What antibiotic should I prescribe for an adult patient with a skin infection and a documented penicillin allergy, assuming no other drug allergies and normal hepatic function?

Antibiotic Selection for Skin Infections in Penicillin-Allergic Patients

For a patient with a skin infection and documented penicillin allergy, clindamycin 300-450 mg orally every 6 hours for 5 days is the preferred first-line agent, providing single-agent coverage for both streptococci and MRSA without requiring combination therapy. 1, 2, 3

Understanding the Type of Penicillin Allergy

The severity and timing of the allergic reaction fundamentally determines your antibiotic choice:

• For non-severe, delayed-type reactions (e.g., simple rash): First-generation cephalosporins like cephalexin 500 mg every 6 hours remain safe options, as cross-reactivity between penicillins and cephalosporins is only 2-4% and primarily based on R1 side chain similarity rather than the beta-lactam ring itself 4, 1

• For severe/immediate hypersensitivity (urticaria, angioedema, bronchospasm, anaphylaxis): Avoid all beta-lactam antibiotics including cephalosporins entirely 2, 5

First-Line Treatment Algorithm

For Typical Non-Purulent Cellulitis

Clindamycin 300-450 mg orally every 6 hours for 5 days is your optimal choice because:

• It provides excellent coverage against both beta-hemolytic streptococci (the primary pathogen in ~85% of typical cellulitis) and methicillin-sensitive Staphylococcus aureus 1, 6, 3
• It covers MRSA if present, eliminating the need to add a second agent 1, 2
• It has no cross-reactivity with penicillins or cephalosporins 2
• The FDA explicitly indicates clindamycin for serious skin and soft tissue infections in penicillin-allergic patients 3

Critical caveat: Use clindamycin only if local MRSA clindamycin-resistance rates are <10%; if resistance exceeds this threshold, you must choose an alternative regimen 1, 6

For Purulent Cellulitis (Visible Drainage or Exudate)

When purulent drainage is present, MRSA coverage becomes mandatory:

• Clindamycin 300-450 mg every 6 hours remains first-line if local resistance is <10% 1, 2
• Alternative: Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily, but you must combine it with a beta-lactam if the patient can tolerate cephalosporins, because TMP-SMX lacks reliable streptococcal coverage 1, 2, 6

Alternative Regimens When Clindamycin Cannot Be Used

If Clindamycin Resistance is High or Patient Cannot Tolerate It

• Doxycycline 100 mg twice daily PLUS a first-generation cephalosporin (if the patient's penicillin allergy was non-severe/delayed-type) provides dual coverage 1, 6
• Never use doxycycline alone for typical cellulitis—it lacks reliable activity against beta-hemolytic streptococci, which cause ~96% of cases 1

If All Beta-Lactams Must Be Avoided (Severe Allergy)

• Doxycycline 100 mg twice daily (after 200 mg loading dose on day 1) for purulent infections where MRSA is the primary concern 6
• Linezolid 600 mg twice daily is reserved for severe infections or treatment failures, given its cost and side-effect profile 1, 7

Treatment Duration

• Treat for exactly 5 days if clinical improvement occurs (warmth and tenderness resolving, erythema improving, patient afebrile) 1, 6
• Extend treatment only if symptoms have not improved within this 5-day window 1, 6
• Traditional 7-14 day courses are no longer necessary for uncomplicated cellulitis and represent overtreatment 1

Essential Adjunctive Measures

Beyond antibiotics, these interventions accelerate recovery:

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema 1, 6
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat if present, as this eradicates colonization and reduces recurrence 1, 6
• Address underlying venous insufficiency, lymphedema, or chronic edema to prevent recurrent episodes 1, 6

Critical Pitfalls to Avoid

• Do not reflexively add MRSA coverage to all skin infections in penicillin-allergic patients—typical non-purulent cellulitis succeeds with streptococcal coverage alone in 96% of cases 1
• Do not use erythromycin or macrolides—resistance rates exceed 40% among S. pneumoniae and are increasing in staphylococci and streptococci 6, 8
• Do not continue ineffective antibiotics beyond 48-72 hours—reassess for resistant organisms, abscess formation, or deeper infection requiring drainage or IV therapy 1, 2, 6

When to Escalate to Intravenous Therapy

Hospitalize and initiate IV antibiotics if any of the following develop:

• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm) 1
• Hypotension, altered mental status, or confusion 1, 6
• Severe pain out of proportion to examination, skin anesthesia, rapid progression, or "wooden-hard" subcutaneous tissues (suggesting necrotizing fasciitis) 1, 6

For severe infections requiring hospitalization, vancomycin 15-20 mg/kg IV every 8-12 hours is first-line, with linezolid 600 mg IV twice daily or daptomycin 4 mg/kg IV once daily as alternatives 1, 2