Does Keflex Cover MRSA?
No, Keflex (cephalexin) does not cover MRSA and should never be used as monotherapy when MRSA is suspected or confirmed. 1, 2
Why Cephalexin Fails Against MRSA
The FDA drug label explicitly states that "methicillin-resistant staphylococci are resistant to cephalosporins, including cephalexin." 2 MRSA resistance is conferred by the mecA gene encoding PBP2a, a penicillin-binding protein with significantly lower affinity for all beta-lactams, allowing cell-wall biosynthesis to continue even in the presence of cephalosporins. 3
The IDSA guidelines clearly separate treatment recommendations for methicillin-susceptible S. aureus (MSSA) versus MRSA, with cephalexin appearing only in the MSSA treatment category. 1 This distinction is critical—cephalexin has no clinically relevant in vitro activity against MRSA. 4
Appropriate Antibiotics for MRSA Infections
For oral treatment of MRSA skin and soft tissue infections:
- Trimethoprim-sulfamethoxazole (TMP-SMX): 1-2 double-strength tablets twice daily 3, 1
- Clindamycin: 300-450 mg four times daily (only if local resistance <10%) 3, 1
- Doxycycline or minocycline: 100 mg twice daily 3
- Linezolid: 600 mg twice daily 3
For intravenous treatment of severe MRSA infections:
- Vancomycin: 15-20 mg/kg IV every 8-12 hours (first-line, A-I evidence) 3, 1
- Daptomycin: 10 mg/kg IV once daily 3
- Linezolid: 600 mg IV twice daily 3
- Ceftaroline, dalbavancin, or tedizolid are newer alternatives 3
The Paradox: Why Some MRSA Infections "Respond" to Cephalexin
Several studies show surprisingly high cure rates (84-92%) when cephalexin was used for MRSA skin infections. 4, 5, 6 However, this apparent success is misleading and must be interpreted with extreme caution. 4
The critical confounding factor is incision and drainage (I&D). In these studies, 97% of patients underwent spontaneous drainage or a drainage procedure. 5, 6 One placebo-controlled trial demonstrated a 90.5% cure rate with drainage alone—no antibiotics whatsoever—for uncomplicated MRSA abscesses. 6 This proves that surgical drainage, not the antibiotic choice, drives clinical success in purulent infections.
The IDSA explicitly states that incision and drainage is the primary treatment for purulent skin infections and may be sufficient for uncomplicated cases without systemic symptoms. 1
When Antibiotics Are Actually Needed for MRSA
Add MRSA-active antibiotics when:
- Systemic inflammatory response syndrome (SIRS) is present 1
- Failed initial antibiotic treatment 1
- Markedly impaired host defenses 1
- Severe or rapidly progressing infections 1
- Moderate/severe infection with systemic symptoms 1
Critical Pitfalls to Avoid
Never assume all staphylococcal infections are methicillin-susceptible without obtaining cultures. 1 The IDSA warns this is a common diagnostic pitfall. Obtain cultures when possible before starting antibiotics. 1
Never use cephalexin monotherapy for purulent cellulitis or infections with MRSA risk factors (penetrating trauma, injection drug use, known MRSA colonization, purulent drainage). 3, 1 These scenarios mandate MRSA coverage.
Always reassess patients who don't improve within 48-72 hours. 1 Failure to respond indicates either resistant organisms or a deeper/different infection than initially recognized.
The Bottom Line Algorithm
- Obtain cultures before starting antibiotics 1
- For purulent infections (abscesses): Perform I&D as primary treatment 1
- Add MRSA-active antibiotic if: moderate/severe OR systemic symptoms present 1
- For typical nonpurulent cellulitis: Beta-lactam monotherapy (cephalexin) remains appropriate—MRSA is uncommon in this presentation 3, 7
- Reassess in 48-72 hours and adjust based on culture results and clinical response 1
The key distinction: Cephalexin works for typical cellulitis (where MRSA is rare) but fails for confirmed or suspected MRSA infections. The apparent success in some MRSA cases reflects the power of drainage, not antibiotic efficacy.