Cephalexin (Keflex) for Uncomplicated Bacterial Skin Infection
Cephalexin 500 mg orally every 6 hours for 5 days is appropriate first-line therapy for adults with typical non-purulent cellulitis, achieving 96% clinical success without requiring MRSA coverage. 1
Standard Dosing Regimen
- Adults: Cephalexin 500 mg orally every 6 hours (four times daily) for 5 days if clinical improvement occurs 2, 3
- Treatment duration: Extend beyond 5 days only if warmth, tenderness, or erythema have not improved within this timeframe 1, 2
- Renal adjustment: No dose modification needed for creatinine clearance 30–70 mL/min 2
When Cephalexin Monotherapy Is Appropriate
- Non-purulent cellulitis without drainage, exudate, or abscess 1, 2
- Absence of MRSA risk factors: no penetrating trauma, injection drug use, purulent drainage, known MRSA colonization, or systemic inflammatory response syndrome 1, 2
- Outpatient setting with ability to self-monitor and close follow-up within 24–48 hours 2
Beta-lactam monotherapy succeeds in 96% of typical cellulitis cases because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, not MRSA. 1
When to Add MRSA Coverage (Do NOT Use Cephalexin Alone)
Add MRSA-active antibiotics only when specific risk factors are present:
- Purulent drainage or exudate visible at the infection site 1, 2
- Penetrating trauma or injection drug use 1, 2
- Known MRSA colonization or prior MRSA infection 1
- Systemic inflammatory response syndrome (fever >38°C, tachycardia, tachypnea) 1
- Failure to respond to cephalexin after 48–72 hours 1, 2
For these scenarios: Use clindamycin 300–450 mg orally every 6 hours (if local MRSA clindamycin resistance <10%) OR combine trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS cephalexin. 1, 2
Essential Adjunctive Measures
- Elevate the affected limb above heart level for 30 minutes three times daily to promote edema drainage 1, 2
- Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat if present to reduce recurrence 1, 2
- Address predisposing conditions: venous insufficiency, lymphedema, chronic edema 1, 2
Reassessment and Red Flags
- Mandatory reassessment within 24–48 hours because oral regimen failure rates reach 21% in some studies 1, 2
- Switch to MRSA-active therapy (vancomycin 15–20 mg/kg IV every 8–12 hours or clindamycin) if cellulitis worsens after 48–72 hours of cephalexin 2
Immediate surgical consultation required for:
- Severe pain out of proportion to examination 1, 2
- Skin anesthesia, rapid progression, or "wooden-hard" subcutaneous tissue 1, 2
- Systemic toxicity (hypotension, altered mental status) 1, 2
Critical Pitfalls to Avoid
- Do not extend therapy to 7–10 days based solely on residual erythema; inflammation persists after bacterial eradication 1, 2
- Do not add MRSA coverage routinely for typical cellulitis without specific risk factors—this overtreats 96% of cases and drives resistance 1, 2
- Do not use cephalexin for Lyme disease—it lacks activity against Borrelia burgdorferi 2
- Do not use cephalexin for animal bites—it has poor activity against Pasteurella multocida; use amoxicillin-clavulanate instead 4
Penicillin Allergy Considerations
- Cross-reactivity between penicillins and cephalosporins is only 2–4%, primarily based on R1 side-chain similarity 5, 4
- Cephalexin shares identical R1 side chains with amoxicillin/ampicillin, so avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy 5, 4
- Patients with anaphylaxis, angioedema, or urticaria to penicillins should NOT receive cephalexin; use clindamycin instead 4
Evidence Quality
The 5-day treatment duration is supported by high-quality randomized controlled trial evidence showing no difference in outcomes compared with 10-day courses for uncomplicated cellulitis. 1 Traditional 7–14-day regimens are no longer necessary. 1