Should Keflex (cephalexin) or Dicloxacillin be used as first-line treatment for skin and soft tissue infections?

First-Line Antibiotic Choice for Skin and Soft Tissue Infections

Both cephalexin (Keflex) and dicloxacillin are appropriate first-line agents for mild, uncomplicated skin and soft tissue infections caused by methicillin-susceptible Staphylococcus aureus (MSSA), but cephalexin is generally preferred due to better tolerability, more convenient dosing, and equivalent efficacy. 1, 2

Guideline-Based Recommendations

WHO Position (Most Recent)

• The World Health Organization elevated cephalexin from second-choice to first-choice status in 2021 for mild skin and soft tissue infections, placing it alongside amoxicillin-clavulanate and cloxacillin as preferred agents 1, 2
• Notably, the WHO Expert Committee excluded dicloxacillin from their first-choice recommendations based on the principle of parsimony, though they acknowledge dicloxacillin has better oral bioavailability than cloxacillin 1

IDSA Guidelines (2014)

• For impetigo: Both dicloxacillin (250 mg QID) and cephalexin (250 mg QID) are listed as equivalent options 1
• For purulent SSTI (abscesses, furuncles): Both dicloxacillin (500 mg QID) and cephalexin (500 mg QID) are recommended when MSSA is suspected 1
• For non-purulent SSTI (cellulitis): Cephalexin is specifically listed among preferred agents 1, 2

Practical Advantages of Cephalexin

Dosing Convenience

• Cephalexin: 500 mg four times daily (can often be given twice daily for compliance) 1
• Dicloxacillin: 500 mg four times daily, must be taken on empty stomach 1
• The IDSA notes that dicloxacillin is "not used much in pediatrics" due to dosing complexity, while cephalexin offers better suspension availability and less frequent dosing requirements 1

Tolerability Profile

• Cephalexin is generally better tolerated with fewer gastrointestinal side effects compared to dicloxacillin 3
• Both have similar efficacy profiles, but cephalexin's improved tolerability enhances medication compliance 4

Clinical Efficacy Evidence

Equivalent Outcomes

• No significant difference exists in treatment effect between penicillins (including dicloxacillin) and cephalosporins for cellulitis 1, 2
• Cure rates of 90% or higher are consistently achieved with cephalexin for streptococcal and staphylococcal skin infections 4
• Cephalexin is comparable to dicloxacillin, cloxacillin, and other agents in treating these infections 4

MRSA Considerations

• Critical limitation: Neither cephalexin nor dicloxacillin has activity against MRSA 2, 3, 5
• If MRSA is suspected (high local prevalence, previous MRSA infection, purulent infection with systemic signs), choose anti-MRSA agents instead: trimethoprim-sulfamethoxazole, doxycycline, or clindamycin 1, 2
• Interestingly, one pediatric RCT found no significant difference between cephalexin and clindamycin for uncomplicated SSTIs (94% vs 97% improvement), even when 69% had MRSA cultured, suggesting that adequate drainage may be more important than antibiotic choice for simple abscesses 5

When to Use Each Agent

Choose Cephalexin for:

• Cellulitis (non-purulent infections) 1, 2
• Pediatric patients (better suspension formulation and dosing) 1
• Patients requiring improved compliance (better tolerability) 4
• Mild diabetic wound infections 1, 2
• Incisional surgical site infections of trunk or extremities 1, 2

Choose Dicloxacillin for:

• Adults with confirmed MSSA where oral bioavailability is paramount 1
• Impetigo (equivalent to cephalexin) 1
• The IDSA specifically notes dicloxacillin as the "oral agent of choice for methicillin-susceptible strains in adults" 1

Critical Situations Where Neither Should Be Used

Absolute Contraindications

• MRSA infections: Use vancomycin (IV), linezolid, daptomycin, ceftaroline, or oral agents like TMP-SMX, doxycycline, clindamycin 1, 2
• Necrotizing fasciitis: Requires combination therapy with clindamycin plus piperacillin-tazobactam or ceftriaxone plus metronidazole 1, 2
• Animal or human bites: Require amoxicillin-clavulanate for anaerobic coverage 1, 2
• Moderate-to-severe diabetic infections: Need broader spectrum coverage 1, 2
• Penicillin allergy with immediate hypersensitivity: Cephalosporins are contraindicated in patients with urticaria, angioedema, bronchospasm, or anaphylaxis to penicillins 3

Algorithm for Decision-Making

1. Assess infection severity and type:

   • Simple abscess with adequate drainage → Consider observation alone or either agent 5, 6
   • Cellulitis/non-purulent SSTI → Cephalexin preferred 1, 2
   • Impetigo → Either agent acceptable 1

2. Evaluate MRSA risk factors:

   • High local MRSA prevalence, previous MRSA, injection drug use, purulent infection with systemic signs → Choose anti-MRSA agent instead 1, 2
   • Low MRSA risk → Either cephalexin or dicloxacillin acceptable 1

3. Consider patient-specific factors:

   • Pediatric patient → Cephalexin preferred 1
   • Compliance concerns → Cephalexin preferred 4
   • Adult with confirmed MSSA requiring optimal bioavailability → Dicloxacillin acceptable 1

4. Ensure adequate source control: Drainage is often more important than antibiotic choice for abscesses 5, 6