What antibiotics are recommended for treating Staphylococcus (Staph) aureus and Streptococcus (Strep) infections?

Antibiotic Selection for Staphylococcus and Streptococcus Infections

For methicillin-susceptible Staphylococcus aureus (MSSA) and Streptococcus infections, use cefazolin (1-2g IV every 8 hours) or cephalexin (500mg PO every 6 hours) as first-line therapy; for methicillin-resistant Staphylococcus aureus (MRSA) with Streptococcus coverage, clindamycin (600mg IV every 8 hours or 300-450mg PO four times daily) is the single best agent that covers both pathogens. 1, 2

Methicillin-Susceptible Staphylococcus aureus (MSSA) and Streptococcus

First-Line Agents

• Cefazolin is the preferred intravenous agent at 0.5-1g every 8 hours for mild-moderate infections or 1-2g every 8 hours for severe infections 1
• Cephalexin 500mg every 6 hours orally is recommended for outpatient treatment of skin and soft tissue infections 1
• Antistaphylococcal penicillins (nafcillin or oxacillin 2g every 6 hours IV) remain guideline-recommended but cefazolin demonstrates equivalent or superior outcomes with better tolerability 1, 3, 4

Evidence Supporting Cefazolin Over Flucloxacillin

• A large retrospective cohort of 7,312 MSSA bacteremia episodes showed no mortality difference between flucloxacillin (11.2%) and cefazolin (10.7%), with propensity-adjusted analysis favoring cefazolin (aOR 0.86) 3
• Cefazolin causes significantly fewer adverse events requiring discontinuation (0% vs 13% with flucloxacillin) 4

Penicillin Allergy Considerations

• For non-anaphylactic penicillin allergy, first-generation cephalosporins remain appropriate 5
• For type 1 hypersensitivity (anaphylaxis, urticaria, angioedema, bronchospasm), cephalosporins are contraindicated and clindamycin should be used 1, 5

Methicillin-Resistant Staphylococcus aureus (MRSA) with Streptococcus Coverage

Single-Agent Coverage for Both Pathogens

• Clindamycin is the only single agent providing excellent coverage against both MRSA and all Streptococcus species 1, 2
• Adult dosing: 600mg IV every 8 hours for severe infections or 300-450mg PO four times daily for mild-moderate infections 1, 6, 2
• Pediatric dosing: 10-13 mg/kg/dose IV every 6-8 hours (maximum 40 mg/kg/day) or 30-40 mg/kg/day PO divided into 3-4 doses 6, 2

Critical Clindamycin Limitations

• Only use when local MRSA clindamycin resistance rates are <10% 6, 2
• Perform D-zone testing for inducible clindamycin resistance in erythromycin-resistant MRSA strains before using for serious infections 6, 2

Alternative Combination Therapy

• TMP-SMX (160-800mg PO every 12 hours) plus amoxicillin (500mg PO every 8 hours) provides dual coverage when clindamycin resistance is present 2
• Doxycycline (100mg PO every 12 hours) plus amoxicillin is another combination option 2
• These combinations are necessary because TMP-SMX and tetracyclines lack reliable Streptococcus coverage as monotherapy 2

Severe/Invasive MRSA Infections

Parenteral Options

• Vancomycin 15-20 mg/kg/dose IV every 8-12 hours (target trough 15-20 mcg/mL for serious infections) 1, 2, 7
• Daptomycin 6 mg/kg IV every 24 hours for bacteremia; higher doses (8-10 mg/kg) may be needed for complicated infections 8, 7
• Ceftobiprole demonstrated noninferiority to daptomycin (70% vs 69% treatment success) in phase 3 trials 7

When to Use Each Agent

• Vancomycin: First-line for severe MRSA infections, but avoid if MIC >1.5 mcg/mL or heterogeneous vancomycin-intermediate S. aureus (hVISA) 5, 9
• Daptomycin: Preferred for MRSA bacteremia with vancomycin MIC ≥1.5 mcg/mL, vancomycin failure, or renal dysfunction limiting vancomycin dosing 8, 7
• Clindamycin IV: Can be used for MRSA bacteremia in stable patients without endocarditis or ongoing bacteremia after initial clearance 6

Specific Clinical Scenarios

Necrotizing Fasciitis or Streptococcal Toxic Shock

• Penicillin G (4 million units IV every 4 hours) plus clindamycin (600-900mg IV every 8 hours) for documented Group A Streptococcus 1, 6
• Clindamycin provides superior toxin suppression and cytokine modulation compared to beta-lactams alone 6
• Empiric broad-spectrum coverage (vancomycin or linezolid plus piperacillin-tazobactam or carbapenem) until pathogen identified 1

Surgical Site Infections

• For trunk/extremity surgery: Cefazolin 0.5-1g IV every 8 hours or oxacillin/nafcillin 2g IV every 6 hours 1
• Add vancomycin 15 mg/kg IV every 12 hours if high local MRSA rates or risk factors present 1
• For axilla/perineum surgery: Add metronidazole 500mg IV every 8 hours for anaerobic coverage 1

Impetigo and Ecthyma

• Dicloxacillin or cephalexin for 7 days when MSSA suspected 1
• Oral penicillin if cultures yield Streptococcus alone 1
• Doxycycline, clindamycin, or TMP-SMX when MRSA confirmed or suspected 1

Duration of Therapy

Uncomplicated Skin and Soft Tissue Infections

• 5-10 days based on clinical response, with 5 days sufficient if improvement occurs 2
• 7 days is standard for most uncomplicated infections 1, 6

Complicated Infections

• 7-14 days depending on severity and clinical response 1, 6, 2
• Transition from IV to oral therapy after clinical improvement (typically 48 hours) 6

Bacteremia and Deep-Seated Infections

• Uncomplicated bacteremia: 14 days minimum 7
• Complicated bacteremia or endocarditis: 4-6 weeks 6, 7
• Osteomyelitis: Minimum 8 weeks 6

Common Pitfalls to Avoid

• Do not use TMP-SMX or doxycycline alone for suspected Streptococcus infections as they lack reliable coverage 2
• Do not underdose clindamycin for serious infections; use 600mg IV every 8 hours, not lower doses 6
• Do not use clindamycin for MRSA if local resistance >10% or if D-zone test positive 6, 2
• Do not continue vancomycin for MSSA once susceptibilities known; switch to cefazolin or antistaphylococcal penicillin for better outcomes 7, 3
• Do not forget source control: Drainage of abscesses, removal of infected devices, and surgical debridement are critical and antibiotics alone are insufficient 1, 7