What oral antibiotic is appropriate for an adult with a mild‑to‑moderate superficial skin infection (e.g., impetigo, cellulitis, erysipelas) who has a documented penicillin allergy?

Oral Antibiotic Selection for Superficial Skin Infections in Penicillin-Allergic Patients

For adults with mild-to-moderate superficial skin infections (impetigo, cellulitis, erysipelas) who are allergic to penicillin, clindamycin 300–450 mg orally every 6 hours for 5 days is the preferred first-line agent, providing single-agent coverage of both streptococci and staphylococci without requiring combination therapy. 1, 2, 3

First-Line Oral Antibiotic: Clindamycin

• Clindamycin is specifically indicated by the FDA for serious skin and soft tissue infections in penicillin-allergic patients, covering both streptococci and staphylococci—the primary pathogens in superficial skin infections. 3

• The standard adult dose is 300–450 mg orally every 6 hours for 5 days, extending only if warmth, tenderness, or erythema have not improved within this timeframe. 1, 2

• Clindamycin provides the critical advantage of single-agent therapy, eliminating the need for combination regimens while covering both beta-hemolytic streptococci (Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus (MSSA), as well as community-acquired MRSA. 1, 2, 4

• Use clindamycin only when local MRSA clindamycin-resistance rates are <10%; in areas with higher resistance, alternative regimens are required. 1, 2

Alternative Oral Options When Clindamycin Is Unavailable or Contraindicated

Combination Therapy for Non-Purulent Cellulitis

• Trimethoprim-sulfamethoxazole (TMP-SMX) 1–2 double-strength tablets twice daily PLUS a beta-lactam alternative (such as a cephalosporin if the penicillin allergy is non-severe) provides dual coverage. 1

• Doxycycline 100 mg orally twice daily PLUS a beta-lactam alternative is another combination option, but doxycycline alone is inadequate because it lacks reliable activity against beta-hemolytic streptococci. 1, 2

• Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis—both agents fail to cover streptococci reliably, which cause the majority of superficial skin infections. 1, 2

Macrolides (Less Preferred)

• Azithromycin 500 mg orally once daily for 5 days or erythromycin 500 mg orally four times daily can be used in penicillin-allergic patients, but macrolide resistance among Group A streptococci is increasing (>10% in many regions), making these agents less reliable. 2, 4, 5, 6

• Macrolides should be avoided as first-line therapy due to rising resistance patterns and inferior efficacy compared to clindamycin. 2

Cephalosporin Use in Penicillin Allergy: When Safe, When Not

• Patients without severe or immediate penicillin reactions (no urticaria, angioedema, bronchospasm, or anaphylaxis) may safely receive first-generation cephalosporins such as cephalexin 500 mg every 6 hours, because cross-reactivity is <1% and primarily side-chain dependent. 2, 7

• Avoid all beta-lactams (including cephalosporins) in patients with documented severe/immediate penicillin hypersensitivity reactions (urticaria, angioedema, bronchospasm, anaphylaxis) or reactions within the past year. 2

• Cefdinir and cefpodoxime (extended-spectrum cephalosporins) carry very low cross-reactivity risk with penicillin and demonstrate excellent activity against S. aureus and S. pyogenes, making them viable alternatives in non-severe penicillin allergy. 7

Treatment Duration and Monitoring

• Treat for exactly 5 days if clinical improvement occurs (resolution of warmth/tenderness, improving erythema, no fever); extend only if symptoms persist. 1, 2

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

When to Add MRSA Coverage

• Routine MRSA coverage is unnecessary for typical non-purulent cellulitis, even in penicillin-allergic patients, unless specific risk factors are present. 1

• Add MRSA-active therapy only when any of the following exist:

  • Purulent drainage or exudate at the infection site 1
  • Penetrating trauma or injection drug use 1
  • Known MRSA colonization or prior MRSA infection 1
  • Systemic inflammatory response syndrome (fever >38°C, tachycardia, hypotension) 1
  • Failure to respond to initial therapy after 48–72 hours 1

Severe Infections Requiring Intravenous Therapy

• For hospitalized penicillin-allergic patients with severe cellulitis, vancomycin 15–20 mg/kg IV every 8–12 hours is first-line, targeting trough levels of 15–20 mg/L. 1, 2

• Alternative IV options include linezolid 600 mg IV twice daily or daptomycin 4 mg/kg IV once daily, both with A-I level evidence for complicated skin infections. 1, 2

• IV clindamycin 600 mg every 8 hours is appropriate for severe infections when local MRSA clindamycin-resistance is <10%. 1, 2

Critical Pitfalls to Avoid

• Do not use beta-lactams (cephalexin, dicloxacillin, amoxicillin) in patients with true severe/immediate penicillin allergy, as cross-reactivity can cause life-threatening reactions. 2

• Do not prescribe doxycycline or TMP-SMX alone for typical cellulitis—these agents lack streptococcal coverage and will fail in the majority of cases. 1, 2

• Do not reflexively add MRSA coverage for all superficial skin infections; MRSA is uncommon in typical non-purulent cellulitis even in high-prevalence settings. 1

• Do not extend therapy beyond 5 days based solely on residual erythema—inflammation may persist after bacterial eradication; extend only if warmth, tenderness, or erythema have not improved. 1

Adjunctive Measures

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema and hasten clinical improvement. 1

• Treat predisposing conditions such as tinea pedis, venous insufficiency, lymphedema, and chronic edema to reduce recurrence risk. 1