What is the recommended treatment for Enterococci infections in patients with varying severity and potential antibiotic resistance patterns, considering factors such as age, underlying medical conditions, and impaired renal function?

Treatment of Enterococcal Infections

For enterococcal infections, ampicillin plus gentamicin remains the gold standard for susceptible strains, while linezolid or high-dose daptomycin are preferred for vancomycin-resistant enterococci (VRE), with treatment selection critically dependent on susceptibility patterns, infection site, and renal function. 1, 2

Treatment Algorithm Based on Susceptibility and Clinical Context

Penicillin, Vancomycin, and Aminoglycoside-Susceptible Enterococci

For endocarditis:

• Ampicillin 200 mg/kg/day IV in divided doses plus gentamicin 3 mg/kg/day IV/IM in 3 divided doses is the preferred regimen 1, 3
• Gentamicin should be dosed every 8 hours (not once daily) to achieve synergy, with target 1-hour serum concentration of approximately 3 μg/mL and trough <1 μg/mL 1
• Duration: 4 weeks for native valve endocarditis with symptoms <3 months; 6 weeks for symptoms ≥3 months or prosthetic valve endocarditis 1, 3
• Alternative: Penicillin G 24 million units/24h IV continuously or in 6 divided doses plus gentamicin 1, 3

For bacteremia (non-endocarditis):

• Ampicillin or penicillin alone is adequate for 10-14 days 1, 2
• Linezolid 600 mg IV/PO every 12 hours for 10-14 days is an alternative 1, 2

For urinary tract infections:

• Ampicillin 500 mg PO/IV every 8 hours for 5-7 days 1
• Amoxicillin 500 mg PO every 8 hours for 5-7 days 1
• Fosfomycin 3 g PO single dose or every other day for uncomplicated cystitis 1
• Nitrofurantoin 100 mg PO four times daily for 3-7 days 1

High-Level Aminoglycoside Resistance (HLAR)

For endocarditis with HLAR:

• Ampicillin 200 mg/kg/day IV plus ceftriaxone 4 g/day IV for 6 weeks is the treatment of choice for E. faecalis 3
• This dual beta-lactam regimen is superior to aminoglycoside-containing regimens and active against E. faecalis with or without HLAR 3
• Alternative: Ampicillin-sulbactam 12 g/24h IV in 4 divided doses for 6 weeks 1

For bacteremia with HLAR:

• Ampicillin or penicillin monotherapy for 10-14 days 4
• Linezolid 600 mg IV/PO every 12 hours for 10-14 days 1, 2

Beta-Lactamase-Producing Strains

• Ampicillin-sulbactam 12 g/24h IV in 4 divided doses plus gentamicin 3 mg/kg/day for 6 weeks for endocarditis 1
• Amoxicillin-clavulanate can substitute for ampicillin-sulbactam 3

Vancomycin-Resistant Enterococci (VRE)

For bacteremia and endocarditis:

• Linezolid 600 mg IV or PO every 12 hours is first-line therapy 1, 2, 5
• Duration: 10-14 days for bacteremia; ≥6 weeks for endocarditis 1, 2
• High-dose daptomycin 10-12 mg/kg IV daily is the alternative 1, 2
• For endocarditis: Daptomycin 10 mg/kg/day IV plus ampicillin 200 mg/kg/day IV for ≥8 weeks is preferred 3
• Combination therapy with daptomycin plus ampicillin or ceftaroline should be considered for persistent bacteremia or strains with daptomycin MIC ≥3 μg/mL 1, 3

For pneumonia:

• Linezolid 600 mg IV every 12 hours for at least 7 days 1

For intra-abdominal infections:

• Linezolid 600 mg IV every 12 hours for 5-7 days 1
• Tigecycline 100 mg IV loading dose, then 50 mg IV every 12 hours for 5-7 days 1

For urinary tract infections:

• Linezolid 600 mg IV/PO every 12 hours for 5-7 days 1
• Daptomycin 6-12 mg/kg IV daily for 5-7 days 1
• For uncomplicated cystitis: fosfomycin, nitrofurantoin, or ampicillin (if susceptible) 1

Multidrug-Resistant Enterococci (Penicillin, Aminoglycoside, and Vancomycin-Resistant)

For endocarditis:

• Linezolid 600 mg IV or orally every 12 hours for >6 weeks 1
• Daptomycin 10-12 mg/kg per dose IV for >6 weeks 1
• Quinupristin-dalfopristin 7.5 mg/kg IV every 8 hours for ≥8 weeks (NOT active against E. faecalis, only E. faecium) 3
• Mandatory infectious disease consultation 1, 3
• Cardiac valve replacement may be necessary for cure 1

