Can Keflex (Cephalexin) Be Used to Treat MSSA Pneumonia?
No, cephalexin (Keflex) should not be used to treat MSSA pneumonia—oxacillin, nafcillin, or cefazolin are the preferred agents for proven MSSA pneumonia, with cephalexin reserved only for less serious skin and soft tissue infections. 1
Why Cephalexin Is Not Appropriate for Pneumonia
Guideline-Based Recommendations
- The IDSA/ATS guidelines explicitly state that oxacillin, nafcillin, or cefazolin are preferred for proven MSSA pneumonia, but these agents "would ordinarily not be used in an empiric regimen for HAP" because they lack gram-negative coverage. 2
- Cephalexin is classified as appropriate only for "less serious MSSA infections such as skin and soft tissue infections," not for invasive or deep-seated infections like pneumonia. 3
- First-generation oral cephalosporins like cephalexin have higher MICs (MIC50 of 2 μg/mL, MIC90 of 4 μg/mL) compared to IV antistaphylococcal agents like oxacillin (MIC50 ≤0.25 μg/mL) or cefazolin (MIC50 0.5 μg/mL), making them less potent for serious infections. 4
Evidence Against Cephalexin for Pneumonia
- Cephalexin is designed for outpatient musculoskeletal and skin infections, not for pneumonia, where adequate lung penetration and bactericidal activity are critical. 4, 5
- Even ceftriaxone—a more potent third-generation cephalosporin—showed 28.5% higher clinical failure rates for MSSA pneumonia compared to ceftaroline or ceftobiprole, demonstrating that not all cephalosporins are equivalent for staphylococcal pneumonia. 6
The Correct Treatment Algorithm for MSSA Pneumonia
First-Line Definitive Therapy
- Nafcillin or oxacillin are the preferred first-line agents for proven MSSA pneumonia due to superior efficacy and established clinical outcomes. 1
- Cefazolin is an acceptable alternative, particularly in patients with non-anaphylactic penicillin allergy. 1, 2
- These agents should replace empiric regimens (piperacillin-tazobactam, cefepime, carbapenems) once MSSA susceptibility is confirmed. 1
Dosing Recommendations
Context: Hospital-Acquired vs. Community-Acquired
- For hospital-acquired pneumonia (HAP), empiric regimens typically include piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem to cover gram-negative pathogens, but these should be narrowed to oxacillin/nafcillin/cefazolin once MSSA is confirmed. 2, 1
- For community-acquired pneumonia (CAP) with proven MSSA, the same definitive agents apply. 1
Penicillin Allergy Considerations
- In patients with documented non-anaphylactic penicillin allergy (e.g., rash without urticaria), cefazolin is a reasonable alternative. 2, 1
- In patients with immediate-type hypersensitivity (urticaria, angioedema, bronchospasm, anaphylaxis), cephalosporins are contraindicated; consider vancomycin or daptomycin as alternatives. 1, 3
Critical Pitfalls to Avoid
- Do not continue broad-spectrum empiric antibiotics (piperacillin-tazobactam, carbapenems, fluoroquinolones) once MSSA is confirmed—this increases antimicrobial resistance and C. difficile risk without improving outcomes. 1
- Vancomycin should not be used for MSSA when beta-lactams can be used, as beta-lactams have superior efficacy for methicillin-susceptible strains. 1
- Do not use oral cephalexin for pneumonia—it lacks the potency and pharmacokinetic properties required for serious pulmonary infections. 4, 3
Special Circumstances
- In cases of CNS involvement (brain abscess, meningitis), nafcillin is preferred over cefazolin due to better CNS penetration. 1
- For complicated pneumonia with bacteremia, the standard duration of therapy is 2 weeks for uncomplicated cases, but 4-6 weeks may be required for complicated infections with metastatic foci. 1
- Cefazolin has been shown equivalent or superior to flucloxacillin for MSSA bacteremia in large observational studies, supporting its use as an alternative to antistaphylococcal penicillins. 7