What are the recommended antibiotic choices, doses, and treatment duration for uncomplicated non‑purulent cellulitis versus purulent cellulitis or cellulitis with methicillin‑resistant Staphylococcus aureus (MRSA) risk, including adjustments for diabetes, peripheral vascular disease, or immunocompromised patients?

Cellulitis Antibiotic Guide

First-Line Treatment for Uncomplicated Non-Purulent Cellulitis

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, achieving 96% clinical success because MRSA is an uncommon cause even in high-prevalence settings. 1, 2

Recommended Oral Regimens (Choose One)

• Cephalexin 500 mg orally every 6 hours for 5 days 1
• Dicloxacillin 250–500 mg orally every 6 hours for 5 days 1
• Amoxicillin 500 mg orally three times daily for 5 days 1
• Penicillin V 250–500 mg orally four times daily for 5 days 1

Treatment Duration

Treat for exactly 5 days if warmth, tenderness, and erythema are improving and the patient is afebrile; extend only if these symptoms have not improved. 1 High-quality randomized controlled trial evidence demonstrates that 5-day courses achieve 98% clinical resolution with no relapses by 28 days, making traditional 7–14-day regimens unnecessary and potentially harmful by promoting resistance. 1

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When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY when specific risk factors are present—do not add coverage reflexively. 1, 3

MRSA Risk Factors Requiring Coverage

• Penetrating trauma or injection drug use 1, 3
• Visible purulent drainage or exudate 1, 3
• Known MRSA colonization or prior MRSA infection 1, 3
• Systemic inflammatory response syndrome (fever >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min) 1, 3
• Failure to respond to beta-lactam therapy after 48–72 hours 1, 3

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Treatment for Purulent Cellulitis (MRSA Coverage Required)

Outpatient Oral Regimens (Choose One)

For purulent cellulitis with visible drainage, empiric MRSA coverage is mandatory. 4, 3

Single-Agent Options

• Clindamycin 300–450 mg orally every 6–8 hours for 5 days – provides coverage for both streptococci and MRSA, but use ONLY if local MRSA clindamycin resistance is <10%; associated with higher risk of Clostridioides difficile infection 4, 3

Combination Therapy (MRSA agent + beta-lactam for streptococcal coverage)

• Trimethoprim-sulfamethoxazole (TMP-SMX) 1–2 double-strength tablets orally twice daily PLUS cephalexin 500 mg every 6 hours for 5 days – TMP-SMX lacks reliable streptococcal coverage, so the beta-lactam is mandatory 4, 3
• Doxycycline 100 mg orally twice daily PLUS cephalexin 500 mg every 6 hours for 5 days – doxycycline alone misses streptococci in ~96% of typical cases 4, 3

Critical caveat: Never use TMP-SMX or doxycycline as monotherapy for typical cellulitis because they lack activity against beta-hemolytic streptococci, the predominant pathogens. 4, 1, 3

Contraindications

• TMP-SMX: pregnancy third trimester, infants <2 months 4
• Doxycycline: children <8 years (tooth discoloration, bone growth effects), pregnancy category D 4

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Inpatient IV Therapy for Complicated Cellulitis

Hospitalization Criteria

Admit patients with any of the following: 1

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

IV Antibiotic Regimens

For Complicated Cellulitis Requiring MRSA Coverage (A-I Evidence)

• Vancomycin 15–20 mg/kg IV every 8–12 hours (target trough 15–20 mg/L) 4, 3
• Linezolid 600 mg IV twice daily 4, 3
• Daptomycin 4 mg/kg IV once daily 4, 3
• Clindamycin 600 mg IV every 8 hours (only if local MRSA resistance <10%) 4, 3

For Severe Cellulitis with Systemic Toxicity or Suspected Necrotizing Fasciitis

Mandatory broad-spectrum combination therapy is required immediately: 1

• Vancomycin 15–20 mg/kg IV every 8–12 hours PLUS piperacillin-tazobactam 3.375–4.5 g IV every 6 hours 1, 3
• Alternative: Vancomycin PLUS meropenem 1 g IV every 8 hours 1
• Alternative: Vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

Duration: 7–14 days for complicated infections, guided by clinical response 4, 1

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Special Populations

Diabetes Mellitus

Diabetic foot infections are polymicrobial and require broader coverage than simple cellulitis. 1

Mild Diabetic Foot Infections (Oral)

• Amoxicillin-clavulanate 875/125 mg twice daily 1
• Levofloxacin 500 mg daily 1
• Cephalexin 500 mg every 6 hours 1

Moderate Diabetic Foot Infections (IV)

• Ceftriaxone 1–2 g IV daily 1
• Ampicillin-sulbactam 1.5–3 g IV every 6 hours 1
• Ertapenem 1 g IV daily 1

Severe Diabetic Foot Infections (IV)

• Piperacillin-tazobactam 3.375–4.5 g IV every 6 hours 1
• Imipenem-cilastatin 500 mg IV every 6 hours 1
• Vancomycin PLUS ceftazidime ± metronidazole 1

Peripheral Vascular Disease

Assess for underlying venous insufficiency, lymphedema, and chronic edema; treat predisposing conditions including tinea pedis and interdigital toe web abnormalities to reduce recurrence risk. 1 Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage. 1

Immunocompromised Patients

Immunocompromised status is a specific MRSA risk factor that mandates empirical MRSA-active therapy regardless of purulence. 1 Use vancomycin 15–20 mg/kg IV every 8–12 hours as first-line therapy. 4, 3 For severe infections, add piperacillin-tazobactam for broader polymicrobial coverage. 1

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Pediatric Dosing

Oral Therapy for Purulent Cellulitis

• Clindamycin: 10–13 mg/kg/dose every 6–8 hours (max 40 mg/kg/day), only if local resistance <10% 4
• TMP-SMX: 4–6 mg/kg/dose (trimethoprim component) twice daily PLUS a beta-lactam 4
• Doxycycline: 2 mg/kg/dose twice daily (max 100 mg/dose) for children ≥8 years and <45 kg 4

IV Therapy for Complicated Cellulitis

• Vancomycin: 15 mg/kg IV every 6 hours 4
• Clindamycin: 10–13 mg/kg/dose IV every 6–8 hours (max 40 mg/kg/day), only if stable, no bacteremia, and local resistance <10% 4
• Linezolid: 10 mg/kg/dose IV every 8 hours (max 600 mg/dose) for children <12 years; 600 mg IV twice daily for children ≥12 years 4

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Critical Pitfalls to Avoid

• Do not add MRSA coverage routinely for typical non-purulent cellulitis without specific risk factors—this overtreats ~96% of cases and promotes resistance 1, 5, 6
• Do not use TMP-SMX or doxycycline as monotherapy for typical cellulitis—they lack reliable activity against beta-hemolytic streptococci 4, 1, 3
• Do not automatically extend therapy to 7–10 days based on residual erythema alone—extend only if warmth, tenderness, or erythema have not improved after 5 days 1
• Do not delay surgical consultation when signs of necrotizing infection are present (severe pain out of proportion, skin anesthesia, rapid progression, "wooden-hard" tissue, gas, bullae)—these infections progress rapidly and require debridement 1
• Do not treat simple abscesses with antibiotics alone—incision and drainage is the definitive therapy; antibiotics are adjunctive only when specific risk factors are present 4, 1

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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 including venous insufficiency, lymphedema, chronic edema, obesity, and eczema to minimize recurrence risk 1, 2
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1