What is the appropriate amoxicillin dosing regimen for an otherwise healthy adult with uncomplicated non‑purulent cellulitis and normal renal function?

Amoxicillin Dosing for Cellulitis

For uncomplicated non-purulent cellulitis in an otherwise healthy adult, prescribe amoxicillin 500 mg orally three times daily for 5 days, extending only if warmth, tenderness, or erythema have not improved within this timeframe. 1

Standard Dosing Regimen

• Amoxicillin 500 mg orally three times daily (every 8 hours) is the appropriate dose for adults with cellulitis, providing adequate coverage against beta-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus, the primary pathogens in typical cellulitis. 2, 3, 4

• The FDA-approved adult dosing range for amoxicillin is 750–1750 mg/day in divided doses every 8–12 hours, and 500 mg three times daily (1500 mg/day total) falls within this therapeutic window. 3

• Beta-lactam monotherapy achieves approximately 96% clinical success in typical non-purulent cellulitis, confirming that amoxicillin alone is sufficient without adding MRSA coverage in uncomplicated cases. 1, 2, 4

Treatment Duration: The 5-Day Standard

• Treat for exactly 5 days if clinical improvement occurs (resolution of warmth and tenderness, improving erythema, absence of fever); extend only if these signs have not improved. 1, 5

• 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 relapse by 28 days in both groups. 1, 5

• Traditional 7–14 day regimens are unnecessary for uncomplicated cases and contribute to antibiotic resistance without improving outcomes. 1

When Amoxicillin Alone Is Appropriate

• Use amoxicillin monotherapy for typical non-purulent cellulitis presenting with acute onset of redness, warmth, swelling, tenderness, and pain, without purulent drainage or systemic toxicity. 2, 4

• Amoxicillin is appropriate when the patient has no MRSA risk factors: no penetrating trauma, no injection drug use, no purulent drainage/exudate, no known MRSA colonization, and no systemic inflammatory response syndrome. 1, 2

• The majority of non-purulent cellulitis cases are caused by beta-hemolytic streptococci or methicillin-sensitive Staphylococcus aureus, making targeted beta-lactam coverage with amoxicillin sufficient. 4

When to Add MRSA Coverage (and Avoid Amoxicillin Monotherapy)

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

• Penetrating trauma or injection drug use 1, 2

• Visible purulent drainage or exudate at the infection site 1, 2

• Known MRSA colonization or prior MRSA infection 1, 2

• Systemic inflammatory response syndrome (fever >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min) 1, 2

• Failure to respond to beta-lactam therapy after 48–72 hours 1, 2

• When MRSA coverage is needed, switch to clindamycin 300–450 mg orally every 6 hours (if local MRSA clindamycin resistance <10%) or use trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS a beta-lactam (such as amoxicillin or cephalexin). 1, 2, 6

Alternative Beta-Lactam Options

• Cephalexin 500 mg orally every 6 hours is the most commonly recommended first-line oral beta-lactam for cellulitis, with equivalent efficacy to amoxicillin. 1, 2, 6

• Dicloxacillin 250–500 mg orally every 6 hours provides excellent streptococcal and MSSA coverage and is another appropriate alternative. 1, 2, 6

• Amoxicillin-clavulanate 875/125 mg orally twice daily may be used when broader coverage is desired, particularly for bite-related cellulitis or when beta-lactamase-producing organisms are suspected. 2, 6, 7

Hospitalization Criteria

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

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status) 1, 2, 6

• Signs of deeper or necrotizing infection (severe pain out of proportion, skin anesthesia, rapid progression, "wooden-hard" tissue) 1, 2, 6

• Severe immunocompromise or neutropenia 1, 2, 6

• Failure of outpatient treatment after 24–48 hours 1, 2, 6

• For hospitalized patients requiring IV therapy, use cefazolin 1–2 g IV every 8 hours or nafcillin 2 g IV every 6 hours for uncomplicated cellulitis without MRSA risk factors. 2, 6

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, which hastens clinical improvement. 1, 2, 6

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration, and treat these conditions to eradicate colonization and reduce recurrent infection. 1, 2, 6

• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema to reduce recurrence risk. 1, 2, 6

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical non-purulent cellulitis without the specified risk factors, as MRSA is an uncommon cause even in high-prevalence settings and routine coverage promotes resistance. 1, 2, 6, 4

• Do not automatically extend therapy to 7–10 days based on residual erythema alone; some inflammation persists even after bacterial eradication, and extension should occur only if warmth, tenderness, or erythema have not improved after 5 days. 1, 2

• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as they lack reliable activity against beta-hemolytic streptococci, the predominant pathogens. 1, 2, 6

• Reassess patients within 24–48 hours to verify clinical response, as treatment failure rates of approximately 21% have been reported with some oral regimens, and inadequate dosing is independently associated with clinical failure. 2, 8