What oral antibiotics can be used instead of cephalexin for an uncomplicated skin infection in an adult who cannot take cephalexin?

Alternate Antibiotics for Skin Infection When Cephalexin Cannot Be Used

For uncomplicated skin infections in adults who cannot take cephalexin, use dicloxacillin 250-500 mg orally every 6 hours or clindamycin 300-450 mg orally every 6 hours for 5 days, extending only if symptoms have not improved. 1, 2

First-Line Alternatives Based on Allergy Type

For True Penicillin/Cephalosporin Allergy (Non-Anaphylactic)

• Clindamycin 300-450 mg orally every 6 hours is the optimal single-agent choice because it covers both streptococci and MRSA without requiring combination therapy 2, 3
• Use clindamycin only if local MRSA clindamycin resistance rates are <10%—this is a critical threshold that determines appropriateness 2, 3
• Clindamycin achieves 90-97% cure rates for uncomplicated skin infections and provides excellent coverage against the primary pathogens: beta-hemolytic streptococci and Staphylococcus aureus 2, 4

For Patients Who Can Tolerate Other Beta-Lactams

• Dicloxacillin 250-500 mg every 6 hours provides excellent streptococcal and MSSA coverage and is comparable to cephalexin in efficacy 1, 2, 5
• Amoxicillin 500 mg three times daily is appropriate for typical nonpurulent cellulitis, as beta-lactam monotherapy achieves 96% clinical success 2
• Amoxicillin-clavulanate 875/125 mg twice daily offers broader coverage and is particularly useful for bite-related infections 2

Treatment Duration and Monitoring

• Treat for exactly 5 days if clinical improvement occurs—this is supported by high-quality randomized controlled trial evidence showing no difference compared to 10-day courses 2
• Extend treatment only if warmth, tenderness, or erythema have not improved within the initial 5-day period 2
• Traditional 7-14 day courses are no longer necessary for uncomplicated cases and represent overtreatment 2

When to Add MRSA Coverage

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

• Penetrating trauma or injection drug use 2
• Purulent drainage or exudate visible on examination 2
• Known MRSA colonization or prior MRSA infection 2
• Systemic inflammatory response syndrome (SIRS) 2
• Failure to respond to beta-lactam therapy after 48-72 hours 2

For purulent cellulitis requiring MRSA coverage:

• Clindamycin 300-450 mg every 6 hours as monotherapy (if local resistance <10%) 2, 3
• OR Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam (amoxicillin or dicloxacillin) 2
• OR Doxycycline 100 mg twice daily PLUS a beta-lactam 2

Critical Caveats

Do NOT Use These as Monotherapy for Typical Cellulitis:

• Doxycycline alone—lacks reliable activity against beta-hemolytic streptococci, which cause ~96% of typical cellulitis cases 2
• Trimethoprim-sulfamethoxazole alone—inadequate streptococcal coverage and intrinsic resistance possible 2
• Fluoroquinolones (levofloxacin, moxifloxacin)—should be reserved for patients with beta-lactam allergies; lack adequate MRSA coverage 2

Cross-Reactivity Considerations:

• Cross-reactivity between penicillins and cephalosporins is only 2-4%, primarily based on R1 side chain similarity 2
• Cephalexin shares identical R1 side chains with amoxicillin, so avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy 2
• For patients with anaphylaxis, angioedema, or urticaria to penicillins, do not use any cephalosporin 1

Essential Adjunctive Measures

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage 2
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat to reduce recurrence 2
• Address underlying venous insufficiency, lymphedema, and chronic edema as part of routine care 2

When to Hospitalize

Admit for IV antibiotics if any of the following are present:

• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm) 2
• Hypotension or hemodynamic instability 2
• Altered mental status or confusion 2
• Severe immunocompromise or neutropenia 2
• Concern for necrotizing infection (severe pain out of proportion, rapid progression, "wooden-hard" tissues) 2

For hospitalized patients: Vancomycin 15-20 mg/kg IV every 8-12 hours is first-line (A-I evidence), with alternatives including linezolid 600 mg IV twice daily or daptomycin 4 mg/kg IV once daily 2