Management of Cellulitis Not Improving on Keflex
If cellulitis is not improving after 48-72 hours on cephalexin (Keflex), extend treatment to a full 5 days before declaring treatment failure, then reassess for inadequate streptococcal coverage, need for MRSA coverage, or alternative diagnoses rather than immediately switching antibiotics. 1
Initial Assessment of Treatment Response
- Continue cephalexin for a minimum of 5 days before considering treatment failure, as the 2014 IDSA guidelines recommend extending therapy if infection has not improved within this timeframe 1
- Evaluate at 48-72 hours for signs of clinical improvement, including reduction in erythema, warmth, swelling, and pain 2
- Look for systemic signs of infection including fever >38.5°C, heart rate >110 bpm, altered mental status, or signs of SIRS that would indicate need for escalation 1, 2
Key Clinical Decision Points
Assess for features suggesting MRSA involvement:
- Purulent drainage (most important indicator) 1, 2
- Penetrating trauma or injection drug use 1, 2
- Evidence of MRSA infection elsewhere or known nasal colonization 1
- Previous MRSA infection or recent hospitalization 1
Important caveat: MRSA is an unusual cause of typical non-purulent cellulitis, with beta-lactam therapy successful in 96% of cases 3, 4. Treatment failure with cephalexin more commonly indicates inadequate streptococcal coverage or misdiagnosis rather than MRSA resistance 2.
Treatment Algorithm for Non-Improving Cellulitis
For Mild to Moderate Cases (Outpatient Management):
If no purulent features or MRSA risk factors:
- Continue cephalexin 500mg four times daily to complete 5-10 days total 1, 3
- Elevate the affected extremity to promote drainage 1
- Address predisposing factors: examine interdigital toe spaces for tinea pedis, treat venous insufficiency or lymphedema 1
If purulent features or MRSA risk factors present:
- Switch to clindamycin 300-450mg three times daily (provides both streptococcal and MRSA coverage in a single agent) 2, 3
- Alternative: Add trimethoprim-sulfamethoxazole to cephalexin for dual coverage 2
- Note: A randomized controlled trial showed adding TMP-SMX to cephalexin did not improve outcomes overall (85% vs 82% cure rate, p=0.66), even in patients with nasal MRSA colonization 5
For Severe Cases or Treatment Failure (Consider Hospitalization):
- Vancomycin IV is the standard choice for severe infection requiring hospitalization 1, 2
- Alternative agents include linezolid or daptomycin 1, 2
- Broad-spectrum coverage with vancomycin plus piperacillin-tazobactam or a carbapenem for severely compromised patients 1
Critical Considerations and Common Pitfalls
Do not assume treatment failure automatically means MRSA:
- Beta-hemolytic streptococci cause the majority of typical cellulitis 3, 4
- Studies from high MRSA-prevalence areas show conflicting results, with some suggesting benefit of MRSA coverage 6 while others show no benefit 5
- The 2014 IDSA guidelines specifically recommend streptococcal coverage as first-line for typical cellulitis without purulent features 1
Consider alternative diagnoses if not improving:
- Venous stasis dermatitis, contact dermatitis, eczema, lymphedema, or erythema migrans can mimic cellulitis 4
- Deeper infections such as necrotizing fasciitis should be considered if rapidly worsening despite antibiotics 1
Address underlying predisposing factors:
- Treat interdigital maceration and tinea pedis (fissuring and scaling provide entry points for pathogens) 1
- Manage venous insufficiency, lymphedema, obesity, or eczema 1, 2
- Keep skin well-hydrated with emollients to prevent cracking 1
Adjunctive Therapy
- Consider systemic corticosteroids (e.g., prednisone 30mg with 8-day taper) in non-diabetic adult patients, as this may hasten resolution by one day 1, 2
- This is based on a single randomized trial showing reduced healing time, treatment duration, and hospital stay without increased relapse 1