What is the first‑line outpatient oral antibiotic regimen for an otherwise healthy adult with uncomplicated acute leg cellulitis who can take oral medication, and how should therapy be modified if there are risk factors for community‑acquired methicillin‑resistant Staphylococcus aureus or a beta‑lactam allergy?

First-Line Outpatient Treatment for Uncomplicated Leg Cellulitis

For an otherwise healthy adult with uncomplicated acute leg cellulitis, beta-lactam monotherapy—specifically cephalexin 500 mg orally four times daily for 5 days—is the standard of care, achieving 96% clinical success without MRSA coverage. 1

Standard First-Line Regimen

Beta-lactam monotherapy is the evidence-based first choice because β-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus cause the vast majority of typical cellulitis, and MRSA is an uncommon pathogen even in high-prevalence settings. 1, 2

Recommended Oral Agents (Choose One):

• Cephalexin 500 mg orally every 6 hours 1
• Dicloxacillin 250–500 mg orally every 6 hours 1
• Amoxicillin 500 mg orally three times daily 1
• Amoxicillin-clavulanate 875/125 mg orally twice daily 1

Treatment duration is exactly 5 days if clinical improvement occurs (resolution of warmth and tenderness, improving erythema, afebrile); extend only if symptoms have not improved within this timeframe. 1, 3 Traditional 7–14 day courses are no longer necessary for uncomplicated cases. 1

When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY when specific risk factors are present: 1, 2

• 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 >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min, or altered mental status 1
• Failure to respond to beta-lactam therapy after 48–72 hours 1

Critical evidence: A landmark randomized 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 However, in MRSA-prevalent areas, antibiotics lacking MRSA activity had 4.22 times higher odds of treatment failure (95% CI 2.25–7.92) when MRSA risk factors were present. 5

MRSA-Active Regimens (When Risk Factors Present)

Option 1: Clindamycin Monotherapy (Preferred)

Clindamycin 300–450 mg orally every 6 hours for 5 days provides single-agent coverage for both streptococci and MRSA, eliminating the need for combination therapy. 1 Use only if local MRSA clindamycin resistance rates are <10%. 1

Option 2: Combination Therapy

• Trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS cephalexin 500 mg four times daily 1
• Doxycycline 100 mg orally twice daily PLUS cephalexin 500 mg four times daily 1

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—both lack reliable activity against β-hemolytic streptococci, which cause the majority of cases. 1

Beta-Lactam Allergy Management

For Penicillin/Cephalosporin Allergy:

Clindamycin 300–450 mg orally every 6 hours for 5 days is the optimal choice, providing coverage for both streptococci (99.5% of S. pyogenes remain susceptible) and MRSA without requiring combination therapy. 1, 6

Alternative if clindamycin resistance >10%: Linezolid 600 mg orally twice daily (expensive, reserve for complicated cases). 1

Cross-Reactivity Nuance:

Cephalosporin-penicillin cross-reactivity is only 2–4%, primarily based on R1 side-chain similarity rather than the beta-lactam ring itself. 1 Patients with suspected immediate-type cephalosporin allergy can receive penicillins with dissimilar side chains, and any carbapenem can be safely used. 1

Essential Adjunctive Measures

Elevation of the affected leg above heart level for at least 30 minutes three times daily hastens improvement by promoting gravity drainage of edema and inflammatory substances—this is critical and often neglected. 1

Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration; treating these eradicates colonization and reduces recurrent infection risk. 1

Address predisposing conditions: venous insufficiency, lymphedema, chronic edema, eczema, and obesity. 1

Common Pitfalls to Avoid

Do not routinely add MRSA coverage for typical nonpurulent cellulitis without specific risk factors—this represents overtreatment, increases antibiotic resistance, and provides no additional benefit. 1, 4

Do not extend treatment to 7–10 days based on residual erythema alone—some inflammation persists even after bacterial eradication; 5 days is sufficient if clinical improvement has occurred. 1, 3

Do not obtain blood cultures for uncomplicated cellulitis—they are positive in only ~5% of typical cases and represent unnecessary resource utilization. 1

Reassess within 24–48 hours to verify clinical response; treatment failure should prompt consideration for resistant organisms, cellulitis mimickers (deep vein thrombosis, stasis dermatitis), or underlying complications (abscess requiring drainage, necrotizing infection). 1

Hospitalization Criteria

Admit if any of the following are present: 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 exam, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues)
• Failure of outpatient treatment after 24–48 hours

For hospitalized patients requiring IV therapy: Cefazolin 1–2 g IV every 8 hours is the preferred beta-lactam; 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