What antibiotics cover gram-positive, gram-negative, Pseudomonas, and Methicillin-resistant Staphylococcus aureus (MRSA)?

Antibiotics Covering Gram-Positive, Gram-Negative, Pseudomonas, and MRSA

For empiric coverage of all four categories—gram-positive organisms, gram-negative organisms, Pseudomonas aeruginosa, and MRSA—you must use combination therapy: vancomycin or linezolid PLUS an antipseudomonal beta-lactam (piperacillin-tazobactam, cefepime, ceftazidime, or a carbapenem). No single antibiotic reliably covers all four categories 1.

Recommended Combination Regimens

First-Line Combination

Vancomycin PLUS piperacillin-tazobactam provides the most comprehensive coverage 1:

• Vancomycin 15 mg/kg IV every 8-12 hours (target trough 15-20 mg/mL) covers MRSA 1
• Piperacillin-tazobactam 4.5 g IV every 6 hours covers gram-negatives including Pseudomonas, plus MSSA and anaerobes 1, 2

Alternative Combinations for MRSA Coverage

If vancomycin is contraindicated or ineffective 1:

• Linezolid 600 mg IV every 12 hours PLUS an antipseudomonal beta-lactam 1, 3
• Daptomycin (dose varies by indication) PLUS an antipseudomonal beta-lactam 1

Alternative Antipseudomonal Agents

When piperacillin-tazobactam cannot be used 1:

• Cefepime 2 g IV every 8 hours (covers Pseudomonas and gram-negatives, but NOT MRSA) 1
• Ceftazidime 2 g IV every 8 hours (covers Pseudomonas and gram-negatives, but NOT MRSA or MSSA reliably) 1, 4
• Meropenem 1 g IV every 8 hours (covers Pseudomonas, gram-negatives, and MSSA, but NOT MRSA) 1, 5
• Imipenem-cilastatin 500 mg IV every 6 hours (similar spectrum to meropenem) 1

Critical Coverage Gaps to Avoid

Single-Agent Limitations

No monotherapy option exists for this coverage requirement 1:

• Carbapenems (meropenem, imipenem) cover MSSA, gram-negatives, and Pseudomonas but have NO reliable MRSA activity 5
• Ceftazidime-avibactam covers multidrug-resistant gram-negatives and Pseudomonas but has NO meaningful Staphylococcus aureus coverage (neither MRSA nor MSSA) 4
• Piperacillin-tazobactam covers MSSA, gram-negatives, and Pseudomonas but does NOT cover MRSA 2
• Vancomycin and linezolid cover MRSA and MSSA but have NO gram-negative or Pseudomonas coverage 3

When to Use Broader Coverage

For severe infections with high mortality risk or recent antibiotic exposure within 90 days 1:

• Add a second antipseudomonal agent (aminoglycoside or fluoroquinolone) to the beta-lactam 1
• Consider vancomycin PLUS cefepime PLUS aminoglycoside for maximum gram-negative and Pseudomonas coverage 1

Clinical Context for Use

Necrotizing Soft Tissue Infections

Empiric therapy must cover MRSA, gram-negatives, Pseudomonas, and anaerobes 1:

• Vancomycin or linezolid PLUS piperacillin-tazobactam or a carbapenem 1
• Continue until surgical debridement is no longer needed and fever resolves for 48-72 hours 1

Diabetic Foot Infections (Severe)

For severe infections requiring parenteral therapy 1:

• Vancomycin PLUS piperacillin-tazobactam covers MRSA, gram-negatives, Pseudomonas, and anaerobes 1
• Pseudomonas is uncommon in diabetic foot infections except in specific circumstances (chronic wounds, prior antibiotic exposure) 1

Hospital-Acquired Pneumonia

For patients at high mortality risk or with recent IV antibiotic use 1:

• Vancomycin or linezolid PLUS two antipseudomonal agents (e.g., piperacillin-tazobactam PLUS aminoglycoside or fluoroquinolone) 1
• Avoid combining two beta-lactams together 1

De-escalation Strategy

Once culture results return, narrow therapy immediately 1, 5:

• If MSSA is isolated (not MRSA), switch from vancomycin to nafcillin, oxacillin, or cefazolin 5
• If Pseudomonas is NOT isolated, discontinue antipseudomonal coverage 1
• If MRSA is NOT isolated, discontinue vancomycin or linezolid after 48-72 hours 1
• De-escalation reduces risk of Clostridioides difficile infection, antibiotic resistance, and adverse effects 5

Common Pitfalls

Never assume a single broad-spectrum agent covers all four categories—this is the most common prescribing error 1, 4. Even "ultra-broad" agents like carbapenems lack MRSA coverage and require vancomycin or linezolid added 5.

Do not use ceftazidime-avibactam as your sole agent if Staphylococcus aureus (MRSA or MSSA) is a potential pathogen—it has no meaningful staphylococcal activity and requires separate anti-staphylococcal coverage 4.

Avoid empiric monotherapy in immunocompromised patients or severe sepsis—combination therapy is mandatory until cultures guide narrowing 1.