What are the recommended antibiotic regimens for Enterococcus and Staphylococcus aureus (Staph aureus) infections, including Methicillin-resistant Staphylococcus aureus (MRSA)?

Antibiotic Coverage for Enterococcus and Staphylococcus aureus

For Enterococcus infections requiring bactericidal therapy, use ampicillin plus ceftriaxone rather than ampicillin plus gentamicin, as this combination is non-inferior for efficacy and significantly reduces nephrotoxicity. For MRSA infections, use vancomycin 15-20 mg/kg IV every 8-12 hours for serious infections, or oral agents (TMP-SMX, clindamycin, or doxycycline) for uncomplicated skin and soft tissue infections.

Enterococcus Coverage

First-Line Regimens

For serious Enterococcus faecalis infections (endocarditis, bacteremia):

• Ampicillin plus ceftriaxone is now the preferred combination over ampicillin plus gentamicin, showing non-inferior efficacy with significantly lower nephrotoxicity (OR 0.45, p=0.0182) and fewer drug withdrawals due to adverse events (OR 0.11, p=0.0160) 1
• Ampicillin alone demonstrates bactericidal activity against 60% of enterococcal strains at achievable serum concentrations 2
• When combined with gentamicin, ampicillin achieves 100% bactericidal activity, compared to 90% when combined with streptomycin 2

Alternative Regimens for Resistant Strains

For ampicillin-resistant enterococci:

• Vancomycin alone shows striking inhibitory activity but poor bactericidal activity at achievable concentrations 2
• Vancomycin combined with an aminoglycoside substantially increases bactericidal activity 2
• For strains with high-level gentamicin resistance (up to 50% of isolates at some centers), streptomycin can be substituted if the strain is not highly streptomycin-resistant 3

For multidrug-resistant enterococci (ampicillin and vancomycin-resistant):

• Linezolid 600 mg IV/PO every 12 hours achieved 67% cure rates in vancomycin-resistant enterococcal infections, compared to 52% with lower doses 4
• Daptomycin demonstrated superior efficacy compared to vancomycin in experimental models of penicillin-resistant enterococcal endocarditis 5
• For strains highly resistant to both streptomycin and gentamicin, ampicillin, penicillin, or vancomycin alone would be expected to cure some patients, though no agent is predictably bactericidal 3

Critical Caveat for Intra-Abdominal Infections

Empiric enterococcal coverage is NOT necessary for community-acquired intra-abdominal infections 6. However, ampicillin should be added to regimens (such as ceftriaxone-metronidazole) that otherwise lack enterococcal coverage in severe cases 6.

Staphylococcus aureus Coverage

MRSA Treatment Algorithm

For serious MRSA infections (bacteremia, pneumonia, complicated skin infections):

• Vancomycin is the first-line IV agent, though the 2024 WHO guidelines note it was excluded from empiric recommendations for intra-abdominal infections due to being more suitable for targeted therapy 6
• Linezolid 600 mg IV/PO every 12 hours achieved 79% cure rates for MRSA skin infections, compared to 73% with vancomycin 4
• Daptomycin 4 mg/kg/day IV is an alternative for complicated infections 7

For uncomplicated MRSA skin and soft tissue infections (outpatient oral therapy):

• TMP-SMX 1-2 double-strength tablets (160/800 mg) twice daily is preferred for purulent cellulitis 7
• Clindamycin 300-450 mg three times daily provides dual coverage for MRSA and beta-hemolytic streptococci, making it ideal for nonpurulent cellulitis 7
• Doxycycline 100 mg twice daily is an effective alternative to TMP-SMX 7, 8
• Duration: 5-10 days for uncomplicated infections, 7-14 days for complicated infections 7

Critical resistance consideration: Clindamycin should only be used when local MRSA clindamycin resistance rates are <10%, and inducible resistance exists in erythromycin-resistant MRSA strains 7

MSSA Treatment

For methicillin-susceptible S. aureus:

• Beta-lactams (oxacillin, nafcillin) remain the drugs of choice for serious infections
• For skin infections, oxacillin 2g IV every 6 hours followed by dicloxacillin 500 mg PO every 6 hours achieved 85% cure rates 4
• Clindamycin 30-40 mg/kg/day in 3-4 doses (pediatric) or 300-450 mg three times daily (adult) is appropriate for oral therapy 9, 7

Special Clinical Scenarios

For osteomyelitis (MRSA):

• TMP-SMX 4 mg/kg/dose twice daily combined with rifampin 600 mg once daily, OR
• Linezolid 600 mg twice daily, OR
• Clindamycin 600 mg every 8 hours
• Minimum 8-week course required 7

For MRSA pneumonia:

• Vancomycin 15-20 mg/kg IV every 8-12 hours, OR
• Linezolid 600 mg twice daily (IV or PO), OR
• Clindamycin 600 mg three times daily (if stable without bacteremia) 7

For necrotizing fasciitis with streptococcal toxic shock:

• Clindamycin 600-900 mg IV every 8 hours combined with penicillin, due to superior toxin suppression 9

Critical Pitfalls to Avoid

• Never use beta-lactam antibiotics alone for MRSA—they are completely ineffective 7
• Never use rifampin as monotherapy—resistance develops rapidly 7
• Failure to drain abscesses leads to treatment failure regardless of antibiotic choice 7
• Ampicillin-sulbactam is not recommended for intra-abdominal infections due to high E. coli resistance rates 6
• Aminoglycosides are not recommended for routine use in adults with community-acquired intra-abdominal infection due to toxicity 6
• Vancomycin was excluded from empiric treatment recommendations by WHO 2024 guidelines for intra-abdominal infections, reserved for targeted MRSA therapy 6