Is Keflex (cephalexin) effective for treating uncomplicated cellulitis?

Keflex (Cephalexin) for Cellulitis

Cephalexin is highly effective as first-line monotherapy for typical uncomplicated cellulitis, with a 96% success rate, and MRSA coverage is unnecessary in most cases. 1

First-Line Treatment Recommendation

For typical nonpurulent cellulitis, use cephalexin 500 mg orally four times daily for 5 days if clinical improvement occurs. 1 The Infectious Diseases Society of America designates beta-lactam monotherapy as the standard of care with A-I level evidence 2, 1. Cephalexin provides excellent coverage against the primary pathogens—beta-hemolytic streptococci (especially group A Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus—which cause the vast majority of cellulitis cases 2, 3.

Treatment Duration

• Treat for exactly 5 days if clinical improvement has occurred; extend only if symptoms have not improved within this timeframe. 1
• Five-day courses are as effective as 10-day courses for uncomplicated cellulitis, based on high-quality randomized controlled trial evidence 1
• Traditional 7-14 day courses are no longer necessary for uncomplicated cases 1

Why MRSA Coverage Is Usually Unnecessary

MRSA is an uncommon cause of typical cellulitis even in hospitals with high MRSA prevalence, and adding MRSA coverage provides no additional benefit in pure cellulitis. 1 A landmark randomized clinical trial demonstrated that combination therapy with trimethoprim-sulfamethoxazole plus cephalexin was no more efficacious than cephalexin alone for nonpurulent cellulitis without abscess, ulcer, or purulent drainage 1, 4. In the per-protocol analysis, clinical cure occurred in 83.5% with combination therapy versus 85.5% with cephalexin alone (difference -2.0%, 95% CI -9.7% to 5.7%, P=0.50) 4.

When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY when specific risk factors are present 1:

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate visible 1
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
• Systemic inflammatory response syndrome (SIRS)—fever, tachycardia, hypotension 1

If MRSA coverage is needed, use clindamycin 300-450 mg orally every 6 hours (covers both streptococci and MRSA as monotherapy), or combine trimethoprim-sulfamethoxazole or doxycycline with a beta-lactam 1.

Alternative Beta-Lactam Options

If cephalexin is unavailable or not tolerated 1:

• Dicloxacillin 250-500 mg every 6 hours 1
• Amoxicillin (appropriate dosing) 1
• Amoxicillin-clavulanate 875/125 mg twice daily (particularly for bite-associated cellulitis) 1

For hospitalized patients requiring IV therapy, cefazolin 1-2 g IV every 8 hours is the preferred parenteral beta-lactam 1.

Critical Adjunctive Measures

These non-antibiotic interventions significantly hasten improvement 1:

• Elevate the affected extremity above heart level to promote gravity drainage of edema and inflammatory substances 1
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treating these eradicates streptococcal colonization and reduces recurrence risk 2, 1
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, and obesity 1

When to Hospitalize

Admit patients with any of the following 1:

• Systemic inflammatory response syndrome (SIRS) criteria—fever, altered mental status, hemodynamic instability 1
• Severe immunocompromise or neutropenia 1
• Concern for deeper or necrotizing infection—severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, bullous changes 1
• Failure of outpatient treatment after 24-48 hours 1

For severe cellulitis with systemic toxicity, use vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1.

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance 1
• Do not extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable 1
• Reassess within 24-48 hours to verify clinical response—treatment failure rates of 21% have been reported with some regimens, indicating need for MRSA coverage or alternative diagnosis 1

Monitoring Response

• If no improvement with cephalexin after 48-72 hours, add empiric MRSA coverage immediately 1
• Consider resistant organisms, cellulitis mimickers (deep vein thrombosis, inflammatory conditions), or underlying complications like abscess requiring drainage 1
• Blood cultures are positive in only 5% of cases and are unnecessary for typical cellulitis 1