What is the appropriate use of cefazolin (Ancef) for a patient with a suspected or confirmed Staphylococcus (Staph) infection, including Methicillin-Sensitive Staphylococcus Aureus (MSSA) and Methicillin-Resistant Staphylococcus Aureus (MRSA)?

Cefazolin for Staphylococcal Infections

Cefazolin is the preferred agent for proven methicillin-sensitive Staphylococcus aureus (MSSA) infections, demonstrating superior safety and equivalent or better efficacy compared to antistaphylococcal penicillins, while MRSA infections absolutely require vancomycin or linezolid as cefazolin has no activity against methicillin-resistant strains. 1

Critical Decision Point: MSSA vs MRSA

The fundamental distinction is methicillin susceptibility:

• For proven MSSA: Cefazolin (or oxacillin/nafcillin) is preferred over all other agents 1
• For proven or suspected MRSA: Vancomycin 15-20 mg/kg IV every 8-12 hours or linezolid 600 mg IV twice daily is mandatory 1
• Cefazolin has ZERO activity against MRSA and should never be used for methicillin-resistant infections 2

When to Use Cefazolin for MSSA

Proven MSSA Infections (Culture-Confirmed)

Cefazolin is the preferred first-line agent for:

• Bacteremia/septicemia due to MSSA 3, 4
• Endocarditis caused by MSSA 3
• Bone and joint infections from MSSA 3
• Skin and soft tissue infections with confirmed MSSA 1, 3
• Respiratory tract infections due to MSSA 3
• Pyomyositis caused by MSSA 1

Dosing for MSSA Infections

Standard cefazolin dosing:

• For serious MSSA infections: 2 g IV every 8 hours 1
• For moderate infections: 1-2 g IV every 8 hours 1
• For pyomyositis: Cefazolin or antistaphylococcal penicillin (nafcillin/oxacillin) after initial vancomycin 1

Evidence Supporting Cefazolin Over Antistaphylococcal Penicillins

Recent meta-analysis demonstrates cefazolin superiority:

• Lower mortality compared to antistaphylococcal penicillins (OR 0.69,95% CI 0.58-0.82) 4
• Lower clinical failure rates (OR 0.56,95% CI 0.37-0.85) 4
• Significantly reduced nephrotoxicity (OR 0.36,95% CI 0.16-0.81) 4
• Dramatically lower hepatotoxicity (OR 0.12,95% CI 0.04-0.41) 4
• 75% reduction in discontinuation due to adverse effects (OR 0.24,95% CI 0.12-0.48) 4
• No increase in bacteremia recurrence compared to antistaphylococcal penicillins 4

When NOT to Use Cefazolin

Empiric Treatment Scenarios

Cefazolin should NOT be used for empiric therapy in:

• Hospital-acquired pneumonia (HAP): Use piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem for empiric MSSA coverage 1
• Ventilator-associated pneumonia (VAP): Same broad-spectrum agents as HAP 1
• Empiric cellulitis treatment: Beta-lactams with broader coverage are preferred empirically 5

The rationale: These agents provide adequate MSSA coverage PLUS necessary gram-negative and Pseudomonas coverage, while cefazolin lacks gram-negative activity 1

MRSA Risk Factors Requiring Different Agents

When MRSA is suspected or confirmed, use vancomycin or linezolid instead:

• Prior IV antibiotic use within 90 days 1
• Units where MRSA prevalence >10-20% among S. aureus isolates 1
• Penetrating trauma or injection drug use 5
• Purulent drainage or exudate 5
• Known MRSA colonization 5
• Systemic inflammatory response syndrome (SIRS) 5

Severe Polymicrobial Infections

Cefazolin is inadequate for:

• Necrotizing fasciitis: Requires vancomycin or linezolid PLUS piperacillin-tazobactam (or carbapenem) 1
• Gas gangrene: Requires penicillin plus clindamycin for clostridial coverage 1
• Severe cellulitis with systemic toxicity: Requires broad-spectrum combination therapy 1, 5

Empiric MSSA Coverage Without Cefazolin

For empiric treatment when MSSA (not MRSA) coverage is needed:

• Piperacillin-tazobactam 4.5 g IV every 6 hours provides MSSA coverage 1
• Cefepime 2 g IV every 8 hours covers MSSA 1
• Levofloxacin 750 mg IV daily has MSSA activity 1
• Imipenem 500 mg IV every 6 hours or meropenem 1 g IV every 8 hours cover MSSA 1

These agents are preferred empirically because they provide MSSA coverage WHILE simultaneously covering Pseudomonas and gram-negative bacilli 1

Treatment Duration

For proven MSSA infections treated with cefazolin:

• Uncomplicated skin/soft tissue infections: 5 days if clinical improvement occurs 5
• Complicated infections requiring hospitalization: 7-14 days guided by clinical response 5
• Pyomyositis: 2-3 weeks total (IV initially, then oral after clinical improvement and bacteremia clearance) 1
• Endocarditis and deep-seated infections: Prolonged courses determined by infection type and response 3

Common Pitfalls to Avoid

Critical errors in cefazolin use:

• Never use cefazolin empirically for HAP/VAP when broader coverage is needed 1
• Never use cefazolin for MRSA under any circumstances—it has zero activity 2
• Do not reflexively add MRSA coverage to cefazolin for typical cellulitis without specific risk factors 5
• Do not use cefazolin alone for necrotizing infections—these require combination therapy 1
• Avoid cefazolin in severe penicillin allergy (immediate hypersensitivity reactions) 1

Transition from Empiric to Definitive Therapy

Once MSSA is confirmed by culture:

• Switch from vancomycin to cefazolin for better outcomes and reduced toxicity 4
• Switch from broad-spectrum agents (piperacillin-tazobactam, carbapenems) to cefazolin for antimicrobial stewardship 6
• This de-escalation improves safety without compromising efficacy 4