Special Populations and Considerations

Patients with Impaired Renal Function

Critical principle: Avoid aminoglycoside-containing regimens in acute kidney injury due to significant nephrotoxicity risk 1, 2

Alternative regimens for renal impairment:

• Linezolid 600 mg IV/PO every 12 hours requires no renal dose adjustment and is the preferred option 1, 2
• Daptomycin requires dose adjustment based on creatinine clearance 2
• Short-course gentamicin therapy (2-3 weeks instead of 4-6 weeks) for endocarditis if aminoglycoside is essential 1
• Streptomycin instead of gentamicin may be considered if the strain is not highly streptomycin-resistant 1
• Double beta-lactam regimen (ampicillin plus ceftriaxone) for HLAR strains avoids aminoglycosides entirely 3

For patients with creatinine clearance <30 mL/min:

• Gentamicin therapy may not be safely completable for 4-6 weeks due to nephrotoxicity risk 1
• Vancomycin dosing must be adjusted: initial dose 15 mg/kg, then maintenance based on creatinine clearance (see dosing table) 6

Elderly Patients

• Greater dosage reductions of vancomycin than expected may be necessary due to decreased renal function 6
• Aminoglycoside monitoring is critical with weekly renal function checks 3
• Linezolid requires no dose adjustment but monitor for hematologic toxicity 2, 5

Pediatric Patients

For VRE infections:

• Linezolid 10 mg/kg IV/PO every 8 hours (for children <12 years) 5
• Vancomycin 10-15 mg/kg IV every 6-24 hours depending on age and renal clearance 5

For neonates:

• Vancomycin: initial dose 15 mg/kg, then 10 mg/kg every 12 hours for first week of life, every 8 hours thereafter up to 1 month 6
• Premature infants require longer dosing intervals due to decreased vancomycin clearance 6

Monitoring Requirements

Aminoglycoside Therapy

• Weekly monitoring of renal function and aminoglycoside levels 3
• Target gentamicin peak 3-4 μg/mL, trough <1 μg/mL 1, 3
• Dose adjustment to achieve 1-hour serum concentration of approximately 3 μg/mL 1

Vancomycin Therapy

• Target trough ≥20 mg/L for endocarditis 3
• AUC/MIC >400 recommended 3
• More frequent monitoring in elderly and renally impaired patients 6

Linezolid Therapy

• Weekly complete blood counts due to risk of thrombocytopenia and anemia with prolonged use (>2 weeks) 2, 5
• Monitor for peripheral neuropathy with prolonged therapy 2

Daptomycin Therapy

• Monitor creatinine phosphokinase (CPK) weekly for myopathy 2
• Consider combination with beta-lactams if MIC ≥3 μg/mL 1, 3

Critical Pitfalls and Caveats

Aminoglycoside dosing for enterococcal synergy:

• Gentamicin must be given in 2-3 divided doses daily, NOT once-daily dosing, for enterococcal endocarditis 1, 3
• Once-daily aminoglycoside dosing has not been proven effective for enterococcal synergy 1

High-level aminoglycoside resistance:

• High-level gentamicin resistance (MIC ≥2000 μg/mL) eliminates synergy with all aminoglycosides except potentially streptomycin 3, 4
• Testing for both gentamicin and streptomycin high-level resistance is essential 1, 3

Vancomycin monotherapy limitations:

• Vancomycin alone is bacteriostatic, not bactericidal, against enterococci 4, 7
• Combination with aminoglycoside is required for bactericidal effect in endocarditis 1, 4

Daptomycin considerations:

• Monotherapy with daptomycin for multidrug-resistant enterococcal endocarditis has insufficient data 1
• Combination with ampicillin or ceftaroline enhances efficacy, especially for strains with daptomycin MIC 3-4 μg/mL 1, 3

Linezolid limitations:

• Bone marrow suppression (thrombocytopenia, anemia) occurs with prolonged use 1, 2
• Peripheral neuropathy risk increases with duration >28 days 2
• Drug interactions are numerous due to monoamine oxidase inhibitor activity 1

Source control:

• Failure to achieve adequate source control (abscess drainage, device removal, valve replacement) leads to treatment failure regardless of antibiotic choice 2
• Cardiac surgery should be considered for enterococcal endocarditis, especially with VRE 1

Tigecycline caution:

• Low serum levels limit use in bacteremia and endocarditis 8
• Reserved for intra-abdominal infections when other options unavailable 1

Quinupristin-dalfopristin:

• NOT active against E. faecalis, only E. faecium 3
• Limited clinical data for enterococcal infections 8