10-14 days [2]
Profound immunosuppression (transplant, neutropenia)	4-6 weeks [2]
Persistent bacteremia >72 hours	4-6 weeks minimum + investigate for endocarditis [2]
Endocarditis or deep-seated abscess	6 weeks minimum [2]

Urinary Tract Infection Treatment

Uncomplicated VRE Cystitis (Oral First-Line Options)

For uncomplicated VRE cystitis, prioritize oral agents that achieve high urinary concentrations rather than systemic agents. 5, 2

• Fosfomycin 3 g PO single dose is the preferred first-line agent for uncomplicated VRE UTI 4, 5, 2
• Nitrofurantoin 100 mg PO every 6 hours for 5-7 days is an effective alternative 4, 5, 2
• High-dose ampicillin (18-30 g IV daily in divided doses) or amoxicillin 500 mg PO/IV every 8 hours can be used even for ampicillin-resistant strains due to high urinary concentrations 4, 2

Complicated VRE UTI or Pyelonephritis (Systemic Therapy Required)

• Linezolid 600 mg IV or PO every 12 hours is the preferred systemic option, with clinical cure rates of 63% in urinary tract infections 5, 2
• High-dose daptomycin 8-12 mg/kg IV daily should be used when bacteremia is present or suspected 5, 2

Intra-Abdominal Infections

Tigecycline 100 mg IV loading dose followed by 50 mg IV q12h is recommended specifically for intra-abdominal infections due to VRE, with treatment duration based on clinical response. 4, 1 However, tigecycline must be avoided for VRE bacteremia despite in-vitro susceptibility, as it achieves poor serum concentrations and is linked to treatment failures in bloodstream infections. 1, 2

Critical Monitoring Requirements

For High-Dose Daptomycin (8-12 mg/kg)

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

For Linezolid

• Monitor for serotonin syndrome symptoms every 4-6 hours during the first 72 hours when used in patients on serotonergic medications, including neuromuscular hyperactivity, autonomic instability, and mental status changes 5, 2
• Monitor for thrombocytopenia in patients receiving courses >14-21 days 6
• Obtain informed consent before initiating linezolid in patients on multiple serotonergic medications, explicitly discussing the risk of serotonin syndrome 5

Essential Clinical Pitfalls to Avoid

• Do not treat VRE colonization or asymptomatic bacteriuria—differentiate true infection from colonization before initiating antibiotics 1, 2, 7
• Remove central venous catheters or other potential sources of persistent infection immediately 1, 2
• Never use tigecycline for VRE bacteremia, regardless of in-vitro susceptibility 1, 2
• Perform transesophageal echocardiography when bacteremia persists >72 hours or when central lines/ECMO cannulas are present to rule out endocarditis 2
• Obtain susceptibility testing before initiating therapy, as approximately 60% of E. faecium are vancomycin-resistant with variable ampicillin susceptibility 5, 2
• Do not use standard-dose daptomycin (6-9 mg/kg) for VRE bacteremia, as it is associated with significantly worse outcomes than both linezolid and high-dose daptomycin 3

Alternative and Investigational Agents

Quinupristin/dalfopristin and tigecycline should be evaluated case-by-case due to concerns about toxicity, resistance, and insufficient supportive data. 7 Quinupristin/dalfopristin has bacteriostatic activity against vancomycin-resistant E. faecium but is not active against E. faecalis, and myalgia/arthralgia is the most frequent treatment-limiting adverse effect. 6