What is the recommended treatment for Methicillin-Sensitive Staphylococcus aureus (MSSA) infections?

Treatment of Methicillin-Sensitive Staphylococcus aureus (MSSA) Infections

For proven MSSA infections, nafcillin, oxacillin, or cefazolin are the preferred first-line agents, with cefazolin emerging as the optimal choice due to superior tolerability and comparable or better clinical outcomes. 1, 2, 3

First-Line Definitive Therapy for Proven MSSA

Preferred Agents (in order of recommendation):

1. Cefazolin - This should be your default choice for most MSSA infections:

• Dosing: 1-2g IV every 8 hours 1, 3
• Advantages: Lower rates of nephrotoxicity (3.3% vs 11.4%), hepatotoxicity (1.6% vs 8.1%), and rash (4.2% vs 13.9%) compared to nafcillin 4, 5
• Efficacy: Associated with 37% reduction in 30-day mortality compared to nafcillin/oxacillin in a large multicenter study of MSSA bacteremia 6
• Completion rates: 93.3% of patients complete therapy with cefazolin vs only 66.2% with nafcillin 4

2. Nafcillin or Oxacillin - Reserve for specific situations:

• Dosing: Nafcillin 12g/day IV in 4-6 divided doses 3, 7
• When to use: Brain abscess complicating MSSA (nafcillin has superior blood-brain barrier penetration compared to cefazolin) 8
• Limitations: Higher discontinuation rates due to adverse effects 4, 5

Critical Exception - The Cefazolin Inoculum Effect:

Important caveat: A subset of MSSA isolates (approximately 50%) exhibit the cefazolin inoculum effect (CzIE), where high bacterial burden causes cefazolin MIC to increase to ≥16 µg/mL 9. This phenomenon is associated with:

• 2.65-fold increased 30-day mortality risk 9
• More common in catheter-associated or unknown source bacteremia 9

Clinical implication: For high-burden infections (extensive osteomyelitis, large abscesses, endocarditis with large vegetations), consider nafcillin/oxacillin as first-line, or ensure aggressive source control if using cefazolin 9.

Oral Step-Down Therapy

For transition to outpatient therapy or less severe infections:

• Cephalexin 500mg PO every 6 hours 1
• Dicloxacillin is an alternative oral antistaphylococcal penicillin

Duration of Therapy by Infection Type

Bacteremia:

• Uncomplicated: Minimum 2 weeks IV therapy (requires: no endocarditis, no prosthetic devices, blood cultures negative by days 2-4, defervescence within 72 hours, no metastatic infection) 3
• Complicated: 4-6 weeks IV therapy 3

Endocarditis:

• 6 weeks of therapy from first negative blood culture 8, 3
• Right-sided uncomplicated: Some data support 2-week regimens, but this cannot be applied to left-sided endocarditis 3
• Do NOT add gentamicin: No longer recommended due to increased nephrotoxicity without improved outcomes 8, 3

Osteomyelitis:

• 4-6 weeks of therapy 1
• Consider adding rifampin for biofilm penetration 1

Skin and Soft Tissue Infections:

• 7-14 days depending on severity 8, 1

Empiric Therapy (When MSSA is Suspected but Not Confirmed)

When awaiting culture results, broader coverage is appropriate:

• Piperacillin-tazobactam 4.5g IV every 6 hours 1, 2
• Cefepime 2g IV every 8 hours 1
• Meropenem 1g IV every 8 hours 1

Key principle: De-escalate to cefazolin or nafcillin/oxacillin once MSSA is confirmed as the sole pathogen 2. The usefulness of empirical combination therapy with vancomycin plus an antistaphylococcal β-lactam until susceptibilities return is uncertain 8.

Special Clinical Scenarios

Polymicrobial Infections (MSSA + Gram-negatives/Anaerobes):

• Continue piperacillin-tazobactam for dual coverage 2
• Alternatively: cefazolin PLUS cefepime (for Pseudomonas) 2

Necrotizing Fasciitis/Pyomyositis:

• Empiric: Vancomycin PLUS (piperacillin-tazobactam OR ampicillin-sulbactam OR carbapenem) 8
• Definitive for MSSA: Cefazolin or antistaphylococcal penicillin 8
• Critical: Urgent surgical debridement is mandatory 8

Severe Penicillin/Cephalosporin Allergy:

• Vancomycin (though inferior to β-lactams for MSSA) 3
• Daptomycin (preferred over vancomycin where available) 3
• Consider penicillin desensitization in stable patients, as vancomycin outcomes are inferior 3

Essential Monitoring and Source Control

Follow-up Blood Cultures:

• Obtain repeat cultures every 48-72 hours until clearance documented 3
• Persistent bacteremia ≥48 hours associated with 39% 90-day mortality 3

Echocardiography:

• All adult patients with MSSA bacteremia require echocardiography to exclude endocarditis 3
• Transesophageal echo (TEE) is superior and required for persistent bacteremia, persistent fever, or concern for metastatic infection 3

Source Control:

• Inadequate source control is the most common cause of treatment failure 3
• Remove infected catheters, drain abscesses, debride infected tissue aggressively 8, 1

Common Pitfalls to Avoid

1. Using vancomycin for proven MSSA: Vancomycin is explicitly inferior to β-lactams and should only be used when β-lactams cannot be administered 3

2. Failing to de-escalate from empiric therapy: Once MSSA is confirmed, transition from broad-spectrum agents to targeted therapy 1, 2

3. Adding aminoglycosides: Gentamicin should NOT be used for MSSA endocarditis or bacteremia—increases nephrotoxicity without benefit 8, 3

4. Inadequate surgical intervention: Particularly for abscesses, osteomyelitis, or necrotizing infections 8, 1

5. Treating penicillin-susceptible staphylococci with penicillin G: Laboratory screening for penicillin susceptibility is unreliable; use antistaphylococcal β-lactams instead 8