Cephalexin for Cellulitis
Cephalexin 500 mg orally every 6 hours for 5 days is the preferred first-line treatment for typical uncomplicated cellulitis in adults, providing excellent coverage against the primary pathogens—beta-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus—with a 96% success rate. 1
First-Line Antibiotic Selection
Beta-lactam monotherapy remains the standard of care for typical nonpurulent cellulitis, and cephalexin is specifically recommended as a preferred oral agent by the Infectious Diseases Society of America with A-I level evidence. 2, 1
Cephalexin is FDA-approved for skin and skin structure infections caused by Staphylococcus aureus and Streptococcus pyogenes, the exact pathogens responsible for most cellulitis cases. 3
The standard dosing is cephalexin 500 mg orally every 6 hours (four times daily) for adults with normal renal function. 1
Alternative oral beta-lactams with equivalent efficacy include dicloxacillin 250-500 mg every 6 hours, amoxicillin, or penicillin V 250-500 mg four times daily. 2, 1
Treatment Duration
Treat for exactly 5 days if clinical improvement has occurred—defined as resolution of warmth and tenderness with improving erythema—extending only if symptoms have not improved within this timeframe. 1
High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis, with no difference in recurrence rates. 2, 1
The traditional 7-14 day courses are no longer necessary for uncomplicated cases and represent overtreatment that increases antibiotic resistance without improving outcomes. 1
When MRSA Coverage Is NOT Needed
MRSA is an uncommon cause of typical nonpurulent cellulitis even in high-prevalence settings, and routine MRSA coverage is unnecessary—beta-lactam monotherapy succeeds in 96% of cases. 1
A landmark randomized controlled trial demonstrated that adding trimethoprim-sulfamethoxazole to cephalexin provided no additional benefit over cephalexin alone for uncomplicated cellulitis (83.5% vs 85.5% cure rates, difference -2.0%, 95% CI -9.7% to 5.7%). 4
Do not reflexively add MRSA coverage simply because community-acquired MRSA prevalence is high in your area—the pathogen causing typical cellulitis remains predominantly streptococcal regardless of local MRSA rates. 1, 5
When to Add MRSA Coverage
Add MRSA-active antibiotics ONLY when specific risk factors are present: 1
- Penetrating trauma or injection drug use
- Purulent drainage or exudate (without a drainable abscess)
- Evidence of MRSA infection elsewhere or known nasal MRSA colonization
- Systemic inflammatory response syndrome (SIRS): fever >38°C, heart rate >90, respiratory rate >24, or altered mental status
- Failure to respond to beta-lactam therapy after 48-72 hours
When MRSA coverage is indicated, use clindamycin 300-450 mg orally every 6 hours as monotherapy (covers both streptococci and MRSA), or combine trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS cephalexin. 1
Renal Dosing Considerations
For patients with GFR 30-59 mL/min, no dose adjustment is needed for cephalexin 500 mg every 6 hours. 1
For GFR 10-29 mL/min, reduce to cephalexin 250-500 mg every 8-12 hours. 1
For GFR <10 mL/min or hemodialysis, use cephalexin 250-500 mg every 12-24 hours. 1
Penicillin/Cephalosporin Allergy Alternatives
For patients with true penicillin or cephalosporin allergy, clindamycin 300-450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA, eliminating the need for combination therapy (but only if local MRSA clindamycin resistance rates are <10%). 1, 6
Cross-reactivity between penicillins and cephalosporins is only 2-4%, primarily based on R1 side chain similarity rather than the beta-lactam ring itself. 1
Cephalexin shares identical R1 side chains with amoxicillin, so avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy. 1
Essential Adjunctive Measures
Elevate the affected extremity above heart level for at least 30 minutes three times daily—this hastens improvement by promoting gravity drainage of edema and inflammatory substances, yet is often neglected. 2, 1
Examine interdigital toe spaces carefully for tinea pedis, fissuring, scaling, or maceration—treating these eradicates streptococcal colonization and reduces recurrent infection risk. 2, 1
Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, and obesity. 2, 1
Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults to hasten resolution, though evidence is limited and this should be avoided in diabetic patients. 2, 1
Hospitalization Criteria
Admit patients with any of the following: 1
- SIRS criteria (fever, tachycardia, hypotension, altered mental status)
- Severe immunocompromise or neutropenia
- Concern for deeper or necrotizing infection (severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues, gas in tissue, bullous changes)
- Failure of outpatient treatment after 24-48 hours
- Inability to tolerate oral medications or poor adherence
For hospitalized patients requiring IV therapy, use cefazolin 1-2 g IV every 8 hours as the preferred beta-lactam, or vancomycin 15-20 mg/kg IV every 8-12 hours if MRSA coverage is needed. 1
Common Pitfalls to Avoid
Do not extend treatment to 10-14 days based on residual erythema alone—some inflammation persists even after bacterial eradication, and extending antibiotics based on tradition rather than evidence increases resistance without improving outcomes. 1
Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—their activity against beta-hemolytic streptococci is unreliable. 1
Do not obtain blood cultures for typical uncomplicated cellulitis—they are positive in only 5% of cases and are unnecessary unless the patient has severe systemic features, malignancy, neutropenia, or unusual predisposing factors. 1
Do not assume treatment failure automatically means MRSA—consider alternative diagnoses including abscess requiring drainage (obtain ultrasound if uncertain), deep vein thrombosis mimicking cellulitis, necrotizing infection, or non-infectious mimickers like venous stasis dermatitis. 1
Monitoring Response to Therapy
Reassess within 24-48 hours for outpatients to ensure clinical improvement—warmth and tenderness should be resolving, erythema should be improving, and the patient should be afebrile. 1
If no improvement with appropriate first-line antibiotics after 48-72 hours, consider resistant organisms (add MRSA coverage), cellulitis mimickers, or underlying complications requiring imaging or surgical consultation. 1