Does Keflex (Cephalexin) provide coverage against Methicillin-resistant Staphylococcus aureus (MRSA)?

Keflex (Cephalexin) Does NOT Provide Reliable Coverage Against MRSA

Cephalexin lacks clinically accepted in vitro activity against MRSA and should not be relied upon for MRSA coverage. While some clinical studies show paradoxical cure rates in MRSA infections treated with cephalosporins, this likely reflects the importance of drainage procedures rather than antibiotic efficacy against MRSA itself.

Microbiological Basis for Lack of MRSA Coverage

• MRSA resistance is conferred by the mecA gene encoding PBP2a (penicillin-binding protein 2a), which has significantly lower affinity for β-lactam antibiotics like cephalexin 1
• This resistance mechanism allows bacterial cell-wall biosynthesis to continue even in the presence of β-lactam antibiotics 1
• Cephalosporins including cephalexin do not have accepted, clinically relevant in vitro activity against MRSA 2

Guideline Recommendations for MRSA Coverage

When MRSA coverage is needed, guidelines consistently recommend alternatives to cephalexin:

For Skin and Soft Tissue Infections:

Oral options for MRSA include:

• Linezolid (strongest recommendation: 1A) 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) (recommendation 1B) 1
• Tetracyclines (doxycycline or minocycline) (recommendation 1B) 1
• Tedizolid (recommendation 1A) 1
• Clindamycin (though resistance is increasingly common) 1

Intravenous options for MRSA include:

• Vancomycin (recommendation 1A) 1
• Daptomycin (10 mg/kg/dose IV once daily) (recommendation 1A) 1
• Linezolid IV (recommendation 1A) 1
• Ceftaroline (recommendation 1A) 1

For Community-Acquired Pneumonia with CA-MRSA:

• Add vancomycin or linezolid when CA-MRSA is suspected 1
• First-generation cephalosporins are adequate only for methicillin-sensitive S. aureus (MSSA), not MRSA 1

Clinical Context: When Cephalexin May Still Be Appropriate

MRSA is an unusual cause of typical cellulitis without purulent drainage 1

• A prospective study demonstrated that β-lactams such as cefazolin or oxacillin were successful in 96% of cellulitis patients, suggesting MRSA cellulitis is uncommon 1
• For pure cellulitis without abscess, ulcer, or purulent drainage, β-lactam monotherapy (including cephalexin) remains appropriate 1
• A randomized trial showed that TMP-SMX plus cephalexin was no more efficacious than cephalexin alone in pure cellulitis 1

When to Consider MRSA Coverage Instead of Cephalexin:

Coverage for MRSA may be prudent in cellulitis associated with:

• Penetrating trauma, especially from illicit drug use 1
• Purulent drainage 1
• Concurrent evidence of MRSA infection elsewhere 1
• Post-flu-like illness and/or severe pneumonia 1
• History of colonization or recent MRSA infection 1
• Recent antibiotic consumption, particularly quinolones or macrolides 1

Important Clinical Caveat: The Drainage Paradox

Clinical cure rates in studies of MRSA infections treated with cephalosporins must be interpreted with extreme caution 2:

• In one study, clinical cure rates for MRSA infections were 92% with cefdinir and 90% with cephalexin 2
• However, incision and drainage (I&D), spontaneous drainage, and needle aspiration likely contributed substantially to clinical response 2
• In a pediatric study, 97% of subjects had spontaneous drainage or underwent drainage procedures, and there was no difference between cephalexin and clindamycin outcomes 3
• These results suggest that appropriate drainage of uncomplicated SSTIs is more important than initial antibiotic choice when MRSA is present 3

Combination Therapy Approach

If coverage for both streptococci and MRSA is desired for oral therapy:

• Clindamycin alone (covers both) 1
• TMP-SMX or doxycycline combined with a β-lactam (e.g., penicillin, cephalexin, or amoxicillin) 1

The activity of doxycycline and TMP-SMX against β-hemolytic streptococci is not well established, necessitating the addition of a β-lactam for streptococcal coverage 1

Treatment of Methicillin-Sensitive S. aureus (MSSA)

For MSSA infections, cephalexin is appropriate:

• First-generation cephalosporins (cefazolin, cephalothin, cephalexin) have important therapeutic roles in less serious MSSA infections such as skin and soft tissue infections 4
• Penicillinase-resistant penicillins (flucloxacillin, dicloxacillin) remain the antibiotics of choice for serious MSSA infections 4