What are the treatment options and rates of endocarditis for Enterococcus infections with resistance mechanisms?

Enterococcus Resistance Mechanisms, Treatment, and Endocarditis Rates

Resistance Mechanisms

Enterococci exhibit multiple resistance mechanisms that critically impact treatment selection, with the most clinically significant being high-level aminoglycoside resistance (HLAR), beta-lactam resistance via altered penicillin-binding proteins or beta-lactamase production, and vancomycin resistance. 1

Key Resistance Patterns

• High-level aminoglycoside resistance (HLAR) occurs through plasmid-mediated aminoglycoside-modifying enzymes, with gentamicin resistance (MIC >500 mg/L) conferring cross-resistance to all aminoglycosides except potentially streptomycin 1

• Beta-lactam resistance develops through two mechanisms: beta-lactamase production (more common in E. faecalis) or altered penicillin-binding protein 5 (PBP5), with E. faecium typically showing MICs ≥16 μg/mL versus E. faecalis at 2-4 μg/mL 1

• Vancomycin resistance is increasingly problematic, with up to 95% of E. faecium strains expressing multidrug resistance, though only 3% of E. faecalis are multidrug-resistant 2

• All E. faecium are intrinsically resistant to amikacin, kanamycin, netilmicin, and tobramycin; E. faecalis often resist kanamycin and amikacin 1

Treatment of Enterococcal Endocarditis

Fully Susceptible Strains (No HLAR, Penicillin-Susceptible, Vancomycin-Susceptible)

For beta-lactam and gentamicin-susceptible enterococci, ampicillin 200 mg/kg/day IV in 4-6 divided doses plus gentamicin 3 mg/kg/day IV/IM in 1 dose for 4-6 weeks is the gold standard treatment. 1

• Native valve endocarditis: 4 weeks for symptoms <3 months, 6 weeks for symptoms ≥3 months 1

• Prosthetic valve endocarditis: minimum 6 weeks of therapy required 1

• Gentamicin duration can be shortened to 2 weeks in some cases, though full-course aminoglycoside therapy traditionally recommended 1

• Alternative: Penicillin G 24 million units/24h IV continuously or in 6 divided doses plus gentamicin with same duration 1

High-Level Aminoglycoside Resistance (HLAR)

For HLAR E. faecalis strains, the dual beta-lactam regimen of ampicillin 200 mg/kg/day IV in 4-6 doses plus ceftriaxone 4g/day IV in 2 doses for 6 weeks is the treatment of choice. 1

• This combination is active against E. faecalis with and without HLAR and is superior to aminoglycoside-containing regimens for these strains 1, 3

• Critical caveat: This regimen is NOT active against E. faecium 1

• If susceptible to streptomycin (despite gentamicin resistance), substitute streptomycin 15 mg/kg/day in 2 divided doses for gentamicin 1

Beta-Lactam Resistance

For beta-lactamase-producing strains, substitute ampicillin-sulbactam or amoxicillin-clavulanate for ampicillin. 1

For resistance due to PBP5 alteration, use vancomycin 30 mg/kg/day IV in 2 doses plus gentamicin 3 mg/kg/day for 6 weeks. 1

• Vancomycin requires 6 weeks (versus 4-6 for ampicillin) due to decreased activity against enterococci 1

• Vancomycin should be reserved for penicillin-allergic patients or beta-lactam-resistant strains 1

Multidrug-Resistant Enterococci (Vancomycin-Resistant)

For vancomycin-resistant enterococci, daptomycin 10 mg/kg/day IV plus ampicillin 200 mg/kg/day IV in 4-6 doses for ≥8 weeks is the preferred regimen. 1, 2

Alternative options include:

• Linezolid 600 mg IV/PO every 12 hours for ≥8 weeks (monitor for hematological toxicity) 1, 2

• Quinupristin-dalfopristin 7.5 mg/kg IV every 8 hours for ≥8 weeks (NOT active against E. faecalis) 1

• Dalbavancin shows promise but limited evidence for endocarditis 4

Species-Specific Considerations

E. faecalis: Ampicillin remains first-line as most strains retain susceptibility; only 3% are multidrug-resistant 2, 5

E. faecium: Intrinsic penicillin resistance is common; vancomycin or newer agents (linezolid, daptomycin) required as first-line therapy 2

Monitoring and Management

• Renal function and aminoglycoside levels: Monitor weekly (twice weekly in renal failure); target gentamicin peak 3-4 μg/mL, trough <1 μg/mL 1

• Vancomycin levels: Target trough ≥20 mg/L; AUC/MIC >400 recommended 1

• Infectious disease consultation: Mandatory for all enterococcal endocarditis cases as standard of care 1, 2

• Aminoglycosides should be given in 2-3 divided doses (not once daily) for enterococcal synergy, unlike other indications 1

Rates of Endocarditis

Enterococci cause 10-20% of all bacterial endocarditis cases. 6

• The genitourinary tract is often the portal of entry 6

• Enterococcal endocarditis typically responds to intravenous therapy, with cure rates comparable between 4-6 week regimens when appropriate antibiotics are used 1

• Treatment failure rates increase with inappropriate monotherapy, as enterococci are relatively resistant to penicillin alone (not bactericidal without aminoglycoside synergy) 1, 6

Critical Pitfalls to Avoid

• Never use cephalosporins alone for enterococcal coverage—they have no intrinsic activity despite synergy when combined with ampicillin 2

• Never use ampicillin monotherapy for endocarditis—combination therapy is required for bactericidal activity 1, 6

• Do not assume E. faecium has the same susceptibility as E. faecalis—species identification is critical for treatment selection 2

• Test susceptibility to both gentamicin AND streptomycin in all enterococcal endocarditis isolates, not other aminoglycosides 1

• Avoid aminoglycosides in patients with creatinine clearance <50 mL/min without dose adjustment and close monitoring 1