What antibiotics to use next for simple cellulitis if Keflex (Cephalexin) is not effective?

Next-Line Antibiotic for Simple Cellulitis After Cephalexin Failure

If cephalexin has failed for simple cellulitis with recent antibiotic exposure, switch to clindamycin 300-450 mg orally every 6 hours for 5 days, as it provides single-agent coverage for both streptococci and MRSA without requiring combination therapy. 1

Critical Decision Points After Beta-Lactam Failure

When cephalexin fails in simple cellulitis, you must immediately reassess for three possibilities:

• MRSA involvement – Recent antibiotic exposure increases MRSA risk, and clindamycin covers both streptococci and MRSA as monotherapy 1, 2
• Necrotizing infection – Evaluate for severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, systemic toxicity, or bullous changes requiring emergent surgical consultation 1
• Misdiagnosis – Consider pseudocellulitis mimics like venous stasis dermatitis, contact dermatitis, or lymphedema 3

Recommended Treatment Algorithm

First-Line After Cephalexin Failure: Clindamycin Monotherapy

• Clindamycin 300-450 mg orally every 6 hours for 5 days is the optimal choice, providing coverage for both streptococci and MRSA without combination therapy 1, 2
• Use clindamycin only if local MRSA clindamycin resistance rates are <10% 1
• Treatment duration is 5 days if clinical improvement occurs, extending only if symptoms persist 1

Alternative Regimens if Clindamycin Resistance is High

If local clindamycin resistance exceeds 10%, use combination therapy:

• Trimethoprim-sulfamethoxazole (SMX-TMP) 320/1600 mg twice daily PLUS a beta-lactam (such as amoxicillin or dicloxacillin) 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam 1
• Never use doxycycline or SMX-TMP as monotherapy – their activity against beta-hemolytic streptococci is unreliable 1

Evidence Supporting This Approach

The critical evidence distinguishing this recommendation:

• Beta-lactam monotherapy succeeds in 96% of typical cellulitis cases, but cephalexin specifically has a 40% failure rate versus 20% for comparator antibiotics in some populations 1, 4
• In MRSA-prevalent settings, antibiotics with MRSA activity (SMX-TMP, clindamycin) have significantly higher success rates than cephalexin (91% vs 74%, P<.001) 5
• However, adding SMX-TMP to cephalexin provides no benefit in pure cellulitis without abscess or purulent drainage 6, 7, suggesting that when cephalexin fails, you should switch entirely rather than add coverage

When to Escalate to IV Therapy

Hospitalize and initiate IV antibiotics if any of these are present:

• Systemic inflammatory response syndrome (SIRS) – fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm 1
• Hypotension, confusion, or altered mental status 1
• Severe immunocompromise or neutropenia 1
• Rapid progression despite 24-48 hours of appropriate oral therapy 1

For hospitalized patients requiring IV therapy:

• Vancomycin 15-20 mg/kg IV every 8-12 hours is first-line (A-I evidence) 1
• Alternative IV options include linezolid 600 mg IV twice daily (A-I evidence) or daptomycin 4 mg/kg IV once daily (A-I evidence) 1, 8

Critical Pitfalls to Avoid

• Do not continue ineffective antibiotics beyond 48 hours – progression despite appropriate therapy indicates resistant organisms or deeper infection 1
• Do not reflexively add MRSA coverage to failed beta-lactam therapy – switch entirely to an MRSA-active regimen rather than combining 1
• Do not delay surgical consultation if necrotizing infection is suspected – these progress rapidly and require debridement 1
• Verify compliance and reassess for abscess with ultrasound if clinical uncertainty exists, as purulent collections require incision and drainage 1

Essential Adjunctive Measures

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote drainage 1
• Examine interdigital toe spaces for tinea pedis and treat toe web abnormalities to reduce recurrence 1
• Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema 1

Mandatory Reassessment Timeline

• Reassess in 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1
• If no improvement or worsening at 24-48 hours, switch to IV therapy or obtain surgical consultation 1