What are the recommended oral medications (po meds) for a patient with mild to moderate cellulitis?

Oral Antibiotics for Mild to Moderate Cellulitis

For typical uncomplicated cellulitis, use beta-lactam monotherapy with cephalexin 500 mg orally every 6 hours, dicloxacillin 250-500 mg every 6 hours, or amoxicillin for 5 days—MRSA coverage is unnecessary in 96% of cases. 1

First-Line Oral Antibiotic Selection

Beta-lactam monotherapy is the standard of care for typical nonpurulent cellulitis, as MRSA is an uncommon cause even in high-prevalence settings. 1 The recommended oral agents include:

• Cephalexin 500 mg orally every 6 hours (four times daily) 1
• Dicloxacillin 250-500 mg every 6 hours 1, 2
• Amoxicillin (standard dosing) 1
• Amoxicillin-clavulanate 875/125 mg twice daily 1
• Penicillin V 250-500 mg four times daily 1

These agents provide excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, which are the primary pathogens in typical cellulitis. 1, 3

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs—extending treatment beyond this timeframe is only warranted if symptoms have not improved. 1 This represents a significant departure from traditional 7-14 day courses, which are no longer necessary for uncomplicated cases. 1 The 5-day duration applies specifically to nonpurulent cellulitis without systemic toxicity, penetrating trauma, purulent drainage, or MRSA risk factors. 1

When to Add MRSA Coverage

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

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Known MRSA colonization or prior MRSA infection 4
• Systemic inflammatory response syndrome (SIRS) 1
• Failure of beta-lactam therapy after 48 hours 4

MRSA-Active Oral Regimens

When MRSA coverage is needed, use one of these options:

• 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 rates are <10%) 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (such as cephalexin or amoxicillin) 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1, 5

Critical caveat: Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable. 1 These agents must be combined with a beta-lactam when treating nonpurulent cellulitis. 1

Special Populations

Penicillin/Cephalosporin Allergy

For patients with true penicillin and cephalosporin allergies:

• Clindamycin 300-450 mg orally every 6 hours (provides single-agent coverage, eliminating need for combination therapy if local resistance <10%) 1
• Levofloxacin 500 mg daily (reserve for beta-lactam allergies; lacks adequate MRSA coverage) 1

Diabetic Patients

Beta-lactam monotherapy remains appropriate for diabetic patients with uncomplicated cellulitis—gram-negative coverage is not warranted despite diabetes status. 4 Among diabetics with cellulitis and positive cultures, gram-negative pathogens were isolated in only 7% of cases, while gram-positive organisms were found in 90%. 4

First-line options for diabetics:

• Cephalexin 500 mg four times daily 4
• Dicloxacillin 250-500 mg every 6 hours 4
• Amoxicillin-clavulanate 875/125 mg twice daily 4

Bite-Related Cellulitis

For animal or human bite-associated cellulitis:

• Amoxicillin-clavulanate 875/125 mg twice daily as monotherapy (provides single-agent coverage for polymicrobial oral flora) 1

Essential Adjunctive Measures

Beyond antibiotics, these interventions hasten improvement:

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema 1
• Examine and treat interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration to eradicate colonization and reduce recurrent infection 1
• Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema 1

Common Pitfalls to Avoid

Do not reflexively add MRSA coverage for typical cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance. 1 Even in hospitals with high MRSA prevalence, MRSA is an uncommon cause of typical cellulitis. 1

Do not extend treatment to 7-10 days based on residual erythema alone—some inflammation persists even after bacterial eradication. 1 Extending treatment to 10-14 days based on tradition rather than evidence increases antibiotic resistance without improving outcomes. 1

Reassess patients within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens. 1

Evidence Quality Note

The recommendation for beta-lactam monotherapy is supported by A-I level evidence from the Infectious Diseases Society of America, with a 96% success rate in typical cellulitis cases. 1 The 5-day treatment duration is supported by high-quality randomized controlled trial evidence showing equivalence to 10-day courses for uncomplicated cellulitis. 1