Can cephalexin (Keflex) be used to treat mild community‑acquired methicillin‑susceptible Staphylococcus aureus (MSSA) pneumonia in an otherwise healthy adult?

Cephalexin is NOT appropriate for treating MSSA pneumonia

Do not use cephalexin (Keflex) to treat MSSA pneumonia—even mild community-acquired cases—because it achieves inadequate lung tissue concentrations and lacks sufficient clinical evidence for pneumonia treatment. 1

Why Cephalexin Fails in Pneumonia

Preferred Agents for Proven MSSA Pneumonia

When MSSA is confirmed by culture, the following agents are explicitly preferred over oral cephalosporins like cephalexin:

• Oxacillin, nafcillin, or cefazolin are the guideline-recommended first-line agents for proven MSSA pneumonia (including hospital-acquired and community-acquired cases). 1
• These agents achieve superior lung penetration and have robust clinical evidence supporting their use in staphylococcal pneumonia. 1

The Ceftriaxone Evidence Problem

• Ceftriaxone—a third-generation cephalosporin with better pharmacokinetics than cephalexin—demonstrates significantly higher clinical failure rates (28.5% absolute increase in failure) compared to ceftaroline or ceftobiprole when treating MSSA pneumonia. 2
• If a parenteral third-generation cephalosporin with superior tissue penetration fails to adequately treat MSSA pneumonia, an oral first-generation agent like cephalexin with poorer lung penetration is even less appropriate. 2

Cephalexin's Limited Role

• Cephalexin is appropriate for skin and soft tissue infections caused by MSSA, not pneumonia. 3
• While cephalexin and cefadroxil (another oral first-generation cephalosporin) show equivalent in vitro activity against MSSA (MIC₅₀ = 2 μg/mL, MIC₉₀ = 4 μg/mL), these MICs are 4–8 times higher than those of oxacillin, cefazolin, or cephalothin (MIC₅₀ ≤ 0.5 μg/mL). 4
• The higher MICs combined with poor lung tissue penetration make oral first-generation cephalosporins unsuitable for serious infections like pneumonia. 4

Correct Treatment Algorithm for MSSA Pneumonia

Community-Acquired MSSA Pneumonia (Mild-Moderate, Outpatient)

• First-line: Amoxicillin-clavulanate 875–1000 mg PO every 8–12 hours 1
• Alternative (penicillin allergy): Moxifloxacin 400 mg PO daily 1
• Not recommended: Cephalexin, cefadroxil, or other oral first-generation cephalosporins 1, 2

Community-Acquired MSSA Pneumonia (Hospitalized, Non-ICU)

• Preferred: Ceftriaxone 1–2 g IV daily plus azithromycin 500 mg IV/PO daily 1
• Alternative: Moxifloxacin 400 mg IV daily or levofloxacin 750 mg IV daily 1
• Once MSSA is confirmed and patient is clinically stable, narrow to oxacillin, nafcillin, or cefazolin 1

Hospital-Acquired MSSA Pneumonia

• Preferred for proven MSSA: Oxacillin 2 g IV every 4 hours, nafcillin 2 g IV every 4 hours, or cefazolin 2 g IV every 8 hours 1
• These agents are superior to broader-spectrum options once MSSA is confirmed. 1

Critical Pitfalls to Avoid

• Never assume oral first-generation cephalosporins are interchangeable with IV agents for serious infections—lung tissue penetration is inadequate. 4, 2
• Do not use ceftriaxone monotherapy for confirmed MSSA pneumonia; it has unacceptably high failure rates compared to anti-staphylococcal agents. 2
• Cephalexin's role is limited to uncomplicated skin/soft tissue infections—it should not be extrapolated to pneumonia based on in vitro susceptibility alone. 3
• If oral therapy is required for MSSA pneumonia (e.g., step-down after IV therapy), use amoxicillin-clavulanate or a respiratory fluoroquinolone, not cephalexin. 1