What is the recommended initial antibiotic regimen for cellulitis, including options for patients with penicillin allergy and for those at high risk of community‑associated methicillin‑resistant Staphylococcus aureus (MRSA)?

Initial Antibiotic for Cellulitis

For typical uncomplicated cellulitis, prescribe a beta-lactam such as cephalexin 500 mg orally every 6 hours or dicloxacillin 250–500 mg orally every 6 hours for 5 days; MRSA coverage is unnecessary in the vast majority of cases and should be reserved only for specific high-risk scenarios. 1

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First-Line Therapy: Beta-Lactam Monotherapy

Beta-lactam antibiotics achieve approximately 96% clinical success in typical non-purulent cellulitis because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus (MSSA). 1, 2 MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, making routine MRSA coverage both unnecessary and a driver of antimicrobial resistance. 1

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
• Penicillin V 250–500 mg orally four times daily 1

Treatment Duration:

Treat for exactly 5 days if clinical improvement occurs (resolution of warmth and tenderness, improving erythema, absence of fever); extend 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 98% clinical resolution at 14 days and no relapses by 28 days. 1 Traditional 7–14-day regimens are unnecessary and promote resistance. 1

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When to Add MRSA Coverage

Add MRSA-active antibiotics only when any of the following specific risk factors are present: 1

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate (visible at the infection site) 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (SIRS): fever >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min 1
• Failure to respond to beta-lactam therapy after 48–72 hours 1

In the absence of these factors, adding MRSA coverage provides no additional benefit and represents overtreatment. 1 A randomized controlled trial demonstrated that adding trimethoprim-sulfamethoxazole to cephalexin for cellulitis without abscess, ulcer, or purulent drainage yielded no improvement in outcomes (85% cure rate with combination vs. 82% with cephalexin alone, risk difference 2.7%, 95% CI -9.3% to 15%, P=0.66). 3

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MRSA-Active Regimens (when indicated)

Oral Options for Purulent Cellulitis:

If MRSA coverage is required, choose one of the following: 1, 4

• Clindamycin 300–450 mg orally every 6 hours – provides single-agent coverage for both streptococci and MRSA, but use only if local MRSA clindamycin resistance is <10% due to inducible resistance concerns 1, 4

• Trimethoprim-sulfamethoxazole (TMP-SMX) 1–2 double-strength tablets twice daily PLUS a beta-lactam (e.g., cephalexin or amoxicillin) – TMP-SMX lacks reliable activity against beta-hemolytic streptococci, so combination therapy is mandatory for non-purulent cellulitis 1, 4

• Doxycycline 100 mg orally twice daily PLUS a beta-lactam – doxycycline also lacks reliable streptococcal coverage and must be combined with a beta-lactam; contraindicated in children <8 years (tooth discoloration, bone growth effects) and pregnancy category D 1, 4

Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis, as they will miss streptococcal pathogens in approximately 96% of cases. 1

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Penicillin Allergy Management

Non-Immediate Hypersensitivity (e.g., maculopapular rash):

• Cephalexin or other first-generation cephalosporins remain acceptable because cross-reactivity between penicillins and cephalosporins is only 2–4%, primarily based on R1 side-chain similarity rather than the beta-lactam ring. 1

Immediate Hypersensitivity (urticaria, angioedema, anaphylaxis):

• Clindamycin 300–450 mg orally every 6 hours (if local MRSA resistance <10%) 1
• Avoid cephalosporins in patients with confirmed immediate-type reactions 5

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Hospitalization Criteria and IV Therapy

Admit patients with cellulitis when any of the following are present: 1

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status) 1
• Signs of deeper or necrotizing infection (severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissue, gas or bullae) 1
• Severe immunocompromise or neutropenia 1
• Failure of outpatient therapy after 24–48 hours 1

IV Regimens for Hospitalized Patients:

Without MRSA risk factors:

• Cefazolin 1–2 g IV every 8 hours (preferred) 1
• Nafcillin or oxacillin 2 g IV every 6 hours (alternative) 1

Severe cellulitis with systemic toxicity or suspected necrotizing infection:

• Vancomycin 15–20 mg/kg IV every 8–12 hours PLUS piperacillin-tazobactam 3.375–4.5 g IV every 6 hours 1
• Alternative combinations: vancomycin plus a carbapenem (meropenem 1 g IV every 8 hours) or vancomycin plus ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

Duration for complicated infections: 7–14 days, individualized based on clinical response 1

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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
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration and treat these conditions to eradicate colonization and reduce recurrent infection 1
• Address predisposing conditions such as venous insufficiency, lymphedema, chronic edema, obesity, and eczema 1

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Common Pitfalls to Avoid

• Do not add MRSA coverage reflexively for typical non-purulent cellulitis without the specified risk factors; this overtreats approximately 96% of cases and drives antimicrobial resistance 1
• Do not automatically extend therapy to 7–10 days based solely on residual erythema; extend only if warmth, tenderness, or erythema have not improved after 5 days 1
• Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis, as they lack reliable activity against beta-hemolytic streptococci 1, 4
• Do not delay surgical consultation when signs of necrotizing infection (disproportionate pain, rapid progression, bullae, gas, necrosis) are present 1
• Do not treat simple abscesses with antibiotics alone; incision and drainage is the primary treatment, with antibiotics serving only an adjunctive role when high-risk features are present 6

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Reassessment and Treatment Failure

Reassess patients within 24–48 hours to verify clinical response; oral regimens have reported treatment failure rates of approximately 21% if no response is seen. 1 If no improvement after 48–72 hours of appropriate therapy, consider: 1

• Resistant organisms (MRSA) requiring culture-directed therapy
• Undrained abscess requiring incision and drainage
• Deeper infection (necrotizing fasciitis, septic arthritis, osteomyelitis)
• Alternative diagnoses (venous stasis dermatitis, contact dermatitis, eczema, lymphedema, erythema migrans) 2