What is the recommended treatment with Keflex (cefalexin) for an adult patient with uncomplicated cellulitis?

Treatment of Uncomplicated Cellulitis with Keflex (Cephalexin)

For uncomplicated cellulitis in adults, prescribe cephalexin 500 mg orally four times daily for 5 days, extending only if clinical improvement has not occurred within this timeframe. 1, 2

Standard Dosing and Duration

• Cephalexin 500 mg orally every 6 hours (four times daily) is the recommended dose for typical nonpurulent cellulitis in adults with normal renal function. 2
• The FDA approves cephalexin for skin and skin structure infections caused by Staphylococcus aureus and Streptococcus pyogenes, the primary pathogens in cellulitis. 3
• Treatment duration is exactly 5 days if clinical improvement occurs—defined as resolution of warmth and tenderness, improving erythema, and absence of fever. 1, 2
• Extension beyond 5 days is warranted only if no improvement in warmth, tenderness, or erythema is observed, at which point reassess for complications or resistant organisms. 2

Why Cephalexin Monotherapy Is Sufficient

• Beta-lactam monotherapy succeeds in 96% of uncomplicated cellulitis cases, confirming that MRSA coverage is unnecessary in typical presentations. 2
• The Infectious Diseases Society of America establishes that MRSA is an uncommon cause of typical cellulitis, even in hospitals with high MRSA prevalence. 1, 2
• Two high-quality randomized controlled trials demonstrated that adding trimethoprim-sulfamethoxazole to cephalexin provides no additional benefit: clinical cure occurred in 85% with combination therapy versus 82% with cephalexin alone (risk difference 2.7%, 95% CI -9.3% to 15%, P=0.66). 4, 5
• Cephalexin provides excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, the predominant pathogens in nonpurulent cellulitis. 2, 6

When Cephalexin Alone Is NOT Appropriate

Do not use cephalexin monotherapy when any of these MRSA risk factors are present: 1, 2

• Penetrating trauma or injection drug use
• Purulent drainage or exudate visible on examination
• Evidence of MRSA infection elsewhere or documented nasal MRSA colonization
• Systemic inflammatory response syndrome (SIRS): fever >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min

For these scenarios, switch to clindamycin 300-450 mg orally four times daily, which covers both streptococci and MRSA without requiring combination therapy. 1, 2 Alternatively, use trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam, or doxycycline 100 mg twice daily PLUS a beta-lactam. 1, 2

Critical Caveats and Common Pitfalls

• Never use cephalexin for suspected Lyme disease presenting as erythema migrans, as it has poor activity against Borrelia burgdorferi and will result in disease progression. 7 In endemic areas during summer months, consider Lyme disease in the differential diagnosis before prescribing cephalexin for presumed cellulitis. 7
• Do not reflexively extend treatment to 7-14 days based on residual erythema alone, as some inflammation persists even after bacterial eradication. 2 This represents overtreatment and increases antibiotic resistance without improving outcomes. 2
• Perform ultrasound if any clinical uncertainty exists about abscess formation, as purulent collections require incision and drainage plus MRSA-active antibiotics, not cephalexin alone. 2
• A pilot trial suggests high-dose cephalexin 1000 mg four times daily may reduce treatment failures (3.2% vs 12.9% with standard dosing), though this requires confirmation in larger trials. 8

Essential Adjunctive Measures

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema and inflammatory substances. 1, 2
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration, as treating these eradicates colonization and reduces recurrent infection risk. 1, 2
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, and eczema to prevent recurrence. 1, 2

When to Hospitalize

Admit patients with any of the following: 2

• Systemic inflammatory response syndrome (SIRS), hypotension, or altered mental status
• Severe immunocompromise or neutropenia
• Signs of necrotizing infection: severe pain out of proportion to examination, skin anesthesia, rapid progression, gas in tissue, or bullous changes

For hospitalized patients requiring IV therapy, use cefazolin 1-2 g IV every 8 hours for uncomplicated cellulitis without MRSA risk factors. 1, 2 For severe cellulitis with systemic toxicity or suspected necrotizing fasciitis, use vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours. 1, 2